Tobacco Documents Online

FOREWORD This 20th Report of the Surgeon General on the health conse- quences of tobacco use provides an additional important piece of evidence concerning the serious health risks associated with using tobacco. The subject of this Report, nicotine addiction, was first mentioned in the 1964 Report of the Advisory Committee to the Surgeon General, which referred to tobacco use as "habituating." In the landmark 1979 Report of the Surgeon General, by which time considerably more research had been conducted, smoking was called "the prototypical substance-abuse dependenoy." Scientists in the field of drug addiction now agree that nicotine, the principal pharmacologic agent that is common to all forms of tobacco, is a powerfully addictifig drug. Recognizing tobacco use as an addiction is critical both for treating the tobacco user and for understanding why people continue to use tobacco despite the known.health risks. Nicotine is a psychoactive drug with actions that reinforce the use of tobacco. Efforts to reduce tobacco use in our society must address all the major influences that encourage continued use, including social, psychological, and phar- macologic factors. After carefully examining the available evidence, this Report concludes that: a Cigarettes and other forms of tobacco are addicting. a Nicotine is the drug in tobacco that causes addiction. a The pharmacologic and behavioral processes that determine tobacco addiction are similar to those that determine addiction to drugs such as heroin and cocaine. We must recognize both the potential for behavioral and pharma- cologic treatment of the addicted tobacco user and the problems of withdrawal. Tobacco use is a disorder which can be remedied through medical attention; therefore, it should be approached by health care providers just as other substance-use disorders are approached: with knowledge, understanding, and persistence• Each health care provider should use every available clinical opportunity to encourage or assist smokers to quit and to help former smokers to maintain abstinence. i

To maintain momentum toward a smoke-free society, we also must take steps to prevent young people from beginning to smoke. First, we must insure that every child in every school in this country is educated as to the health risks and the addictive nature of tobacco use. Most jurisdictions require that school curricula include preven- tion of drug use; therefore, education on the prevention of tobacco use should be included in this effort. Second, warning labels regarding the addictive nature of tobacco use should be required for all tobacco packages and advertisements. Young people in particular may not be aware of the risk of tobacco addiction. Finally, parents and other role models should discourage smoking and other forms of tobacco use among young people. Parents who quit set an example for their children. Smoking continues to be the chief preventable cause of premature death in this country. Nicotine has addictive properties which help to sustain widespread tobacco use. It is gratifying to see the decline in reported smoking prevalence and cigarette consumption in the United States during the past 25 years. However, we cannot expect to see a sustained decline in rates of smoking-related cancers, cardiovascular disease, and pulmonary disease without sustained public health efforts against tobacco use. The Public Health Service is committed to preventing tobacco use among youth and to promoting cessation among existing smokers. We hope that this Report will assist the health care community, voluntary health agencies, and our Nation's schools in working with us to reduce tobacco use in our society. Robert E. Wlndom, M.D. Assistant Secretary for Health ii

@ PREFACE This Report of the Surgeon General is the U.S. Public Health Service's 20th Report on the health consequences of tobacco use and the 7th issued during my tenure as Surgeon General. Eighteen Reports have been released previously as part of the health consequences of smoking series; a rePOrt on the health consequences of using smokeless tobacco was released in 1986. Previous Reports have reviewed the medical and scientific evi- dence establishing the health effects of cigarette smoking and other forms of tobacco use. Tens of thousands of studies have documented that smoking causes lung cancer, other cancers, chronic obstructive lung disease, heart disease, complications of pregnancy, and several other adverse health effects. Epidemiologic studies have shown that cigarette smoking is responsible for more than 300,000 deaths each year in the United States. As I stated in the Preface to the 1982 Surgeon General's Report, smoking is the chief avoidable cause of death in our society. From 1964 through 1979, eacl~ Surgeon General's Report ad- dressed the major health effects of smoking. The 1979 Report provided the most comprehensive review of these effects. Following the 1979 Report, each subsequent Report has focused On specific populations (women in 1980, workers in 1985.), specific diseases (cancer in 1982, cardiovascular disease in 1983, chronic obstructive lung disease in 1984), and specific topics (low-tar, low-nicotine cigarettes in 1981, involuntary smoking in 1986). This Report explores in great detail another specific topic: nicotine addiction, Careful examination of the data makes it clear that cigarettes and other forms of tobacco are addicting. An extensive body of research has shown that nicotine is the drug in tobacco that causes addiction. Moreover, the processes that determine tobacco addiction are similar to those that determine addiction to drugs such as heroin and cocaine. Actions of Nicotine All tobacco products contain substantial amounts of nicotine. Nicotine is absorbed readily from tobacco smoke in the lungs and from smokeless tobacco in the mouth or nose. Levels of nicotine in iii

the blood are similar in magnitude in people using different forms of tobacco. Once in the blood stream, nicotine is rapidly distributed throughout the body. Nicotine is a powerful pharmacologic agent that acts in a variety of ways at different sites in the body. After reaching the blood stream, nicotine enters the brain, interacts with specific receptors in brain tissue, and initiates metabolic and electrical activity in the brain. In addition, nicotine causes skeletal muscle relaxation and has cardiovascular and endocrine (i.e., hormonal) effects. Human and animal studies have shown that nicotine is the agent in tobacco that leads to addiction. The diversity and strength of its actions on the body are consistent with its role in causing addiction. Tobacco Use as an Addiction Standard definitions of drug addiction have been adopted by various organizations including the World Health Organization and the American Psychiatric As,~ociation. Although these definitions are not identical, they have in common several criteria for establish- ing a drug as addicting. The central element among all forms of drug addiction is that the user's behavior is largely controlled by a psychoactive substance (i.e., a substance that produces transient alterations in mood that are primarily mediated by effects in the brain). There is often compul- sive use of the drug despite damage to the individual or to society, and drug-seeking behavior can take precedence over other important priorities. The drug is "reinforcing" - that is, the pharmacologic activity of the drug is sufficiently rewarding to maintain self- administration. "Tolerance" is another aspect of drug addiction whereby a given dose of a drug produces less effect or increasing doses are required to achieve a specified intensity of response. Physical dependence on the drug can also occur, and is characterized by a withdrawal syndrome that usually accompanies drug absti- nence. After cessation of drug use, there is a strong tendency to relapse. This Report demonstrates in detail that tobacco use and nicotine in particular meet all these criteria. The evidence for these findings is derived from animal studies as well as human observations. Leading national and international organizations, including the World Health Organization and the American Psychiatric Associa- tion, have recognized chronic tobacco use as a drug addiction. Some people may have difficulty in accepting the notion that tobacco is addicting because it is a legal product. The word "addiction" is strongly associated with illegal drugs such as cocaine and heroin. However, as this Report shows, the processes that Q

determine tobacco addiction are similar to those that determine addiction to other drugs, including illegal drugs. In addition, some smokers may not believe that tobacco is addicting because of a reluctance to admit that one's behavior is largely controlled by a drug. On the other hand, most smokers admit that they would like to quit but have been unable to do so. Smokers who have repeatedly failed in their attempts to quit probably realize that smoking is more than just a simple habit. Many smokers have quit on their own ("spontaneous remission") and some smokers smoke only occasionally. However, spontaneous remission and occasional use also occur with the illicit drugs of addiction, and in no way disqualify a drug from being classified as addicting. Most narcotics users, for example, never progress beyond occasional use, and of those who do, approximately 30 percent spontaneously remit. Moreover, it seems plausible that spontaneous remitters are largely those who have either learned to deliver effective treatments to themselves or for whom environmental circumstances have fortuitously changed in such a way as to support drug cessation and abstinence. Treatment Like other addictions, tobacco use can be effectively treated. A wide variety of behavioral interventions have been used for many years, including aversion procedures (e.g., satiation, rapid smokingl, relaxation training, coping skills training, stimulus control, and nicotine fading. In recognition of the important role that nicotine plays in r~aintaining tobacco use, nicotine replacement therapy is now available. Nicotine polacrilex gum has been shown in controlled trials to relieve withdrawal symptoms. In addition, some (but not all/ studies have shown that nicotine gum, as an adjunct to behavioral interventions, increases smoking abstinence rates. ]n recent years, multicomponent interventions have been applied successfully to the treatment of tobacco addiction. Public Health Strategies The conclusion that cigarettes and other forms of tobacco are addicting has important implications for health professionals, educa- tors, and policy-makers. In treating the tobacco user, health profes- sionals must address the tenacious hold that nicotine has on the body. More effective interventions must be developed to counteract both the psychological and pharmacologic addictions that accompa- ny tobacco use. More research is needed to evaluate how best to treat those with the strongest dependence on the drug. Treatment of tobacco addiction should be more widely available and should be

considered at least as favorably by third-party payor8 as treatment o? alcoholism and illicit drug addiction. The challenge to health professionals is complicated by the array of new nicotine delivery systems that are being developed and introduced in the marketplace. Some of these products are produced by tobacco manufacturers; others may be marketed as devices to aid in smoking cessation. These new products may be more toxic and more addicting than the products currently on the market. New nicotine delivery systems should be evaluated for their toxic and addictive effects; products intended for use in smoking cessation also should be evaluated for efficacy. Public information campaigns should be developed to increase community'awareness of the addictive nature of tobacco use. A health Warning on addiction should be rotated with the other warnings now required on cigarette and smokeless tobacco packages and advertisements. Prevention of tobacco use should be included along with prevention of illicit drug use in comprehensive school health education curricula. Many children and adolescents who are experimenting with cigarettes and other forms of tobacco state that they do not intend to use tobacco in later years. They are unaware of, or underestimate, the strength of tobacco addiction. Because this addiction almost always begins during childhood or adolescence, children need to be warned as early as possible, and repeatedly warned through their teenage years, about the dangers of exposing themselves to nicotine. This Report shows conclusively that cigarettes and other forms of tobacco are addicting in the same sense as are drugs such as heroin and cocaine. Most adults view illegal drugs with scorn and express disapproval (if not outrage) at their sale and use. This Nation has mobilized enormous resources to wage a war on drugs -- illicit drugs. We should also give priority to the one addiction that is killing more than 300,000 Americans each year. We as citizens, in concert with our elected officials, civic leaders, and public health officers, should establish appropriate public policies for how tobacco products are sold and distributed in our society. With the evidence that tobacco is addicting, is it appropriate for tobacco products to be sold through vending machines, which are easily accessible to children? Is it appropriate for free samples of tobacco products to be sent through the mail or distributed on public property, where verification of age is difficult if not impossible? Should the sale of tobacco be treated less seriously than the sale of alcoholic beverages, for which a specific license is required (and revoked for repeated sales to minors)? In the face of overwhelming evidence that tobacco is addicting, policy-makers should address these questions without delay. To e Q vi •

achieve our goal of a smoke-free society, we must give this problem the serious attention it deserves. C. Everett Keep, M.D., So.D. Surgeon General vii

ACKNOWLEDGMENTS This Report was prepared by the Department of Health and Human Services under the general editorship of the Office on Smoking and Health, Ronald M. Davis, M.D., Director. The Manag- ing Editors were Thomas E. Novotny, M.D., and William R. Lynn, Office on Smoking and Health. Scientific editors were Neal L. Benowitz, M.D,, Professor "of Medicine, Chief, Division of Clinical Pharmacology and Experimen- tal Therapeutics, San Francisco General Hospital, University of California, San Francisco, California; Nell E. Grunborg, Ph.D., Department of Medical Psychology, Uniformed Services University of the Health Sciences, Bethesda, Maryland; Jack E. Henningfield, Ph.D., Chief, Biology of Dependence and Abuse Potential Assessment, Laboratory, Addiction Research Center, National Institute on Drug Abuse, Baltimore, Maryland; and Harry A. Lando, Ph.D., Professor, Department of Psychology, Iowa State University, Ames, Iowa. The following individuals prepared draft chapters or portions of the Report. David B. Abrams, Ph.D., Assistant Professor of Psychiatry and Human Behavior, Brown University Program in Medicine, The Miriam Hospital, Center for Health Promotion, Providence, Rhode Island Timothy B. Baker, Ph.D., Department of Psychology, University of Wisconsin, Madison, Wisconsin Neal L. Benowi~z, M.D., Professor of Medicine, Chief, Division of Clinical Pharmacology and Experimental Therapeutics, San Fran- cisco General Hospital, University of California, San Francisco, California Thomas H, Brandon, M.S., Department of Psychology, University of Wisconsin, Madison, Wisconsin Richard F. Catalano, Ph.D., Research Assistant Professor, Center for Social Welfare Research, School of Social Work, University of Washington, Seattle, Washington Larry D. Chait, Ph.D., Research Associate (Assistant Professor), Department of Psychiatry, University of Chicago, Chicago, Illinois Paul B.S. Clarke, Ph.D., Department of Pharmacology and Thera- peutics, MeGill University, Montreal, Quebec, Canada ix

Richard R. Clayton, Ph.D., Professor, Department of Sociology, University of Kentucky, Lexington, Kentucky Allan C. Collins, Ph.D., Institute for Behavioral Genetics, School of Pharmacy, University of Colorado, Boulder, Colorado Thomas M. Cooper, D.D.S., Professor, Department of Community Dentistry, University of Kentucky, Lexington, Kentucky Lori A. Crane, M.P,H., Division of Cancer Control, Jonsson Compre- hensive Cancer Center, University of California, Los Angeles, California D. Layten Davis, Ph.D., Director, Tobacco and Health Research Institute, University of Kentucky, Lexington, Kentucky Ronald M. Davis, M.D., Director, Office on Smoking and Health, Center for Health Promotion and Education, Centers for Disease Control, Reckville, Maryland Edward F. Domino, M.D., Prol'essor, Department of Pharmacology, University of Michigan, Ann Arbor, Michigan John L. Egle, Jr., Ph.D., Department of Pharmaoclogy/Toxioclogy, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia Joan Ershler, Ph.D., Research Associate, Mr. Sinai Medical Center, Milwaukee, Wisconsin Raymond Fleming, Ph.D., Assistant Professor, University of Wiscon- sin-Milwaukee, Mt. Sinai Medical Center, Milwaukee, Wisconsin Kathleen A. Fletcher, Ph.D., M.P.H., Consultant, The University of Texas ttealth Science Center, Houston, Texas Paul J. Fudala, Ph.D., Addiction Research Center, National Institute on Drug Abuse, Baltimore, Maryland C. Gary Gairola, Ph.D., University of Kentucky, Tobacco and Health Research Institute, Lexington, Kentucky David Gilbert, Ph.D., Department of Psychology, Southern Illinois University, Carbondale, Illinois Lewayne D. Gilchrist, Ph.D., Research Associate Professor, School of Social Work, University of Washington, Seattle, Washington Donna M. Goldberg, M.A., Annapolis, Maryland Steven R. Goldberg, Ph.D., Preclinical Pharmacology Research Branch, Addiction Research Center, National Institute on Drug Abuse, Baltimore, Maryland John Grabowski, Ph.D., Department of Psychiatry and Behavioral Science, The University of Texas Health Science Center, Houston, Texas Dorothy K. Hatsukami, Ph.D., Department of Psychiatry, University of Minnesota, Minneapolis, Minnesota J. David Hawkins, Ph.D., Professor, Center for Social Welfare Research, School of Social Work, University of Washington, Seattle, Washington x •

Jack E. Henningfield, Ph.D., Chief, Biology of Dependence and Abuse Potential Assessment Laboratory, Addiction Research Cen- ter, National Institute on Drug Abuse, Baltimore, Maryland. Ronald I. Herning, Ph.D., Addiction Research Center, National Institute on Drug Abuse, Baltimore, Maryland Matthew Owen Howard, M.S., M.S.W., Research Assistant, Center for Social Welfare Research, School of Social Work, University of Washington, Seattle, Washington John R. Hughes, M.D., Departments of Psychiatry, Psychology, and Family Practice, University of Vermont, Burlington, Vermont Edgar T. Iwamoto, Ph.D., Department of Pharmacology, College of Medicine, University of Kentucky, Lexington, Kentucky Murray E.. Jarvik, M.D., Ph.D., The Neuropsychiatric Institute and Hospital, School of Medicine, University of California, Los An- geles, Veterans' Administration Medical Center, Brentwood Divi- sion, Los Angeles, California Robert C. Klesges, Ph.D., Associate Professor, Center for Applied Psychological Research, Department of Psychology, Memphis State University, Memphis, Tennessee Lynn T. Kozlowski, Ph.D., Head, Behavioral Research on Tobacco Use, Addiction Research Foundation, Professor of Psychology and of Preventive Medicine and Biestatistics, University of Toronto, Toront:o, ()ntario, Canada Howard Levanthal, Ph.D., Professor and Chairman, Department of Psychology, University of Wisconsin, Madison, Wisconsin Edythe D. London, Ph.D., Chief, Neuropharmacology Laboratory, Addiction Research Center, National Institute on Drug Abuse, Baltimore, Maryland Scott E. Lukas, Ph.D., Assistant Professor of Psychiatry (Pharmacol- ogy), Harvard Medical School, Department of Psychiatry, Alcohol and Drug Abuse Research Center, McLean Hospital, Belmont, Massachusetts Alfred C. Marcus, Ph.D., Associate Director, Division of Cancer Control, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, California Andrew W. Meyers, Ph.D., Professor, Center for Applied Psychologi- cal Research, Department of Psychology, Memphis State Universi- ty, Memphis, Tennessee Thomas E. Novotny, M.D., Medical Epidemiologist, Office on Smok- ing and Health, Center for Health Promotion and Education, Centers for Disease Control, Rockvine, Maryland C. Tracy Orleans, Research Associate, Health Services Research Center, University of North Carolina at Chapel Hill, President, Smoking and Health Consultants, Inc., Princeton, New Jersey xi

John P. Pierce, M.Sc., Ph.D, Chief, Edidemiology Branch, Office on Smoking and Health, Center for Health Promotion and Education, Centers for Disease Control, Rockville, Maryland Ovide F. Pomerleau, Ph.D., Behavioral Medicine Program, Universi- ty of Michigan, Department of Psychiatry, Ann Arbor, Michigan Amelie G. Ramirez, M.P.H., Faculty Associate, The University of Texas Health Science Center, Assistant Professor, Baylor College of Medicine, Houston, Texas Jed E. Rose, Ph.D., Veterans' Administration Medical Center, Wadsworth and Brentwood Divisions, Los Angeles, California J.A. Rosecrans, Ph.D., Department of Pharmacology, Medical Col- lege of Virginia, Virginia Commonwealth University, Richmond, Virginia Mary Anne Salmon, Ph.D., Research Associate, Health Services Research Center~ University of North Carolina, Chapel Hill, North Carolina Nina G. Schneider, Ph.D., Associate Research Psychologist, Depart- ment of Psychiatry and Biobehaviorai Sciences, UCLA School of Medicine, Research Psychologist, Psychopharmacology Unit, Vet- erans' Administration Medical Center, Brentwood Division, Los Angeles, California V.J. Schoenbach, Ph.D., Associate Professor, Department of Epide- miology, Research Associate, Health Services Research Center, University of North Carolina, Chapel Hill, North Carolina Saul Shiffman, Ph.D., Associate Professor, Department of Psycholo- gy, University of Pittsburgh, Pittsburgh, Pennsylvania Victor J. Strecher, Ph.D., Research Associate, Health Services Research Center, Assistant Professor, Department of Health Education, University of North Carolina, Chapel Hill, North Carolina David M. Warburton, Professor, Department of Psychology, Univer- sity of Reading, Whiteknighte, Reading, United Kingdom Elizabeth A. Wells, Ph.D., Past-Docteral Fellow, Center for Social Welfare Research, University of Washington, Seattle, Washington Thomas Ashby Wills, Ph.D., Assistant Professor of Psychology, Assistant Professor of Epidemiology and Social Medicine, Depart- ment of Epidemiology and Social Medicine, Ferkauf Graduate School of Psychology and Albert Einstein College of Medicine, Bronx, New York Phillip P. Woodson, Dr.sc.nat., Addiction Research Center, National Institute on Drug Abuse, Baltimore, Maryland The editors acknowledge with gratitude the following distin- guished scientists, physicians, and others who lent their support in the development of this Report by coordinating manuscript prepara- tion, contributing critical reviews of the manuscript, or assisting in other ways. xii •

Leo G. Abood, Ph.D., Department of Pharmacology, University of Rochester Medical Center, Rochester, New York John S. Baer, Ph.D., Department of Psychology, University of Washington, Seattle, Washington Timothy B. Baker, Ph.D., Department of Psychology, University of Wisconsin, Madison, Wisconsin Claudia R. Baquet, M.D., M.P.H., Chief, Special Populations Studies Branch, Division of Cancer Prevention and Control, National Cancer Institute, Bethesda, Maryland Glen Bennett, M.P.H., Field Studies Advisor, Office of Prevention, Education, and Control, National Heart, Lung, and Blood Insti- tute, Bethesda, Maryland George E. Bigelow, Ph.D., Associate Professor of Behavioral Biology, Director, Behavioral Pharmacology Research Unit, Department of Psychiatry and Behavioral Sciences, The Johns Hopkins Universi- ty School of Medicine, Baltimore, Maryland Clarice Brown, M.S., Data Analyst, Office of Prevention, Education, and Control, National Heart, Lung, and Blood Institute, Bethesda, Maryland David M. Burns, M.D., Associate Professor of Medicine, Division of Pulmonary and Critical Care Medicine, University of California Medical Center, San Diego, California Donald R. Cherek, Ph.D., Department of Psychiatry and Behavioral Sciences, Mental Sciences Institute, The University of Texas Health Science Center, Houston, Texas Paul B.S. Clarke, Ph.D., Department of Pharmacology and Thera- peutics, McGin University, Montreal, Quebec, Canada Re Nemeth-Coslett, Ph.D., Psychologist, Prevention Research Branch, Division of Clinical Research, National Institute on Drug Abuse, Rockville, Maryland Thomas J. Crowley, M.D., University of Colorado Health Sciences Center, Denver, Colorado Joseph W. Cullen, Ph.D., Deputy Director, Division of Cancer Prevention and Control, National Cancer Institute, Bethesda, Maryland K. Michael Cummings, Ph.D., M.P.H., Research Scientist, Depart- ment of Cancer Control and Epidemiology, Roswell Park Memorial Institute, Buffalo, New York Susan Curry, Ph.D., Center for .Health Studies, Group Health Cooperative of Puget Sound, Seattle, Washington Vincent T. DeVita, Jr., M.D., Director, National Cancer Institute, National Institutes of Health, Bethesda, Maryland Sir Richard Doll, University of Oxford, Oxford, England Manning Feinleib, M.D., Dr.P.H., Director, National Center for Health Statistics, Centers for Disease Control, Hyattsville, Mary- land xiii

Richard R. Frecker, M.D., Ph.D., Head, Biomedical Research, Department of Pharmacology, Addiction Research Foundation, Toronto, Ontario, Canada K.H. Ginzel, Ph.D., Professor, Department of Pharmacology and Interdisciplinary Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas Russell E. Glasgow~ Ph.D., Oregon Research Institute, Eugene, Oregon Nancy P. Gordon, Sc.D., Behavioral Scientist, Division of Research, Kaiser Permanente Medical Group, Oakland, California Roland R. Grlffiths, The Johns Hopkins University School of Medicine, Baltimore, Maryland Ellen R. Gritz, Ph.D., Director, Division of Cancer Control, Joasson Comprehensive Cancer Center, University of California, Los Angeles, California Sharon M. Hall, Ph.D., Professor, Department of Psychiatry, Center for Social and Behavioral Sciences, University of California, San Francisco, California Louis S. Harris, Ph.D., Senior Science Advisor, National Institute on Drug Abuse, Alcohol, Drug Abuse, and Mental Health Administra- tion, Rockville, Maryland Ronald I. Herning, Ph.D., Addiction Research Center, National Institute on Drug Abuse, Baltimore, Maryland Dietrich Hoffmann, Ph.D., Associate Director, Naylor Dana Insti- tute, Valhalla, New York Leo Hollister, M.D., Medical Director, Harris County Psychiatry Center, Houston, Texas Enid Hunkeler, Senior Investigator, Kaiser Permanente Medical Care Program, Oakland, California Peyton Jacob III, Ph.D., Division of Clinical Pharmacology, San Francisco General Hospital, University of California, San Francis- co, California Jerome Jaffas, M.D., Director, Addiction Research Center, National Institute on Drug Abuse, Baltimore, MaiTland Murray E. Jarvik, M.D., Ph.D., The Neuropsychatric Institute and Hospital School of Medicine, University of California, Los Angeles, and Veterans' Administration Medical Center West Los Angeles, Brentwood Division, Los Angeles, California Martin Jarvis, M.Phil., Senior Lecturer, Addiction Research Unit, Institute of Psychiatry, London, England Chris-Ellen Johanson, Ph.D., Department of Psychiatry, Pritzker School of Medicine, University of Chicago Drug Abuse Research Center, Chicago, Illinois Reese T. Jones, Ph.D., Department of Psychiatry, University of California School of Medicine, San Francisco, California xiv •

Ken J. Kellar, Ph.D., Department of Pharmacology, Georgetown University Medical Center, Washington, D.C. Lynn T. Kozlowski, Ph.D., Head, Behavioral Research on Tobacco Use, Addiction Research Foundation, Toronto, Ontario, Canada Richard J. Lamb, Ph.D., Addiction Research Center, National Institute on Drug Abuse, Baltimore, Maryland Charles L. LeMaistre, M.D., President, University of Texas Systems Cancer Center, Houston, Texas Claude Lenfant, M.D., Director, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland Howard Leventhal, Ph.D., Professor of Psychology, University of Wisconsin, Madison, Wisconsin Edward Lichtenstein, Ph.D., Oregon Research Institute, Eugene, •Oregon Donald Inn Macdonald, M.D., Administrator, Alcohol, Drug Abuse, and Mental Health Administration, RockviUe, Maryland G. Alan Marlatt, Ph.D., Professor of Psychology, University of Washington, Seattle, Washington William R. Martin, M.D., Chairman, Department of Pharmacology, University of Kentucky College of Medicine, Lexington, Kentucky James O, Mason, M.D., Dr.P.H., Director, Centers for Disease Control, Atlanta, Georgia J. Michael McGinnis, M.D., Deputy Assistant Secretary (Disease Prevention and Health Promotion), Washington, D.C, A. Thomas MeLelian, Ph.D., Substance Abuse Treatment Research Center, Philadelphia Veterans' Administration Medical Center and The University of Pennsylvania, Philadelphia, Pennsylvania Nancy K. Mello, Ph.D, Alcohol and Drug Abuse Research Center, McClean Hospital, Belmont, Massachusetts Gregory J. Morasco, Ph.D., M.P.H., Smoking Education Program Coordinator, National Heart, Lung, and Blood Institute, Bethesda, Maryland Joseph P. Mulholland, Ph.D., Bureau of Economics, Federal Trade Commission, Washington, D.C. Herbert W. Niekens, M.D., M.A., Director, Office of Minority Health, Public Health Service, Washington, D.C. Richard Pete, M.A., M.Sc., Imperial Cancer Research Fund, Cancer Studies Unit, Nuffield Department of Clinical Medicine, Radcliffe Infirmary, University of Oxford, Oxford, England Roy W. Pickens, Ph.D., Director, Division of Clinical Research, National Institute on Drug Abuse, Rockville, Maryland John P. Pierce, M.Sc., Ph.D., Chief, Epidemiology Branch, Office on Smoking and Health, Center for Health Promotion and Education, Centers for Disease Control, Rockville, Maryland XV

John M. Pinney, Executive Director, Institute for the Study of Smoking Behavior and Policy, John F. Kennedy School of Govern- ment, Harvard University, Cambridge, Massachusetts Michael R. Polen, M.A., Research Associate, Division of Research, Kaiser-Permanento Medical Group, Oakland, California William Pollin, M.D., Former Director, National Institute on Drug Abuse, Bethesda, Maryland David C. Ramsey, M.P.H., Health Educator, Division of Health Education, Center for Health Promotion and Education, Centers for Disease Control, Atlanta, Georgia Everett R. Rhoades, M.D., Assistant Surgeon General and Director, Indian Health Service, Rockville, Maryland M.A.H. Russell, F.R.C.P., Addiction Research Unit, Institute of Psychiatry, University ofLondon, London, England Charles R. Schuster, Ph.D., Director, National Institute on Drug Abuse, Rockville, Maryland Burt Sharpe, M.D., Hennepin County Medical Center, Department of Medicine, Minneapolis, Minnesota Donald R. Shopland, Public Health Advisor, Smoking, Tobacco, and Cancer Program, National Cancer Institute, Bethesda, Maryland Jerome E. Singer, Ph.D., Medical Psychology, Uniformed Services University of the Health Sciences, Bethesda, Maryland Maxine L. Stitzer, Ph.D, Associate Professor, Behavioral Biology, The Johns Hopkins School of Medicine; Behavioral Pharmacology Research, Francis Scott Key Medical Center, Baltimore, Maryland David N. Sundwall, M.D., Assistant Surgeon General and Adminis- trator, Health Resources and Services Administration, Rockville, Maryland Dennis D. Tolsma, M.P.H., Director, Center for Health Promotion and Education, Centers for Disease Control, Atlanta, Georgia Frederick L. Trowbridge, M.D., Director, Division of Nutrition, Center for Health Promotion and Education, Centers for Disease Control, Atlanta, Georgia Frank J. Voccl, Jr., Ph.D., Acting Chief, Drug Abuse Staff, Center for Drug Evaluation and Research, Food and Drug Administration, Washington, DC Ronald W. Wilson, M.A., National Center for Health Statistics, Centers for Disease Control, Hyattsville, Maryland Roy A. Wise, Ph.D., Department of Psychology, Concordia Universi- ty, Montreal, Quebec, Canada Faye Wright, Center for Applied Psychological Research, Depart- ment of Psychology, Memphis State University, Memphis, Tennes- see Ernst L. Wynder, M.D., President, American Health Foundation, New York, New York ×vi

James B. Wyngaarden, M.D., Director, National Institutes of Health, Bethesda, Maryland Tomoji Yanagita, M.D., Ph.D., Preclinical Research Laboratories, Central Institute for Experimental Animals, Kawasaki, Japan Frank E. Young, M.D., Commissioner, Food and Drug Administra- tion, Rockville, Maryland The editors also acknowledge the contributions of the following staff members and others who assisted in the preparation of this Report. Margaret Anglia, Secretary, Office on Smoking and Health, Rock- vine, Maryland Charles Appiah, Project Clerk, Smoking and Health Project, The Circle, Inc., McLean, Virginia John L. Bagroski, Associate Director for Program Operations, Office on Smoking and Health, Rockville, Maryland Sonia Balakirsky, Secretary, Office on Smoking and Health, Rock- ville, Maryland Carol Bean, Associate Project Director, Smoking and Health Project, The Circle, Inc., McLean, Virginia Tamara Blair, Production Coordinator, Information Management Department, ATLIS Federal Services, Inc., Rockville, Maryland Catherine E. Burckhardt, Editorial Assistant, Office on Smoking and Health, Rockville, Maryland Gayle Christman, Word Processing Specialist, Smoking and Health Project, The Circle, Inc., McLean, Virginia Carol K. Cummings, Secretary, Office on Smoking and Health, Roekville, Maryland Stephanie D. DeVoe, Programmer, Information Systems Depart-ment, ATLIS Federal Services, Inc., Rockville, Maryland Michael C. Fiore, M.D., M.P.H., Medical Epidamiologist, Office on Smoking and Health, Rockville, Maryland David Fry, Editor, Smoking and Health Project, The Circle, Inc., McLean, Virginia Lynn Funkhauser, Word Processing Specialist, Smoking and Health Project, The Circle, Inc., McLean, Virginia Mary Gardner, Senior Editor, Smoking and Health Project, The Circle, Inc., McLean, Virginia Amy Garson, M.P.H. student, Office on Smoking and Health, Rockville, Maryland Arnetta G. Glover, Secretary, Office on Smoking and Health, Rockville, Maryland Evridiki Hatziandreu, M.D., M.P.H., Epidemic Intelligence Service Officer, Office on Smoking and Health, Rockville, Maryland Patricia E. Healy, Technical Information Specialist, Office on Smoking and Health, Rockville, Maryland xvii

Terri L. Henry, Clerk-Typist, Office on Smoking and Health, Rockvine, Maryland Timothy K. Hensley, Technical Publications Writer, Office on Smoking and Health, Rockville, Maryland Shirley K. Hickman, Data Entry Operator, Information Manage- ment Department, ATLIS Federal Services, Inc., Rockville, Mary- land Robert S. Hutchings, Associate Director for Information and Pro- gram Development, Office on Smoking and Health, Rockville, Maryland Karen Jacob, Senior Editor, Smoking and Health Project, The Circle, Inc., McLean, Virginia Sheila Jones, Word Processing Specialist, Smoking and Health Project, The Circle, Inc., McLean, Virginia R~ck Keir, Senior Editor, Smoking and Health Project, The Circle, Inc., McLean, Virginia Julie Kurz, Graphics Specialist, Information Management Depart- ment, ATLIS Federal Services, Inc., Rockville, Maryland Gerri E. Mast, Secretary, Center for Health Promotion and Educa- tion, Centers for Disease Control, Atlanta, Georgia Judy J. Mast, Secretary, Center for Health Promotion and Educa- tion, Centers for Disease Control, Atlanta, Georgia Dixie McGough, Program Manager, Information Management De- partment, ATLIS Federal Services, Inc., Rockville, Maryland Dan McLaughlin, Editorial Assistant, Smoking and Health Project, The Circle, Inc., McLean, Virginia Nancy Miltenberger, Editor, Smoking and Health Project, The Circle, Inc., McLean, Virginia Cathie O'Donnell, Senior Editor, Smoking and Health Project, The Circle, Inc., McLean, Virginia Ruth C. Palmer, Secretary, Office on Smoking and Health, Rockville, Maryland Russell D. Peek, Library Acquisitions Specialist, Information Man- agement Department, ATLIS Federal Services, Inc., Rockville, Maryland Margaret E. Pickerel, Public Information and Publications Special- ist, Office on Smoking and Health, Rockville, Maryland Renate Phillips, Desktop Publishing/Graphic Artist, Smoking and Health Project, The Circle, Inc., McLean, Virginia Karen Sherman, Production Assistant, Information Management Department, ATLIS Federal Services, Inc., Roekville, Maryland Linda R. Spiegelman, Administrative Officer, Office on Smoking and Health, Roekville, Maryland Tamara Shipp, Publications Assistant, Smoking and Health Project, The Circle, Inc., McLean, Virginia xviii •

O Evelyn L, Swarr, Systems Management Projects Supervisor, Infor- mation Systems Department, ATLIS Federal Services, Ino,, Rock. ville, Maryland Daniel R. Tisch, Project Director, Smoking and Health Project, The Circle, Inc., McLean. Virginia Louise G. Wiseman, Technical Information Specialist~ Office on Smoking and Health, Rockville, Maryland O xix

TABLE OF CONTENTS Foreword ................................................................. i Preface .................................................................. ill Acknowledgments .......... : ......................................... ix I. Introduction, Overview, Summary, and ' Conclusions ..................................................... 1 II. Nicotine: Pharmacokinetics, Metabolism, and Phar- maeodynamies ................................................. 21 III. Nicotine: Sites and Mechanisms of Actions ........... 75 IV. Tobacco Use and Drug Dependence ................... 145 V. Tobacco Use Compared to Other Drug Dependencies ............................................. :... 241 VI. Effects of Nicotine That May Promote Tobacco Use ......................................................... :.,.. 375 VII. Treatment of Tobacco Dependence ..................... 459 Appendix A: Trends in Tobacco Use in the United States ............................................... 561 Appendix B: Toxicity of Nicotine ............................. 589 xxi

CHAPTER I INTRODUCTION, OVERVIEW, SUMMARY, AND CONCLUSIONS

CONTENTS Introduction Development and Organization of this Report Overview Major Conclusions Brief History Relevant to this Report Chapter Conclusions Chapter II: Nicotine: Pharmacokinetics, Metabolism, and Pharmacodynamics Chapter hi: Nicotine: Sites and Mechanisms of Ac- tions Chapter IV: Tobacco Use as Drug Dependence Chapter V: Tobacco Use Compared to Other Drug Dependencies Chapter VI: Effects of Nicotine That May.Promote Tobacco Use Chapter VII: Treatment of Tobacco Dependence Appendix A! Trends in Tobacco Use in the United States Appendix B: Toxicity of Nicotine 3

Introduction Development and Organization of this Report This Report was developed by the Office on Smoking and Health, Center for Health Promotion and Education, Centers for Disease Control, Public Health Service of the U.S. Department of Health and Human Services as part of the Department's responsibility, under Public Law 91-222, to report new and current information on smoking and health to the United States Congress. The scientific content of this Report reflects the contributions of more than 50 scientists representing a wide variety of relevant disciplines. These experts, known for their understanding of and work in specific content areas, prepared manuscripts for incorpora- tion into this Report. The Office on Smoking and Health and its consultants edited and consolidated the individual manuscripts into appropriate chapters. These draft chapters were subjected to an extensive outside peer review (see Acknowledgments for individuals and their affiliations) whereby each chapter was reviewed by up to 11 experts. Based on the comments of these reviewers, the chapters were revised and the entire volume was assembled. This revised edition of the Report was resubjected to review by 20 distinguished scientists inside and outside the Federal Government, both in this country and abroad. Parallel to this review, the entire Report was also submitted for review to 12 institutes and agencies within the U.S. Public Health Service. The comments from the senior scientific reviewers and the agencies were used to prepare the fi~al volume of this Report. This Report contains a Foreword by the Assistant Secretary for Health, a Preface by the Surgeon General of the U.S. Public Health Service, and the following chapters and appendices: Chapter ]. Introduction, Overview, Summary, and Conclusions Chapter lI. Nicotine: Pharmacokinetics, Metabolism, and Phar- macodynamics Chapter IIL Nicotine: Sites and Mechanisms of Actions Chapter IV. Tobacco Use as Drug Dependence Chapter V. Tobacco Use Compared to Other Drug Dependencies Chapter VI. Effects of Nicotine That May Promote Tobacco Use Chapter VII. Treatment of Tobacco Dependence Appendix A. Trends in Tobacco Use in the United States Appendix B. Toxicity of Nicotine Overview This Report of the Surgeon General on tobacco and health focuses on the pharmacologic basis of tobacco addiction. Previous Surgeon General's Reports have reviewed the medical and scientific evidence establishing that cigarette smoking and tobacco use in other forms

are deleterious to health. Several reports emphasized particular diseases (e.g., 1982 Report on cancer (US DHHS 1982), 1983 Report on caMiovascular disease (US DHHS 1983a), 1984 Report on chronic obstructive lung disease (US DHHS 1984a)); some reports concentrat- ed on specific populations (e.g., 1980 Report on women (US DHHS 1980)); and some reports dealt with particular aspects of smoking (e.g., 1986 Report on involuntary smoking (US DHHS 1986a)). These reports have been important because so many individuals engage in a behavior that causes morbidity and premature mortality. The present Report addresses a central issue of the tobacco and health problem: Why do people smoke and in other ways consume tobacco products? Specifically, this Report reviews the pharmacolog- ic basis of the disease- producing and life-threatening behavior of tobacco use. Psychological and social factors are also important influences on tobacco use, but a detailed review of these factors is beyond the scope of this Report. Reviews of this literature include previous reports of the Surgeon General (US DHEW 1979; US DHHS 1980, 1982, 1983a, 1984a), research monographs from the National Institute on Drug Abuse (NIDA) (Jarvik et hi. 1977; Krasnegor 1978, 1979a,b,c; Grabowski and Bell 1983), and articles by scientists who study tobacco use and nicotine (Russell 1971, 1976; Gritz 1980; Henningfleld 1984). This Report reviews evidence that tobacco use is addicting and that nicotine is the active pharmacologic agent of tobacco that causes this addictive behavior. Previous Surgeon General's Report~ have focused on evidence that cigarette smoking and tobacco use are health hazards. Now that those relationships are well-documented and well-known, this Report addresses addictive properties of cigarette smoking and tobacco use in order to help develop more effective prevention and cessation programs. This Report topic is particularly timely because of recent advances and extensive data gathered in the 1980s relevant to the issue of tobacco addiction. Since the early 1900s scientific literature and historical anecdotes have provided evidence that tobacco use is a form of drug addiction. In the 1970s, however, research efforts increased considerably on various aspects of tobacco addiction, including nicotine pharmacokinetics, pharmacodynamics, self-ad- ministration, withdrawal, dependence, and tolerance. In addition, advances in the neurosciences have begun to reveal effects of nicotine in the brain and body that may help to explain why tobacco use is reinforcing and difficult to give up. These issues are addressed in this Report. Finally, recent developments in the use of nicotine replacement in smoking cessation emphasize the importance of pharmacologic aspects of cigarette smoking. Concepts of drug addiction or drug dependence are discussed in detail in Chapters IV and V. It is useful to begin this Report with a 6

brief summary of main points about drug dependence that provide the foundation for the findings of the Report. The terms "drug addiction" and ~'drug dependence" are scientifi- cally equivalent: both terms refer to the behavior of repetitively ingesting mood-altering substances by individuals. The term '~drug dependence" has been increasingly adopted in the scientific and medical literature as a more technical term, whereas the term "drug addiction" continues to be used by NIDA and other organizations when it is important to provide information at a more general level. Throughout this Report, both terms are used and they are used synonymously. The main conclusions of the Report are based upon concepts of drug dependence that have been developed by expert committees of the World Health Organization, as well as in publications of NIDA and the American Psychiatric Association. These concepts were used to develop a set of criteria to determine whether tobacco-delivered nicotine is addicting. The criteria for drug dependence include primary and additional indices and are summarized below. CRITERIA FOR DRUG DEPENDENCE Primary Criteria • Highly controlled or compulsive use • Psychoactive effects • Drug-reinforced behavior Additional Criteria • Addictive behavior often involves: -stereotypic patterns of use -use despite harmful effects -relapse following abstinence .recurrent drug cravings • Dependence-producing drugs often produce: -tolerance -physical dependance -pleasant (euphoriant) effects The primary criteria listed above are sufficient to define drug dependence. Highly controlled or compulsive use indicates that drug- seeking and drug-taking behavior is driven by strong, often irresisti- ble urges. It can persist despite a desire to quit or even repeated attempts to quit. Such behavior is also referred to as "habitual" behavior. To distinguish drug dependence from habitual behaviors not involving drugs, it must be demonstrated that a drug with

psychoactive (mood-altering) effects in the brain enters the blood stream. Furthermore, drug dependence is defined by the occurrence of drug-motivated behavior; therefore, the psychoactive chemical must be capable of functioning as a reinforcer that can directly strengthen behavior leading to further drug ingestiom Additional criteria are often used to help characterize drug dependence. Several are associated with the drug-taking behavior itself: (1) the behavior may develop into regular temporal and physical patterns of use (repetitive and stereotypic); (2) drug use may persist despite adverse physical, psychological, or social conse- quences; (3) quitting episodes are often followed by resumption of drug use (relapse); (4) urges (cravings) to use the drug may be recurrent and persistent, especially; during drug abstinence. Similar- ly, several common effects of dependence-producing drugs can strengthen their control over behavior and increase the likelihood of harm by contributing to the regularity and overall level of drug intake: (l/ diminished responsiveness (tolerance) to the effects of e drug occurs, and may be accompanied by increased intake over time; (2) abstinence-associated withdrawal reactions (due to physical dependence) can motivate further drug intake; (3) effects that are considered pleasant (euphoriant) to the drug user can be provided by the drug itself. Dependence-producing drugs can also produce effects that individuals find useful. For example, many addicting drugs have therapeutic uses in medical treatments of various disorders. Most medically approved drugs that are addicting, however, are generally only available by prescription. Effects era drug considered by the individual to be useful can promote initiation of drug use, strengthen the addiction, and contribute to relapse following cessa- tion of use. Tobacco and nicotine are considered in the Report in light of the above criteria. In brief, the organization of the Report is as follows: review of evidence that tobacco use is accompanied by orderly patterns of uptake of nicotine in the body and brain resulting in the development of tolerance (Chapter II); review of how effects of nicotine in the brain and the rest of the body are chemically mediated (Chapter III); review of the evidence that tobacco is addicting and that nicotine is an addicting drug (Chapter IV); comparison of tobacco use with other addictions and of nicotine with other addicting drugs (Chapter V); review of possible effects of nicotine that may promote the use of tobacco and present impedi- ments to quitting smoking (Chapter VI); review of strategies for helping people to achieve and maintain tobacco abstinence (Chapter VII). In addition, appendices are included that summarize informa- tion regarding trends in tobacco use (Appendix A) and information regarding the toxicity of nicotine itself (Appendix B). A summary of the main findings of the Report follows. •

Major Conclusions 1. Cigarettes and other forms of tobacco are addicting. 2. Nicotine is the drug in tobacco that causes addiction. 3. The pharmacologic and behavioral processes that determine tobacco addiction are similar to those that determine addiction to drugs such as heroin and cocaine. Brief History Relevant to this Report Tobacco products have been used for centuries. The tobacco plant was native to the New World. The oldest cited evidence of tobacco use apl~oars on a Mayan stone carving dated from 600 to 900 A.D. There are reports of tobacco smoking in Christopher Columbus' diary in 1492; reports of tobacco smoking appear in the logs of other European explorers of the New World in the 16th contury, Since the colonial period, tobacco has been an integral part of the American economy (Robert 1949). Tobacco use permeated the Now World and quickly spread throughout the rest of the world during the 16th and 17th centuries. As use of tobacco products spread, so did controversy over the effects of these products. Throughout history, while some persons extolled the virtues of tobacco (including numerous alleged medicinal uses), others condemned its use. George Washington is attributed with exhorting the home front during the Revolutionary. War, "If you can't send money, send tobacco." In contrast, Dr. Benjamin Rush condemned tobacco use in his 1798 book Essays. The controversy continued into the 19th century with no convincing scientific or medical evidence to support either position (Robert 1949). In 1856-57 the British medical journal Lancet published opinions of 50 physicians on tobacco use. Many opponents attributed in- creased crime, nervous paralysis, loss of intellectual abilities, and visual impairment to tobacco use-all of these claims lacked convinc- ing evidence. In restating the main arguments of the tobacco proponents, the Lancet editors wrote that tobacco use "...must have some good or at least pleasurable effects; that, if its evil effects were so dreadful as stated the human race would have ceased to exist" (Lancet 1857). While the health-promoting and health-damaglng effects of tobac- co products were being debated throughout the 17th and 18th centuries, scientists were trying to determine the chief active ingredient in tobacco, In the early 1800s the oily essence of tobacco was discovered by Cerioli and by Vauquelin. This active substance was named "Nicotianine," after Jean Nicot, who sent tobacco seeds from Portugal to the French court at the end of the 16th century. In 1828, Posselt and Reimann at the University of Heide]berg isolated 9

the pure form of Nicotianine and renamed it "Nikotin." The chemical's empirical formula, C~oH~4N~, was determined in the 1840s, and "nicotine" was synthesized in the 1890s (Robert 1949). Since the late 1800s, research on the pharmacologic actions of nicotine has contributed substantially to basic information about the nervous system (Kharkevich 1980; Voile 1980). The classic work by Langley and Dickinson (1889) on nicotine's effects in autonomic ganglia led to the postulates that chemicals transmit information between neurons and that there are receptors on cells that respond functionally to stimulation by specific chemicals. As early as the 1920s and 1930s, some investigators were concluding that nicotine was responsible for the compulsive use of tobacco products (Arm- strong-Jones 1927; Dorsey 1936; Lewin 1931). Johnston (1942) concluded that, "smoking tobacco is essentially a means of adminis- tering nicotine, just as smoking opium is a means of administering morphine." Throughout the 20th century, research has continued to investi- gate the role of nicotine in tobacco use. The 1964 Report of the Surgeon General's Advisory Committee on Smoking and Health (US PHS 1964) held that'. "The habitual use of tobacco is related primarily to psychological and social drives, reinforced and perpetu- ated by the pharmacologic actions of nicotine on the central nervous system. Nicotine-free tobacco or other plant materials do not satisfy the needs of those who acquire the tobacco habit.!' The 1964 Report, relying upon a distinction (that is no longer made) between "habituating" and "addicting" drugs, asserted that tobacco was habituating and not addicting. The distinction in 1964 between habituating drugs (including cocaine and amphetamines) and addict- ing drugs (including opiates and barbiturates) was based on: (1) whether the drug produced clear physical dependence; (2) whether damage was mainly to the individual user (habituating drugs) or to society (addicting drugs); and (3) the strength of the habitual behavior that developed. There was no question at the time of the 1964 Report that nicotine was the critical pharmacologic agent for tobacco use, but its role was then considered to be more similar to cocaine and amphetamines than to opiates and barbiturates. Later in 1964 the World Health Organization dropped this semantic distinction between habituating and addicting drugs because it was recognized that habitual use could be as strongly developed for cocaine as for morphine~, that social damage generally accompanied personal damage, and that behavioral characteristics of drug use could be similar for the so-called habituating and addicting drugs. In an effort to shift the focus to dependent patterns of behavior and away from moral and social issues associated with the term addiction, the term dependence was recommended. Q 10 •

It is now clear that even by the earlier distinction in nomencla- ture, cigarettes and other forms of tobacco are addicting and actions of nicotine provide the pharmacologic basis of tobacco addiction. The term ~'dependenee producing" may also be used to describe cigarettes and other forms of tobacco use, analogous to actions of other drugs (e.g., opiates, cocaine). Since 1964, considerable additional evidence has been compiled that substantiates these conclusions. The present Report reviews this information and the relevant literature. Previous Surgeon General's Reports provided current reviews of the health consequences of cigarette smoking particularly relevant to public health. For example, despite the accumulating evidence, in the early 1960s there was little recognition by the public of the health hazards of smoking. Each Report examined specific informa- tion considered to be important for public dissemination. A brief review of topics addressed in these reports provides the background for the present Report. In the late 1950s, the U.S. Public Health Service, the National Cancer Institute, the National Heart Institute, the American Cancer Society, and the American Heart Association appointed a study group to examine the available evidence on smoking and health. This study group concluded that excessi~e cigarette smoking is a causative factor in lung cancer. In 1962, Surgeon General Luther Terry established an advisory committee on smoking and health. This committee released its Report on January 11, 1964, concluding that cigarette smoking is a cause of lung cancer in men and a suspected cause of lung cancer in women, and increased the risk of dying from pulmonary emphysema. The next Report was issued in 1967 (US PHS 1968a) and stated that "the case for cigarette smoking as the principal cause of lung cancer is overwhelming." Further, the 1967 Report concluded that: "There is an increasing convergence of many types of evidence.., which strongly suggests that cigarette smoking can cause death from coronary heart disease." The 1967 Report also concluded that "Cigarette smoking is the most important of the causes of chronic non-neoplastic bronchopulmonary disease in the United States." The 1968 and 1969 Reports (US PHS 1968b, 1969) strengthened the conclusions reached in 1967, The 1971 Report provided a detailed review of the evidence to date regarding health consequences of smoking (US DHEW 1971). The subsequent reports (1972 to 1976) continued to review the increasing evidence associating cigarette smoking with many health hazards. The 1972 Report also discussed involuntary or passive smoking (US DHEW 1972). The 1973 Report included some data on the health hazards of smoking pipes and cigars (US PHS 1973). The 1975 Report updated information on the health effects of involuntary or passive smoking (US DHEW 1975). 11

The combined 1977-78 Report discussed smoking-related problems unique to women (US DHEW 1978). At the time of its release, the 1979 Report was the most comprehensive review by a Surgeon General's Report of the health consequences of smoking, smoking behavior, and smoking control. In addition to providing a thorough review of the health consequences of smoking, the 1979 Report discussed the health consequences of using forms of tobacco other than cigarettes (pipes, cigars, and smokeless tobacco). Moreover, the ]979 Report expanded the scope of the previous reports and examined behavioral, pharmacologic, and social factors influencing the initiation, maintenance, and cessation of cigarette smoking. Relevant to the topic of the present Report, the 1979 Report concluded that "it is no exaggeration to say that smoking is the prototypical substance-abuse dependency and that improved knowledge of this process holds great promise for preven- tion of risk." Since the release of the 1979 Report, each subsequent Report has focused on a specific population or setting (women in 1980 (US DHHS 1980), the workplace in 1985 (US DHHS 1985)), a specific topic (health effects of low-tar and low-nicotine cigarettes in 1981 (US DHHS 1981), involuntary smoking in 1986 (US DHHS 1986a)), or a specific disease (cancer in 1982 (US DHHS 1982), cardiovascular diseases in 1983 (US DHHS 1983a), chronic obstruc- tive lung disease in 1984 (US DHHS 1984a)). In addition to the prevlous Surgeon General's Repoi:ts, several other developments and publications provide relevant background for the present Report. For example, numerous monographs pre- pared in the 1970s by the National Institute on Drug Abuse (NIDA) considered tobacco use as a form of drug dependence. In 1980, the American Psychiatric Association, in its Diagnostic and Statistical Manual of Mental Disorders, included tobacco dependence as a substance abuse disorder and tobacco withdrawal as an organic mental disorder (APA 1980). The 1987 revised edition of this manual (APA 1987), in recognition of the role of nicotine, changed "tobacco withdrawal" to "nicotine withdrawal." In 1982, the Director of NIDA testified to Congress that the position of NIDA was that tobacco use could lead to dependence and that nicotine was a prototypic dependence-producing drug. In a 1983 publication, "Why People Smoke Cigarettes," the U.S. Public Health Service supported this position of NIDA regarding tobacco and nicotine (US DHHS 1983b). In the 1984 NIDA Triennial Report to Congress, nicotine was labeled a prototypic dependence-producing drug and the role of nicotine in tobacco use was considered to be analogous to the roles of morphine, cocaine, and ethanol, in the use of opium, coea-derived product~, and alcoholic beverages, respectively (US DHHS 1984b). In 1986, a consensus conference of the National Institutes of Health and the Report of the Advisory Committee to the Surgeon General on the 12 •

health consequences of using smokeless tobacco concluded that smokeless tobacco can be addicting and that nicotine is a depen- dence-producing (i.e., addicting) drug (US DHHS 1986b). The present Report is the 20th such report issued by the Public Health Service on the health consequences of tobacco use. The deleterious effects of cigarette smoking are now well known. Therefore, this Report focuses on pharmacologic information to help understand why people smoke. Such information will assist health professionals in developing effective strategies to prevent initiation and to promote cessation. The literature reviewed in this Report indicates that tobacco use is an addictive behavior. It is the purpose of this Report to thoroughly review the relevant literature. Chapter Conclusions In addition, to the three overall conclusions of this Report, there are many other substantive conclusions. These points are listed under the appropriate Chapter and Appendix headings. Chapter Ih Nicotine: Pharmacokinetics, Metabolism, and Phar- macodynamics 1. All tobacco products contain substantial amounts of nicotine and other alkaloids. Tohaccbs from low-yield and high-yleld cigarettes contain similar amounts of nicotine. 2. Nicotine is absorbed readily from tobacco smoke in the lungs and from smokeless tobacco in the mouth or nose. Levels of nicotine in the blood are similar in magnitude in people using different forms of tobacco. With regular use, levels of nicotine accumulate in the body during the day and persist overnight. Thus, daily tobacco users are exposed to the effects of nicotine for 24 hr each day. 3. Nicotine that enters the blood is rapidly distributed to the brain. As a result, effects of nicotine on the central nervous system occur rapidly after a puff of cigarette smoke or after absorption of nicotine from other routes of administration. 4. Acute and chronic tolerance develops to many effects of nicotine. Such tolerance is consistent with reports that initial use of tobacco products, such as in adolescents first beginning to smoke, is usually accompanied by a number of unpleasant symptoms which disappear following chronic tobacco use. Chapter III: Nicotine: Sites and Mechanisms of Actions 1. Nicotine is a powerful pharmacologic agent that acts in the brain and throughout the body. Actions include electrocortical 13

activation, skeletal muscle relaxation, and cardiovascular and endocrine effects. The many biochemical and electrocortlcal effects of nicotine may act in concert to reinforce tobacco use. Z. Nicotine acts on specific binding sites or receptors throughout the nervous system. Nicotine readily crosses the blood-brain barrier and accumulates ia the brain shortly after it enters the body. Once in the brain, it interacts with specific receptors and alters brain energy metabolism in a pattern consistent with the distribution of specific binding sites for the drug. 3. Nicotine and smoking exert effects on nearly all components of the endocrine and neuroendocrine systems (including catechol- amines, sorotonin, corticosteroids, pituitary hormones/. Some of these endocrine effects are mediated by actions of nicotine on brain neurotransniitter systems (e.g., hypothalam- ic-pituitary axis). In addition, nicotine has direct peripherally mediated effects (e.g., on the adrenal medulla and the adrenal cortex). Chapter IV: Tobacco Use as Drug Dependence L Cigarettes and other forms of tobacco are addicting. Patterns of tobacco use are regular and compulsive, and a withdrawal syndrome usually'accompanies tobacco abst]nence. 2. Nicotine is the drug in tobacco that causes addiction. Specifi- cally, nicotine is psychoactive ("mood altering") and can provide pleasurable effects. Nicotine can serve as a reinforcer to motivate tobacco-seeking and tobacco-using behavior. Toler- ance develops to actions of nicotine such that repeated use results in diminished effects and can be accompanied by increased intake. Nicotine also causes physical dependence characterized by a withdrawal syndrome that usually accompa- nies nicotine abstinence. 3. The physical characteristics of nicotine delivery systems can affect their toxicity and addietiveness. Therefore, new nicotine delivery systems should be evaluated for their toxic and addictive affects. Chapter V: Tobacco Use Compared to Other Drug Dependen- cies 1.The pharmacologic and behavioral processes that determine tobacco addiction are similar to those that determine addiction to drugs such as heroin and cocaine. 2. Environmental factors including drug-associated stimuli and social pressure are important influences of initiation, patterns 14 •

i• of use, quitting, and relapse to use of opioids, alcohol, nicotine, and other addicting drugs. 3. Many persons dependent upon opioids, alcohol, nicotine, or other drugs are able to give up their drug use outside the context of treatment programs; other persons, however, re- quire the assistance of formal cessation programs to achieve lasting drug abstinence. 4, Relapse to drug use often occurs among persons who have achieved abstinence from opioids, alcohol, nicotine, or other drugs. 5. Behavioral and pharmacologic intervention techniques with demonstrated efficacy are available for the treatment of addiction to opioids, alcohol, nicotine, and other drugs. Chapter VI: Effects of Nicotine That May Promote Tobacco Dependence 1. After smoking cigarettes or receiving nicotine, smokers per- form better on some cognitive tasks (including sustained attention and selective attention) than they do when deprived of cigarettes or nicotine. However, smoking and nicotine do not improve general learning. 2. Stress increases cigarette consumption among smokers. Fur- ther, stress has been identified as a risk factor for initiation of smoking in adolescence. 3. In general, cigarette smokers weigh less (approximately 7 lb less on average) than nonsmokers. Many smokers who quit smoking gain weight, 4. Food intake and probably metabolic factors are involved in the inverse relationship between smoking and body weight. There is evidence that nicotine plays an important role in the relationship between smoking and body weight. Chapter VII: Treatment of Tobacco Dependence I. Tobacco dependence can be treated successfully, 2. Effective interventions include behavioral approaches alone and behavioral approaches with adjunctive pharmacologic treatment. 3. Behavioral interventions are most effective when they include multiple components (procedures such as aversive smoking, skills training, group support, and self-reward). Inclusion of too many treatment procedures can lead to less successful out- come. 4. Nicotine replacement can reduce tobacco withdrawal symp- toms and may enhance the efficacy of behavioral treatment. • 15

Appendix A: Trends in Tobacco Use in the United States 1. An estimated 32.7 percent of men and 28.3 percent of women smoked cigarettes regularly in 1985. The overall prevalence of smoking in the United States decreased from 36.7 percent in 1976 (52.4 million adults) to 30.4 percent in 1985 (51.1 million adults). 2. In 1985, the mean reported number of cigarettes smoked per day was 21.8 for male smokers and 18.1 for female smokers. 3. Smoking is more common in lower socioeconomic categories (blue-collar workers or unemployed persons, less educated persons, and lower income groups) than in higher socioeconom- ic categories. For example, the prevalence of smoking in 1985 among persons without a high school diploma was 35.4 percent, compared with 16.5 percent among persons with postgraduate college education. 4. An estimated 18.7 percent of high school seniors reported daily use of cigarettes in 1986. The prevalence of daily use of one or more cigarettes among high school seniors declined between 1975 and 1986 by approximately 35 percent. Most of the decline occurred between 1977 and 1981. Since 1976, the smoking prevalence among females has consistently been slightly higher than among males. 5. The use of cigars and pipes has declined 80 percent since 1964. 6. Smokeless tobacco use has increased substantially among young men and has declined among older men since 1975. An estimated 8.2 percent of 17- to 19*year-old men were users of smokeless tobacco products in 1986. Appendix B: Toxicity of Nicotine 1. At high exposure levels, nicotine is a potent and potentially lethal poison. Human poisonings occur primarily as a result of accidental ingestion or skin contact with nicotine-containing insecticides or, in children, after ingestion of tobacco or tobacco juices. 2. Mild nicotine intoxication occurs in first-time smokers, non- smoking workers who harvest tobacco leaves and people who chew excessive amounts of nicotine polacrilex gum. Tolerance to these effects develops rapidly. 3. Nicotine exposure in long-term tobacco users is substantial, affecting many organ systems (Chapters II and III). Pharmaco- logic actions of nicotine may contribute to the pathogenesis of smoking-related diseases, although direct causation has not yet been determined. Of particular concern are cardiovascular Q 16 $

disease, complications of hypertension, reproductive disorders, cancer, and gastrointestinal disorders, including peptic ulcer disease and gastroesophageal reflux. 4. The risks of short-term nicotine replacement therapy as an aid to smoking cessation in healthy people are acceptable and substantially outweighed by the risks of cigarette smoking. 17

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RUSSELL, M.A.H. Tobacco smoking and nicotine dependence. In: Gibbons, R.J., Israel, Y., Kalant, H., Popham, R.E., Schmidt, W., Smart, R.O. (eds.} Research Advances in Alcohol and Drug Problems, New York: Wiley, 1976, pp. 1-46. U.8. DEPARTMENT OF HEALTH AND HUMAN SERVICF~. The Health Corse. quences of Smoking for Women. A Report of the Surgeon General U.S, Department of Health and Human Service6, Public Health Service, Office of the Assistant Secretary for Health, Office on Smoking and Health. 1980. U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES, The Health Conse. quences of Smoking: The Changing Cigarette. A Report of the Surgeon Crener~L U.S. Department of Health and Human Services, Public Health Service, Office of the Assistant Secretary for Health, Office on Smoking and Health. DHHS Publication No. (PHS) 81-50156, 1981. U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES. ~he Health Con~e. quenees of Smohlng: Cancer. A Report of the Surgeon General. U,S. Department of Health and Human Services, Public Health Service, Office on Smoking and Health. DHHS Publication No, (PHS) 82.50179, 1982. U.S. DEPAETMENT OF HEALTH AND HUMAN SERVICES. The Health Con~e. quenee~ of Smoking: Cardiovascular Disease. A Report of the Surgeon General U.S, Department of Health and Human Services, Public Health Service, Office on Smoking and Health. DHHS Publication No. (PHS) 84-50204, 1988a. U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES, Why People Smoke Cigarettes, U.S. Department of Health and Human Services, Public Health Service. 1983b. U,S. DEPARTMENT OF HEALTH AND HUMAN SERVICES, The Health Come- quencea of Smoking. Chronic Obstructive Lung Disease, A Report of the Surgeon General, U.S. Department of Health and Human Services, Public Health Service, Office on Smoking and Health. DHHS Publication No. (PHS) 94-50205, 1984a. U.S, DEPARTMENT OF HEALTH AND MUMAN SERVICES. DrugAbuse and Drug Abuse Research. Triennial Report to Congre~ from the Secreta~,, Department of Health and Human Servicer. U.S. Department of Health and Human Services, Public Health Service, Alcohol, Drug Abuse, and Mel~tal Health Administration, National Institute on Drug Abuse. DHHS Publication No. (ADM) 85-1972, January 1984b. U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES, The Health Conse- quences of Smoking: Cancer and Chronic Lung Dleesse in the Worh,olaee. A Report of the Surgeon General. U.S. Department of Health and Human Services, Public Health Service, Office on Smoking and Hsalth, DHHS Publication No. (PHS) 85- 50207, 1985. U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES. The Health Conse- quences of Involuntary Smoking. A Report of the Surgeon General. U.S. Depart- ment of Health and Human Services, Public Health Service, Office on Smoking and Health. DHHS Publication No. (CDC) 87-8398, 1985a. U.S. DEPARTMENT OF HEALTIi AND HUMAN SERVICES. The Health Conse. quenee~ of Using 6mokeleaa Tobaeco. A Report of the Advisory Committee to the Surgeon General U.S, Department of Health and Human Services, Public Health Service, National Institutes of Health. NIH Publication No. 86-2874, 1986b. U.S. DEPARTMENT OF HEALTH. EDUCATION, AND WELFARE. The Health Consequences of Smokin~ A Report of the Surgeon General: 1971. U.S. Department of Health, Education, and Welfare, Public HeaLth Service, Health Services and Mental Itealth Administration, DHEW Publication No. (HSM) 71-7513, 1971. U.S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE. The Heallh Consequences of SrnoMng. A Reporl of the Surgeon General: 197~ U.8. Department of Health, Education, and Welfare, Public Health Service, Health Services and Mental Health Administration. DHEW Publication No. (HSM) 72-7516, 1972. 19

U.S. DEPARTMENT OF HEALTH, EDUCATION. AND WELFARE. The HPalth Conseql~ences of Smoking, 1975. Department of [lealth. Education, and Welfare, Public Health Service, Center for Disease Control. DHEW Publication No. (CDC) 77-8704, 1975. U.S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE. Tile Health Consequences of Smoking, 1977-1978. U.S. Department of Health, Education, and Welfare. Public Health Service, Office of the Assistant Secretary for Health, Office on Smoking and Health. DHEW Publication No. (PHS) 79-50065, ]978. U.S, DEPARTMENT OF HEALTH. EDUCATION. AND WELFARE Smoking and Health: A Report of the Surgeon General. U,S, Department of Health, Education. and Welfare. Public Itealth Service, Office of the Assistant Secretary for Health. Office on Enmking and tIealth. DHEW Publication No. (PHS) 79-509~6. 1979. U,S, PUBLIC HEALTH SERVICE. Smoking and Health. Report of the Advisor), Committee to the Slirgeor, General of the Public Health Service. U.S. Department of Health, Education, and Welfare. Public Health Service. Centers for Disease Control. PHS Publication No, 1103. 1964. U,S. PUBLIC HEAL'ITrl SERVICE. The Health Cot~sequec~oe# of Smoking. A Pllblic Service Review: 196Z U.S. Department of Health. Education, and Welfare, Public liealth Service. HeaRh Services and Mental Health Administration. PHS Publica- tion No. 1696 Revised, 1968a. U.S. PUBLIC HEALTIf SERVICE. The Health Cotwequenees of Smoking. 1968 Supplement to the 1967 Public Health Sere, ice Review. U.S. Department of Health, Education, and Welfare, Public Health Service, Health Services and Mental Health Administration. DHEW Publication No. 1696. 1969b, U.S, PUBLIC HEALTH SERVICE. The Health Consequences of Smoking 1969. Supplement to the 1967 Public Health Service Review. Department of Health, Education, and Welfare. Public Health Service, Health Services and Mental Health Administration. DHEW Publication No. 1969-2, 1969. U.S, PUBLIC HEALTH SERVICE. The Health Consequences of Smoking. A Report of the Su~eon General U.S. Department of Health, Education, and Welfare, Public Health Service, Health Services and Mental Health Administration, DHEW Publication No. (HSM) 73-8704, 1973 U.S. PUBLIC HEALTH SERVICE, The Health Consequences of Smoking, 1974. U,S Department of Health, Education, and Welfare, Public Health Service, Centers for Disease Control. DHEW Publication No. (CDC) 74-8704, [974. U.S. PUBLIC HEALTH SERVICE, The Health Consequences of Smoking A Reference Edition: 1976. U.S. Department of Health, Education, and Welfare, Public Health Service, Centers for Disease Control. DHEW Publication No. (CDC) 78-8957. 1976 VOLLE, R.L Nicotinic ganglion-stimulating agents. PharmacoL Ganglion. Transmiss, 9:281-307. 1980. @ @ @ 2O •

CHAPTER II NICOTINE: PHARMACOKINETICS, • METABOLISM, AND , PHARMACODYNAMICS 21

O CONTENTS Introduction Nicotine and Other Alkaloids in Various Tobacco Prod- ucts Pharmacokinetics and Metabolism of Nicotine Absorption of Nicotine Distribution of Nicotine in Body Tissues Elimination of Nicotine Pathways of Nicotine Metabolism Rate of Nicotine Metabolism Renal Excretion Nicotine and Cotiniae Blood Levels During Tobacco Use Nicotine Levels Cotlnine Levels Intake of Nicotine Cigarette Smoking Elimination Rate as a Determinant of Nicotine Intake by Cigarette Smoking Biochemical Markers of Nicotine Intake Analytical Methods for Measuring Nicotine and Coti- nine in Biological Fluids Pharmacodynamics of Nicotine General Considerations Dose-Response Tolerance Acute Sensitivity Human Studies Animal Studies Mechanisms of Differences in Acute Sensitivity Tachyphylaxis (Acute Tolerance) Human Studies Animal Studies Mechanisms of Tachyphylaxis Chronic Tolerance Human Studies Animal Studies 23

O Mechanisms of Chronic Tolerance Pharmacodynamics of Nicotine and Cigarette Smok- ing Constituents of Tobacco Smoke Other Than Nicotine With Potential Behavioral Effects Minor Tobacco Alkaloids "Tar" and Selected Constituents of Tobacco Smoke Which Contribute to Taste and Aroma Carbon Monoxide Acetaldehyde and Other Smoke Constituents Summary and Conclusions References Q 24 •

Introduction Chemicals with behavioral and physiological activity are delivered to tobacco users when they smoke a cigarette or use other tobacco products. Whether these chemicals are absorbed in quantities that are of biological significance and whether such absorption is related to the behavior of the tobacco user are critical issues in understand* ing their role in addictive tobacco use. The scientific study of the absorption processes, distribution :within the body, and elimination from the body of drugs and chemicals is called pharmacokinetics. The study of drug and other chemical actions on the body, over time, is called pharmacodynamics. Pharmacokinetic and pharmacody,3amic studies can be done separately or together. An example of the.latter is when a drug is administered and its concentrations in the blood and its behavioral and physiological actions are measured over time. Such studies can reveal relationships among the dose of a drug, levels in the blood, and effects on body functions. The pharmacokinetics and pharmacodynamics of some tobacco smoke constituents, particularly nicotine and carbon monoxide, have been extensively studied. These studies show an orderly relationship between the use of tobacco and the absorption of nicotine. Similarly, the effects on behavioral and physiological functions, although complex, are orderly and related to the pbar~acokinetics of nicotine. These data will be reviewed in this Section. Research shows that nicotine is well absorbed from tobacco; that it is distributed rapidly and in biologically active concentrations to body organs, including the brain; and that nicotine is the major cause of the predominant behavioral effects of tobacco and some of its physiologic conse- Quences. One effect of nicotine, development of tolerance to its own actions, is similar to that produced by other addicting drugs. Tolerance refers to decreasing responsiveness to a drug or chemical such that larger doses are required to produce the same magnitude of effect. Tolerance to many actions of nicotine occurs in animals and humans. Evidence for tolerance to nicotine and mechanisms of tolerance development will be reviewed in this Chapter (see also Chapter VI). Although nicotine has long been considered as the primary pharmacologic reason for tobacco use, and the source of a number of the physiological effects of tobacco, thousands of other chemicals are present in tobacco. Most of these are delivered in such small quantities that they appear to have little or no behavioral conse- quence. However, a few chemicals do appear to have behavioral effects and there is n potential for numerous chemical interactions that conceivably could have behavioral consequences. This Chapter will conclude with an examination of tobacco smoke constituents 25

other than nicotine that may contribute to behavioral effects of cigarette smoking. The toxicity of nicotine is discussed in detail in Appendix B. Nicotine and Other Alkaloids In Various Tobacco Products Nicotine is a tertiary amine composed of a pyridine and a pyrrolidine ring (Figure 1). Nicotine may exist in two different three- dimensionally structured shapes, called stereoisomers. Tobacco contains only (S)-nicotine (also called l-nicotine), which is the most pharmacologically active form. Tobacco smoke also contains the less potent (R)-nicotine (also called d-nicotine) in quantities up to 10 pert;ent of the total nicotine present (Pool, Godin, Crooks 1985). Presumably some racemization occurs during the combustion pro- cess. The nicotine yield of cigarettes, as determined by standardized smoking machine tests, is available for most brands. However, the amount of nicotine in cigarettes or other tobacco products is not specified by manufacturers. Because tobacco is a plant product, there are differences in the amount of nicotine among and within different types and strains of tobacco, including variations in different parts of the plant, as well as differences related to growing conditions.,Table I shows concentrations of nicotine and uther alkaloids in several different tobacco leaves used in making commercial tobacco prod- ucts. Within a tobacco plant, leaves harvested from higher stalk positions have higher concentrations of nicotine than from lower stalk positions; ribs and stems of the leaves have the least (Rath- kamp, Tso, Hoffmann 1973). Combining different varieties of tobacco and different parts of the plant is a way to change the nicotine concentration of commercial tobacco. In a study of amounts of nicotine in the tobacco of 15 American cigarette brands of differing machine-determined yields (Benowitz, Hall et el. 1983), tobacco contained on average 1.5 percent nicotine by weight, Nicotine yield of the cigarettes, as defined by Federal Trade Commission smoking machine tests, was correlated inversely with nicotine concentrations in the tobacco. Thus, tobacco of lower. yield cigarettes tended to have higher concentrations of nicotine than did tobacco of higher*yield cigarettes. However, lower-yield cigarettes also contained less tobacco per cigarette, so the total amount of nicotine contained per cigarette, averaging 8.4 mg, was similar in different brands. Thus, low.yield cigarettes are low yield not because of lower concentrations of nicotine in the tobacco, but because they contain less tobacco and have characteristics which remove tar and nicotine by filtration or dilution of smoke with air. Concentrations of nicotine in commercial tobacco products are summarized in Table 2. O 26 •

NICOTINE ANATABINE ANABASIN~ ANABASEINE NORNICOT~N E N'- ME ~dyLAN ATABINE N'.METHyLANABA~INE 2,3'.DIp VRIDYL N*.~tTf~O$O~ORNICOTINE N~JOT'~C;NE NORN~OTYR~ ~TAN~OTINE NICO~NE N~)XIDE COTtNINE 6'.OXOANABASINE PSEUDOOXYNICOTINE . (OXYNI~3TINE) FIGURE 1,.--Chemlea] structures of nicotine and minor tobacco alkaloids SOURCE: Lele 11983k Although the major alkaloid in tobacco is nicotine, there are other alkaloids in tobacco which may be of pharmacologic importance. These include nornicotine, anabasine, myosmine, nicotyrine, and anatabine (Figure 1). These substances make up 8 to 12 percent of the total alkaloid content of tobacco products (Table 1) (Piade and Hoffmann 1980). In some varieties of tobacco, nornicotine concentra- tion8 exceed those of nicotine (Schmeltz and Hoffmann ]977). Typical quantities of the minor alkaloids in the smoke of one cigarette arc: nornicotine (27 to 88 ~g), cotinine (9 to 50 Itg), anabasine (3 to 12 I~g), anatabine (4 to 14 t~g), myosmine (9 ~tg), and 2,3'bipyridyl (7 to 27 i~g). N'.methylanabasine, nicotyrine, nornicoty- fine, and nicotine-N'-oxide have also been identified in cigarette smoke (Schmeltz and Hoffmann ]977). Puffing characteristics, especially puff frequency, influence the delivery of the component alkaloids (Bush, Grfinwald, Davis 1972). 27

TABLE 1.--Alkaloid content of various tobaccos (mg/kg, dry basis) Dark commercial tobacco Alkaloid A B Buriey Bright Nicotine LL500 10,000 15AOC 12,900 Nornicoline 550 200 630 :710 Anatabine 360 380 570 603 Anabasine [40 150 ~0 150 Cotinine 195 140 90 40 Myosmine 45 50 60 30 2,3'-aipyridyl 1CO ll0 30 10 N'-For myl.nor nicotine 175 210 140 40 SOURCe: Piade ond Hoffmann 119801 TABLE 2.--Nicotine content of various tobacco products Number Concentration Typical Nicotine in Nicotine in dose of brands of nicotine single dose~ single dcse~ typically consumed Product tested (mgfg tc, bac¢o) {g tobaccol (rag) in a day Cigarettesk 15 157 C13.3-26 9)~ 054 84 168 rag/20 cig~ Moist snuff~¸~ 8 105 (61-16.6p 1,4 145 157 rag/15 g Chewing tobacco:~4 2 168 19.1-24.5i 7.9 133 1,176 rag/70 g ¸¸Single dose refers Io a cigarette Or an ~mount Of smokeless tobacco placed in the mouth ~ Range SOURC[~ 11]¢nc~wit z' }Jail et al q ] ~*~3J: ~ Ko21owski et al (19821: = Gritz el al {19~ 11; , Benowit z porc}~el et ~l 11988k Nornicotine and anabasine have pharmacologic activity qualita- tively similar to that of nicotine, with potencies of 20 to 75 percent compared with that of nicotine, depending on the test system and the animal (Clark, Rand, Vanov 1965). In addition to direct activity, some of the minor alkaloids may influence the effects of nicotine. For example, nicotyrine inhibits the metabolism of nicotine in animals (Stalhandske and Slanina 1982). The pharmacology of the minor tobacco alkaloids is discussed in more detail in the last section of this Chapter. 28

Pharmacokinetics and Metabolism of Nlootine Absorption of Nicotine Nicotine is distilled from burning tobacco and is carried proximal- ly on tar droplets (mass median diameter 0.3 to 0,5 ~tm) and probably also in the vapor phase (Eudy et al. 1985), which are inhaled. Absorption of nicotine across biological membranes depends on pH (Armitage and Turner 1970; Schievelbein et al. 1973). Nicotine is a weak base with a pKa (index of ionic dissociation) of 8.0 (aqueous solution, 25°C). This means •that at pH 8.0, 50 percent of nicotine is ionized and 50 percent is nonionized. In its ionized state, such as in acidic environments, nicotine does not rapidly cross membranes. The pH of tobacco smoke is important in determining absorption of nicotine from different sites within the body. The pH of individual puffs of cigarettes made of flue-cured tobacco, the predominant tobacco in most American cigarettes, is acidic and decreases progres- sively with sequential puffs from pH 6.0 to 5.5 (Brunnemann and Hoffmann 1974). At these pHs, the nicotine is almost completely ionized. As a consequence, there is little buccal absorption of nicotine from cigarette smoke, even when it is held in the mouth (Gori, Benowitz, Lynch 1986). The smoke from air-cured tobaccos, the predominant tobacco in pipes, cigars, and in a few European cigarettes, is alkaline with progressive puffs increasing its pH from 6.5 to 7.5 or higher (Brunneman and Hoffmann 1974)~ At alkaline pH, nicotine is largely nonionized and readily crosses membranes. Nicotine from products delivering smoke of alkaline pH is well absorbed through the mouth (Armitage et al. 1978; Russell, Raw, Jarvis 1980). When tobacco smoke reaches the small airways and alveoli of the lung, the nicotine is rapidly absorbed. The rapid absorption of nicotine from cigarette smoke through the lung occurs because of the huge surface area of the alveoli and small airways and because of dissolution of nicotine at physiological pH (approximately 7.4), which facilitates transfer across cell membranes. Concentrations of nic- otine in blood rise quickly during cigarette smoking and peak at its completion (Figure 2). Armitage and coworkers (1975), measuring exhalation of radiolabelod nicotine, found that four cigarette smok- ers absorbed 82 to 92 percent of the nicotine in mainstream smoke, another smoker presumed to be a noninhaler absorbed 29 percent, and three nonsmokers (who were instructed to smoke as deeply as possible) absorbed 30 to 66 percent. Chewing tobacco, snuff, and nicotine polacrilex gum are of alkaline pH as a result of tobacco selection and/or buffering with additives by the manufacturer. The alkaline pH facilitates absorp- tion of nicotine through mucous membranes. The rate of nicotine absorption from smokeless tobacco depends on the product and the 29

.o o 0 0 0 ,_o C "0 0 ~Q 12 8 a 0 J -10 I 1 I I I I I .~ 0 30 60 gO 120 Minutes FIGURE 2.--Blood nicotine concentrations during and after smoking cigarettes (1 1/3 cigarettes), using oral snuff (2,5 g), using chewing tobacco (average, 7.9 g), and chewing nicotine gum (two 2-mg pieces) ~OUI~CE Benowitz. Porchet et it[ (1988) route of administration, With fine-ground nasal snuff, blood levels of nicotine rise almost as fast as those observed after cigarette smoking 3O •

O (Russell et al. 1981). The rate of nicotine absorption with the use of oral snuff and chewing tobacco is more gradual. Nicotine is poorly absorbed from the stomach due to the acidity of gastric fluid (Travell 1960), but is well absorbed in the small intestine (Jenner, Gorrod, Beckett 1978), which has a more alkaline pH and a large surface area. Bioavailability of nicotine from the gastrointestinal tract (that is, swallowed nicotine) is incomplete because of presystemic (first pass) metabolism, whereby, after absorption into the portal venous circulation, nicotine is metabolized by the liver before it reaches the systemic venous circulation. This is in contrast to nicotine absorbed through the lungs or oral/nasal mucosa, which reaches the systemic circulation without first passing through the liver. Nicotine base can be absorbed through the skin, and there have been cases of poisoning after skin contact with pesticides containing nicotine (Faulkner 1933; Benowitz, Lake et el, 1987; Saxena and Scheman 1985). Likewise, there is evidence of cutaneous absorption of and toxicity from nicotine in tobacco field workers (Gehlbach at el. 1975). Because of the complexity of cigarette smoking processes and use of smokeless tobacco products, the dose of nisotine cannot be predicted from the nicotine content of the tobacco or its absorption characteristics. To determine the dose, one needs to measure blood levels and know how fast the individual eliminates nicotine. This topic, estimation of systemic doses of nicotine consumed from various tobacco products, will be considered in a later section after discussion of relevant pharmasokinetie issues. Distribution of Nicotine in Body Tissues After absorption into the blood, which is at pH 7.4, about 69 percent of the nicotine is ionized and 31 percent nonionized. Binding to plasma proteins is less than 5 percent (Benowitz, Jacob et ah 1982), The drug is distributed extensively to body tissues with a steady state volume of distribution averaging 180 liters (2.6 times body weight (in kilograms)) (Table 3). This means that when nicotine concentrations have fully equilibrated, the amount of nicotine in the body tissues is 2.6 times the amount predicted by the product of blood concentration and body weight. The pattern of tissue uptake cannot be studied in humans, but it has been examined in tissues of rabbits by measuring concentrations of nicotine in various tissues after infusion of nicotine to steady state (Table 4). Spleen, liver, lungs, and brain have high affinity for nicotine, whereas the affinity of adipose tissue is relatively low. After rapid intravenous (i.v.) injection, concentrations of nicotine decline rapidly because of tissue uptake of the drug. Shortly after i.e. injection, concentrations in arterial blood, lung, and brain are high, while concentrations in tissues such as muscle and adipose (major storage tissues at steady state) are low. The consequence of this 31 !

TABLE 3.--Human pharmacokinetics of nicotine and cotinine Nicotine Cotinine Half.life 120 rain 18 hr Volume of distribution 180 L 88 L Total clearance 1,300 rnL/min 72 mL/min Renal clearance 20~ mL/min 12 mL/min (acid urlnel Nonrenal clearance l,ICO mL/mln 60 mL/min SOURCE: Average va]ues b~sed on data from Benowit~ Jacob et st 119821 antl Benowit~ Kuyt el a] {19831 TABLE 4.--Steady state distribution of nicotine Tissue Ti~ue to blood ratio B[ood 1.0 Brain 3.0 Heart 3.7 Muscle 22 Adipose 95 Kidney 21.6 Liver 3.7 Lung 2.0 Gastrointestinal 2,5 NOTS: Tissue to blood nicot irte concentration ratios based oh 24.hr constant Lv. in fusiDa of nicotine in rabbits SOURCE¸ Benowitz 11986b) distribution pattern is that uptake into the brain is rapid, occurring within 1 or 2 rain, and blood levels fall because of peripheral tissue uptake for 20 or 30 min after administration. Thereafter, blood concentrations decline more slowly, as determined by rates of elimination and rates of distribution out of storage tissues. Rapid nicotine uptake into the brain has been demonstrated in animal studies. Oldendorf (1974) showed a high degree of nicotine uptake from blood in the first pass through the brains of rats. SchmitorlSw and colleagues (1967) showed by autoradiographic techniques that high levels of nicotine were present in the brain 5 min after i.v. injections in mice and that most nicotine had been 32 •

cleared from the brain by g0 rain. Stalhandske (1970) showed that intravenously injected ~4C-nicotine is immediately taken up in the brains of mice, reaching a maximum concentration within 1 min after injection. Similar findings based on positron emission tomogra- phy of the brain were seen after injection of l~C.nicotine in monkeys (Mazi~re et al. 1976). Nicotine inhaled in tobacco smoke enters the blood almost as rapidly as after rapid i.v. injection except that the entry point into the circulation is pulmonary rather than systemic venous. Because of delivery into the lung, peak nicotine levels may be higher and lag time between smoking and entry into the brain shorter than after i.e. injection. After smoking, the action of nicotine on the brain is expected to occur quickly. Rapid onset of effects after a puff is . believed to provide optimal reinforcement for the development of drug dependence. The effect of nicotine declines as it is distributed to other tissues. The distribution half-life, which describes the move- ment of nicotine from the blood and other rapidly perfused tissues, such as the brain, to other body tissues, is about 9 rain (Feyerabend et al. 1985). Distribution kinetics, rather than elimination kinetics (half-life, about 2 hr), determine the time course of central nervous system (CNS) actions of nicotine after smoking a single cigarette. Nicotine is secreted into saliva (Russell and Feyerabend 19"18). Passage of saliva containing nicotine into the stomach, combined with the trapping of nicotine in the acidic gastric fluid and reabsorption from the small bowel, provides a potential route for enteric nicotine recirculation. This recirculation may account for some of the oscillations in the terminal decline phase of nicotine blood levels after i.v. nicotine infusion or cessation of smoking (Russell 1976). Nicotine freely crosses the placenta and has been found in amniotic fluid and the umbilical cord blood of neonates (Hibberd, O'Connor, Gorred 1978; Luck et al. 1982; Van Vunakis, Langone, Milunsky 1974). Nicotine is found in breast milk and the breast fluid of nonlactating women (Petrakis et ah 1978; Hill and Wynder 1979) and in cervical mucous secretions (Sasson et al. 1985). Nicotine is also found in the freshly shampooed hair of smokers and of nonsmokers environmentally exposed to tobacco smoke (Haley and Hoffmann 1985). Elimination of Nicotine Nicotine is extensively metabolized, primarily in the liver, but also to a small extent in the lung (Turner et al. 1975). Renal excretion of unchanged nicotine depends on urinary pH and urine flow, and may range from 2 to 35 percent, but typically accounts for 5 to 10 percent of total elimination (Benowitz, Kuyt et al. 1983; Rosenberg et al. 1980). 33

NICOTINE I.HYDROXYNICO|IN/ I FLAVOPROT~ N~ ~O~NC UR(NARY H EXCRETION H~ NICOTINE N'-OXIDE NICOTINE IMINIUM ION ALDEHYDE~ OXIOASE COTININE FIGURE 3.--Major pathways of nicotine metabolism Pathways of Nicotine Metabolism The primary metabolites of nicotine are cotinJne and nicotine-N'- oxide (Figure 3). Cotinine is formed in the liver in a two-step process, the first of which involves oxidation of position 5 of the pyrrolidine ring in a cytochrome P-45O-mediated process to nicotine-~t<~',-imini- um ion (Petcrson, Trevor, Castagnoli 1987). In the second step the iminium ion is metabolized by a cytoplasmic aldehyde oxidase to cotinine (Hibberd and Gorrod 1983). Cotinine itself is also extensively mehabolized, with only about 17 percent excreted unchanged in the urine (Benowitz, Kuyt et al. 1983). Several metabolites of cotinine have been reported, including trans-3'-hydroxycotinine (McKennis, Turnbull et al. 1963), 5'-hydrox- ycotinine (Bowman and McKennis 1962), cotinine-N-oxide (Shulgin et al. 1987), and cotinine methonium ion (McKennis, Turnbull, Bowman 1963) (see Figure 4). Little is known about the quantitative impvrtance of these metabolites. Trans-3'-hydroxycotlnine appears to be a major metabolite (Jacob, Benowitz, Shulgin 1988; Neurath et al. 1987), with urinary concentrations exceeding eotinine concentra- tions by twofold to threefold. Cotinine N-oxide is a minor metabolite in humans, accounting for approximately 3 percent of ingested nicotine (Shulgin et al. 1987). Subsequent oxidative degradation of the pyrrolidine ring gives rise to 3-pyridylacetic acid. This compound has been identified in human urine (MeKennis, Schwartz, Bowman 1964), but no quantitative data are available. 34 •

3¸ NJCOTINE .;'~o COTININE ~JCOTINE.N.OXIDE OH TRANS. 3,. HYDROXYCOT~NINE O COTIN]NE-N-OXIDE HO O • = CP~ $'.h*YOROXYC~TINtNE ~', I3. PYRIOYLI ,~. O )CO. N,M E TH yL BUTYR AMIO¢= CH= NICOTINE ISOMETHONIUM ION ~O CH3 COTININE METHONIUM ION FIGURE 4.--Structures of nicotine and its major metabolites SOURCE P, Jacob Ill {with permission~ 35

Nicotine-l'-N-oxide is quantitatively a minor metabolite of nlc- otine. Oxidation of the nitrogen atom of the pyrrolidlne ring depends on a microsomal flavoprotein system and produces a mixture of the two diasterisomers, l'-(R)-2'-(S)-cis- and l'-(S)-2'-(S)-trans.nicotine-l'- N'-oxide (Booth and Boyland 1970}. After i.v. injection, 100 percent of nicotine-N'-oxide is excreted unchanged in the urine, indicating no further metabolism (Beckett, Gorrod, Jenner 1971a). However, after oral administration only 30 percent is recovered in the urine as nicotine-N'-oxide; the remainder is recovered as nicotine and its metabolites. To evaluate the possibility of reduction of nicotlne-N'- oxide in the gastrointestinal tract, rectal administration of nicotine- N'-oxide was performed for experimental purposes. Less than 10 percent was recovered in the urine as aicotine-N'-oxide (Beckett, Gorrpd, Jenner 1970). These findings indicate reduction of nicotine- N'-oxide back to nicotine within the human gastrointestinal tract, believed to be a consequence of bacterial action. Experiments in rats indicate that significant amounts of nicotine- N'-oxide are converted to nicotine both in vitro and in vivo (Dajani, Gorrod, Beckett 1975a,b}. Nicotine and cotinine have been measured in the blood of rats administered nicotine-N,N'-dloxide and nicotine- N'-oxide in drinking water (Sepkovic et al. 1984, 1986). Thus, while reduction of nicotine-N'-oxide to nicotine appears to be bacterial in humans, it may be mediated by endogenous enzymes in other species. Quantitative aspects of the conversion of nicotine to its metabo- lites have not been well defined. Studies of cotinine excretion in urine collected for 24 hr after i.w nicotine injection indicate less than l0 percent of nicotine is excreted as cotinine in nonsmokers compared with an average of 25 percent in smokers (Beckett, Gorrod, Jenner 1971b). Another study, comparing 24-hr urinary excretion of cotinine with nicotine content of cigarette butts after smoking, indicated 46 percent recovery as cotinine (Schievelbein 1982). However, both of these studies underestimate the conversion of nicotine to cotlnine because the urine collection period was too short. In cigarette smokers, cotinine has a half-life averaging 18 to 20 hr (Benowitz, Kuyt et al. 1983), so that in 24 hr only a little more than half of cotiniae is recovered. Urine collection for at least 72 hr is necessary to recover more than 90 percent of cotinine in most subjects. In addition, since only 17 percent of cotinine is excreted unchanged (Benowitz, Kuyt et al. 1983), urinary recovery analysis underestimates the cotinlne generation rate. At steady state, the rate of metabolites excretion reflects the rate at which the metabolites are generated. After i.v. dosing, 100 percent of nicotine-N'-oxide but only 17 percent of cotinine is excreted unchanged in the urine. Based on a ratio of urinary cotinine to nicotine-N'-oxide of 2.9 and based on excretion of that 17 percent of t 36 •

cotinine and 100 percent of nicotine-N'-oxlde unchanged in the urine, the relative generation rate of cotinine compared with that of nicotine-N'-oxide is calculated to be 17 to 1 (Benowitz 1986b). Because 4 percent of nicotine is excreted as nicotine-N'-oxide (Jacob et al. 1986; Beckett, Gorred~ Jenner 1971a), about 70 percent of nicotine appears to be converted to cotinine. Quantitative data on other metabolites that may have pharmacologic activity, such as nicotine isomethonium ion and nornicotine, are not available. Rate of Nicotine Metabolism The rate of nicotine metabolism can be determined by measuring blood levels after administration of a known nicotine dose. In one study, cigarette smokers were given i.v. infusions of nicotine for 30 to 60 rain, and total and renal clearances were comptited (Benowitz, Jacob et al. 1982). Total clearance (a term which describes the capacity to eliminate a drug) averaged 1,300 mL/min. Nonrenal clearance averaged 1,100 mL/min (Table 3), which represents about 70 percent of liver blood flow. Because nicotine is metabolized mainly by the liver (data in animals indicate only a small degree of metabolism by the lung) (Turner, Sillett, McNicol 1977), this means that about 70 percent of the drug is extracted from the blood in each pass through the liver. On the average, 85 or 90 percent of nicotine is metabolized by the liver. Renal Excretion Nicotine is excreted by glomerular filtration and tubular seci~etion within the kidney. Depending on urinary pH and urine flow rate, variable amounts of nicotine are reabsorbed by the kidney tubules. In acidic urine, where nicotine is mostly ionized and tubular reabsorption is minimized, renal clearance of nicotine may be as high as 600 mL/min (urinary pH 4.4) (Benowitz, Kuyt et al. 1983; Rosenberg et al. 1980). In alkaline urine, a larger fraction of nicotine is not ionized. Tubular reabsorption of nonionized nicotine results in lower rate of excretion and reduced renal clearances as low as 17 mL/min (urine pH 7.0). When urine pH is uncontrolled, averaging 5.8, renal clearance averages about 100 mL/min, accounting for the elimination of 10 to 15 percent of the daily nicotine intake. Nicotine and Cottnine Blood Levels During Tobacco Use Nicotine Levels Plasma nicotine concentrations (or concentrations in blood, which are similar) sampled in the afternoon in smokers generally range from 10 to 50 ng/mL. The increment in blood nicotine concentration after smoking a single cigarette ranges from 5 to 30 ng/mL, depending on how the cigarette is smoked (Armitage et ah 1975; 37

Herning e$ al. 1983; Isaac and Rand 1972). Peak blood levels of nicotine are similar, although the rate of nicotine increase is slower for cigar smokers and snuff and chewing tobacco users compared with that for cigarette smokers (Armitage et al. 1978; Turner, Sillett, McNicel 1977; Gritz et al. 1981; Russell, Raw, Jarvis 1980; Russell et al. 1981) (Figure 2). Pipe smokers, particularly those who have previously smoked cigarettes and who inhale, may have blood and urine levels of nicotine as high as those of cigarette smokers (McCusker, McNabb, Bone 1982; Turner, Sillett, McNicol 1977; Wald et al. 1984). The earliest published studies of nicotine elimination kinetics reported half-llves of 20 to 40 min (Armitage etal. 1975; Isaac and Rand 1972). In those studies, drug.blood levels were followed only for 30 to 60 rain, which is not long enough to determine the elimination half-life. Thus, half-lives were based on blood levels which included the distribution phase. When blood levels are followed for several hours after the end of nicotine infusion, a log-linear decline of blood levels with a half-life of about 2 hr is observed (Benowitz, Jacob et al. 1982; Feyerabend, Ings, Russell 1985). The half-life of a drug is useful in predicting its accumulation rate in the body with repetitive doses and the time course of its decline after cessation of dosing. Assuming a half-life of 2 hr, one would predict nicotine to accumulate over 6 to 8 hr'(3 to 4 half-lives) of regular smoking and persist at significant nicotine levels for 6 to 8 hr after cessation of smoking. If a smoker smokes until bedtime, significant nicotine levels should persist all night. Studies of blood levels in regular cigarette smokers confirm these predictions (Figure 5) (Russell and Feyerabend 1978; Benowitz, Kuyt, Jacob 1982). Peaks and troughs follow the use of each cigarette, but as the day progresses, trough levels rise and the influence of peak levels becomes less important. Thus, nicotine is not a drug to which people are exposed intermittently and that is eliminated rapidly from the body. To the contrary, smoking represents a multiple dosing situation with considerable accumulation during smoking and with persistent levels for 24 hr of each day. Cotinine Levels Cotinine levels are of particular interest as qualitative markers of tobacco use and quantitative indicators of nicotine intake. Cotlnine is present in the blood of smokers in much higher concentrations than nicotine. Cotinine blood levels average about 250 to 300 ng/mL in groups of cigarette smokers (Benowitz, Hall et al. 1983; Haley, Axelrad, Tilton 1983; Langone, Van Vunakis, Hill 1975; Zeidenberg et al. 1977). After stepping smoking, levels decline with a halfqife averaging 18 to 20 hr (range 11 to 37 hr). But because of the long half-life, there is much less fluctuation in sotinine concentrations 38 •

~. ~r. ~'~ L Carboxyhemoglobin (percent) Blood nicotine concentration (ng/mL) I I I I I I i $ I I I / -' / ~~

throughout the day than in nicotine concentrations. As expected, there is a graduallncreasein cotinine levels during the day, peaking at the end of smoking and persisting in high concentrations overnight. Intake of Nicotine Cigarette Smoking Nicotine intake from single cigarettes has been measured by spiking cigarettes with ~4C-labeled nicotine (Armitage et al. 1975). That study of eight subjects, each smoking a single filter-tipped cigarette, indicated an intake range of 0.36 to 2.62 rag. Intake was higher in smokers than .in nonsmokers. Intake of nicotine from smoking a single cigarette or with daily cigarette smoking has been estimated by methods similar to those used in drug bioavailability studies (Benowitz and Jacob 1984; Feyerabend, Ings, Russell 1985). Metabolic clearance of nicotine was determined after i.v. injection. Metabolic clearance data were then used in conjunction with blood and urinary concentrations of nicotine measured during a period of smoking to determine the intake of nicotine. In five subjects, average intake of nicotine per cigarette was 1.06 mg (range, 0.58 to 1.49 mg) (Feyerabend, ]ngs, Russell 1985). In 22 cigarette smokers, 13 men and 9 women who smoked an average of 36 cigarettes/day (range 20 to 62), the average daily intake was 37.6 rag, with a range from 10.5 to 78.6 mg (Benowitz and Jacob 1984). Nicotine intake per cigarette averaged 1.0 mg (range 0.37 to 1.56 rag). Intake per cigarette did not correlate with yields obtained by smoking machine using standard Federal Trade Commission methods. This is because smoking machines smoke cigarettes in a uniform way, using a fixed puff volume (35 mL), flow rate (over 2 sec), and interval (every minute). Smokers smoke cigarettes differently, changing their puffing behav- ior to obtain the desired amount of tobacco smoke and nicotine. Elimination Rate as a Determinant of Nicotine Intake by Cigarette Smoking There is considerable evidence that smokers adjust their smoking behavior to try to regulate or maintain a particular level of nicotine in the body (Gritz 1969; Russell 1976). For example, when the availability of cigarettes is restricted, habitual smokers can increase intake of nicotine per cigarette 300 percent compared with the intake of unrestricted s~-noklng (Benowitz, Jacob, Keslowski et al. 1986). Techniques for measuring daily intake of nicotine (Benowitz and Jacob 1984) have been applied to study the influence of elimination on nicotine intake. The rate of renal elimination of nicotine was manipulated by administration of ammonium chloride or sodium 4O

bicarbonate to acidify or alkalinize the urine, respectively (Benowitz and Jacob 1985). Compared with daily excretion during placebo treatment (3.9 mg nicotine/day), acid loading increased (to 12 rag/day) and alkaline loading decreased (to 0.9 mg/day) daily excretion of nicotine. The total intake of nicotine averaged 38 mg/day. Average blood nicotine concentrations were similar in placebo and bicarbonate treatment conditions but were 15 percent lower during ammonium chloride treatment. Daily intake of nicotine was 18 percent higher during acid loading, indicating compensation for increased urinary loss. The compensatory increase in nicotine consumption was only partial, replacing about half of the excess urinary nicotine loss. Bicarbonate treatment had no effect on nicotine consumption, consistent with the small magnitude of effect on excretions of nicotine in comparison to 'total daily intake. These results seem compatible with the suggestion of Schachter (1978) that emotional stress, which results in more acidic urine, might accelerate nicotine elimination from the body and thereby increase cigarette smoking. But caution must be exercised in applying these findings to usual smoking situations. These studies were performed under conditions of extreme urinary acidification or alkalinization, so that the changes in renal clearance would be maximized. Even with extreme differences in urinary pH, differ- ences in overall nicotine elimination rate and smoking behavior were modest. This is because renal excretion is a minor pathway for elimination of nicotine; most is metabolized. Smaller changes in urinary pH, such as occur spontaneously throughout the day or that might be related to stressful events, would not be expected to substantially influence nicotine elimination or smoking behavior. Biochemical Markers of Nicotine Intake Absorption of nicotine from tobacco smoke provides a means of verification and quantitation of tobacco consumption. The general strategy is to measure concentrations of nicotine, its metabolltes (such as cotinine), or other chemicals associated with tobacco smoke in biological fluids such as blood, urine, or saliva. Different measures vary in sensitivity, specificity, and difficulty of analysis. Different investigators have used blood or urinary nicotine concentrations, blood or salivary or urinary cotinine concentrations, expired carbon monoxide or carboxyhemoglobin concentrations, or plasma or sali- vary thicoyanate (a metabolite of hydrogen cyanide, a vapor phase constituent) concentrations as measures of tobacco smoke consump- tion. Relationships among daily intake of nicotine, daily exposure to nicotine (that is, blood concentrations of nicotine integrated over 24 hr), various parameters of cigarette consumption, and different measures of nicotine intake have been examined experimentally 41

during ad libitum cigarette smoking on a research ward (Benowitz and Jacob 1984), The best biochemical correlate to nicotine intake and exposure in this study was a random blood nicotine concentra- tion measured at 4 p.m. This level did not depend on when the last cigarette was smoked. This finding is consistent with the observation that nicotine levels accumulate throughout the day and plateau in the early afternoon (see Figure 5). At steady state, with regular. smoking throughout the day, there should be a reasonably good correlation between nicotine concentrations and daily intake. Car- boxyhemoglobin (COHb) concentrations in the afternoon were the next best markers of nicotine intake. Also, morning (8 a.m./levels of nicotine and COHb correlated with intake, presumably reflecting persistence of nicotine and COHb in the blood from exposure on the previous .day. Although cotinine is a highly specific marker for nicotine expo- sure, blood levels of cotinine across subjects in this study did not correlate as closely with nicotine intake as did blood levels of nicotine or COHb (Benowitz and Jacob 1984). This is probably due to individual variability in fractional conversion of nicotine to cotinine and in the elimination rate of cotinine itself. Because of its relatively long half-life, cotinine levels are less sensitive than nicotine levels to smoking pattern, that is, when the last cigarette was smoked. For longitudinal within.subject studies, the cotinine level would be expected to be a good marker of changes in nicotine intake. Cotinine measurements have become the most widely accepted method for assessing the intake of nicotine in long* term gt~dies of tobacco use (see also Chapter V). As expected by the known variation in renal clearance due to effects of urinary flow and pH, urinary concentrations of nicotine did not correlate well with nicotine intake (Benowitz and Jacob 1984). In contrast, urinary cotinine, which is less influenced by urinary flow or pH, was as good a marker as blood cotinine concentration. Salivary and urinary cotinine concentrations correlate well (r=0.8 to 0.9) with blood cotinine concentrations (Ha]ey, Axelrad, Tilten 1983; Jarvis et al. 1984). Therefore, salivary or urine cotinine concentrations should be almost as useful as blood levels in indicating nicotine intake. Analytical Methods for Measuring Nicotine and Cotinine in Biological Fluids Determination of nicotine concentrations in biological fluids requires a sensitive and specific method, because concentrations of nicotine in smokers' blood are generally in the low nanogram per milliliter range and a number of metabolites are also present. Cotinine concentrations in blood are generally about tenfold greater than nicotine concentrations, and as a result, less sensitive analyti- 42 Q O

cal methodology may be acceptable. Methods with adequate sensitiv- ity for determination of nicotine and cotinine in smokers' blood include gas chromatography (GC) (Curvall, Kazemi-Vala, Enzell 1982; Davis 1986; Feyerabend, Levitt, Russell 1975; Hengen and Hengen 1978; Jacob, Wilson, Benowitz 1981; Vereby, DePace, Mulb 1982), radioimmunoassay (RIA) (Langone, Gjika, Van Vunakis 1973; Castro et al. 1979; Knight et al. 1985), enzyme-linked immunosorbent assay (ELISA) (Bjercke et al. 1986), high performance liquid chroma- tography (HPLC) (Machacek and Jiang 1986; Chien, Diana, Crooks, in press), and combined gas chromatograph-mass spectrometry (GC- MS) (Dew and Hall 1978; Gruenke et.al; 1979; Jones et al. 1982; Daeneas etal. 1985). For reasons of sensitivity, specificity, and economy, GC and RIA are the most frequently used methods. GC-MS is a highly sensitive and specific technique, but the •expense has discouraged its routine use. HPLC is less sensitive than GC for . nicotine and cotinine determination. Although recently reported methods (Machacek and Jiang 1986; Chien, Diana, Crooks, in press) appear to have adequate sensitivity for determining concentrations in plasma, relatively large sample volumes are required. Concentra- tions of nicotine and cotinine in urine are tenfold to hundredfold greater than concentrations in plasma or saliva (Jarvis et al. 1984), and a variety of chromatographic and immnnoassay techniques meet sensitivity requirements. The choice of a particular method depends on the biological fluid to be assayed; the need for sensitivity, precision, and acoura'cy; and economic considerations. Chromatographic methods, particularly • those utilizing high-resolution capillary columns and specific detec-. tors such as nitrogen-phosphorus detectors or a mass spectrometer, provide the greatest specificity. On the other hand, immunoassay techniques are operationally simpler, generally require smaller samples, and may be less expensive than chromatographic methods. A drawback to immunoassay methods is the potential for crass- reactivity of the antibody with metabolites or endogenous sub- stances. There is generally a good correlation between results obtained by GC and RIA for plasma cotinine concentrations (r =0.94) (Gritz etal. 1981; Biber etal. 1987). In an interlaboratory comparison study (Biber etal. 1987), cotinine concentrations in smokers' urine measured by RIA were generally higher than concentrations deter- mined by GC, whereas in nonsmokers' urine spiked with cotinine RIA and GC values were similar. These results suggest that nicotine metabolites cross-react with the antibody against cotinine, at least in some of the RIA methods. Pharmacodynamlcs of Nicotine General Considerations This Section will focus on the relationship between nicotine levels in the body and their effects on behavior and physiological function 43

(pharmacodynamics). These data show how pharmacodynamic fac- tors determine some of the consequences of cigarette smoking. Two issues are particularly relevant in understanding the pharmacody- namics of nicotine: a complex dose-response relationship and the level of tolerance that is either preexisting or is produced by administration of nicotine. Dose-Response The relationship between the dose of nicotine and the resulting response (dose-response relationship) is complex and varies with the specific response that is measured. In pharmacology textbooks, nicotine is commonly mentioned as an example of a drug which in low doses causes ganglionic stimulation and in high doses causes ganglionic blockade following brief stimuiatiQn (Comroe 1960). This. type of effect pattern is referred to as "biphasic." Dose-response characteristics in functioning organisms (in rive) are often biphasic as well, although the mechanisms are far more complex. For example, at very low doses, similar to those seen during cigarette smoking, cardiovascular effects appear to be mediated by the CNS, either through activation of chemoreceptor afferent pathways or by direct effects on the brain stem (Comroe 1960; Su 1982). The net result is sympathetic neural discharge with an increase in blood pressure and heart rate. At higher doses, nicotine may act directly on the peripheral nervous system, producing ganglionic stimulation and the release of adrenal catecholamines. With high doses or rapid administration, nicotine produces hypotension and slowing of heart rate, mediated either by peripheral vagal activation or by direct central depressor effects (Ingeaito, Barrett, Procite 1972; Porsius and Van Zwieten 1978; Henningfield, Miyasate, Jasinski 1985). Tolerance A second pharmacologic issue of importance is development of tolerance; that is, after repeated doses, a given dose of a drug produces less effect or increasing doses are required to achieve a specified intensity of response. Functional or pharmacodyaamic tolerance can be further defined as where a particular drug concentration at a receptor site (in humans approximated by the concentration in blood) produces less effect than it did after a prior exposure. Dispesitional or pharmacokinetic tolerance refers to accelerated drug elimination as a mechanism for diminished effect after repeated doses of a drug. Behavioral tolerance refers to compensatory behaviors that reduce the impact of a drug to adversely affect performance. Such tolerance can occur following intermittent exposures to a drug such that there is minimal development of functional or dispositional tolerance. 44

O Most studies of drug tolerance have focused on tolerance which develops as a drug is chronically administered. If the tolerance develops within one or two doses, it is referred to as acute tolerance or tachyphylaxis. If tolerance develops after more prolonged use, the tolerance is referred to as acquired or chronic tolerance. Individual differences in sensitivity to the first dose of a drug also frequently exist. Those individuals who exhibit n reduced response to a specified drug dose or require a greater dose to elicit a specified level of response are said to be tolerant to the drug. This form of tolerance is referred to as first-dose tolerance, drug sensitivity, or innate drug responsiveness. For sake of clarity, this Report will reserve the term tolerance to describe reduction in the response to nicotine during the course of or following a previous exposure and will use acute drug sensitivity to describe responsiveness to an initial dose. Studies of tolerance to nicotine began in the late 19th century. In a series of studies of fundamental importance to the understanding of the nervous system, as well as to understanding the pharmacology of nicotine, Langley (1905) and Dixon and Lee (1912) studied the effects of repeated nicotine administration on a variety of animal species and on in vitro tissue preparations. Several findings emerged which have been widely verified and extended to other species and responses. These include: (i) With repeated dosing, responses dimin- ished to nearly negligible levels; (2) After tolerance occurred, responsiveness could be restored by increasing the size of the dose; (3) ARer a few hours without nicotine, responsiveness was partially or fully restored. After smoking a cigarette, people who have not smoked before ("naive smokers") usually experience a number of effects that become generally uncommon among experienced smokers. For example, retrospective reports by smokers indicate that initial exposure to tobacco smoke produced dizziness, nausea, vomiting, headaches, and dysphoria, effects that disappear with continued smoking and are rarely reported by chronic smokers (Russell 1976; Gritz 1980). Tolerance may also develop to toxic effects, such as nausea, vomiting, and pallor, during the course of nicotine poisoning, despite persistence of nicotine in the blood in extremely high concentrations (200 to 300 ng/mL) (Benowitz, Lake et al, 1987). A systematic analysis of the various forms of tobacco smoke tolerance has not been carried out. There are a few studies comparing the effects ellcited by an acute exposure to tobacco in nonsmokers and smokers. Clark and Rand (1968) studied the effect of smoking cigarettes of varying nicotine content on the knee-jerk reflex and reported that high-nicotine cigarettes suppressed this reflex to a greater degree than did low-nicotine cigarettes. This effect was more pronounced at each nicotine dose in nonsmokers and light smokers compared to heavy smokers. These findings suggested that • 45

tolerance is due to altered sensitivity to nicotine. Tolerance to nicotine is not complete because even the heaviest smokers experi- ence symptoms such as dizziness, nausea, and dysphoria when they suddenly increase their smoking rates (Danaher 1977). Evidence indicates that the majority of the psychological actions of tobacco smoke result from nicotine (Russell 1976; Chapter VII). Thus, most of the tolerance to effects of tobacco smoke that occurs following chronic tobacco use is due to the development of tolerance to nicotine. Acute Sensitivity Human Studies Studies which have indicated that individuals differ in response to tobacco smoke or nicotine have used smokers as the experimental subjects. Consequently, whether individual differences are due to differences in acute sensitivity to nicotine that have persisted during chronic tobacco use or are due to differences in the development of tolerance is unknown. Nesbitt (1973) and Jones (1986) noted that individual smokers differ with respect to the effects of smoking a standard cigarette on heart rate, but it is not clear from these studies whether these differences in responsiveness are due to differences in sensitivity to nicotine or to differences in the dose and kinetics of nicotine. Benowitz and colleagues (1982) observed individual differences in the effects of i.v: injections of nicotine on heart rate, blood pressure, and fingertip skin temperature, Differences were not explained by differences in blood levels, indicating differential sensitivity to nicotine. Animal Studies Studies using laboratory animals indicate that differences in acute sensitivity to nicotine exist. Inbred rat and mouse strains differ in sensitivity to the effects of nicotine on locomotor activity (Garg 1969; B~ittig et al. 1976; Schlatter and B~ittig 1979; Hatchell and Collins 1980; Marks, Burch, Collins 1983b). Mouse strains also differ in the direction of the effect (increased or decreased activity). The mouse strains that differ in sensitivity to the effects of injected nicotine on locomotor activity also differ in the magnitude of response to a standard dose of tobacco smoke (Baer, McClearn, Wilson 1980). Inbred mouse strains also differ in sensitivity to the effects of nicotine on body temperature, heart rate, and acoustic startle response (Marks, Burch, Collins 1983a; Marks et al. 1985, 1986), as well as in sensitivity to nicotine-induced seizures (Tepper, Wilson, Schlesinger 1979; Miner, Marks, Collins 1984, 1988). These findings indicate that genetic factors may influence the sensitivity of rats and 46 D O O

$ mice to the first dose of nicotine. The importance of genetically deterr~ined differences in human sensitivity to the effects of nicotine administered in tobacco smoke remains to be determined. Mechanisms of Differences in Acute Sensitivity Differences between inbred mouse and rat strains in sensitivity to the effects elicited by a single injected dose of nicotine do not appear to result from differences in rate of nicotine metabolism (Petersen, Norris, Thompson 1984) or from differences in brain nicotine concentration following intraperitoneal injection (Hatehel[ and Collins 1980; Rosecrans 1972; Rosocrans and Schechter 1972). Thus, rat and mouse strains differ in tissue sensitivity to the effect~ of nicotine. Differences among mouse strains in sensitivity to nicotine do not appear to be due to differences in the number or affinity of brain nicotine receptors that are measured viathe binding of ~H- nicotine (Marks, Butch, Collins, 1983b). Mouse stocks that are more sensitive to nicotine-induced seizures do have greater numbers of hippocampal nicotine receptors that bind zs~I-bungaretoxin (BTX) (Miner, Marks, Collins 1984, 1986). Some of the differences in sensitivity to nicotine between genetically defined stocks of animals may be related to differences in the number of nicotine receptors in specific regions of the bl'ain. Tachyphylaxis (Acute Tolerance) Human Studies Systematic studies of tachyphylaxis or acute tolerance to effects of tobacco in nonsmokers have not been reported. There is evidence that tachyphylaxis does develop to effects of tobacco and nicotine in humans. Smokers frequently report that the first cigarette of the day is the best and that subsequent cigarettes are "tasteless" (Russell 1976; Henningfield 1984). Smoking a single standard cigarette after 24 hr of abstinence increases heart rate, whereas smoking an identical cigarette during the course of a normal day fails to change heart rate (West and Russell 1987). Fewer standard puffs were required to produce nausea at the beginning of the day (following 8 to 10 hr of tobacco abstinence) or from high-nicotine cigarettes than at the end of the day or from low-nicotine cigarettes (Henningiield 1984). Complete tolerance to nausea and vomiting developed over 8 hr in a woman in the course of an accidental nicotine poisoning, despite persistently toxic blood levels of nicotine (Benowitz, Lake et al. 1987). These findings suggest that tolerance which is lost and regained during short periods of abstinence from tobacco is tolerance to nicotine. Tolerance develops very rapidly to several effects of nicotine. Rosenberg and colleagues (1980) studied the effects of i.v. nicotine 47

injections on arousal level, heart rate, and blood pressure. In these experiments, six healthy smokers, 21 to 35 years of age, received six series of nicotine injections spaced 30 min apart. Each series of injections consisted of 10 2-~g/kg injections spaced 1 min apart. Subjects reported a pleasant sensation after the first series of injections, but this response was not observed thereafter. Heart rate and blood pressure values remained above baseline, but there was little increment with successive injections, despite nicotine blood level increases which were similar to those observed after the first series of injections. In contrast, skin temperature fell progressively during the period of nicotine dosing, gradually returning to baseline at the end of the study. These data indicated rapid development of tolerance to subjective effects and heart rate and blood pressure responses, but tolerance was not complete because heart rate and blood pressure remained above baseline. Hennlngfield (1984) also assessed subjective responses of human subjects after i.v. injections with nicotine at 10-min intervals. The subjective response of"liking" the effects of nicotine was lost after five or six injections. Benowitz and coworkers (1982) studied the effect of a 30-min infusion of nicotine at a rate of 1 to 2 ~tg/kg/min. Shortly after initiation of infusion, heart rate and blood pressure increased, but the increase did not continue even though plasma nicotine concentrations continued to rise during the continuous infusion. Maximal cardiovas- cular changes were seen within 5 to 10 min, whereas maximal plasma nicotine levels were not reached until 30 min. These findings indicate that tachyphylaxis to the effects of nicotine may develop in humans witl~in 5 to I0 min, the time required to smoke one cigarette. In contrast to heart rate, skin temperature (reflecting cutaneous vascular tone) declined and rose in association with changes in blood nicotine concentrations, showing no evidence of tolerance. The above studies indicate rapid development of tolerance to some (but not all) actions of nicotine in people. These studies were performed with cigarette smokers who had abstained from smoking the night before the study. Since significant quantities of nicotine persist in the body even after overnight abstinence, there is probably some persistence of tolerance. Experimental data supporting this conclusion were obtained in a study of cardiovaseular responses to infused nicotine in smokers following either an overnight or 7-day tobacco abstinence (Lee, Benowitz, Jacob 1987). Heart rate and blood pressure responses were significantly greater after more prolonged abstinence. However, within 60 to 90 rain, the blood concentra- tion-effect relationship in subjects after brief abstinence approxi- mated that observed after prolonged abstinence. Thus, a significant level of tolerance persists throughout the daily smoking cycle, but is lost with prolonged abstinence. Tolerance, at least after abstinence for one week, is rapidly reestablished with subsequent exp.osure. Q 48 •

Animal Studies Many studies demonstrate that acute tolerance or tachyphylaxis develops very quickly to actions of nicotine. Barrass and cowcrkers (1969) demonstrated that pretreatment of mice with a single i.e. dose (0.8 mg/kg/ of nicotine resulted in an increase in the LDso (dose which is lethal to 50 percent of animals) for nicotine. Maximal protection was seen 5 min after the injection, but this protection diminished steadily over the next hour. Tachypbylaxis develops to the effects of nicotine on locomotor activity. Stolerman, Bunker, and Jarvik (1974) noted that pretreating rats with a 0.75-mg/kg dose of nicotine 2 hr before challenge doses of nicotine (0.25 to 4.0 mg/kg) resulted in a shift of the nicotine dose-response curves, indicating reduced sensitivity. The EDBo values (doses that are effective in producing the measured response in 50 percent of animals)for nicotine-induced decreases in locomotor activity were nearly 2.g-fold greater in nicotine-pretreatod rats than in saline-pretreated animals. Nicotine prctreatment also results in tachyphylaxis to the effects of nicotine on body temperature (hypothermia) in cats (Hall 1972), water-reinforced operant responding in rats (Stitzcr, Morrison, Domino 1970), discharge of lateral geniculate neurons of cats (Roppolo, Kawamura, Domino 1970), repolarization of sartorius muscle in frogs (Hancock and Henderson 1972), blood pressure elevation in rats (Wenzel, Azmeh, Clark 1971), contraction of aortic strips in rabbits (Shibata, Hattori, Sanders 1971), respiratory gtimu- lation in cats (McCarthy and Borison 1972), and gastrointestinal contraction in squid (Wood 1969) and guinea pigs (Hobbiger, Mitchal- son, Rand 1969). More recent studies have demonstrated that pretreatment with as little as one dose of nicotine will attenuate nicotine-induced elevations of plasma corticosterone (Balfour 1980) and adrenocorticotropic hormone (ACTH) (Sharp and Beyer 1986) levels in rats (see also Chapter liD. The interval between the pretreatment and challenge doses of nicotine is a critical factor that determines whether tachyphylaxis is observed. Aceto and coworkers (1986) examined the effect of i.v. nicotine infusion on heart rate and blood pressure in the rat. Tolerance did not develop when the interval between pretreatment and challenge doses was 30 rain; marked tolerance was detected when the interval was reduced to 1 rain. However, Stolerman, Fink, and Jarvik (1973) observed that after a single intraperitoneal dose of nicotine to rats, acute tolerance to a second dose did not become maximal until 2 hr after the initial injection. Mechanisms of Tachyphylaxis Although tachyphylaxis has been described for a wide variety of nicotine's effects, very little is known about mechanisms. A nicotine 49

metabolite may play a role in the development of tachyphylaxis. Barrass and colleagues (1969) argued that nicotine metabolites may block nicotine receptors and thereby antagonize nicotine's lethal effects. This argument was made because pretreatment with nic- otine-N'-oxide protected mice from the lethal effects of large doses of nicotine. LD~o values were increased approximately ninefold by pretreatment with nicotine-N'-oxide. These authors hypothesized that this protection may involve conversion of nicotine-N'-oxlde to hydroxynicotine. Their results indicated that injection of a reduction product of cotinine, believed to be hydroxynicotine, gave immediate protection, whereas maximum protection was not seen until 40 mln after injection of nicotine-N'-oxide, Thus it appears that metabolism, possibly to hydroxynicotine, is required for the protective action of nicotine-N'-oxide. Another hypothesis is that tachyphylaxis is the result of desensiti- zation of nicotine receptors. Desensitization of the receptor involves a conformational chan~ge that results in increased affinity of the nicotinic receptor for agonists coupled with decreased ability of the receptor to transport ions (Weiland et al, 1977; Sakmann, Patlak, Neher 1980; Boyd and Cohen 1984). Desensitization of nicotinic receptors at the motor end-plate was first described by Katz and Thesleff (1957) and has since been studied by a large number of investigators, using either skeletal muscle or the electric .organs of the eel, Torpedo californica. Although tachyphylaxls has been commonly suggested as being due to desensitization of brain nicotinic receptors, the role of desensitization in tachyphylaxis to specific behavioral effects of nicotine has not been studied. This is because concentrations of nicotinic receptors in specific areas of the brain corresponding to the behavioral effects being measured are not high enough to use available methods. Chronic Tolerance Human Studie~ Chronic tolerance to tobacco and nicotine has not been studied systematically in human subjects, but it is clear, as noted previously, that some tolerance does develop. Tolerance is not complete; symptoms of nicotine toxicity such as nausea appear when smokers increase their normal tobacco consumption by as little as 50 percent (Danaher 1977). These findings are consistent with the observations that smokers increase their tobacco consumption and intake of nicotine with experience. Such escalating dose patterns may be observed for several years after initiation of either cigarette smoking or smok- eless tobacco use. Cigarette smokers may achieve such increases by augmenting the number of cigarettes smoked and by increasing the amount of nicotine extracted from each cigarette. For users of Q 5O •

smokeless tobacco, switching to products with greater nicotine delivery may also contribute to nicotine dose escalation (US DHHS 1986). Animal Studies Animal studies have proved useful in establishing the actual development of tolerance to nicotine, the magnitude of such toler- ance, and mechanisms that underlie this tolerance. The majority of these studies have used the rat and mouse as experimental subjects. Most of the chronic tolerance studies using the rat have focused on the effects of nicotine on locomotor activity. Depression of locomotor activity typically occurs following the injection of nicotine in doses exceeding 0.2 mg/kg in drug-naive rats. Tolerance to this depression develops following chronic treatment (Keenan and Johnson 1972; Stolerman, Fink, Jarvik 1973; Stolerman, Bunker, Jarvik 1974). The magnitude of this tolerance is influenced by the dose and dosing interval Tolerance persists for greater than 90 days when nicotine is injected chronically. Tolerance to the effects of injected nicotine on depression of locomotor activity could also be produced with nicotine administered in the rats' drinking water or through subcutaneously implanted reservoirs (Stolerman, Fink, Jarvik 1973}. Under certain experimental conditions, rats treated chronically with nicotine exhibit an increase in locomotor activity following nicotine challenge (Morrison and Staphensen 1972; BaA6ttig et al. 1976; Clarke and Kumar 1983a,b). A careful analysis of the response to an acute challenge dose of nicotine demonstrated that soon after the first dose of nicotine, depressed locomotor activity was observed; after 40 min or more, increased locomotor activity became apparent (Clarke and Kumar 1983b). Chronically injected rats exhibited this enhanced activity progressively earlier postinjeetion. More recently, Ksir and others (1985, 1987) demonstrated that chronic nicotine injections may result in enhanced locomotor activity immediately after nicotine injection if the rats were acclimated to the test apparatus for 1 hr before nicotine injection. These findings indicate that in the rat, tolerance develops to the depressant effects of nicotine and that this tolerance uncovers a latent stimulatory action. If mice are injected chronically with nicotine, tolerance develops to the locomotor depressant effects elicited by a challenge dose of nicotine (Hatehell and Collins 1977). The degree and rate of development of tolerance appear to be influenced by the sex, as well as the strain, of the animals. Tolerance development has been studied by continuously infusing mice of several inbred strains with nicotine and assessing tolerance by measuring locomotor activity, body temperature, respiratory rate, heart rate, and acoustic startle response following nicotine challenge. Such studies have demon- strated that: I:1) Tolerance to nicotine increases with the nicotine 51

infusion dose (Marks, Burch, Collins 1983a); (2) Tolerance is specific for nicotinic cholinergic agonists in that nlcotine-infused animals are not cross-tolerant to the muscarinic chollnergic agonist oxotremo- fine (Marks and Collins 1985); (3} Maximal tolerance is attained within 4 days following the initiation of infusion and is lost within 8 days following the cessation of infusion (Marks, Stitzel, Collins 1985); (4) Tolerance development varies between inbred mouse strains, with some strains exhibiting marked tolerance and other strains showing very little (Marks, Romm et al. 1986); and (5) Mouse strains that fail to develop tolerance to nicotine are also relatively insensitive to the effects elicited by an acute injection of nicotine {Marks, Stitzel, Collins 1986). More recently these investigators compared the effects of continuous and pulse infusions of nicotine on tolerance develop- ment (Marks, Stitzel, Collins 1987). Pulse infusion was used to simulate the conditions obtained when tobacco is smoked. Although the total dose infused was the same in continuously infused and pulse-infused animals, marked differences in tolerance were seen. The pulse-infused animals exhibited a greater degree of tolerance. The degree of tolerance was most correlated with peak nicotine concentrations. Chronic nicotine administration results in tolerance to a number of other nicotinic effects. Tolerance develops to depression of operant responding elicited by high doses of nicotine, such that after sufficient chronic treatment, enhanced rather than depressed oper. ant responding is seen (Clarke and Kumar 1983c; ttendry and Rosecrans 1982). Attenuationof the effects of nicotine on electroem cephalogram (EEG) activity is seen in the rat following chronic injection (Hubbard and Gohd 1975), These altered EEG responses paralleled the development of tolerance to behavioral effects de. scribed by these anthem as "arousal." In contrast to the findings of Hubbard and Gohd (1975), other studies indicate that chronic tolerance does not develop to the behavioral stimulation effect of nicotine (Biittig et al. 1976; Morrison and Stephanson 1972; Clarke and Kumar 1983a,c). Likewise, little or no tolerance to nicotine. induced prostration after i.v. administration was observed after chronic exposure in rats (Abood et al. 1981, 1984). In addition, tolerance has been reported to develop to nicotine- induced increases in plasma corticosterone, bat not adrenal catechol- amine release in rats (Balfour 1980; Van Loon at al. 1987). Anderson and colleagues (1985) studied the effects of chronic exposure to cigarette smoke on neuroendocrine function of the rat hypothala- mus. These researchers observed that chronic exposure to cigarette smoke over a period of 9 days did not result in tolerance to the ability of acute intermittent exposure to cigarette smoke to reduce serum levels of prolactin, luteinizing hormone, and follicle stimulating hormone. 52 •

Mechanisms of Chronic Tolerance Chronic tolerance to drugs may be due to an increase in the rate of drug metabolism or to a decrease in sensitivity of the tissue to the drug. Considerable differences exist among humans in the rate of nicotine metabolism (Benowitz et al. 1982). Metabolism is faster (shorter half-life) in smokers than in nonsmokers (Schievelbein et al. 1978; Kyerematen et al. 1982; Kyerematen, Dvorchlk, Vesen 1983). The contribution of enhanced nicotine metabolism to the develop- ment of nicotine tolerance in humans is unclear. Studies of rats which clearly demonstrate that chronic nicotine treatment results in tolerance to nicotine also indicate that chronic nicotine administra- tion does not increase the rate of nicotine metabolism in rats (Takeuchi, Kurogochi, Yamaoka 1954) or mice (Hatchell and Collins ][977; Marks, Burch, Collins 1993b). These findings indicate that tolerance to nicotine primarily involves reduced sensitivity of target tissues. Chronic tolerance to nicotine may be due to alterations in brain nicotinic receptors (see Chapter Ill for further discussion of nicotine receptors). At least two types of nicotinic receptors exist in rodent brain (Marks and Collins 1982). One of these receptor types may be measured with 3H-nicotine or 8H-acetylcholine (~H-ACh) (Marks, Stitzel et al. 1986; Martino.Bafrows and Keller 1987), while the other type may be measured with ~sSI-bungarotoxln (BTX). The nicotine- binding site has higher affinity for nicotine than does the BTX site (Marks and Collins 1982). Chronic nicotine injection, once or twice daily for approximately 7 days, increased the number of 3H-nic- otine/~H.ACh.binding sites in the brain (Ksir et al. 1985, 1987; Morrow, Loy, Creese 1985; Schwartz and Kellar 1983, 1985). This increase in nicotine-binding sites appeared to correlate with the emergence of nicotine-induced increases in locomotor activity in the rat. Studies of tolerance to nicotine in one inbred mouse strain (DBA) also demonstrated that chronic nicotine treatment elicits an increase in the number of brain nicotinic receptors as measured with both ~H- nicotine and BTX as the ligands (Marks, Butch, Collins 1983a; Marks and Collins 1985; Marks et ah 1985, 1986; Marks, Stitzel, Collins 1985, 1986, 1987). These studies have also shown that the number of ~H-nicotine-binding sites increases at lower doses of nicotine than do the BTX-binding sites. An increase in all-nicotine binding (Marks, Burch, Collins 1983a) parallels development of tolerance to various responses during chronic infusion. In chronically infused DBA mice, tolerance acquisition and disappearance parallel the up-regulation and return to control, respectively, of brain aH-nicetine binding (Marks, Stitzel, Collins 1985). These findings suggest that the increase in ~H-nicotine binding is related to the development of tolerance to nicotine. However, further studies indicate that factors other than receptor number must also be considered, because mouse 53

strains that do not develop tolerance to nicotine also demonstrate up- regulation of nicotinic receptors following chronic infusion (Marks et al. 1986; Marks, Stitzel, Collins 1986). That chronic nicotine treatment results in a decrease in response to the drug (tolerance) and an increase in the number of nicotinic receptors was an unexpected finding, Marks, Butch, and Collins (1983a) and Schwartz and Kellar (1985) have suggested that chronic nicotine treatment results in chronic desensitization of nicotinic receptors. Chronic desensitization of the nicotinic receptor is compa- rable to chronic treatment with an antagonist and could be the stimulus for up-regulation of the receptors. According to this hypothesis, there is an increase in number of brain nicotinic receptors but a decrease in the absolute number of "activatable" (nondesensitised) receptors: This would result in a decreased re. sponse to nicotine (tolerance). Marks and eoworkers suggest that inbred mouse strains failing to exhibit tolerance to nicotine, under the procedures used by these investigators, have brain nicotinic receptors that resensitize more rapidly than do those strains that do exhibit tolerance. BY treating rats chronically with the acetylcholinesterase inhibi- ter disulfoton, Costa and Murphy (1983) have found a decrease in rat brain ~H-nicotine binding. Disulfoton-treated rats were also tolerant to the antinociceptive effects of nicotine. Thus, tolerance to nicotine effects may be seen when the number of nicotinic receptors are increased or decreased by chronic drug treatment. The observation that tolerance to at least one effect of nicotine can be obtained by a technique that decreases brain nicotinic receptor numbers supports the idea that chronic nicotine treatment results in an increase in the total number of receptors but a decrease in those that may be activated by nicotine; that is, a high fraction of the up-regulated receptors are desensitized. In contrast to the studies reviewed above, some investigators have found no change in the number or affinity of ZH-nicotine-binding sites in the brains of rats chronically exposed to nicotine (Abood et al. 1984; Benwell and Balfour 1985). Other potential neurochemical explanations for tolerance to nicotine have been considered. Several reports (Westfall 1974; Giorguieff etal. 1977; Arqueres, Naquira, Zunino 1978; Giorguieff- Chesselet et ah 1979) indicate that nicotine stimulates dopamine release in vitro, and a recent study demonstrated that nicotinic agonists are less effective in stimulating dopamine release in slices of striatum obtained from rats that had been chronically treated with the nicotinic agonist dimethylphenylpiperazinium (DMPP) (Westfall and Perry 1986). These findings are consistent with the idea that chronic nicotinic agonist treatment results in a decrease in the absolute number of receptors that can be activated. 54

@ Pharmacodynamics of Nicotine and Cigarette Smoking As the foregoing review has shown, the intensity of nicotine's effects is related to the dose given, the time since the last dose, end the level of preexisting or acquired tolerance. Since nicotine can produce effects that lead to further use (reinforcing effects) (Hen- ningfield and Goldberg 1983) and can also produce effects that limit use (aversive effects, usually at higher dose levels) (Danaher 1977), the strength of the effect of a given dose can determine whether more or less nicotine will be subsequently taken. Thus, factors such as tolerance can affect the manner in which, nicotine controls behavior (Chapter IV). Similarly, an individual's ability to develop tolerance to the toxic actions may be critical in determining whether smoking will occur and, if smoking is initiated, whether there will be . an increase in the number of cigarettes consumed each day. Pharmacodynamic considerations may help explain the pattern of cigarette smoking throughout the day. Intervalsbetween smoking cigarettes may be determined at least in part by the time required for tolerance to disappear. With regular smoking there is accumula- tion of nicotine in the body resulting in a greater level of tolerance. Transiently high brain levels of nicotine following smoking individu- al cigarettes may partially overcome tolerance. But the effects of individual cigarettes tend to lessen throughout the day. Overnight abstinence allows considerable resensitization to effects of nicotine~ and the daily smoking cycle begins again. Pharmacodynamic observations with i.v, dosing of nicotine explain the pattern of cardiovascular changes observed in cigarette smokers. That brief infusions of nicotine increase heart rate to a maximum suggests that heart rate will increase mast with the first few cigarettes of the day, but subsequently will not vary in relation to the amount of nicotine consumed. That only partial tolerance develops to heart rate acceleration due to nicotine suggests that effects on heart rate may persist as long as significant levels of nicotine persist, including overnight. These predictions were con- firmed in a study in which volunteer cigarette smokers smoked either high- or low-yield nonfilter research cigarettes or abstained from smoking (Benowitz, Kuyt, Jacob 1984). Full compensation for the low-yield research cigarettes, which contained only small amounts of nicotine, was impossible. Resultant nicotine blood levels were different by fourfold. As predicted, heart rate (assessed by continuous ambulatory electrocardiogram (EKG) monitoring) in- creased in the morning--more on smoking than nonsmoking days-- and the increase occurred with the first few cigarettes of the day. Subsequently, heart rate followed a normal circadian pattern, but was always higher during smoking than during abstinence. Also, as predicted, heart rate was no different during the smoking of low- 55

yield or high-yield cigarettes, despite the fourfold difference in blood nicotine concentration. Pharmacodynamic aspects of the actions of nicotine may explain in part how cigarette smoking causes coronary heart disease (US DHHS 1983). As noted before, because of the accumulation of nicotine and its dose-response characteristics, heart rate is increased during cigarette smoking for 24 hr a day. Plasma catecholamine concentrations and urinary catecholamine excretion remain in- creased as well (Benowitz 1986c), consistent with the theory that cigarette smoking produces sympathetic neural activation 24 hr each day. Persistent sympathetic activation could result in the following effects: (1) Alteration in lipid metabolism, resulting in a more atherogenic lipid profile; (2) Promotion of platelet.aggregation and hypercoagulability; (3) Induction of vasoconstriction and coronary spasm; and (4) Increased heart rate and myocardial con{,ractility, thereby an increase in the oxygen demands of the heart and of circulating catecholamines, which can promote cardiac arrhythmias. These factors could accelerate atherosclerosis and contribute to acute myocardial infarction in a person with preexisting coronary atherosclerosis (Benowitz 1986a) (see also Appendix B). There is no apparent correlation between acute coronary events and the time at which a person smokes a cigarette, perhaps because of the persistent effects of nicotine throughout the day. Constituents of Tobacco Smoke Other Than Nicotine With Potential Behavioral Effects Tobacco smoke contains more than 4,000 constituents, many of which may have biological activity (US DHHS 1983). Although nicotine is the major pharmacologic factor which determines the use of tobacco, other constituents may also be involved. The behavioral effects of tobacco constituents other than nicotine are described in the Section below and in Chapter IV, This Section focuses more on the chemicals that may be involved, whereas Chapter IV focuses more on cigarette smoking behavior. Minor Tobacco Alkaloids Most of the research on the minor tobacco alkaloids has been directed to determining physiological effects, such as the effect on blood pressure and other cardiovascular responses and toxicological effects, rather than the potential for behavioral effects. The pharma- cologic effects of alkaloids of the nicotine group have been discussed by Bovct and Bovet-Nitti (1948) and Clark, Rand, and Vanov (1965). Nornicotine and anabasine were found to have qualitatively similar actions but to be less potent than nicotine. Larson and Haag (1943) 56

reported that the potency of nornicotine as determined by effects on blood pressure in dogs was about one-twelfth that of nicotine. Nicotine analogs have been studied for discriminative stimulus effects by using animal models (Chance et al. 1978) (see also Chapter IV). The only chemical shown to produce a positive response in that test system was 3-methylpyridylpyrrolidine. Recent research has focused on binding at specific brain receptor sites. Martin and coworkers compared binding characteristics of nicotine-related com- pounds (Martin et al. 1986; Sloan et al. 1985). Lobeline, anabasine, and oytisine were evaluated for effects on heart rate, blood pressure, respiration rate, minute volume, and tidal volume (Sloan et al. 1987). Lobeline and anabasine bound to low-affinity sites in the brain, whereas cytisine bound only at a high*affinity site. The binding data are consistent with the pharmacologic data, indicating that lobeline and anabasine have different pharmacologic actions than cytlsine. Kanne and others (1986) and Abood and Grassi (1986) evaluated two nicotine analogs, including a new radioligand, to study brain nicotinic receptors. Kachur and others (1996) studied the pharmaco- logic effects of a bridged-nicotine analog (methylene bridge between the methyl of the pyrrolidine ring and the a-position of the pyridine ring). The magnitude of presser effect depended on the particular enantiomer and dosage. These results emphasize that compounds other than nicotine may act at the nicotine receptors; however, there 'may be sub~opulations of receptors to which different agonists and • antagonists bind (Chapter III). N-Methylated derivatives of nicotine, including nicotine isometho- nium ion (N-methylnicotinium ion, NMN), have been shown to have presser and neuromuscular effects in some species (Shimamoto et al. 1958). Nicotine isomethonium ion was first reported to be a metabolite of nicotine present in smokers' urine by MoKennis and coworkers in the 1960s, and its presence in smokers' urine has been recently confirmed (Neurath et al. 1987). Recently Crooks and coworkers (Cundy, Godin, Crooks 1985) have shown that only the (R)- isomer of nicotine is converted to nicotine isomethonium ion in vitro in guinea pig tissue homogenates or in vivo in guinea pigs. Consequently, it is uncertain as to whether the nicotine isomethonl- um ion present in smokers' urine arrives from the small amount of (R}-nicotine present in tobacco smoke, or whether the human enzyme systems have different specifications than the guinea pig enzymes. Because little if any nicotine isomethonium ion penetrates the blood- brain barrier (Pool 1987; Acoto et al. 1983), it would appear that this rnetabolite could have behavioral actions only if it were formed in the CNS. These findings emphasize the complexity of the pharmacol- ogy of nicotine-related compounds. It can be concluded from research on these compounds that some do bind to specific brain receptors and may result in centrally mediated physiological changes• However, 57

there is inadequate evidence to date that any of these compounds produces either aversive or rewarding effects in human smokers. "Tar" and Selected Constituents of Tobacco Smoke Which Contribute to Taste and Aroma "Tar" is used to describe the dry particulate matter without the nicotine in tobacco smoke (Pillsbury et aL 1969). The possible role of tar in the maintenance of the cigarette smoking habit has been considered. Goldfarb and coworkers (1976) studied the effects of the tar content (determined by cigarette smoking machine testing) on the subjective reactions to cigarette smoking. Ratings of strength were not related to the tar index of the cigarettes. The results were interpreted as indicating that tar did not have a role in the maintenance of cigarette smoking behavior. In a later study, Sutton and coworkers (1982) found that when nicotine yield was held constant, smokers of lower-tar cigarettes puffed more smoke and had higher drug plasma levels. These results suggested that smokers were compensating for reduced delivery of tar by inhaling a greater volume of smoke. Because these two studies used different experi- mental designs, it is difficult to draw a conclusion as to the role of tar in relation to smoking behavior. However, based on knowledge about the taste and aroma constituents of cigarette smoke, it is likely that some of the chemicals in the tar fraction contribute to tobacco use, if only by providing distinct sensory stimuli (Chapter VI). Consistent with this possibility, minimal levels of tar are held by tobacco manufacturers to be important to the taste characteristics of tobacco smoke (Tobacco Reporter 1984). Several thousand compounds have been isolated from tobacco and tobacco smoke (Dube and Green 1982), and many of these may be biologically active (IARC 1986). The precursors to the carotenoids and diterpeniods, selected nitrogenous and sulfur constituents, waxes and lipids, and phenolics and acids contribute to the taste and aroma of tobacco (Enzell and Wahlberg 1980; Heekman et al. 1981; Davis, Stevens, Jurd 1976). A number of the isoprenoid compounds that influence the taste and aroma of smoke may be formed by sequential oxidation, rearrangement, and reduction reactions (Davis, Stevens, Jurd 1976). Enzell and Wahlberg (1980) described several norisoprenoid compounds which are derived from the cyclic carat- enoids and are important to smoke aroma. The particular taste and aroma of a cigarette can be influenced by the selection of the grade (quality and leaf positiofi on the plant) and type of tobacco used in the blend. Taste and smell receptors in the pharynx, larynx, and nose provide the first sensory input to the smoker as he or she lights up, an experience which is generally perceived as pleasurable (Rose et aL 1985). The taste and smell of tobacco smoke may be important 58

reinforcers for tobacco smoking (Jarvik 1977)---at least following repeated association with the reinforcing effects of nicotine adminis- tration(Chapter VI). By such behavioral conditioning, sensory cues provided by tar and flavor additives could come to control the tobacco-consuming behavior of the tobacco user. Changes in smoking patterns when brands are switched and brand selection may be a response in part to the particular flavor and aroma of the product (Thornton 1978). Carbon Monoxide The mainstream and sidestream carbon monoxide (CO) deliveries of cigarettes are influenced by cigarette design and puffing charac- teristics of the smokers. Depending upon these factors, the main- stream clelivery usually ranges from 10 to 20 mg/cigarette. In a study of 29,000 blood donors in 18 locations around the United States, smokers were found to have median carboxyhemoglobin (COHb) levels ranging from 3.2 to 6.2 percent (Stewart et al. 1974). Anderson, Rivera, and Bright (1977) found the COMb levels in 50 smokers to vary from 3.9 to 14.0 percent, with the mean of 8.1 percent. The mean increment in COHb immediately after smoking 1 cigarette was 0.64 percent. COHb levels gradually decrease in blood after cessation of smoking. Carbon monoxide is eliminated in expired air. The rate of elimination depends on pulmonary blood flow and ventilation. The half-life of COHb is 2 to 4 hr during daytime hours, but as COHb is related to the level of exercise, the half-life may be as long as 8 hr during sleep (Wald et al. 1975). For these reasons, many smokers awaken in the morning with substantial levels of COHb, despite not smoking overnight (Benowitz, Kuyt, Jacob 1982). Persons smoking cigarettes with lower nicotine and CO yields have only slightly lower levels of COHb when compared with those smoking higher-yield products (Wald at al. 1980, 1981; Sutton et al. 1982; Hill, Halay, Wynder 1983; Benowitz, Jacob, Yu et al. 1986). Benowitz and colleagues (1986) studied tar, nicotine, and CO exposure in smokers switched from their usual brand to low-, high-, and ultra-low-yield cigarettes. This study indicated that there were no differences in exposure comparing low- and high-yield, but tar and nicotine exposure were reduced by about 50 percent and CO by 38 percent while smoking ultra.low.yield cigarettes. Switching from a high to lower yield cigarette does not significantly reduce blood COHb although switching to ultra low cigarettes has been shown to lead to a significant reduction. The toxic effects of high CO levels are well documented (US DHHS 1983). Some studies have tried to determine whether CO levels in the blood similar to those observed in smokers can affect behavior. Beard and Wertheim (1967) and Wright, Randall, and Shephard (1973) reported performance decrements with COHb levels below 5.0 59

percent; however, Guillerman, Radziszewski, and Caille (1978) found no psychomotor performance effects at COHb levels of 7 and 11 percent. Thus, the data are inconclusive with regard to the possible influence of CO on psychomotor performance at levels normally encountered in smokers. Acetaldehyde and Other Smoke Constituents Acetaldehyde is a major constituent of tobacco smoke, with mainstream smoke levels in commercial cigarettes ranging from 0.5 to L2 mg/cigaretto (IARC 1986). The delivery of volatile aldehydes is influenced by cigarette design, with reductions achieved by specific filtration and air dilution techniques. Yields over 5.9 mg have been reported for large cigars (Hoffmann and Wynder 1977). Acetalde- hyde is the primary metabolito of ethanol, and its toxic potency is 20 to 30 times that of ethanol. Acetaldelhyde has been suggested to have an adverse effect on the heart (James et al. 1970). Acetaldehyde and acrolein, another important aldehyde in the gas phase of cigarette smoke, activate the sympathetic nervous system (Egle and Hudgins 1974). Acetaldehyde, by releasing norepinephrine, results in a pressor effect (Kirpekar and Furchgott 1972; Green and Egle 1983). Depressor effects occur at high doses of the aldehydes in guanethidine-pretreated hypertensi'~e rats. Frecker (1983) indicated that condensation products of acetaldehyde may be active on endogenous opioid systems. Torreilles, Guerin, and Prevlero (1985) reviewed the synthesis and biological properties of beta.carbolines, the condensation products of tryptophan and indole alkylamines with aldehydes. Beta-carbolines occur as plant constituents, includ- ing minor constituents in tobacco. For example, harman (1-methyl-B- carboline) has been identified in tobacco and tobacco smoke (Snook and Chortyk 1984). Carbolines from other plant species have been used as hallucinogens. The research conducted to date indicates a potential pharmacologic effect of the aldehydes, especially with regard to cardiovascular physiology; however, the evidence is inadequate to determine if these volatile smoke constituents in the doses delivered in tobacco smoke contribute to the behavioral effects of cigarette smoking. Summary and Conclusions 1. All tobacco products contain substantial amounts of nicotine and other alkaloids. Tobaccos from low-yield and high-yield cigarettes contain similar amounts of nicotine. 2. Nicotine is absorbed readily from tobacco smoke in the lungs and from smokeless tobacco in the mouth or nose. Levels of nicotine in the blood are similar in people using different forms of tobacco. With regular use, levels of nicotine accumulate in 60 •

the body during the day and persist overnight. Thus, daily tobacco users are exposed to the effects of nicotine for 24 hr each day. 3. Nicotine that enters the blood is rapidly distributed to the brain. As a result, effects of nicotine on the central nervous system occur rapidly after a puff of cigarette smoke or after absorption of nicotine from other routes of administration. 4. Acute and chronic tolerance develops to many effects of nicotine. Such tolerance is consistent with reports that initial use of tobacco products, such as in adolescents first beginning to smoke, is usually accompanied by a number of unpleasant symptoms which disappear following chronic tobacco use. gl

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TRAVELL, J. Absorption of nicotine from various sit~. Annals of the New Fork Academy of Sciences 9011):13-30, September 27, 1960. TURNER, D.M., ABMITAGE, A.K., BRIANT, R.H., DOLLERY, C.T. Metabolism of nicotine by the isolated perfused dog lung. Xenobiotica 8i9):839-581, 1975. TURNER, J.A.M., SILLEq~, R.W., McNICOL, M.W. Effect of cigar smoking on carboxyhaemoglobin and plasma nicotine ¢oncetltrations in primary pipe and cigar smokers and ex-eigaretto smokers. Brit~h Medical Journal 2(9099}:1397-1389, November 26, 1977. U,S. DEPARTMENT OF HRALTH AND HUMAN SERVICES. The Health Conse. quences of Smoking: Cardiovascular Disease, A Report of the Surgeon General U.S. Department of Health and Human Services, Public Health Service, Office on Smoking and Health. DHHS Publication No. (PHS) 84-50204, 1993. VAN LOON, G.R., KIRITSY-ROY, J.A, BROWN, L.V., BOBBIqF'T, F.A. Nicotinic regulation of sympathoadrenal eatecholamine secretion. In: Martin, W.R., Van Loon, G.R., lwamote, EY£,, Davis, L. (eds.I Tobacco Smoking and Nicotine. New York: Plenum Press, 1997, pp. 268-276. VAN VUNAKIS, H,, LANGONE, d,J., MILUNSKY, A. Nicotine and cotinlne in the amniotic fluid of smokers in the second trimester of pregnancy. American Journal of Obstetrics and Gynecology 120(1):64-66, September 1974. VEREBEY, K.G., DEPACE, A., MULE, S.d. A rapid, quantitative GLC method for the ' simultaneous determination of nicotine and cotinine, Journal of Analytical Toxicology 6:294-296, November-Devember 1982. WALD, N.J., BOREHAM, J., BAILEY, A., RITCHIE, C., HADDOW, J.E., KNIGHT, G. Urinary cotinine as marker of breathing other people's tobacco smoke. (Letter.) Lancet 1(8370}:230-231, January 28, 1984. WALD, N., HOWARD, S., SMITH, P.O., BAILEY, A. Use of earboxyhaemoglobin levels to predict the development of diseases as~oclatod with cigarette smoking. Thorax 30:133-140, 1975. WALD, N.J., IDLE, M., BOREHAM, J., BAILEY~ A. Inhaling habits among smokers of different types of cigarette, Thorax 35(12):925-928, December 1980. WALD, N.J., IDLE, M, BOREHAM, J., BAILEY, A. Carbon monoxide in breath in relation to smoking and carboxysemoglobin levels. Thorax 36(5l:366-36, May 1991. WEILAND, G., GEORGIA, B., LAPPA, S., CHIGNELL, C.F, TAYLOR, P. Kinetics of ogonist.mediated transitions in state of the ehollnergic receptor. Journal of Biological Chemistry 252(21l:7648-7656, November 10, 1977. WENZEL, D,G., AZMEH, N., CLARK, 1.J. Studies on the acute and chronic depressor actions of nicotine in the rat. Archive8 Internationales de Pharmacodynomie et de Theraple 193(1);23-36, September 1971. WEST, R.J., RUSSELL, M.A.H. Cardiovascular and subjective effects of smoking before and after 24 h of abetinence from cigarettes. Psychopharmocology 92:118-191, 1987. WESTFALL, T.C. Effect of nicotine and other drugs on the release of ~H-norepineph- fine and ~H-dopamine from rat brain slices. Heuropharmacology 13(8):693-700, August 1974. WESTFALL, T.C., PERRY, H. The nicotinic-induced release of endogenous dopamine from rat striatal slices from animals chronically exposed to dimethylphenylpipera- zinium (DMPP). Neurascience Letters 71(3):343-344, November 21, 1996. WOOD, J.D. Eleetrophysiological and pharmacological properties of the stomach of the squid loligo pealii (Losueur). Comparative Bioehemstry and Physiology 30(5):813~24, September 1, 1969. WRIGHT, G., RANDELL, P., SHEPHARD, R.J. Carbon monoxide and driving skills. Atvhives of Environmental Health 27(6):349-954, December 1973, ZEIDENBERG, P., JAFFE, J.H., KANZLER, M., LEVITT, M.D., LANGONE, J.J., VAN VUNAK1S, H. Nicotine: Catinine levels in blood during eessation of smoking, Comprehensive Psychiatry 18(1):93-101, January-February 1977. 73

CHAPTER III NICOTINE: SITES AND MECHANISMS OF ACTIONS 75

CONTENTS Overview Peripheral Effects of Nicotine Central Sites of Nicotine Actions Neuroendocrine Effects of Nicotine Electrophysiological Effects of Nicotine Distribution and Cerebral Metabolic Effects of Nicotine Distribution of Nicotine Tissue Distribution of Nicotine: Time Course and Other Considerations Heterogeneity of Nicotine Uptake: Microautora- diographic and Subcellular Studies Effects of Nicotine on Cerebral Metabolism Nicotine Receptors Peripheral Nicotine Receptors Redioligand Binding to Putative Nicotine Cholinergic Receptors in Mammalian Brain Agonist Binding Radioligand Binding Antagonist Binding Functional Significance of Nicotinic Binding Sites High-Affinity Agonist Binding Sites Alpha-Bungarotoxin Binding Sites Behavioral and Physiological Studies The Neuroanatomical Distribution of Nicotinic Bind- ing Sites in the Brain High-Affinity Agonist Binding Sites Rodent Monkey Human Alpha.Bungarotoxln Binding Sites Molecular Biology Central Nicotinic Cholinergie Receptors: Pre- or Post- synaptic? Presynaptic Regulation of Neurotransmitter Re- lease Somatodendritic Postsynaptic Actions 77

Neuroendocrine and Endocrine Effects of Nicotine Cholinergie Effects Modulation of Catecholamine and Serotonin Activity Effects on Serotonergic Neurons Effects on Catecholaminergic Neurons Stimulation of Pituitary Hormones Arginine Vasopressin The Pro-Opiomelanocorticotropin Group of Hor- mones Thyroid Adrenal Cortex Androgens Estrogens Pancreas and Carbohydrate Metabolism Electrophysiological Actions of Nicotine Electrocortical Effects Spontaneous Electroencephalogram Sensory Event-Related Potentials Cognitive Event-Related Potentials Motor Potentials Other Peripheral Effects Relevant to Tobacco Use Psychophysiological Reactivity and Smoking Psyehophy~iological Reactivity, Smoking Cessation, and Relapse .. Summary and Conclusions References 78 •

Overview Nicotine, in tobacco smoking concentrations, is a powerful psy- choactive drug (Domino 1973; Kumar and Lader 1981; Balfour 1984). A wide variety of stimulant and depressant effects is observed in animals and humans that involves the central and peripheral nervous, cardiovascular, endocrine, gastrointestinal, and skeletal motor systems. These heterogeneous effects, along with behavioral and psychological variables, result in self-administration of tobacco, tobacco dependence, and withdrawal phenomena with abrupt cessa- tion of tobacco smoking. This Chapter discusses sites and mechan- isms of nicotine actions that may help to explain why tobacco products are self-administered. The first Section of this Chapter provides general summaries of several major effects of nicotine in the body. Following this broad overview, the Chapter presents.detailed discussions of sites and mechanisms of nicotine action that may be particularly important to understand tobacco use. Tissue distribution of nicotine, cerebral metabolic effects, and nicotine receptor binding are reviewed. Next, neuroendocrine and endocrine effects of nicotine are discussed. Then, electrophysiological effects of nicotine are presented. Finally, the effects of smoking on psychophysiologisal reactivity are discuss- ed. Peripheral Effects of Nicotine Nicotine exerts its action on the cardiovascular, respiratory, skeletal motor, and gastrointestinal systems through stimulation of peripheral oholinerglc neurons via afferent chemoreceptors and ganglia of the autonomic nervous system (ANS) (Ginzel 1967b). Inasmuch as both sympathetic and parasympathetic ganglia are stimulated by levels of nicotine derived from tobacco smoking, the end result depends on the summation of the effects of autonomic ganglion stimulation and reflex effects. The resulting peripheral physiological changes generally resemble sympathetic nervous sys- tem (SNS) arousal, but there are also some effects of nicotine and smoking that lead to physiological relaxation. For example, there is usually an increase in heart rate and blood pressure immediately following cigarette smoking. In addition, there is cutaneous vasocon- striction of the distal extremities, in contrast, nicotine can relax skeletal muscles (e.g., reduce patellar reflex) in humans and animals via effects on Renshaw cells (Domino and Von Baumgarten 1969; Ginzel and Eldred 1972; Ginzel 1987). But it also can enhance tension in some muscles (e.g., trapezius muscle) (Fagerstr~m and Gotestam 1977). Nicotine in small doses can enhance respiration through stimulation of peripheral chemoreceptors. Yet, high nicotine deses can cause respiratory failure. (See Appendix B for a discussion of 79

nicotine toxicity.) The gastrointestinal effects of nicotine are com- plex, involving an increase in secretions and reduced motility for a short period of time. The peripheral actions of nicotine as a cholinergic agonist have made it a valuable pharmacologic tool for studying nicotinic cholinergic actions and functioning in many physiological systems. This Chapter focuses on the mechanisms of nicotine's actions relevant to tobacco use. Several peripheral actions of nicotine, for instance muscular relaxation, may contribute to the habitual use of tobacco products (see smoking and stress in Chapter VI). However, because the central nervous system (CNS) actions of nicotine and resulting neuroohemical and electrical effects mediate subsequent biological and behavioral responses, a review of these actions contributes to an understanding of the reinforcing effects of nicotine. Central Sites of Nicotine Actions Nicotinic binding sites or receptors in the brain have been differentiated as very high, high, and low affinity types (Shimohama et aL 1985; Sloan, Todd, Martin 1984; Sloan et el. 1985). In the rat brain, when eholinergic musoarinic receptors are blocked, the autoradiographie distribution of aH-acetylcholine (ACh) and all- nicotine are essentially identical (Clarke and Kumar 1984; Clarke, Pert, Pert 1984). However, these brain binding sites differ from peripheral nicotinic receptors in ganglia and skeletal muscle. Chronic nicotine administration results in up-regulation in region- al rat brain aH-ACh binding sites measured in the presence of atropine to block the muscarinio sites (Schwartz and Kellar 1985). Up-regulation of all-nicotine binding sites also has been reported after continuous nicotine infusions in mice (Marks, Burch, Collins 1983a). In contrast, most agonists that act on receptor sites in the body, when given chronically, produce a reduction (or down-regula- tion) in the number of receptors. Both Marks, Butch, and Collins (1983b) and Schwartz and Kellar (1983, 1985) have suggested that nicotinic cholinergic receptors undergo a functional blockade but that sufficient recovery would allow enhanced behavioral responses to low doses of nicotine to occur within 24 hr, as has been shown behaviorally by Clarke and Kumar (1983) and Kslr and coworkers (1985). This phenomenon may help to explain the tolerance to nicotine that develops with repeated exposure. However, the time course of changes in receptor number and other biological effects of nicotine must be carefully compared to determine mechanisms underlying tolerance. (See Chapter I! for additional discussion.) Several investigators have used in vitro autoradiography to identify all-nicotine binding sites in the rat brain. These audioradio- graphic binding studies suggest where nicotine is acting. London, Waller, and Wamsiey (1985) have found the most intense localization 80 •

of ell-labeled nicotine in the interpeduncular nucleus and medial habenula. Cerebral metabolism studies also suggest key sites of action. London and colleagues (1985) have reported .that nicotine stimulated local cerebral glucose utilization (LCGU) by 139 percent over that of the control in the medial habenula and by 59 to I00 percent in the superior colliculus and the anteroventral thalamic and interpedun- cular nuclei. Other areas of the brain showed moderate or no significant changes. These effects of nicotine were blocked by mezamylamine, a nicotinic receptor antagonist, confirming that they acted via nicotinic receptors. Furthermore, they correlated well with the distribution of ~H-nicotine binding in the brain except in layer IV of the neoeortex, which showed nicotine binding but no change in LCGU. Sites that show increased glucose utilization after nicotine administration arc probably functionally important loci of nicotinic actions. When nicotine binding and increased energy utilization both occur at a given site, it is likely to be involved in nicotine's actions. Neuroendocrine Effects of Nicotine Some of the actions of nicotine result from the release of ACh and other neurotransmitters, including norepinephrine (NE). Nicotinic cholinergic agonists including nicotine, Carbachol, and 1,1-dimethyl-4- phenylpiporasinium (DMFP) release endogenous ACh from the presynaptic cholinergie nerve terminals in addition to stimulating postsynaptic nicotinic receptors (Chiou 1973; Chiou and Long 1969). Nicotinic sgonists also release ACh from rat cerebral cortical synaptic vesicles and can release newly synthesized SH-ACh from synaptesomes prepared from the myenteric plexus of guinea pig ileum and from mouse cortical synapses (Briggs and Cooper 1982; Eowen and Winkler 1984). These effects arc Ca2+-dependent and are blocked by hexamethonium, a quarternary nicotinic receptor antago- nist. In addition, nicotine-induced release of ACh in the hippocampal synaptesomes is blocked by the ion channel blocker, histrionicotoxin (Rapier et al. 1987). There is good evidence that nicotine releases ACh by n presynaptic mechanism. In contrast, presynaptic musca- rinic receptors, mostly of the M~-subtype, inhibit ACh release. Nicotine administration increases the amounts of other chemicals in the blood and brain, including serotonin, endogenous opioid peptides, pituitary hormones, catecholamines, and vasopressin (Domino 1979; Gilman et aL 1985; Marry and colleagues 1985). These chemicals may be involved in reinforcing effects of nicotine (see Chapters IV, VI). Electrophysiological Effects of Nicotine Nicotine administration is accompanied by brain wave or electro- encephalogram (EEG) activation in animals (Domino 1997). The EEG- activating effects of small doses of nicotine occur in intact as well as 81

brainstem-transected animals, Nicotine acts primarily directly on bralnstem neuronal circuits to produce these effects (Domino 1967), However, stimulation of peripheral afferents (Ginzel 1987) and release of cateoholamines and possibly neurotransmitters and modu- lators, such as serotonin or histamine, may enhance the direct central effects of nicotine. The EEG-activating effects of nicotine result in behavioral arousal (Domino, Dren, Yamamoto 1967). In cigarette smokers, nicotine produces sedative o:nd stimulant effects (Kumar and Lader 1981). Aceto and Martin (1982) have reviewed the large variety of nicotine effects on behavior including facilitation of memory, the increase in spontaneous motor activity, nicotine's antinoeiceptive properties, and its suppression of irritability. These behavioral and psychologi- cal effects are discussed in Chapters IV and VI. Distribution and Cerebral Metabolic Effects of Nicotine Nicotine, administered by various routes, rapidly enters the brain and also distributes to specific, peripheral organs. Nicotine produces a distinct pattern of stimulation of cerebral metabolic activity that suggests where nicotine acts in the brain, This Section reviews studies on the distribution of nicotine after its administration to experimental animals, data on the relationship between tissue levels of nicotine and the drug's biological effects, and studies on mapping the cerebral metabolic effects of nicotine in the rat brain. Distribution of Nicotine Tissue Distribution of Nicotine: Time Course and Other Considerations The distribution in the body of exogenously administered nicotine has been a topic of interest for more than a century and has been reviewed several times (Larson, Haag, Silvette 1961; Lareon and Silvette 1968, 1971). As early as 1851, Orfila described experiments in which he detected nicotine in various organs (e.g., liver, kidney, lungs) and in the blood of animals after nicotine administration. In the 1950s the development of radiotracer methods led to a reexami- nation of nicotine distribution in the body. Werle and Meyer (1950) found that the brain, compared with other organs, contained the highest nicotine levels immediately after injection of a lethal dose in guinea pigs, Tsujimoto and colleagues (1955) found a high concentration of nicotine in the brain after the drug was administered to rabbits and dogs, Yamamoto (1955) observed that 1 hr after a subcutaneous (s.c.) injection of 5 mg/kg in the rabbit, the nicotine content'was highest in the kidney. The pancreas, ileum, ventricular muscle, skeletal muscle, lung, spleen, cerebral cortex, omental fat, and liver showed progressively lower Q 82 •

levels of nicotine at 1 hr. None of the tissues had detectable levels at 6 hr. In the dog, the highest level at 1 hr was in the kidney, followed by the pancreas, brain, ileum, liver and omental fat, spleen, heart, muscle, and lung. SchmiterlSw and colleagues used radiolabeled nicotine and whole- body autoradiography to study the distribution of nicotine in several species (Hansson and SchmitorlSw 1962; Appelgren, Hansson, SchmiterlSw 1962, 1963; Hansson, Hoffman, SehmiterlSw 1964; Schmiterl~iw etal. 1965; SchmiterlSw et al. 1967). After radiolabeled nicotine was administered, radioactivity representing nicotine and its metabolitas was concentrated in some organs, particularly the brain. Hansson and SchmiterlSw (1962) injected (S)-nicetine-methyl- ~4C intramuscularly or intravenously (i.v.) in mice. Within 5 mjn, high concentrations were found in the brain, adrenal medulla, stomach wall, and kidney. Lower concentrations were observed in the liver, skeletal muscle, and blood, but all concentrations were higher in tissue than in blood. Activity was high in the kidney from 5 rain to 4 hr after the nicotine injection, with the highest activity occurring within the first hour. The adrenal medulla maintained a high concentration at 1 hr and 4 hr after injection, but little or no activity was observed at 24 hr. At 30 min, the levels were high in the walls of large blood vessels and in the bone marrow. Radioactivity disappeared rapidly from the brain. Appelgren, Hansson, and SchmiterlSw (1962) prepared whole-body autoradiograms of mice and cats given i.v. injections of 14C-nicetine. An initial, heterogeneous accumulation of radioactivity occurred in the CNS. FiReen minutes after the radiotracer injection, the cat brain showed distinctly more intense labeling of grey than of white matter. Also apparent was a regional distribution within grey matter areas, particularly in the hippecampus. By 30 rain, radioac- tivity was reduced. Studies of mice demonstrated a high concentra- tion of label in the brain at 5 min. By 30 rain, the concentration was high in salivary glands, stomach contents, liver, and kidneys, while the brain was almost devoid of radioactivity. The same group also showed the accumulation of ~4C-nicetine in the retina of the eye after i.v. administration (Schmiterlitw etal. 1965). Fishman (1963) reported that in rats given randomly labeled 14C- nicotine intraperitoneally (i.p.) and killed 3 hr later, the kidney contained the highest concentration of radioactivity, followed by the lung, liver, brain, skeletal muscle, spleen, and heart. In the dog, more 14C-nicetine was present in the stomach wall than in any other tissue analyzed 3 hr after i.v. injection of radioactive nicotine. Yamamoto, Inoki, and Iwatsubo (1967) gave mice s.c. injections of 5 mg/kg methyl-14C-nicetine. Five minutes later, they found 0.5 to 1 ~g/g (wet weight) of nicotine in various brain regions, including the cerebral cortex, superior and inferior portions of the brain stem, and 63

the cerebellum. Highest levels were detected 5 to 10 rain after injection. Maximum levels in liver and whole blood were observed 2 and 10 min, respectively, after the injection. Yamamoto, Inoki, and Iwatsubo (1968) studied penetration of t4C- nicotine in rat tissues in vivo and in vitro. They found that 5 mg/kg, i.p., in male Wister rats produced the following maximum tissue-to- blood ratios of ~4C-nlcotine activity after 10 to 20 min: kidney, 8.7; liver, 6.7; submaxillary gland, 6.2; cerebral cortex, 3.5; brainstem, 2.4; and heart, 1.8. When they incubated tissue slices with 10-4 M ~4C. nicotine for 30 min at 37°C, the relative uptake of the label was similar: kidney cortex, 2.6; liver, 2.1; submaxillary gland, 2,1; and cerebral cortex, 2,0. Penetration in slices was unaffected by uncou- pling oxidative phosphorylation or blocking metabolic pathways, indicating that the uptake was not by active transport, In vivo, tlssue-to-blood ratios were greater than slice-te-medium ratios, indicating that a process other than passive diffusion was involved. Because the respiratory tract is a major route by which nicotine from tobacco smoke enters the body, SchmiterlSw and eoworkers (1965) sprayed ~4O-nicotine solution directly onto the trachea of mice. Autoradiograms from mice killed at 2 min exhibited a high amount of radioactivity in the respiratory tract and lungs and showed that nicotine enters the CNS rapidly by this route as well, At 15 min, radioactivity still persisted in the lungs, was reduced in the brain, and appeared in large amounts in the kidneys and stomach, Uptake and distribution of nicotine from tobacco smoke have also been assessed. Harris and Negronl (1965) exposed mice to cigarette smoke and extracted nicotine from the lungs (5 to 25 ~g). Mattila and Airaksinen (1966) exposed guinea pigs to the smoke of one 4-g cigar over a period of 40 min, with intermittent ventilation with fresh air, and found that the same tissues which concentrated nicotine administered by other routes also showed nicotine uptake from smoke. Organ-to-blood ratios were lung, 2.0; spleen, 3.0; intestine, 2.9; and brain, 1.1. The use of positron-emitting radiotracers permits in vivo estima- tion of nicotine uptake into the brain and other organs, offering the potential of eventually relating nicotine action in the living human brain to behavioral and disease states. Masiere and coworkers (1976) prepared (S)-nicotine-methyl-"C, which they administered by i.v, injection to mice and rabbits. The time course of the radiotracer confirmed earlier studies and showed a maximum concentration in the 5 min following injection, except in the liver and spleen. Highest radioactivity was in kidneys and brain, followed by liver and lungs. The brain activity dropped rapidly, whereas the kidney concentra- tion remained high (8 percent of injected dose) at 50 min after the injection. External imaging by a y camera showed considerable Q 84 •

radioactivity in the head, kidneys, and liver. Brain activity decreased sharply over 1 hr, while activity remained high in liver and kidneys. Maziere and coworkers (1979) used ~C-nicotine and positron emission tomography (PET) in baboons and found that L~C-nicotine readily penetrated into the brain and then dropped sharply with time. Radioactivity was high in the temporal lobe, cerebellum, occipital cortex, pens, and medulla oblongata. There was also a high, stable radioactivity level in the retina, consistent with the earlier observation that radioactivity from 14C-nicotine is found in the retina after i,v. administration (SchmiterlSw et al. 1965). Heterogeneity of Nicotine Uptake: Microautoradiographic and Subcellalar Studies Appelgren, Hansson, and Schmiterl~w (1963) used a microautera- diographic method to study the localization of nicotine within the superior cervical ganglion of the cat. Most of the radioactivity was localized in the ganglion cells, with little labeling of satellite cells and connective tissue. SehmitorlSw and coworkers (1967), using microautoradiograms of mouse brains after injection of ~4C-nicotine and 3H-nicotine, reported that nicotine is concentrated in nerve cells. Brain areas with a high density of nerve cells, such as the molecular and pyramidal cell layers of the hippocampus and the molecular layer of the cerebel- lum, contained high amounts of radioactivity. Yamamoto, Inoki, and Iwatsubo (1967) studied accumulation of 14C-nicotine into subeellular fractions (nuclear, mitochondrial, nerve ending, microsomal, soluble) of mouse brain after i.p. injection of 5 mg/kg (20 ~Ci/kg). Most of the radioactivity was in the soluble fraction. Less than one:tenth of the radioactivity in the soluble fraction was found in microsomes and nerve endings; however, radioactivity levels in mierosomes were somewhat higher than in nerve endings. Effects of Nicotine on Cerebral MetaboBsm Following the demonstration that °H-nicotine binds stsreoselec- tively and specifically in preparations of rat brain (Yoshida and Imura 1979; Martin and Aceto 1981; Marks and Collins 1982), brain binding sites were visualized (Clarke, Pert, Pert 1984) and quantified (London, Waller, Wamsley 1985) by light microscopic autoradiogra- pby. However, mapping nicotinic binding sites or identifying specific binding sites for any drug or neurotransmittor does not necessarily mean that receptors are coupled to pharmacologic actions. An example of nonfunctional, stereoseloctive, specific binding is that of ~H-naloxone to glass fiber filters (Hoffman, Altschuler, Fex 1981). In addition, because the brain is a highly interconnected organ, drugs 85

may produce effects in brain regions remote from their initial receptor interactions. Receptor maps would show primary binding sites but not sites where important secondary actions might occur. Functional mapping procedures, such as the use of autoradio- graphic techniques to measure rates of LCGU and regional cerebral blood flow, are another way to determine the sites of the in vivo effects of nicotine in the brain. The 2-deoxy-D-[1-~4C]glucose (2-DG) method for measuring LCGU (Sokoloff et al. 1977) has been used to demonstrate a relationship between local cerebral function and glucose utilization under a wide variety of experimental conditions, including pharmacologic treatments (Sokoloff 1981; McCulloch 1982). The effects of acute, s.c. i~ections of nicotine on LCGU were examined by London and colleagues (~985, 1986) and by London, Szikszay, and Dam (1986),.while Grtinwald, Schr6ck, and Kuschinsky (1967) measured the effects on LCGU of constant plasma levels of nicotine produced by i.v. infusion. Subcutaneous injections of nicotine stimulated LCGU in specific brain regions (Table 1, Figure 1), including portions of the visual, limbic, and motor systems. Effects of nicotine infusion generally paralleled those obtained with s.c. injections. The greatest increase in response to s.c. nicotine occurred in the medial habenula. Marked increases in LCGU were noted in the anteroventral thalamic nucleus, interpeduncular nucleus, and superior colliculus. Moderate increases were seen in the retresplenial cortex, interanteromedial thalamic nucleus, lateral geniculate body, and ventral tegmental area. No significant effects were observed in the frontoparietal cortex, lateral habenula, or central grey matter. LCGU responses to s.c. injection of nicotine were completely blocked by mecamylamine, indicating the specificity of nicotine effects. The effects of nicotine on LCGU correlate well with the distribu- tions of 3H-nicotine binding sites (Clarke, Pert, Pert 1984; London, Waller, Wamsley 1985). Areas such as the thalamic nuclei, the interpeduncular nucleus, medial habenula, and the superior collicu- lus, where there is dense labeling with ~H-nicotine, show moderate to marked nicotine.induced LCGU increases. Areas with less specific binding show smaller LCGU responses to nicotine, and the central grey matter, which lacks specific ~H-nicotine binding, shows no LCGU response. Similarly, nicotine dramatically increases LCGU in the medial hut not the lateral habenula, reflecting different densities of 8H-nicotine binding sites. In general, 3H-nicotine binding sites visualized autoradiographically in the rat brain are functional nicotine receptors. However, layer IV of the neocortex displays significant 3H-nicotine binding, but lacks an LCGU response. In most brain areas, significant LCGU stimulation was obtained with 0.3 mg/kg of nicotine s.c. (London etal. 1988), a dose similar to one used successfully in training rats to distinguish nicotine from 86

D TABLE 1.--R,S-Nicotine effects on glucose utilization in the rat brain Loea[ cerebral glucc~e utilization (~molll00 g tlssue/minute) Brain region Saline control Nicotin~ {1.75 mg/kg) Frontoparietal cortex, [ayvr IV 110 ~: 8.1 I~ :c 6.5 Retrusp/enia/ eorlex, ]~¥er ~ 98 ± K5 ]9.~ #. &l L Tha~amic n.clei Ante~ventral 109 a. 6.6 201 ~ ~I i It~teranteromedial IP./i ± 8~ 17~ ~. 12.3L Lateral gerdculate body 82 ± 6,~ 106 ± 4,4* Interpedun~uLar nucleus 99 ~ 9~ 182 ± 9.31 Medial habenu]a 70 ± 5.2 167 ± 3.7l Superior eolllculus 72 ± 52 142 ± L6L Central grey matter 68 ~: 4,0 77 ~. 4.3 NOTg: ~olts ~*r¢~ exprv~*d as the mearm plus or miflul it~rd deviation f0r fQUT TatS per group ~Signifi¢~*ntl~" different from ~llno vont~l {p~0.05}. SOURCS: London ct I*L (198.5). @ FIGURE /.--Effect of subcutaneous R,S-nlcotine (1 mg/kg, 2 min before 2-deoxyglucose) on autoradiographic grain densities, representing glucose utilization NOTE: Photv~apl~ Cf x-ray film exp~ed to 20-pro brain ~¢tiovs f~o~ ©ontroi rat (A) glv~h 0,9 paint ~ium ©h[orkle tl mL/kg) m,A another mt (B) given nicotine; note the increMcd density Ifl medici hmbenu[a (mh) and (~¢kuius retr~flext~ {~r). ~O0"RCg: Lsn~ et ~l, (1~61. saline in a T-maze apparatus (0.4 mg/kg, s.c.) (Overton 1969). Nicotine-induced stimulation of LCGU in the ventral tegmentai area 87

and the habeaular complex (London et al. 1985, 1986} may relate to the reinforcing properties of the drug (see Chapter IV). These regions of the brain have been implicated in drug- and stimulation-induced reward systems, respectively (Wise 1980; Nakajima 1984). Additional studies, using specific conditions under which nicotine is reinforcing, are needed to elucidate the anatomical loci involved in nicetine- induced reward and to identify the neurophysiological mechanisms by which nicotine acts as a reinforcer. Nicotine Receptors Nicotine exerts diverse pharmacologic effects in both the peripher- al nervous system (PNS) and CNS. The peripheral actions of nicotine are important, and some may reinforce the self-administration of nicotine. For example, stimulation in the trachea (Rose et al. 1984) seems to be involved in some of the pleasurable effects of smoking. Skeletal muscle relaxation and electrocortical arousal, both stimu- lated by actions of nicotine in the lung (Ginzel 1967a,b, 1975, 1987), may contribute to. habitual tobacco use (Chapter VI). However, it is generally believed that the central actions of nicotine are of primary importance in reinforcing tobacco use (Chapter IV). In animals, the neuropsychopharmacologic effects of this drug are, with few if any exceptions, mediated through central sites of action. These effects are likely to contribute to the drug's reinforcing properties in animals and humans (Clarke 1987b). In addition, the effects of nicotinic antagonists on tobacco smoking in humans (Stolerman et aL 1973) and in rhesus monkeys <Glick, Jarvik, Nakamura 1970) suggest a central site of reinforcement, but do not rule out a peripheral site. To understand these actions, it is important to know exactly where nicotine acts in the body. This Section discusses evidence for nicotine receptors. Peripheral Nicotine Receptors In the mammalian PNS, nicotine and muscarine mimic different actions of ACh by acting at different types of cholinergic receptors. Nicotinic cholinergic receptors (nAChRs) have been subdivided according to location and sensitivity to nicotinic antagonists. Recep- tors of the C6 or "ganglionic" type are found principally at autonomic ganglia, in the adrenal medulla, and at sensory nerve endings; nicotinic cholinarglc transmission in autonomic ganglia is selectively blocked by hexamethonium and certain other compounds. Receptors of the "neuromuscular" type (sometimes referred to as C10 type) are located on the muscle endplate, where transmission is selectively blocked by compounds such as decamethonium and alpha- bungarotoxin (a-BTX). 88 •

Higher doses of nicotine are required to stimulate nAChRs in skeletal muscle than at autonomic ganglia. Ganglionic nAChRs appear to be more sensitive than their neuromuscular counterparts, not only to the stimulant but also to the desensitizing actions of nicotine (Paten and Savini 1968). Doses of nicotine obtained by smoking cigarettes do not appear to affect the muscle endplate directly. Therefore, if the CNS were to possess both types of nAChR, doses of nicotine obtained by normal cigarette smoking might affect only the C6-recoptor population. Accordingly, many of the central effects of nicotine in vivo and in vitro are reduced or •blocked by nicotinic antagonists that are C6-zeloctive in the periphery. The most widely used C6-selective antagonist is mecamylamine, which passes freely into the CNS after systemic adminisi~ration. Mecamyla- mine antagonizes actions of nicotine in the bl'ain and spinal cord, as revealed by behavioral (Collins et al. 1986; Goldberg, Spealman, Goldberg 1981) and electrophysiological experiments (Ueki, Koketsu, Domino 1961) and also by studies of neurotransmitter release (Hery et al. 1977; Chesselet 1984). There have been few attempts to determine whether these central nicotinic actions are also blocked by neuromuscular antagonists, while several studies support the existence of central C6 nAChRs (Aceto, Bentley, Dembinski 1969; Brown, Docherty, Halliwell 1983; Canlfield and Higgins 1983; Egan and North 1986). The search for putative central a-BTX nAChRs has been hindered by several factors, including the central convulsant actions of a-BTX antagonists (Cohen, Morley, Snead 1981) and the probable need to deliver locally high concentrations of nicotine. Nevertheless, several studies have demonstrated actions of nicotine or cholinergic agonists that can be reduced or blocked by a-BTX, which acts selectively at neuromuscular nAChRs (Zatz and Brownstein 1981; Farley et al. 1983; de la Garza et al. 1987a). Radioligand Binding to Putative Nicotine Cholinergic Receptors in Mammalian Brain Many receptors for neurotransmitters in the brain have been identified through the use of radiolabeled probes (radioligands). Attempts to label putative brain nAChRs have used compounds with known potency at peripheral sites (see Table 2l. Agonist Binding The stereaspecific, saturable, and reversible binding of 8H-nicotine to rodent brain is well-described (Romano and Goldstein 1980; Marks and Collins 1982; Costa and Murphy 1983; Benwen and Balfour 1985a; Clarke, Pert, Pert 1984). Most studies have demonstrated the existence of a population of high-affinity binding sites (reflected by a dissociation constant in the low nanomolar range) that is potently 89

TABLE 2.--RadioBgands for putative nicotinic cholinergic receptors in mammals Functional Antagonists Bind an~gonbsm S~tes examined Agomsls Iz~I-BTX Yes Yes Muscle endptate Yes Yes Autonomic ganglia, splna] cord Yes Ye~ Stain ~certaln sites onlyP I~[-nala toxin Yes Yes Muscle enciplate Yes NDj Brain JH,dTC ND yes Muscle. spinal cord. ganglia yes Y~s Dram ~H-DHBE NI) Yes Muscle, autonomic ganl~[ia Yes Yes Brain, spiaal cord N~uruga~oxin ND No Muscle endplate ND Yes AutonQmic ganglia Yes Yes Brain ~inhibit~ ~H-nicolinel ~ H-nicotine J H.rnet hyl.car bacho] ~H ACh Lwith e~cess nl u~ca rlnl¢ an tagon ~sl and AChE inh~bitorp 'NDffino data¸ inhibited by nicotinic agonists including ACh. In contrast, most nicotinic antagonists have very low affinity for this site. Binding with similar characteristics has been reported in rat brain ti~ue with 3H-methyl-sarbachol (Abood and Grassi 1986; Boksa and Quirion 1987) and with ~H-ACh in the presence of excess atropine to prevent binding to muscarinic receptor sites (Schwartz, McGee, Kellar 1982). In the presence of atropine, tritiated nicotine and 3H-ACh proba- bly bind to the same population of high-affinity sites in rat brain. Thus, the two radioligands share the same neuroanatemical distribu. tion of binding (Clarke, Schwartz et al. 1985; Marks et al. 1986; Martino-Barrows and Keller 1987). Binding of both ligands is inhibited with similar potency by a range of nicotinic agents, is up- regulated by chronic nicotine treatment in vivo, is down-regulated by chronic treatment with acetylcholinesterase inhibitors, and is dimin- ished by disulfide reducing agents in vitro (Marks et al. 1986; Martino-Barrows and Kellar 1987; Schwartz and Kellar 1983). Although less well studied, it appears that sites labeled by 3H- rnethyl-earbaehol are the same as those labeled by 3H-ACh and all- nicotine (Abood and Grassi 1986; Boksa and Quirion 1987). High- affinity nicotine binding sites have been found in brain tissue of mice (Marks and Collins 1982), rats (Romano and Goldstein 1980), monkeys (Friedman et al. 1985), and humans (Shimohama et al. 1985; Flynn and Mash 1986; Whitehouse et el. 1986). Some investigators have reported a second class of sites which are characterized by lower binding affinity and higher capacity for 3H- 9O •

O nicotine. With no demonstrated differential anatomical distribution or stereoselectivity (Romano and Goldstein 1980; Marks and Collins 1982; Benwell and Balfour 1985b), these low-affinity sites are of questionable pharmacologic significance, but may be the result of post mortem proteolysis (Lippiello and Fernandes 1986). Careful analysis of ~H-nicotine binding conducted in the absence of protease inhibitors has revealed the existence of five affinity sites or states (Sloan, Todd, Martin 1984). Functional studies (Martin et al. 1986) suggest that some of these different sites may represent in vivo sites of action for nicotine, although it is not clear which if any would be activated by nicotine doses obtained from typical cigarette smoking. Radioligand Binding Many receptors of different nicotine binding affinities have been reported. ]t is unclear whether these reflect different conformational states or binding sites of a single type of receptor, distinct receptor populations, or a single type of high-affinity site which has under- gone proteolytic degradation. Preliminary evidence supports the existence of distinct receptor subtypes labeled by agonists. Two components of high-affinity all-nicotine binding, differing in their affinity for neosurugutexin, can be distinguished in rat brain. The relative proportion of these two components differs in different regions of the rat brain, suggesting that they are physically distinct receptors (Yamada et al. 1985). Antagonist Binding Most studies of nicotine binding in mammalian brain have used radioiodinated a-BTX (~2~I-BTX), which binds with high affinity and in a saturable manner to sites in mammalian brain (Schmidt, Hunt, Polz-Tejera 1980; Oswald and Freeman 1981). This binding is selectively inhibited by nicotinic agents, including nicotine and ACh. Cobra (naja) alpha-toxin, like a-BTX, is a selective neuromuscular blocker in the mammal, and appears to label the same sites as a-BTX in mammalian brain. Binding is potently inhibited by unlabeled a- BTX and has a regional distribution resembling that of '~U-BTX binding (Speth etal. 1977). The antagonist dihydro.beta-erythroidine (DHBE) binds to two sites in rat brain, but the regional distribution of binding differs from that of ~z~I-BTX (Williams and Robinson 1984). DHBE acts with similar potency at both types of peripheral nAChR in vivo. It is not clear whether 3H-d-tubocurarine binding is selectively inhibited by nicotinic agents. In rat brain, '*eI-BTX binds to a distinct population of sites that are not labeled with high affinity (nanomolar kD) by tritiatsd nicotinic agonists. Radioiodinated a- BTX sites have a different nouroanatemical distribution (Marks and Collins 1982; Schwartz, McGee, Kellar 1982; Clarke, Schwartz etal. 91

1985) and can be physically separated from tritiated agonisL binding sites by affinity chromatography (Schneider and Betz 1985; Wonna- cott 1986), This type of study helps to determine the location and numbers of nicotine binding sites. Functional Significance of Nicotinic Binding Sites High-Affinity Agonist Binding Sites Brain sites which bind ~H-ACh and 8H-nicotine with high affinity represent nAChRs that respond in some ways like the C6 type of receptor found in the periphery (Clarke 1987a). Studies using the 2- DG technique have revealed that the neuroanatomical pattern of cerebral activation following the systemic administration of nicotine in rats is strikingly similar to Ahe distribution of high-affinity agonist binding demonstrated autorediographically (London et al. 1985; Grunwald, Schrok, Kuschinsky 1987). Pretreatment with mecamyla- mine blocks the effects of nicotine on LCGU, suggesting' that putative ganglionic (C6-type} receptors in the brain are associated with high-affinity agonist binding. Most of nicotine's actions on central receptors are blocked by the C6-seleetive antagonist mecamylamine, The relevant nAChRs are probably those which are labeled with high affinity by tritiated agonists. However, the absence of high-affinity agonist binding sites in PC12 cells (derived from a pheochromocytoma cell line) known to express C6-type receptors (Kemp and Morley 1986) indicates that although central and ganglionic nAChRs have pharmacologic simi- larities, they may not be identical at the molecular level. High-affinity agonist binding sites are relevant to long-term effects of human tobacco smoking. Recently, Benwell, Balfour, and Ander- son (in press) observed that the density of high-affinity 3H-nicotine binding in post mortem human brain is higher in smokers than in nonsmokers. The increased density of sites in smokers is consistent with studies in animals that show that chronic treatment with nicotine leads to an increased number of nicotinic receptors in the brain (Schwartz and Kellar 1983; Marks, Butch, Collins 1983b). Alpha-Bungarotoxin Binding Sites Although a-BTX does not block nicotinic actions in all areas of the CNS (Duggan, Hall, Lee 1976; Egan and North 1986), there are several reports of antagonism (Zatz and Brownstein 1981; Farley et al. 1983; de la Garza et al. 1987a). In the rat cerebellum, locally applied nicotine alters single-unit activity in a manner dependent on cell type: nicotine excites interneurons but inhibits Purkinje cells. Both actions are directly postsynaptic (de la Garza et al. 1987, in press(b)). The inhibitory effects of nicotine are blocked by hexame- 92 O

thonium but not by mBTX, which does block the excitatory effects (de la Garza et al., in press(n)). Strain differences exist in mice in the physiological and behavioral effects of nicotine, in the devdlopment of tolerance to these effects, and in the regional distribution of ~I.BTX binding density (Marks, Burch, Collins 1983a; Marks, Stitzel, Collins 1986). The genetically determined variation in response is not readily explained by differences in brain nicotinic receptors. However, a classical genetic analysis indicates that the density of ~26I-BTX binding sites in mouse hippocampus correlates with susceptibility to seizures induced by high doses of nicotine (Miner, Marks, Collins 1984). These and other considerations (Clarke 1987a) suggest that ~2~I-BTX may label a subtype of nAChR in the brain and that this receptor is pharmaco- logically akin to the nAChR found in muscle. Although ~I.BTX binding sites are found in human brain, the available evidence suggests that nicotine at doses obtained from cigarette smoking does not activate this population of brain nAChRs. Rather, the pattern of neuronal activation that follows the in vivo administration of nicotine in animal experiments, even in doses far greater than these likely to occur during smoking, resembles the neuroanatomical distribution of high-affinity agonist binding sites (London et al. 1985; Grunwald, Sehrok, Kuschinsky 1987). However, this issue is not conclusively resolved, and a potential role for bungarotoxin binding receptors in mediating effects of smoking cannot be completely excluded. Behavioral and Physiological Studies The effects of mecamylamine on several responses elicited by nicotine in mice have been examined (Collins et al. 1986}. The responses are of two major classes: those blocked by low doses of mecomylamine (inhibitory concentrations for 50 percent of mice tested (ICso <0.1 mg/kg)) (seizures and startle response) and these blocked by higher doses (ICso approximately 1 mg/kg) (effects on respiratory, heart rate, body temperature, and Y-maze activity). Strain differences are also apparent in the sensitivity to mecamyla- mine blockade. These findings are consistent with the existence of at least two types of central nAChR. The Neuroanatomical Distribution of Nicotinic Binding Sites in the Brain High.Affinity Agonist Binding Sites Rodent Autoradiographic maps of high-affinity nicotinic binding sites in rat brain are essentially identical for ~H-nieotine, ~H-ACh, and ZH- methyl-carbaehol (Clarke, Pert, Pert 1984; Clarke, Schwartz et al. 93

1985; London, Waller, Wamsley 1985; Boksa and Quirion 1987). Dense labeling is observed (1) in the medial habenula and interpe- duncular nucleus, which appear to belong to a common cholinergic system; (2) in the so-called specific motor and sensory nuclei of the thalamus and in layers III and IV of cerebral cortex with which they communicate; (3) in the substantia nigra pars compacta and ventral tegmental area, where labeling is associated with dopaminergic cell bodies (Clarke and Pert 1985); and (4) in the molecular layer of the dentate gyrus, the presubicuium, and the superficial layers of the superior colliculus. Labeling is sparse in the hippocampus and hypothalamus. Monkey The autoradiographic distribution of high-affinity SH-nicotine binding in rhesus monkey brain is similar to that in the rat (Friedman et al. 1985; O'Neill et al. 1985). Dense labeling has been noted in the anterior thalamic nuclei and in a band within cerebral cortex layer III. The latter band is densest and widest in the primary sensory areas. Several other thalamic nuclei are moderately labeled, but as in the rat, the label is sparse in the midline thalamic nuclei. In contrast to findings for the rat, the medial habenula appears unlabeled. Human High.affinity agonist binding has not been mapped autoradio- graphically in human brain. However, assays of a few dissected brain areas suggest the following pattern: nucleus basalis of Meynert > thalamus > putamen > hippocampus, cerebellum, cerebral cortex, and caudate nucleus (Shimohama et al. 1985). Two affinity sites for 3H-nicotine have been detected, and the regional distribution observed reflects the presence of both sites. Alpha.Bungarotoxin Binding Sites Because ~H-BTX sites may not be relevant to tobacco smoking, they will be discussed only briefly here. There are clear differences of regional distribution not only between mice and rats, but also between different strains of mice (Marks et al. 1986). The autoradio- graphic distribution of ~2H-BTX labeling in rat brain is strikingly different from the pattern of ~H-agonist labeling, with highest site density in hippocampus, hypothalamus, and superior and inferior colliculi (Clarke, Schwartz et al. 1985). An attempt to map ~H-BTX binding in human brain was hampered by a high degree of nonspecific binding, with diffuse specific labeling in the hippocam- pus and cerebral cortex (Lang and Henke 1983). 94 •

Molecular Biology Goldman and colleagues have mapped regions in the brain which contain cell bodies expressing RNA that codes for putative nAChRs. The RNA identified is homologous to eDNA clones encoding the alpha subunits of the muscle nACbR and a putative neuronal nAChR (Goldman et al. 1988; Goldman et al. 1987). These and related findings show that a family of genes exists that codes for proteins similar to, but not identical with, the muscle nAChR. The functional role of these putative nAChR subtypes in the CNS is not clear. Central Nicotinic Cholinergic Receptors: Pre- or Postsynaptic? Presynaptic Regulation of Neurotransmitter Releaze The release of ACh from some nerve terminals in the CNS (Rowell and Winkler 1984; Beani et el. 1985) and periphery (Briggs and Cooper 1982) is increased by activation of presynaptic nicotinic "autoreceptors." Preliminary evidence from lesion experiments suggests that some nicotinic autorecepters in the brain may be high- affinity ~H-nisotine binding sites (Clarke et al. 1986). Nicotine also modulates the release of certain other neurotrans- mitters by acting at receptors located on nerve terminals. This form of regulation has been shown for dopaminergic, noradrenergic, and serotonergic terminals (Starke 1977; Chceselet 1984). Lesion studies suggest that these recepters are labeled by 8H-agonists (Schwartz, Lehmann, Kellar 1984; Clarke and Pert 1985; Prutsky, Shaw, Cynader 1987). Somatodendritic Postsynaptic Actions Much of ~H-agonist labeling probably represents nAChRs located on neuronal cell bodies or dendrites. For example, nicotine excites neurons postsynaptieany in the medial habenula, locus cceralens, and .interpoduncular nucleus, all areas of moderate to dense 3H- agonist binding (Brown, Docherty, Halliwell 1983; Egan and North 1986; McCormick and Prince 1987). Neuroendocrlne and Endocrine Effects of Nicotine Nicotine has direct and indirect effects on several neuroendocrine and endocrine systems (Balfour 1982; Clarke 1987a; Hall 1982), This Section reviews research on the effects of nicotine in animals and humans that are relevant to understanding cigarette smoking. Nicotine effects on cholinergic and noncholinergic nicotinic recep- tors, as well as on the release of cetacholamines, monoaminas, pituitary hormones, cortisol, and other neuroendocrine chemicals, 95

are discussed. Effects on single neuroregulators are emphasized, but it is important to recognize that there are extensive interrelation- ships among these substances (Tuomiste and Mannisto 1985). Nicotine has effects on peripheral endocrine as well as on central neuroendocrine functions. In the early 1900s researchers discovered that nicotine stimulated autonomic ganglia (ganglia were painted with tobacco solutions), inducing such effects as the release of adrenal catecholamines (Larson, Hang, Silvette 1961). As the health consequences of cigarette smoking have become clearer, many investigators have sought to determine tobacco's effects on the endocrine system, with the possibility that understanding such effects may help to explain smoking behavior. Nicotine is regarded as the major pharmacologic agent in tobacco and tobacco smoke responsible for alterations in endocrine function. However, there has not been a systematic evaluation of the effects of metabolites of nico$1ne or constituents of tobacco other than nicotine on the endocrine system. The functional significance of nicotine.induced perturbations in hormonal patterns and the role of neuroregulators in smoking are poorly understood. Extensive literature using nicotinic agonists and antagonists indicates relationships between cholinergic activity and particular behavioral effects ¢Henningfield et el. 1983; Kumar, Reavill, Stelerman, in press). Similar strategies have been employed to explore the contributions of catechelamines to smoking-related behavior. However, the exploration of the importance of neuroregu- Inters in the reinforcement of cigarette smoking is still at an early stage. • • Cholinergic Effects Nicotine has cholinergic effects in the PNS and CNS. Nicotine is a eholinergie agonist at peripheral autonomic ganglia and somatic neuromuscular junctions at low doses and becomes an antagonist at high doses (Voile and Koelle 1975). Nicotine also releases ACh in the cerebral cortex (ArmlCage, Hall, Morrison 1968; Eowell and Winkler 1984) and in the myenteric plexus of the peripheral ANS (Briggs and Cooper 1982). Balfour (1982) has suggested that cortical arousal (see Electrophysiological Actions of Nicotine for a detailed discussion) is mediated by ACh release but that behavioral stimulation (see Chapter IV) either is not mediated by ACh release or does not depend on the action of ACh at a muscarinie receptor. Studies involving intracerebral administration of nicotine have been used to determine the locl of nicotine's action (Kammerling et el. 1982; Wu and Martin 1983). The injection of nicotine into the cerebral ventricles of cats, dogs, and rats produces a variety of effects including changes in cardiovascular activity, body temperature, respiration, salivation, muscle reflex tone, and electrccortical indices 96 •

of sleep and arousal; the direction and duration of effects depend on dosage and on baseline response parameters (Hall 1982). Nicotine's cholinerglc actions can affect other neuroregulaters in the body (Andersson 1985). Nicotine stimulates NE release in the hypothalamus by a Ca2+-dependent process that can be inhibited by prior administration of hexamethonium or ACh (Hall and Turner 1972; Westfall 1974). The mechanism resembles nicotine's effects on peripheral adrenergic nerve terminals (Westfall and Brasted 1972). At high dose levels, nicotine stimulates NE release by displacing it from vesicle stores at sites outside the hypothalamus (Balfour 1982). These actions are relevant to understanding the reinforcing effects of nicotine. For example, using drug discrimination procedures, Rosecrans (1987) has demonstrated that intact central NE and dopamine (DA) function were required to elicit the cue properties of nicotine. Intravenous administration Of nicotine medulates the release of both neurohypophyseal and adenohypophyseal hormones (Bisset et ah 1975; Hall, Francis, Morrison 1978). Hifihouse, Burden, and Jones (1975) found that the in vitro application of ACh to the hypophysio- tropic area of the rat caused a significant increase in the basal secretion of corticotropin-releasing hormone (as measured by bioas- say), which in turn controls, via the anterior pituitary, the release of the pro-opiomelanocortin (POMC) group of hormonas-13-endorphin, ~-lipotropin, melanocyte-stimulating hormone-releasing factor, and adrenocorticotropic hormone (ACTH) (Meites and Sonntag 1981). The humoraI mechanism for the release of vasopressin has been traced from the medulla to the paraventricular nuclei of the hypothalamus (Bisset et el. 1975; Castro de Souza and Roche e Silva 1977). Similarly, Risch and colleagues (1980) have demonstrated a cholinergie mechanism for the release of ~-endorphin. Modulation of Catecholamine and Serotonin Activity Dale and Laidlaw (1912) found that the presser response of the cat to nicotine was due in part to the release of epinephrine from the adrenal glands. Over the past 75 years, a large body of research has confirmed and further investigated this phenomenon. Stewart and Rogoff (1919) quantified the effect of nicotine on adrenal epinephrine release. Kottegeda (1953) observed that nicotine releases catoehol- amines from extra-adrenal chromaffin tissues. Watts (1961) demon- stratod the effect of smoking on adrenal secretion of epinephrine. Hill and Wynder (1974) reported that increasing the nicotine content in cigarette smoke progressively increased the serum concentration of epinephrine, but not NE. Winternitz and Quillen (1977) found that the excretion of urinary eatecholamines tended to be higher on smoking days than on nonsmoking days. Several recent studies have focused on the role of nicotine and the mechanisms involved in the 97

release of cateeholamines from cultured chromaffin cells (Forsberg, Rojas, Pollard 1986). Earlier experiments by Douglas and Rubin (1961), using denervated perfused cat adrenal glands, indicated that nicotine augments eatecholamine release from chromaffin cells by promoting an influx of extracellular calcium. Forsberg, Rojas, and Pollard (1986) suggested that nicotine-induced catecholamine secre- tion may be mediated by phosphoinositide metabolism in bovine adrenal chromaffin cells. The anatomical localization and importance of biogenic mono- amines such as serotonin (5-HT [5-hydroxytryptamine]), DA, and NE have been the subject of intense research for the past 30 years. The classic studies of Dahlstrom and Fuxe (1966} revealed that neurons containing these amines were localized in speclfic-ascending projec- tion systems; descending monoaminergie neurons have also been described. The physiological integrity of these systems was further demonstrated by Aghajanian, Rosecrans, and Sheard (1967), who observed that stimulation of 5-HT cell bodies localized in the. midbrain raph/nucleus released 5-HT from nerve endings located in the more rostral forebrain. The recognition that these amine systems constitute a unique interneuronal communication system has played a central role in understanding underlying neurochemical and behavioral mechanisms. The chollnergic system has undergone a similar analysis (Fibiger 1962) but the delineation of specific cholinergic pathways has been more difficult 'becaus~ no histechemical method has been available for ACh.' It does appear, however, that the ehollnergie system is similarly organized and interacts with specific biogenic amine pathways. For example, Robinson (1983) has clearly shown that both 5-HT and DA systems exert tonic inhibitory control over ACh turnover in both the hippocampus and frontal cortex regions. Lesions of the medial raph~ nuclei increase the ACh turnover rate in hippocampal sites, while lesions of the dorsal raphb elicit a similar. effect in frontal cortical areas. Evidence of DA control comes from the observation that the catecholamine neurotexin, 6-OHDA, when injected into the DA-rich septal area, facilitated hippocampal ACh turnover.. The research of Kellar, Schwartz, and Martino (1987) and others also suggests that nicotinic receptors may occupy a presynap- tic site on select DA and 5-HT nerve endings. Westfan, Grant, and Perry (1983), using a tissue slice preparation, have shown that the DMPP-induced stimulation of nicotinic receptors in the striatum will facilitate the release of both 5-HT and DA. This preparation is devoid of cell bodies or 5-HT- and DA-eontaining axon terminals, suggesting that these nicotinic eholinergic receptors are primarily presynaptic. Further, hexamethonium, but not atropine, attenuated nicotine- induced amine release, confirming that these effects are nicotinic in nature. Q 98 •

Nicotine may have simultaneous actions on many types of neurons. Even though only one kind of receptor may be stimulated, either activation or inhibition of a particular 5-HT, NE, or DA neuron may be the ultimate outeome. Conversely, the activity of specific cholinergic neurons may also be controlled by one of these biogenie-amine-centaining projection systems. Nicotine appears to produce its discriminative stimulus effect in at least one major brain area, the hlppocampus. This site is rendered insensitive if DA neurons innervating this area are destroyed (Rosecrans 1987), The interrelationships of these amine pathways are important to under- stand nicotine's effects on behavior and its effects on the neuroendoc- rine system because of the central role that these amine systems play in the hypothalamic control of the pituitary. Effects on Serotonergic Neurons Research evaluating the relationship between nicotine and 5-HT has involved several different approaches. Hendry and Roseerans (1982) compared the effects of nicotine on conditioned and uncondi- tioned behaviors in rats selected for differences in physical activity and 5-HT turnover. Balfour, Khuller, and Longden (1975) observed that acute doses of nicotine were capable of attenuating hippseampal 5-HT turnover, an effect specific to the hippocampus. Fuxe and colleagues (1987) did not observe any acute changes in 5-HT function following acute nicotine dosing but did'observe a significant reduc- tion of 5-HT turnover following repeated doses (3 x 2 mg/kg/hr). This effect, however, was suggested to be due to cotinine, the primary metabolits of nicotine. In addition to attempts to correlate 5-HT function with some pharmacologic effect of nicotine, investigators have evaluated poten- tial links between 5-HT and neuroendoerine function. Balfour, Khuller, and Longden (1975) showed a relationship between 5-HT and nicotine's ability to induce the release of plasma corticcetsrone, presumably by activation of the pituitary-adrenal axis. Following acute nicotine injections in the rat, a reduction in 5-HT turnover correlated with an increase in plasma eorticosterone. Rats exhibited tolerance to pituitary activation fallowing repeated nicotine doses, but not to the attenuation of hippocampal 5-HT turnover. Stress antagonized nicotine-induced reductions of hippoeampal 5-HT. Also, nicotine was reported to inhibit the adaptive response to adrenocerti- cal stimulation fallowing chronic stress (Balfour, Graham, Vale 1986). One interpretation of these data is that nicotine can modify how rats adapt to stress, which may be mediated by changes in hippocampal 5-HT function. At this point, however, it is difficult to draw firm conclusions concerning how nicotine affects 5.HT neurons and whether this neurotransmitter is involved in any of nicotine's 99

effects on neuroendocrine function, Hippocampal 5-HT turnover appears to be selectively attenuated by nicotine. Effects on Catecholaminergic Neurons Studies of the effects of nicotine on NE-containing neurons have produced mixed results. Earlier work suggested that nicotine may affect behavior via a NE component, but recent research has not supported such claims (Balfour 1982). It has been reported that nicotine releases DA from brain tissue (Westfall, Grant, Perry 1983}. Lichtensteiger and colleagues (1982) observed that nicotine releases DA through an acceleration of the firing rate of DA cell bodies located in substantia nigra zona compacta when nicotine is adminis- tered via iontophoretic application or s.c. (0.4 to 1.0 mg/kg). This acHvation was marked by a significant increase in striatal DA turnover; DHBE, but not atropine, attenuated nigrostriatal activa- tion. Evidence that nicotine facilitates the firing of DA cell bodies by stimulating nicotinic cholinergic receptors has recently been report- ed by Clarke, Hemmer, and coworkers (1985), who showed a specific effect of nicotine antagonized by mecamylamine on pars compacta cell bodies. Connelly and Littleten (1983) noted that DA release from synaptosomes lacked stereoselectivity but was blocked by the ganglionic-blocking drug pempidine. Fuxe and coworkers (1986, 1987) have studied nicotine's effects on central catecholamine neurons in relation to neuroendocrine func- tion. These investigators use quantitative histofluorometric tech- niques that measure the disappearance of catecholamine stores by administering a tyrosine hydroxylase inhibitor (AMPT) to rats receiving various doses of nicotine or exposed to tobacco smoke. Tissues are then exposed to formaldehyde gas, and histefluoresence in AMPT-treated rats is evaluated in comparison to controls. Nicotine is a potent activator of both DA and NE neuron systems located primarily in the median eminence and in areas of the hypothalamus. These effects result from a stimulation of nicotinic cholinergic receptors, generally antagonized by mecamylamine. Intermittent nicotine dosing (4 x 2 mg/kg, s.c. every 30 min) or tobacco smoke exposure (rats were exposed to one to four cigarettes with a smoking machine-determined nicotine yield of 2.6 mg; rats received 8 puffs at 10-min intervals) results in a decrease of prolactin, thyroid-stimulating hormone (TSH), and luteinizing hor- mone (LH) and an increase of plasma eorticosterone levels. Nicotine doses of 0.3 mg/kg administered i.v. induce an overall activation of the hypothalamic-pituitary axis, causing an increase of both ACTH and prolactin that subsides within 60 rain. Tolerance to the eorticosterone response develops after repeated nicotine doses and there is evidence that it develops after a single dose of nicotine (Sharp and Boyer 1986; Sharp et al. 1987). Restraint stress increases 100 •

ACTH, corticosterone, and prolactin levels and decreases DA and NE levels in hypothalamic regions. This stressor attenuates nicotine's activation of NE neurons but does not reverse its attenuating effects on prolactin. Nicotine appears to be associated with neuroondocrine activity by NE and DA activation (Fuxe et al. 1987). Immunohlstechemlcal studies suggest that alterations in NE function are more important for the control of the pituitary-adrenal-axis, while DA turnover appears to be crucial for nicotine's effects on prolactiu, LH, and follicle-stimulating hormone (FSH). Moreover:, these studies indicate' that similar aAChRs are located within both DA mesolimbic and neostriatal systems. Stimulation of Pituitary Hormones Nicotine administration and cigarette smoking stimulate the release of several anterior and posterior pituitary hormones. Seyler and coworkers (1986) had human subjects smoke two high-nicotine (2.87 rag) cigarettes in quick succession. Plasma levels of prolactin, ACTH, ~ondorphin/6-lipoprotein, growth hormone (GH), vesopres- sin, and neurophysin I increased. No change was seen in TSH, LH, or FSH. The rapid smoking paradigm used by Seyler and coworkers (1986) may have contributed to the effects of nicotine. Growth hormone levels exhibited a prolonged increase after subjects smoked three cigarettes in rapid succession (Sandberg et al. 1973). In experiments conducted by Winternitz and Quillen (1977) with male habitual ~mokers~ GHbegaa to riseafter two cigarettes, peaked at 1 hr, and then returned to control levels while smoking continued. Wilkins and colleagues (1982) also found that smoking increases GH levels and presented evidence that the effect is nicotine mediated. Coiro and coworkers (1984) reported that the increase in GH produced by clonidine was greatly enhanced by cigarette smoking, suggesting that nicotinic cholinergic and adrenergic mechanisms might interact in the stimulation of GH secretion. The TSH plasma levels were not affected when nicotine was administered over a 60-rain period to female rats (Blake 1974). In studies involving exposure to cigarette smoke, Andersen and col- leagues (1982) reported a lowering of TSH secretion in rats, but as noted, Seyler and coworkers (1986) found no change in human subjects. Thus, the data on the effects of nicotine on TSH release are inconclusive at this time. ACTH plasma levels increased after i.p. injection of nicotine in the rat (Conte-Devolx et al. 1981). In similar experiments, Cam and Bassett (1983b) found that elevated ACTH levels peaked and rapidly declined to a sustained plateau level. Sharp and Beyer (1986) reported that the effects of nicotine on ACTH in rats show a rapid and marked desensitization. Seyler and eoworkers (1984) had male 101

subjects smoke cigarettes containing 0.48 or 2.87 mg of nicotine. No increases in ACTH or cortisol were detected after subjects smoked 0.48-rag-nicotine cigarettes. Cortisol levels rose significantly in 11 of 15 instances after smoking the high-nlcotine cigarettes, but ACTH rose in only 5 of the 11 instances when cortisel increased. Each ACTH increase occurred .in a subject who reported nausea and was observed to be pale, sweaty, and tachycardic, Seyler and coworkers (1984) studied smokers and concluded that ACTH release occurs only in smokers who become nauseated. LH levels were reduced in male rats exposed to anfiJtered cigarette smoke, while FSH was unchanged (Andersen et el. 1982). In experiments by Winternitz and Quillen (1977), there were no differences in LH and FSH among male cigarette smokers while smoking as compared with net smoking. Seyler and colleagues (1986) found no change in human LH or FSH levels after smoking. There is no evidence of gonadotropin release stimulated by nicotine or smoking. Prolactin plasma levels were lowered considerably in lactating rats injected twice daily with nicotine (Terkel et el. 1973). It was suggested that failure of prolactia release following chronic nicotine administration was responsible for low milk production and starva- tion of pups. Blake and Sawyer (1972) found that, in lactating rats, the rapid suckling-induced release of prolactin into the blood is inhibited by s.c. injections of nicotine. Ferry. McLean, and Nikitito- vjch-Winer (1974) reported that tobacco smoke inhalation in rats delays the suckling-induced release of prolactin, Andersen and coworkers (1982) found that prolactin secretion was reduced in mule rats in a dose-dependent manner by exposure to unfiltered cigarette smoke. However, Sharp and Bayer (1986} reported that the effects of nicotine on prelactin in rats shows a biphasic effect, first increasing and then decreasing. Suppressed prolactin levels were found in female smokers who were breast feeding (Andersen et al. 1982). These researchers noted that smokers weaned their babies signifi- cantly earlier than nonsmokers. However, Wilkins and coworkers (1982) observed an increased level of prolactin in male chronic smokers. Arginine Vazopressin In addition to its antidiuretic effects, arginine vasopressin acts as a vasoconstrictor (Munck, Guyre, Holbrook 1984; Waeber et aL 1984), Arginine vasopressin may also act as a neuromodulator in pathways that affect behavior. It has been shown to promote memory consolidation and retrieval in rats (Bohus, Kovacs, de Wied 1978) and there are reports of memory enhancement following intranasal administration of a vasopressin analog in both normal and memory- deficient humans (LeBoeuf. Lodge, Eames 1978; Legros et al. 1978; $ 102 •

Weingartner et al. 1981l. Nicotinic cholinergic receptors in the medial basal hypothalamas and muscarinic cholinergic receptors in the neurohypophysis (posterior pituitary) have been implicated in the release of vasopressin (Gregg 1985). Nicotine has been found to stimulate vaseprossin release in a dose-related manner in animals (Reaves et al. 1981; Siegel et al. 1983) and in humans (Dietz et al. 1984; Pomerleau et al. 1983; Seyler et al. 1986). These observations are consistent with the effects of nicotine on cognitive performance (Chapter VI). The Pro.Opiomelanocorticotropin Group of Hormones The POMC hormones are released in response to stress and in response to corticetropin-raleasing hormone (Munck, Guyre, Hol- brook 1984; Krieger and Martin 1981). ACTH has behavioral effects and" stimulates the release of steroids such as cortiso~ from the adrenal cortex. ACTH produces rapid cycling between sleeping and waking as well as sexual stimulation, grooming/scratching, blocking of opiate effects such as analgesia, and the enhancement of attention and stimulus discrimination (Bertolini and Gessa 1981). Endogenous opioids, such as [~-endorphin, potentiate vagal reflexes, cause respira- tory depression, lower blood pressure, block the release of catcchol- amines (Beaumont and Hughes 1979; Schwartz 1981), have antinoci- ceptive effects (van Ree and de Wied 1931), and modulate neuro- transmitter systems leading to amnesic effects (Izquierdo et al. 1980; Introini and Barattj 1984). It has been suggested that the primary function of the endogenous opioids is metabolic, serving to conserve body resources and energy (Amir, Brown, Amit 1980; Margules 1979; Millan and Emrlch 1981). Nicotine appears to stimulate the release of cor ticetropin-releaslng hormone from the hypothalamas through a nicotinic cholinergie mechanism (Hillhoues, Burden, Jones 1975; Weidenfeld et al. 1983). Using an isolated perfused mouse brain preparation, Marty and coworkers (1985) demonstrated that nicotine stimulates secretion of f~-endorphin and ACTH in a dose-related manner when applied directly to the hypothalamus but not when applied to the pituitary. The work of Sharp and Beyer (1986) supports this finding; they reported that the secretion of ACTH following nicotine was unaffect- ed by adronalectomy. Nicotine administration to rats has also been shown to increase the plasma levels of corticosterone, ACTH, and ~- endorphin in a dose-relatcd manner (Conte-Devolx et al. 1981). Termination of chronic nicotine administration reduced hypotha- lamic [3-endorphin levels (Rosecrans, Hendry, Hong 1985). Hurlick and Corrigal (1987) have also observed that the narcotic antagonist naltrexone inhibits some nicotine-modulated behavior in mice, providing a possible link between nicotine stimulation of endogenous opioid activity and behavioral responses. Acute administration of 103

nicotine increases levels of plasma ACTH and corticosterone sharply (Cam and Bassett 1983b), while chronic exposure results in complete adaptation (Cam and Bassett 1984). Melanocyte-stimulating hor- mone was decreased and B-endorphin was increased by i.p. injections of nicotine in the rat (Conte.Devolx et al. 1981). Jlisch and colleagues (1980, 1982) have accumulated evidence for eholinergic control of eortisol, prolactin, and 13-endorphin release in humans. Rapid smoking increases circulating cortisol. 13-endorphin, and neurophysin l (Pomerleau et al. 1983; Seyler et al, 1984; Novack and Allen-Rowlands 1985; Novack, Allen-Rowlands, Gann, in pressL Moreover, in a study that examined the role of endogenous opioid mechanisms in smoking, Tobin, Jenouri, and Sackner (1982) ob- served that mean inspiratory flow rate increases during the smoking of a cigarette but is depressed shortly after smoking. Naloxone had no effect on the initial stimulation of respiration in response to smoking but did significantly blunt the subsequent depression of respiration. The significance of these findings for the control of cigarette smoking remains equivocal (Karras and Kane 1980; Nemeth-Coslett and Griffiths 1986; Chapter IV), Thyroid Most of the earlier work (1930s through 1950s) assessing the effects of nicotine on thyroid function involved histologlcal studies of the thyroid glands from animals treated chronically with nicotine. The findings are incbnsistent in that some studies suggest elevated thyroid activity and others' do not (Cam and Baszett 1983a). In a more recent study of nicotine's action on the plasma levels of the thyroid hormones, thyroxine (T4) and triiodothyronine (TS), Cam and Bassett (1983a) found that a single i.p. injection of 200 ~g/kg did not alter the level of either hormone, although it did produce an increase in plasma corticosterone. As mentioned earlier, nicotine does not consistently affect TSH in animals or humans (Blake 1974; Seyler et al. 1986). Adrenal Cortex Several studies in animals and human subjects have reported that nicotine and cigarette smoking lead to elevated levels of corticoste- roids. Kershbaum and colleagues (1968) administered nicotine i.v. to anesthetized dogs and found a 64 percent rise in plasma corticoste- roids. In rats, corticosteroid concentrations increased 50 percent after i.p. administration of nicotine. Suzuki and coworkers (1973) also reported adrenal cortical secretion in response to nicotine in conscious and anesthetized dogs. The effects of nicotine on plasma corticosteroids in stressed and unstressed rats were studied by Balfour, Khuller, and Longden (1975). The administration of nicotine to unstressed rats caused a rise in corticosterone which persisted for 104 •

60 rain. Nicotine did not affect plasma corticosterone concentration in rats stressed by being placed on an elevated platform. Other studies showed increased plasma corticosteroid levels after nicotine administration (Turner 1975; Cam, Bassett, Cairncross 1979; Cam and Bassett 1983b). Andersen and colleagues (1982) exposed male rats to unfiltered cigarette smoke and found a dose-related increase in corticosterone secretion. Filtered cigarette smoke was inactive. Seifert and coworkers (1984) found that the chronic administration of 0.5 or 1.0 mg/kg of nicotine s.c. twice daily for 8 weeks to rats produced a marked decrease in plasma aldosterone levels. In this study, nicotine had no effect on plasma corticosterone concentration. Hokfelt (1961) reported increases in plasma cortisol and urinary 17-hydroxycorticosteroids following cigarette smoking in human subjects. Kershbaum and coworkers (1968) reported similar results involving elevations of 11-hydrexycorticosteroids. Hill and Wynder (1974) found that serum eorticosteroids were markedly elevated after high.nicotine (2.73 mg) cigarettes were smoked. No increase was seen with cigarettes containing less nicotine, Cryer and colleagues (1976) also found an increase in circulating levels of corticesteroids after smoking. Winternitz and Quillen (1977) reported a sharp increase in circulating cortisol after two cigarettes. The levels were maintained through the smoking period and fell gradually to normal. Wilkins and coworkers (1982) also observed increased levels of cortisol after 2-rag-nicotine cigarettes were smoked. No increases in eortisol were detected after smoking 0.48-rag-nicotine cigarettes, but cortisol rose significantly in 11 of 15 cases smoking 2.87-mg-nicotine cigarettes (Seyler et al. 1984). Consistent with these results is the observation of Puddey and colleagues (1984) that cessation of smoking is associated with a significant fall in cortisol levels. In contrast to these findings, Tucci and Sode (1972) reported intact diurnal circadian variations of cortisol and unchanged 24-hr 17- . hydroxycorticosteroids during smoking. Benowitz, Kuyt, and Jacob (1984) studied 10 subjects who either smoked their usual brand of cigarettes, some of which contained 2.5 mg nicotine, or abstained. Plasma cortisol concentrations throughout the day did not differ during smoking or abstaining. Thus, while the majority of human and animal data indicates that nicotine or smoking elevates cortico- steroid levels, the effects appear to be influenced by dose, time, and perhaps other factors. Many investigators cited above have proposed that nicotine's effects on corticosteroids are mediated by the release of ACTH. Indeed, hypophysectomy abolished the increase in adrenocortical secretion following nicotine administration (Suzuki et al. 1973; Cam, Bassett, Cairncross 1979) and nicotine-induced increase in plasma ACTH precedes the increase in cortisol (Conte-Devolx et ah 1981). However, Turner (1975) found that bilateral adrenal demedullation 105

abolished the rise in corticosterone in response to nicotine and suggested that the effect of nicotine is mediated via adrenal release of catecholamines and that centrally mediated stimulation is not significant. In contrast, the work of Matta and associates (1987) demonstrates that the effects of nicotine on ACTH secretion are centrally mediated. Rubin and Warner (1975) have also shown that nicotine directly stimulates isolated adrenocortieal cells of the cat. The stimulant effect was dose-dependent and required the presence of calcium, These experiments also indicated that nicotine enhances the steroidogenic effect of ACTH. Androgens In male beagles, chronic smoking of h!gh-nieotine/tar cigarettes was associated with decreased activity of 7a-hydroxylase active on testosterone (Mittler, Pogach, Ertel 1983). Tostieular 6~- and 16a- hydroxylases were not altered, while the hepatic androgen 6/3: hYdroxylase activity in the testis was stimulated markedly by smoking. Serum testosterone levels were reduced to 54 percent of control levels by heavy smoking. It was concluded that chronic cigarette smoking increased hepatic metabolism of testosterone, resulting in lowered serum testosterone levels. However, it may be that total testosterone is lower while free testosterone is not. Estrogens Cigarette smoking is associated with antiestrogenic effects in women, including earlier menopause, lower incidence of breast and endometrial cancer, and increased osteoporosis. MacMahon and colleagues (1982) reported lower urinary estrogen levels in premeno- pausal smokers than in premenopausal nonsmokers and suggested that the low estrogen secretion reflected lower estrogen production, based on decreased ostrone, estradiol, and estriol. However, 2- hydroxyestrogens, the major metabolites of estradiol in women, were not measured. Jensen, Christlansen, and Roflbro (1985) presented evidence for increased hepatic metabolism of estrogens as a result of smoking based on an observation of decreased serum estrogen levels in postmenopausal smokers receiving exogenous hormone therapy. This study examined 136 women treated for I year with different doses ofostregen. Reduction of serum estrogen was most pronounced in the highest estrogen-dose group. There was a significant inverse correlation between the number of cigarettes smoked daily and changes in serum estrogen. Michnoviez and colleagues (1986) found a significant increase in estradlol 2-hydroxylation in premenopausai women who smoked at least 15 cigarettes/day. They concluded that smoking exerts a powerful inducing effect on the 2-hydrexylation pathway of estradiol metabolism, which is likely to lead to decreased bioavailability of hormone at estrogen target tissues. 106 •

Pancreas and Carbohydrate Metabolism The body weight of smokers is consistently lower than that of nonsmokers, and smokers tend to gain weight after cessation of smoking (see Chapter VI for a detailed discussion of these relation- ships). These phenomena are thought to contribute to tobacco use. Glauser and coworkers (1970) and Hofstetter and coworkers (1986) suggested that a change in metabolic rate is partially responsible for these effects. Scheehter and Cook (1976) and Grunberg, Bowen, and Morse (1984) showed that rats which were administered nicotine lost body weight without reducing food intake, although the body weight changes were not as great as when eating behavior declined as well (Grunberg 1982). Grunborg (1986) has pointed out that differences in body weight between smokers and nonsmokers result from changes in energy consumption (via changes in specific food consumption) and changes in energy utilization. Recently, Grunborg and eowork- ers (1988) have reported reductions of insulin levels accompanying nicotine administration in rats which could result in an increase in the utilization of fat, protein, and glycogen. This finding is consistent with work of Tj~ilve and Popov (1973), using rabbit pancreas pieces, and studies by Florey, Milner, and Mian (1977) of human smokers versus nonsmokers. Grunberg and coworkers (1988) have suggested that the effects of nicotine on insulin levels also may be involved in the nicotine-induced decrease of sweet food preferences. Elcctrophyslologlcal Actions of Nicotine Electrocortical Effects The brain responds to electrical as well as to chemical stimuli. Therefore, measurements of the electrophysiological actions of nicotine complement studies of its chemical effects. In addition, eleetrophysiologieal activity reflects function that may relate to sensory and cognitive changes observed in humans after smoking (see Chapter VI). In animals, nicotine produces changes ranging from subtle latency decreases in the primary auditory pathway to seizures. The electrophysiologieal actions of nicotine may help to relate the anatomical and receptor date (discussed earlier in" this Chapter) with sensory and cognitive data (discussed in greater detail in Chapter VI). The human studies on electrocortieal effects of nicotine have some methodological limitations. Most of the human studies had subjects smoke cigarettes and did not measure blood levels of nicotine. Also, most studies were performed on smokers whose immediate and long- term smoking history was determined by questionnaires which may not accurately reflect tolerance and physical dependence (Chapter IV). In some studies the subjects were deprived of cigarettes, but no objective measures such as expired carbon monoxide or blood 107

nicotine levels were collected to verify compliance with the depriva- tion conditions. Spontaneous Electroencephalogram Historically, nicotine and ACh were used in animal experiments to study the cholinergic mechanisms in the midbrain and thalamus which produced EEG and behavioral activation (Longo, yon Berger, Bovet 1954; Rinaldi and Himwich 1955a,b). The administration of nicotine produced EEG activation, consisting of desynchrenized low- voltage, fast activity, and behavioral arousal or alerting. These EEG and behavioral responses resembled those produced by electrical stimulation of the midbrain reticulomesencephalic activating system (Moruzzi and Magorin 1949). With the discovery by Eecles, Eccles, and Fatt (1956) of nicotinic receptors in the Renshsw cell of the spinal cord., other investigators began to study the precise pharma- cology of the EEG and behavioral alerting produced by nicotine and electrical stimulation of the midbrain. Cigarette smoking in humans also produced EEG desynehronization (Hauscr et al. 1958; Wechsler 1958; Bickford 1960) or EEG desynchrenization with an increase in alpha frequency (Lambiase and Serra 1957). By the late 1959s and early 1960s it was generally known that nicotine or tobacco smoke caused EEG and behavioral arousal in animals and humans, but several important issues were unresolved. The central effects of nicotine were originally thought to result from its action on the cardiovascular system (Heymans, Bouckeart, Dautrebande 1931). Early studies found that EEG desynchronization occurred when the subjects smoked nicotine cigarettes, nicotine-free cigarettes, or sucked on glass tubes filled with cotton (Hauser et al. 1958; Wechsler 1958). Schaeppi (1968) injected nicotine into the vertebral artery, carotid artery, and third and fourth ventricles of a cat's brain and was able to dissociate the effects of nicotine on the EEG from those on the cardiovascular system. Kswamura and Domino (1969) demonstrated that the EEG changes induced by nicotine could be obtained in animals whose blood pressure increase was blocked, Prevention of release of catecholamines in reserpine- pretreated animals did not interfere with the EEG desynchreniza- tion produced by nicotine (Knapp and Domino 1962). Inhaled tobacco smoke (2-mL samples with about 2 ~g/kg of nicotine) and 2 ~g of nicotine injected every 30 sec in a cat encephale isol$ preparation produced EEG desynchronization, EEG and behav- ioral activation after cigarette smoke inhalation was also observed in unanesthetized cats with implanted electrodes (Hudson 1979). Lukas and Jasinski (1983) found that i.v. doses (0.75 to 3.0 rag) in human smokers resulted in dose-dependent decreases in alpha (8 to 12 Hz EEG activity) power and EEG desynchronization. In an inpatient study where nicotine deprivation was carefully controlled and 108 I

monitored by measurement of expired carbon monoxide, the smok- ing of non-nicotine cigarettes did not change the EEG (Herning, Jones, Bachman 1988), but EEG changes did occur when subjects smoked nicotine-containing cigarettes. These studies confirm that nicotine has a direct action on the CNS separate from the cardiovas- cular effects and that the effects are produced primarily by the nicotine in inhaled tobacco smoke. As experimental physiological manipulations, EEG recording, and EEG quantification techniques improved, the specific nature of the nicotine-induced cortical EEG changes and their relationship to behavior were found to be more complex than originally thought. The desynchronization produced by nicotine (20 to 10O I~g/kg) in the cat was blocked by anterior pontine transections, but not by midpontine transections:(Knapp and Domino 1962). The midbrain reticular activating system was needed for .the cortical ERG desyn- chronization produced by nicotine. However, larger doses of nicotine injections also produced synchronous slow high-voltage EEG activity in the hippocampas (hippocampal theta). Injections of the mascarin- ic agonist arecoline (20 to 40 mg/kg) in the anteriorly transeeted midbrain preparations still produced the hippocampal theta activity without the cortical desynchronization. Atropine (1 mg/kg) and mseamylamine (1 mg/kg), but not the ganglionic antagonist trimeth- idinium (1 mg/kg) block the nicotine induced EEG desynchroniza- tioh in an intact animal. The convulsions observed after nicotine injections (1 to 6 mg/kg in cats; 0.05 to 0.25 pg/g in mice) (Laurence and Stacey 1952; Stone, Mechlenburg, Zorehiane 1958; Stumpf, Petsche, Gogolak 1962; Anderson and Curtis 1964; Stumpf and Gogolak 1967) appear to be due to nicotine's ability in large doses to stimulate musearinie cholinergic receptors in the hippocampus. Because a high concentration of labeled nicotine binds to hippocam- pal cells of the eat (SchmiterlSw et al. 1967) and areas adjacent to the hippocampus in the rat (Clarke, Pert, Pert 1984), the possibility that nicotine-induced limbis electrical activity contributes to its behavior- al effects cannot be discounted. Nicotine's alerting effect on the brain may also involve a peripher- al component. Eleetrocortisal and behavioral arousal occurs in the cat within 1 to 2 sec after injection of 10 to 15 ttg/kg into the right atrium of the heart, originating in vagal pulmonary C fiber afferents (Ginzel 1987). The human counterpart to this finding is the observation by Murphree, Pfeiffer, and Price (1967) that an initial EEG change occurred within 5 sec after cigarette smoke inhalation, which is shorter than a chest-to-head circulation time. Another input from the periphery arises from nicotinic sites in the arterial tree. Injection of small amounts (2 to 4 Ilg/kg) of nicotine, even as far away from the brain as into the lower aorta or femoral artery, causes 109

instantaneous arousal from all types of sleep (Ginzal and Lucas 1980). The nicotine-induced release of ACh (Macintosh and Oborin 1953; Mitchell 1963) may be responsible for the EEG desynchronization in animals (Armitage, Hall, Sellers 1969). The effect does not appear to be due to the direct action of nicotine on the cortex because the cortical cholinergic receptors are largely muscarinic (Kuhar and Yamamura 1976; Rotter et al. 1979). Lower doses of nicotine (20 ttg/kg/30 sec for 20 min) induced EEG desynchronization and ACh release in the cat, whereas higher doses (40 pg/kg/30 sec for 20 rain) produced either an increase or decrease in EEG desynchronization • with corresponding increase or decrease in ACb release (Armltage, Hall, Sellers 1969). The effect of nicotine on the EEG was short lived relative to the release of ACh. Two separate, pathways have been proposed to explain these results: an ascending cholinergic pathway mediating the cortical desynehronlzation and a limbic pathway mediating the ACh release. In one strain ef mice, C57BL, nicotine increased cortical high. voltage activity and decreased homovanillic acid (HVA) and 3- methoxy-4-hydrexyphenthyleneglycol (MHPG) production in a per- fused brain preparation (Erwin, Cornell, Towell 1986). The decrease in HVA and MHPG levels reflects an increase in brain DA and NE levels. In intact C57BL mice, nicotine decreased locomotor activity (Marks, Burch, Collins 1983a). Thus, at least in one strain of mice, nicotine induces an increase in cortical EEG synchronization, a decrease in locomotor activity, and an increase in brain eatechol- amines. Little evidence relates the cortical desynchronization ob- served in animals and humans to an increase in catecholamine changes in the brain. As trends in neuroseience research have shifted away from spontaneous EEG recording in animals to intracellular recording, receptor localization, and binding techniques, the precise quantifica- tion of the nicotine-induced EEG desynehronization and hippocam- pal synchronization has not been done. This type of quantification has been done in humans by power spectral analysis. This technique quantifies the EEG by the distribution and amplitude of brain waves at different frequencies. Alpha power includes BEG activity in the 8- to 12-Hz frequency range. Theta power includes EEG activity in the 4- to 7-Hz frequency range. Beta power includes EEG activity in the frequency range of 13 Hz and higher. The comparison of nicotirLe-iuduced EEG changes in animals and humans is complicated by an important methodological difference. Animals usually have not previously been given nicotine, while in studies of humans, the subjects always are experienced tobacco smokers. Moreover, in human studies that included a deprivation 110 •

@ @ period, nicotine abstinence may have produced electrephysiological changes that are reversed by smoking or nicotine. EEG desynchrenization or increased beta power was observed in smokers after smoking a tobacco cigarette (Hauser et al. 1958; Wechsler 1958; Bickford 1960; Ulett and Itil 1969). These findings essentially replleated the animal studies of alcotiae. Using power spectral analysis, Ulett and Itil (1969) also observed a decrease in theta power and an increase in alpha frequency. The increase in alpha frequency was previously noted with visual inspection by Lambriase. However, the increase in there was not. The subjects in the study by Ulett and Itil had smoked one pack or more of cigarettes/day and had been deprived of tobacco cigarettes for 24 hr when the baseline EEG was recorded. Comparisons of the postsmok- ing EEG were made with this baseline period. Therefore, the decrease in alpha frequency and increase in theta power relative to the data from the postsmoking session may be the result of nicotine deprivation (Chapter IV). Knott and Venables (1978) compared the alpha frequencies of nonsmokers, 12-hr nicotine-deprived smokers, and nondeprived smokers. They observed a decrease of about 1 Hz in the dominant alpha frequency of the deprived smokers relative to the nonsmokers and nopdeprived smokers in a passive eyes-closed situation. An active behavioral task and other frequencies of the BEG were not studied. Knott and Venables hypothesize that smokers were consti- tutionally different from nonsmokers. The slower aIpha frequency was interpreted as an arousal deficit, and smoking as compensation to reduce the arousal deficit. Knott and Venables (1976) and Ulet and Itil (1969) both found an attentional deficit during tobacco deprivation. Herning and coworkers (1983) Investigated the EEG changes related to cigarette smoking in a hospitalized group of healthy smokers who smoked at least a pack and a half of tobacco cigarettes with a machine nicotine delivery of 0.8 mg or more. A serial subtraction task was administered and EECo were recorded from subjects in an eyes-open state. Alpha frequency was not affected by periods of smoking and deprivation. However, theta and alpha power increased during periods of depdvatlon and decreased after smoking tobacco but not placebo cigarettes. The effects were most pronounced on theta power. Increases in theta power occurred as early as 80 rain after the last cigarette, and were of the same magnitude as those after 10 to 19 hr of nicotine deprivation. The increase in EEG theta was interpreted to be a sign of tobacco deprivation (Chapter IV). An indirect method of observing an increase in cortical activation was the measurement of alpha power changes after tobacco smoking. A number of investigators reported a decrease in alpha power or abundance with cigarette smoking (Murphree, Pfeiffer, Price 1967; III

Philips 1971; Caille and Bassano 1974, 1976; Murphree 1979; Herning, Jones, Bachman 1983; Cinciripini 1986), with nicotine polacrilex gum (Pickworth, Herning, Henningfield 1986, in press), and with i.v. doses of nicotine (Lukas and Jasinski 1983). In spite of differences in the number of cigarettes regularly smoked by the subjects, the length of tobacco deprivation, the type of tobacco cigarette smoked during the experiment, and the route of adminis- tration, nicotine reduced alpha power. Brown (1968) measured the resting EEG for heavy smokers and nonsmokers. No cigarettes were smoked. The EEG of the heavy smokers had less alpha and more beta activity, Twelve hours of nonconfirmed deprivation in the heavy smokers did not change the EEG patterns. The EEG of neonates of mothers who smoke 'is not different from that of neonates of control mothers (Chernick, Childiaeva, loffe 1983). Whether acute periods of smoking may affect the EEG of the child before birth is not known. In limited animal and human work, individual or species differ- ences in the effects of nicotine on the EEG have been observed. Nicotine produced a dose-dependent cortical EEG desynchronization in C3H mice and an increase in synchronized EEG similar to hippocampal theta activity in C57BL mice (Erwin, Cornell, Towell 1986). Both effects have been observed at different doses in the same preparation (Kawamura and Domino 1969). Lower doses produce EEG desynchronization, and higher doses produce hippocampal theta. Tobacco cigarette smoking decreased EEG alpha power in Type A subjects and increased theta power in Type B subjects deprived of nicotine for about 4 hr (Cinciripini 1986). The relation- ship between hippocampal theta in animals and cortical theta in humans is not yet understood. In nondrugged animals cortical dasynchronization and hippocampal theta activity often occur simul- taneously. Nicotine at low doses produces cortical desynchronization and at high doses produces both types of EEG activity. Animal data indicate that nicotine has effects on at least two systems in the brain: a midbrain area responsible for EEG desynehronization and a limbic system generating hippocampal theta activity. These findings are consistent with the observation that some smokers indicate that they smoke for nicotine's stimulating effects and others smoke for its sedating effects. Sensory Event-Related Potentials In animals and humans, the brainstem auditory-evoked potential technique provides a noninvasive method for studying the effects of nicotine on primary auditory sensory function. In the rat, nicotine reduced the amplitudes of Waves HI and IV of the brainstem auditory-evoked response (BAER) (Bhargava and MeKean 1977; 112

Bhargava, Salamy, McKean 1978; Bhargava, Salamy, Shah 1981). Serotonergic mechanisms may mediate the nicotine-induced reduc- tion in latency. Lavernhe-Lemaire and Garand (1985) found essen- tially the opposite. Nicotine increased Waves I-IIl and did not decrease Waves IV and V of BAER. Auditory event-related potentials (AERPs) recorded directly from the cortex of rat have provided conflicting information about nicotine's effects on auditory transmission from the inferior collicu- lus to the cortical areas. Guha and Pradhan (1976), using pontobarhi- tal anesthesia, found a dose-dependent increase in P1 (40 ms) and N1 (110 ms) of the AERP. Bhargava, Salamy, and McKean (1978), using chloralose anesthesia with atropine pretreatment, reported no nicotine-related change in P1 (11 ms), N1 (28 ms), P2 (75 ms), and N2 (121 ms) of the AERP. After smoking, the P1 (50 ms) of the human AERP is increased during passive tasks at all intensity levels and the N1 (110 ms) is increased in both passive and active tasks (Knott 1985). The N2 (about 215 ms) to P2 (about 260 ms) component of the AERP recorded during a passive task was reduced after cigarette smoking when compared with data from the baseline deprivation test (Friedman and Meares 1980). P2 was also reduced by nicotine in the study by Knott (1985). These components also increased in amplitude as the tobacco deprivation period was lengthened. Any attempt to relate this finding to results in the anesthetized'rat would be speculative because AERPs recorded from the cortex of unanesthetized animals and humans are difficult to compare (Wood et al. 1984). Alterations in AERP components in the 75- to 150-ms latency range have been attributed to change in attention. The decrease in the later N2-P2 component is more likely to reflect reduced habituation to auditory stimuli. The effects of nicotine on visual event-related potentials (VERPs) are more complicated than those on the AERPs. In unaesthetized rabbits, i.v. nicotine (0.025 to 0.500 mg/kg) produced a complex VERP change (Sabelli and Giardini 1972). At 2 min, nicotine depressed the P1 (100 ms) and the N1 (250 ms). At 5 rain, these components were enhanced. At doses below 0.050 mg/kg, the N1 was again depressed from 10 to 20 rain after the injection. Fretreatment with catecholamina inhibitors diminished the nicotine-induced VERP changes. The authors suggested that the effect of nicotine on VERPs was mediated in part by catscholaminergic mechanisms. The effects of nicotine on the human VERP using multiple flash intensities were the focus of four studies. The studies were designed to test Buchsbaum and Silvernmn's (1968) concept of stimulus intensity control and its modulation by nicotine. According to their theory, sensory processing in different individuals varies in at least two ways. Some persons, "augmenters," are more sensitive to higher 113

intensities than to lower intensities, and others, "reducers," are more sensitive to lower than to higher intensities. Smokers might be one particular type of stimulus processer and may smoke to alter or normalize stimulus intensity. In all studies the comparison was between results after 12 hr or more of unconfirmed tobacco deprivation and those after recent smoking. Components of the VERP increased after smoking in three studies (Hall et el. 1973; Friedman and Meares 1980; Woedson et al. 1982) but decreased in another study (Knott and Venables 1978). The increases and decreases occurred in components of the same latency range (75 to 250 ms) after flash onset. The fourth study differed only slightly from the others in that it used a between-subjects and not within- subject experimental design. Using a single flash intensity, Vasquez and Toman (1967) also observed a decrease in components IV ('40 ms) and V (170 ms) of the VERP when compared with results after 36 hr of tobacco deprivation, Two studies found a nicotine-induced increase at earlier components (III-IV and IV-V) for the lower intensities only. The other study reported an increase in later components (V.VI and VI-VII} at the higher flash intensities. Knott and Venables (1978} observed the decrease after smoking in the middle components (IV-V and V-VI) for the lower intensities. Because of these divergent results, it,is premature to conclude that smokers are exclusively augmenters or reducers who are attempting to optimally adjust stimulus intensity by smoking. Cognitive F~vent-Related Potentials Cognitive event-related potentials reflect neural events which appear to be related to different aspects of cognition, such as attention and stimulus evaluation. They usually follow the sensory components of event-related potentials when human subjects are performing active behavioral tasks. They provide information not normally available from performance measures such as reaction time. Increases or decreases in these potentials after smoking can aid in our understanding the effects of nicotine on performance. When two task-relevant stimuli are separated by a short interval (1 to 3 sec), a negative slow wave develops between them. In particular, this contingent negative variation (CNV) develops in warned or cued reaction times, successive discrimination, and some language processing tasks. The CNV appears to reflect brain preparation to process and respond to the second stimulus. Smoked tobacco and i.v. nicotine either increase or decrease the CNV (Ashten et el. 1973, 1974, 1980; Minnie and Comer 1978). Extraverted smokers took longer to smoke and nicotine increased the CNV, Introverted subjects smoked faster and nicotine decreased the CNV. Reaction time was inversely correlated with CNV amplitude; that is. shorter reaction time was associated with larger CNV, With i,v, 114 •

doses of nicotine (12.5 to 800.0 ~g), larger doses produced a decrease and small doses produced an increase in the CNV in the same subject. O'Connor (1982) studied the effects of smoking on the orienting (O wave) and expectancy (E wave) components of the CNV in introverted and extraverted subjects. The O wave was not affected by smoking. The E wave, recorded in frontal areas, was increased in extraverted subjects after smoking. The E wave has been interpreted by some investigators as cortical preparation for a response. Smok- ing decreased a positive parietal E wave in introverts. Nicotine's effect on the E wave suggests the possible enhancement of motor preparation in the extraverted subjects. The decrease of parietal pesitivity indicates a possible enhancement of stimulus-processing capacities in the introverts. Poststimulus components P2(00) and P3(00) were affected by cigarette smoking and nicotine pelaerilex gum. P2 is thought to be an index of habituation (Hillyard and Picton 1979), and P3 an index of stimulus evaluation (Johnson 1986). Both components were reduced in deprived smokers after smoking (Knott 1985; Herning and Jones 1979). Knott (1985) interprets the reduction in P2 as a more efficient habituation of sensory screening of relevant stimuli. The reduction in P3 amplitude after smoking indicates a poorer evaluation of task-relevant stimuli. The P3 latency and reaction time were reduced only by cigarettes with higher machine-tested nicotine yields. (Edward et al. 1985). Such data indicate faster stimulus and response processing. These authors did not report any P3 amplitude changes. If none were preseht or P3 was reduced, the argument for enhanced stimulus processing would be weak. Herning and Pick- worth (1985) reported both dose-dependent increases and decreases in P3 amplitude as a function of background noise levels when deprived smokers chewed nicotine polacrilex gum (4 mg and 2 mg doses). The respective increase or decrease was blocked by mecamy- lamina pretreatment. Thus, the effect of nicotine on stimulus evaluation remains unclear and is perhaps confounded by cognitive deficits after periods of nicotine deprivation. Motor Potentials O'Connor (1986) investigated the effect of tobacco smoking on motor potential and motor performance. Smoking increased the motor readiness potential in extraverts, but not in introverts. These results are consistent with his earlier finding of an increased E wave in extraverts after smoking. For introverts, smoking improved task performance, but did not increase the motor readiness potential. Other Peripheral Effects Relevant to Tobacco Use In addition to vast central and peripheral effects, cigarette smoking and nicotine have other peripheral effects that may 115

contribute to tobacco use. These additional factors have received less research attention, mainly because they involve relatively new theory or methodological approaches. For example, there is evidence that direct stimulation of the trachea is important for cigarettes to satisfy smokers (Rose et al. 1984) (Chapter IV). There is also evidence that nicotine acts directly on the lung to stimulate afferent neurons that, in turn, result in skeletal muscle relaxation and electrocortical arousal (Ginzel 1987). These effects may contribute to the relation- ship between smoking and stress (Chapter VI). Other research indicates that smoking affects psychophysiological reactivity, an integrative mechanism that is different from the classic, physiologi- cal approach of examining individual systems or pathways. There- fore, psychophysiological reactivity and its relevance to smoking are discussed. Psychophysiological Reactivity and Smoking Psychophysiological reactivity is emerging as a useful construct in smoking research, linking basic biological processes (genetic vulnera- bility, central neurochemieal factors) to behavioral coping and other psychesocial factors. Psychophysiological reactivity refers to a physiological response to e specific stimulus or as a result of the absence of stimulation. This response can, in some cases, act as a stressor. Within the broader conceptual framework of a stress-coping model of smoking addiction (Shjffman and Wills 1985), smoking behavior can be viewed both as a potential stimulus and as a coping response that modulates psychophysiological reactivity. Studies of psychophysiological reactivity illustrate the value of controlled laboratory procedures to study person-environment inter- actions. Psychophysiological reactivity reflects an interaction of the organism and the environment. It is affected by individual differ- ences in multiple response modes (physiological, cognitive, behavior- al) and takes into account the genetic and learning historyand current state of the organism. This Section reviews two separate but interrelated lines of psychophysiological reactivity research with humans. The first is the effect of smoking on psychophysiologieal reactivity. Related issues include identification of mechanisms that may help to reveal why some individuals smoke and the relationship between smoking and coronary heart disease (CHD). The second research line addresses the relationship among situational events (general and drug-specif- ic), psychophysiological reactivity, and relapse. The effects of smoking on the cardiovascular aspects of physiologi- cal reactivity have been well documented and appear to be primarily duo to effects of nicotine and carbon monoxide (Suter, Buzzi, B~ttig 1983; Koch et el. 1980; Resenberg etal. 1980). In individuals with no cardiovascular disease, some of the typical effects of smoking and 116

nicotine are elevated heart rate and blood pressure and a fall in fingertip temperature and capillary blood flow (Richardson 1987; Ashton et al. 1982; Epstein and Jennings 1986; Henningfield et al. 1983). Accompanying cardiovascular reactions to smoking are cognitive reactlons, mcludlng perceptlons of relaxatlon, and anxlolytlc~ antmc- ciceptive, euphoric, stimulative, and dysphoric effects (Kozl0wski, Director, Harford 1981). Although there is consistency in the literature with regard to the self-reportod emotional changes experi- enced as a result of smoking, there are clear differences in response and direction of effects between individuals and within ind'viduals over time (Best and Hackstian 1978; Gilbert 1979; Gilbert and Welser, in press). Smoking can produce physiological changes that are concurrent with subjective tranquilizing effects (Nesbitt 1973; Shiffman and Jarvik 1984; Gilbert 1979). This phenomenon has led investigators to emphasize the importance of incorporating physic- logical, psychological, and environmental factors into more biobeha- vioral models to better understand the cognitive and physiological components of reactivity to smoking (Pomerleau and Pomerleau 1984; Baum, Grunberg, Singer 1982; Abrams et al. 1987; Grunberg and Baum 1985). For example, nicotine has direct and indirect actions on central neuroregulatory systems and has biphasic effects of both stimulation and blockade. These factors can help explain effects such as the anxiolytic and antinociceptive phenomena (Pomerleau 1986) at a cognitive and neurechemical level, while at the same time resulting in increased heart rate and blood pressure and decreased perception of muscle tension (Epstein et al. 1984). In addition to dosage, biphasic, and physiological factors, the influence of setting and expectancy set, the current state of the individual (smoking, deprived, stressed, not stressed), and individual differences in dependence, genetic, demographic, and learning history can all influence psychophysiological reactivity. For exam- ple, smoking a 1.3.mg-nicetine cigarette under conditions of mild sensory isolation produced consistent arousal effects (i.e., elevations in heart rate and skin conductance level with decreases in EEG alpha waves) in smokers compared with sham smoking or a situational control group. However, under conditions of stress, as induced by intermittent noise bursts, a mixed stimulant (heart rate) and depressant (EEG, skin conductance) response was observed (Golding and Mangan 1982). Woodson and coworkers (1986) also reported that during noise, smoking induced cardiovascular stimula- tion (i.e., heart rate acceleration, peripheral vascenstriction) but electrodermal depression (i.e., lowered skin conductance response amplitude). These findings are consistent with the conclusions of Gilbert and Welser (in press) that unidimensional models are inadequate to explain the effects of smoking. 117

In addition to research on the impact of smoking on psychological and physiological processes, studies have also examined the com- bined cardiovascular effects of smoking and stress. In this context the concept of cardiovascular psychophysiological reactivity is used to help clarify the relationship among stress, smoking, and CHD (Epstein and Jennings 1986). MacDougall and colleagues (1983) randomly assigned 51 male smokers to smoking versus sham smoking and stress versus no stress conditions in a 2.x 2 factorial design. The stressor was a difficult video game performed under challenging conditions. Subjects who sham smoked under no stress showed minimal cardiovascular response. Subjects who smoked under no stress or who sham smoked under stress evidenced similar degrees of response of about a 15-bpm increase in heart rate, a 12- • mmHg increase in systolic blood pressure, and a 9-mmHg increase in diastolic blood pressure. Subjects in the combined smoking and stress condition had larger increases in all cardiovascular measures. The combination of mild stress and smoking produced effects that were twice those of either condition alone. Smoking and stress combined to increase cardiovascular response in men. In a followup study of women, using the game 2 x 2 factorial design, Dembroski and colleagues (1985) found that the combined effect of stress and smoking produced blood pressure and heart rate ipereases that exceeded the sum of the individual effects. However, • because modifications were made in dosage and psychological challenge, the two studies were not identical. The gender differences noted could therefore reflect methodological differences, uncon- trolled factors, or possibly differences between the sexes in response to the stress and smoking stimuli. Indeed, it has been noted that females may be more likely than males to smoke to regulate affect (Ikard and Tomkins 1973), are more likely to relapse after quitting (Grits 1986), may differ in biological factors relating to stress reactivity/sensitivity (Abrams et al. 1987), and show greater changes in body weight and eating behavior in response to nicotine (Grun- berg, Bowen, Winders, 1986; Grunberg, Winders, Popp 1987). (See Chapter VII for a discussion of treatment implications of these possible sex differences.) In a conceptually related study, the relationship between physio- logical responses to cognitive (mental arithmetic) and physical (cold pressor) strossers was examined in female smokers and nonsmokers who either used or did not use oral contraceptives (Emmons and Weidner, in press). All subjects showed some physiological response (heart rate and blood pressure responses) to the stressors, but in smokers oral contraceptive use significantly enhanced the systolic blood pressure response to cognitive stress. This finding may be related to the fact that smokers who use oral contraceptives are 5.6- times more likely to have a myocardial infarction than are smokers 118

who do not use oral contraceptives, 9.7-tlmes more likely than nonsmoking users, and 39-times more likely than nonsmokers who do not use oral contraceptives (Shapiro etal. 1979; Jain 1978; Ory 1977). In studies of psychophysiological reactivity, it is critical to identify, measure, and control for factors that might confound or alter the intended impact of the independent variables. For instance, time since last drink and beliefs, expectations, and setting are important variables to consider in the study of alcohol addiction (Abrams and Wilson 1979; Abrams 1983; Mariatt and Rohsenow 1980). The 2 x 2 balanced placebo design (Marlatt, Detaining, Reid 1973), where expectancy set (told to expect the drug or told to expect no drug) and actual content (drug versus placebo) are fully controlled, has been used extensively in the alcohol addiction field to isolate the separate and interactive elements of cognitive and pharmacologic effects. With smoking, little is known about the separate and interactive impacts of expectations of cigarettes' effects versus their actual pharmacologic effects. This is partially because it is difficult to find a method of administration that closely resembles smoking but where the required manipulations to achieve a credible balanced placebo design can be accomplished. Another methodological concern is control over the dosage of nicotine absorbed by the smoker. Nicotine is thought to be the most important tobacco constituent responsible for the acute effects of smoking on reactivity, attention and task performance, mood, and withdrawal following cessation (Perkins etal., in press; Pomerleau, Turk, Fertig 1984; Hughes et al. 1984). However, in tobacco smoking, nicotine is accompanied by more than 4,000 other compounds (Dube and Green 1982) and smokers are known to smoke in individualized ways (Epstein etal. 1981) (Chapter IV). The coaching of puff frequency and other attempts to standardize intake of smoke are imperfect (Perkins et al., in press). An aerosol nasal spray appears to be a promising alternatlve to smoking in stud'es of behavioral and physiological effects. It allows for rapid uptake through inhalation, and a dose-response study indicates patterns of heart rate, blood pressure, and serum nicotine levels that are very similar to those obtained by smoking cigarettes of equivalent nicotine content (Perkins etal., in press). Perkins and coworkers (in press) studied the separate and interac- tive effects of nicotine administered by nasal aerosols and stress on psychophysiol0gical reactivity. The authors note that the previous studies (MacDougall etal. 1983; Dembroski etal. 1985) could be confounded because smokers usually smoke more under stress and therefore they may inhale more mootine or alter the'r smoking in other ways when stressed (Mangan and Golding 1978; Rose, Ananda, Jarvik 1983) (Chaptar VI). In other words, the additive effects of 119

/ stress and smoking on physiological responses could have resulted from uncontrolled changes in smoking pattern between the smokers in the no-stress and stress conditions. Perkins and colleagues (in press) studied 12 male smokers in a repeated-measures design, where subjects received all 4 conditions (stress plus nicotine, stress plus placebo, rest and nicotine, and rest and placebo) on separate days with the order of condition counterbalanced within subjects. Follow- ing the methodology of previous studies of psychophysiological reactivity, the researchers used an active stressor consisting of a video game under conditions of competitive challenge. Nicotine was administered in measured 1.0-mg doses by the aerosol nasal method (Perkins et al., in press)• Consistent with observations of MacDougall and ooworkers (1983), results were additive for heart rate reactivity. However, effects were less than additive for systolic and diastolic blood pressure. Taken together, the studies of the effects of smoking cigarettes and of nicotine aerosol stimuli on the physiological responses of adult males demonstrate a consistent effect for the stimuli alone, additive in combination with stress on heart rate, and additive or less than additive with stress on blood pressure. There is some suggestion that effects may be more than additive for women, but this finding x:equires replication. Psychophysiological Reactivity, Smoking Cessation, and Relapse Psychophysialogical reactivity also serves as a conceptual frame- work to study relapse after cessation from smoking (Shiffman 1986b; Abrams 1988). Individual differences in psychophysiolagical reactivi- ty and associated coping responses, as a function of general and smoking-specific stressful stimuli, have been hypothesized to medi- ate relapse• For example, smokers who smoke more when stressed might be particularly vulnerable to relapse (Pomerleau, Adkins, Pertsehuck 1978). This idea is consistent with the observation that relapse may be triggered by life stress events and other psychesoclal demands (Ockene et al. 1982l and by high-risk situations including negative emotions, social conflicts and pressures, and the presence of alcohol or smoking cues (Marlatt and Gordon 1985; Shiffman 1979, 1982, 1984, 1986a; Abrams et al. 1986). If certain psychophysiologioal reactivity responses distinguish potential abstainers from relapsers, cessation may be better maintained by identifying "relapse-prone" individuals (Chapter VII). Stressful environmental demands, sensitivity of the individual to these demands, and the repertoire of coping responses are important factors in relapse (Shiffman and Wills 1985; Abrams et al. 1987)• These same factors also may contribute to initiation of smoking among adolescents. Wills (1985) provides evidence for the stress- 12o

coping model of smoking in adolescence, relating both stress and coping patterns to substance use. Results are consistent with ether findings that, in addition to peer pressure to smoke, adolescents actively seek methods of coping with their perceptions of stress (Wills 1985; Friedman, Lichtenstein, Biglan 1985; Botvin and MeAlistor 1981). Although these survey studies are consistent with the notioh of smoking as a means of coping with psychophysiological reactivity to environmental demands, research has not yet measured reactivity in adolescents prior to smoking onset. Observational and retrospective studies of relapse have identified other smoking-speclfic stressful stimuli and cogni- tive/psychophysiological measures of reactivity that are relevant to relapse. Situations or stimuli that cue smoking and are associated with relapse'include pharmacologic dependence and withdrawal symptoms (Jarvik 1977; Pomerleau and Pomerleau, in press; Hughes et al. 1984), stimuli previously associated with smoking (e.g, coffee drinking, alcohol) (Shiffman 1984, 1986a; Best and Hakstian 1978), and urges to smoke (Myrsten, Elgerot, F..dgren 1977). Situational stimuli may or may not have previously been paired with smoking and may or may not include smoking cues as a trigger for relapse, Substance use cues themselves (e.g., the sight and smell of cigarettes) also may precipitate relapse, perhaps in combination with other stressful stimuli or in a vulnerable individual (Shiffman 1986b; Abrams et ai.'1987). Models of how substance use cues are related to relapse have been proposed on the.basis of classical, operant, and social learning principles. Reactions may be conditioned to stimuli repeatedly paired with smoking, resulting in craving and physiologi- cal reactivity in their presence and moderated by dependence, tolerance, and nonpharmacelogic withdrawal (Siegel 1983; Cooney, Baker, Pomerleau 1983; Grits 1980)~ Psyehophysiological reactivity to smoking cues could mimic the prior drug response (Wikler 1965), result in a drug-oppesite (compensatory) response (Siegel 1883), or have other effects on psychological processes such as perceived anxiety, urges to smoke, and self-efficacy in resisting relapse according to a social learning model of relapse (Marlatt and Gordon 1985). Abrams and colleagues (1987) studied the psychophysiologieal reactivity and behavioral coping responses of male and female relapsers and quitters in four Simulated situational contexts: general social situations, smoking-specific negative emotional and interper- sonal role-plays, hlgh-demand social stress, and relaxation. Com- pared to abstainers, relapsers had higher heart rates and higher perceived anxiety and were rated as less skillful at coping in the smoking-spocific intrapersonal (negative affect) situations. There were no differences on any measures in the high-performance- demand general-social-stress procedure. There were some differences 121

in heart rate and self-reported anxiety in the general social situations and in heart rate in the relaxation interval, with relapsers having higher levels than abstainers. Abstainers and relapsers did not differ in heart rate, perceived anxiety, or coping skills in the high-demand social anxiety procedure, but they did differ in the other situations. The results suggest that selected situational demands prompt situation.specific psychophysiological changes. Rickard-Figueroa and Zeichner (1985) used a within-subjects design to examine the responses of smokers to a confederate of the experimenter lighting and smoking the subject's preferred brand of cigarette behind a glass window. Cigarette paraphernalia were placed adjacent to the subject but smoking was not permitted until after the session. The cue exposure manipulation resulted in higher urges to smoke, increased systolic and diastolic blood pressure, and increased heart rate variability compared with a no-cue condition. Urges were significantly positively correlated with diastolic blood pressure, the use of active mastery to cope with urges, and the more rapid smoking of a standard cigarette after the trial. In a study that shows some evidence for a conditioned response, Saumet and Dittmar (1985) measured finger-pulse amplitude, a measure of peripheral vasoconstrictive activity, while subjects placed an unlit cigarette into their mouths and waited for it to be lit. Heavy smokers showed an anticipatory vasoconstrictive response to the cigarette compared with light smokers and nonsmokers. Abrams and colleagues (in press) used smoking cues and a social stressor to simulate an interpersonal situation with high risk for relapse. Relapsers, abstainers, and never smokers were examined for psychophysiological reactivity. Compared with controls (never smok- ers), relapsers had significant heart rate reactivity, stronger urges to smoke, and subjective anxiety. Trained raters, unaware of subject smoking status, judged relapsers as having significantly less effec- tive coping skills to resist smoking. In a second study, the same assessment was used prospectively in a treatment outcome context to determine whether patterns of psychophysiological reactivity could discriminate between quitters who maintain abstinence from those who do not. Both heart rate reactivity and subjective anxiety were greater in quitters who relapsed at 5-month followup compared with those who continued to abstain. The groups did not differ with regard to urges to smoke or behavioral judgments of coping skill. Thus, the two studies were consistent for heart rate and perceived anxiety but not for urges or objective ratings of coping effectiveness. In a reanalysis of the heart rate data from Abrams and ¢oworkers (in press), Niaura and colleagues (in press) examined beat by boat event-related heart rate during the period immediately before and for the 10 sec following the lighting of a cigarette by a confederate (subjects did not smoke throughout). Prospective relapsers showed a 122 @

strong decelerative trend at the point of lighting, whereas prospec- tive abstainers did not, The results may reflect a conditioned compensatory response (Siegel 1983) or some other information prc~cessihg/attentlonal phenomenon (Sokolov 19(}3; Knott 1984). In another treatment study, Emmons (1987) examined smokers' cardio- vascular reactivity to mental arithmetic or deep knee bends before and 6 months after smoking cessation. There was no change in reactivity (heart rate, systolic and diastolic blood pressure) to either stressor before and after quitting. Heightened pretreatment heart rate reactiv/ty significantly discriminated relapse at 6-month follow- up. Individual differences in psychophysiologlcal reactivity may influ- ence the likelihood of relapse, This possibility is discussed in Chapter VII. Summary and Conclusions i. Nicotine is a powerful pharmacologic agent that acts in the brain and throughout the body. Actions include electrocertical activation, skeletal muscle relaxation, and cardiovascular and endocrine effects. The many biochemical and electrocortical effects of nicotine may act in concert to reinforce tobacco use. 2. Nicotine acts sn specific binding sites or receptors throughout the nervous system. Nicotine readily crosses the blood-brain barrier and accumulates in the brain shortly after it enters the body. Once in the brain, it interacts with specifie receptors and alters brain energy metabolism in a pattern consistent with the distribution of specific binding sites for the drug. 3. Nicotine and smoking exert effects on n~arly all components of the endocrine and neuroendoerine systems (including catechol- amines, serotonih, eortieosteroids, pituitary hormones). Some of these endocrine effects are mediated by actions of nicotine on brain neuretransmitter systems (e.g., hypothalamic-pitu- itary axis). In addition, nicotine has direct peripherally mediat- ed effects (e.g., on the adrenal medulla and the adrenal cortex). 123

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CHAPTER IV TOBACCO USE AS DRUG DEPENDENCE 145

CONTENTS Introduction Cigarette Smoking: Controlled Drug Self-Administration Measurement of Cigarette Smoking Characterization of Cigarette Smoking Behavior Patterns of Puffing and Inhaling Dose-Related Determinants of Tobacco Intake Control of Nicotine Intake Smoke Concentration Cigarette Length Cigarette Brand Cigarette Yield of Nicotine Urine pH Tobacco Administration and Deprivation Nicotine Pretreatments Nicotine Antagonist Pretreatnlents Effects of Nonnicotinic Drugs on Cigarette Smoking Effects of Nonnicotine Constituents of Tobacco Smoke and Citric Acid Aerosol Nicotine: Psychoaetivity, Reinforcing and Related Behav- ioral Mechanisms of Nicotine Dependence Interoceptive, Discriminative, and Subjective Effects of Nicotine Drug Discrimination Testing in Animals Specificity of the Nicotine Stimulus Peripheral Versus Central Discriminative Stimu- lus Effects of Nicotine Interactions with Noncholinergie Neurons Subjective Effects of Nicotine in Humans Psychoactivity of Nicotine Sensory Effects of Nicotine State-Dependent Learning Nicotine as a Positive Reinforcer Animal Studies of Nicotine as a Reinforcer Human Studies of Nicotine as a Reinforcer Nicotine as an Aversive Stimulus Nicotine as an Unconditioned Stimulus Conditioned Place Preference and Aversion 147

Conditioned Taste Aversion and Rapid Smoking • Nicotine: Withdrawal Reactions (Physical Dependence) Criteria for Physical Dependence on Nicotine and Clinical Characteristics of the Withdrawal Syn- drome Retrospective Survey Data Prospective Data From Laboratory and Nonlaboratory Studies Time Course of Responses to Nicotine Abstinence Alleviation of Withdrawal Symptoms by Cigarette Smoking Relationship Between Preabstinence Nicotine Intake and Magnitude of Wi~thdrawal Syndrome Smokeless Tobacco Withdrawal Syndrome Nicotine Polacrilex Gum: Treatment and Physical De- pendence Treatment of Withdrawal Symptoms Maintenance of Physical Dependence Tobacco Craving Alternate Nicotine Delivery Systems Kinds of Nicotine Delivery Systems Safety of Alternate I~icotine Delivery Systems. Conclusions References 148 •

Introduction This Chapter reviews the evidence that tobacco is a pharmacologi- cally addicting substance and that tobacco use can be considered a form of drug addiction. Specific criteria to identify a substance as pharmacologically addicting are discussed in Chapters I and V. Iri brief, the criteria are: (1) that highly controlled or compulsive patterns of drug taking occur, (2) that a psychoactive or mood- altering drug is ingested by use of the substance and is involved in the resulting patterns of behavior, and (3) that the drug is capable of functioning as a reinforcer that can directly strengthen behavior leading to further drug ingestion. Addicting drugs can be character- ised by other properties that include the following: they can produce p!easurable effects in users, they can cause tolerance and physical dependence, and they can have adverse or toxic effects. Drawing upon data from studies of tobacco and nicotine, involving both humans and animals, the present Chapter reviews the evidence that tobacco meets the criteria as a pharmacologically addicting sub- stance. A specific comparison of tobacco to other pharmacologically addicting substances is provided in Chapter V. Cigarette Smoking: Controlled Drug Self-AdmlnlatraUon Highly controlled or compulsive drug use refers to drug-seeking and drug-taking behavior that is driven by strong, often irresistible urges. It can persist despite a desire to quit or even repeated attempts to quit. Basic observations and experimental research indicate that ciga- rette smoking is not a random or capricious behavior that simply occurs at the will or pleasure of those who smoke. Rather, smoking is the result of behavioral and pharmacologic factors that lead to highly controlled or compulsive use of cigarettes. The many consis- tent patterns in cigarette smoking illustrate the controlled nature of the behavior. For example, following initiation of smoking the individual gradually increases cigarette intake over time until he or she achieves a level that remains stable, day after day, during the smoker's lifetime (Schuman 1977; US DHHS 1987a). The dependent smoker tends to adopt a pattern in which the initial cigarette of the day is smoked soon after waking (FagerstrSm 1978) and in which smoking throughout the day is regular from day to day (Griffiths and Henningfield 1982; Griffiths, Hcnningfield, Bigelow 1982). "Occasional" cigarette smoking (or "chipping") occurs just as does occasional use of other addicting drugs (see Chapter V); however, the 1985 National Health Interview Survey showed that only 10.6 percent of current smokers smoke 5 or fewer cigarettes/day (unpublished data, Office on Smoking and Health; see also Russell 1976 and US DHHS 1987a). 149

Strong evidence that cigarette smoking is a highly controlled or compulsive behavior is provided by survey data showing that a majority of smokers have tried to quit or at least would like to quit. For example, several Gallup surveys have shown that a large majority of smokers report a desire to quit smoking; in fact, the proportion of smokers who would like to quit increased from 66 percent in 1977 to 77 percent in 1987 (Gallup 1987), perhaps because of a declining social acceptability of smoking and the growing awareness of the health hazards of smoking. In addition, the 1986 Adult Use of Tobacco Survey (US DHHS 1987b) showed that 65 percent of cigarette smokers had made at least one serious attempt to quit; another 21 percent said that they would try to quit "if there were an ~asy way to do so" (Fiore etal., in press; US DHHS 1986). The compulsive nature of cigarette smoking is most apparent in extreme cases: for example, the laryngectomized patient who, having already suffered severe consequences of smoking, continues to smoke through a tracheostomy hole. Similarly, 50 percent or more of patients recovering from surgery for a smoking-related disease (e.g., cancer, cardiovascular disease) resume smoking while in the hospital or shortly after discharge (Burling, Singleton et al. 1986; West and Evans 1986). In this Section, the behavioral process of cigarette smoking and the factors which determine the course of the behavior are described. Evidence that cigarette smoking is repetitious and stereotypic, common features of compulsive drug use, is reviewed in this Section, as well as evidence that actions of nicotine are responsible for patterns of smoking behavior. Initially, however, it is necessary to briefly review the methods by which the behavioral process of cigarette smoking is studied, as well as the main findings from such studies. Measurement of Cigarette Smoking Cigarette smoking behavior may be analyzed at different levels ranging from epidemiological surveys to the analysis of cigarette puffing. In fact, many thousands of scientific articles have been published in which some aspect of cigarette smoking is described. Much of this research has been reviewed in the tobacco research compendia of Larson and his colleagues (Lareon, Haag, Silvette 1961; Larson and Silvette 1968, 1971, 1975), a previous report of the Surgeon General (US DHEW 1979), several monographs of the National Institute on Drug Abuse (NIDA) (Jarvik et al. 1977; Kresnegor 1978, 1979a,b,c; Grabowski and Bell 1983; Grabowski and Hall 1985) and in articles by others (Russell 1971, 1976; Gritz 1989; Henningfield 1984). It is characteristic of drug dependence that the drug-seeking and self-administration behaviors become stereotypical and automatic in Q O 150 •

Tobocco comprises: 1 - Cigarette constituents • Organic maIter • Nicotinic alkyloids • Additives 2- Pyrolysis products • Carbon dioxide • Carbon monoxide Fil~er traps some pa~lioulat es ( Smoke production by pyrolysis (1600- 1800° F) g g Air dilution end cooling v=a porous paper TO lungs, where ." tption occurs Absorption factors= • inhalation amount * inhalation depth • Inhalation duration • pH of smoke • Absorption characteristics of Indivldual constituents FIGURE 1.--Production and fate of eigarotto smoke constituents NOTE: Description of complexity of pr~'et~ by which nicotine is extracted from cilarette, Amount of n~cotine ulttmately abeorf~d is M much a function of smoker behsvlor as of cigarette characteristi¢~ 80URCE: Hennln~eld (1984) appearance; cigarette smoking is no excoptipn. The behavior of lighting, smoking, and extinguishing cigarettes, including puffing and inhaling, also becomes regular in smokers over time. The measurement techniques that permit such conclusions, however, must address a complex behavior. There are many variables (e.g., number of puffs, depth of inhalations) that might change and thereby affect the intake of tobacco smoke and its various constitu- ents (e.g., nicotine, tar, carbon monoxide (CO)). As shown in Figure 1, the process of producing cigarette smoke constituents itself is complex (see US DHEW 1979; US DHHS 1981, for amore thorough discussion of these factors). This complexity emphasizes the impor- tance of the use of careful measurement and multiple measures to ensure accurate characterization of cigarette smoking. Quantification of cigarette smoking behavior has improved with the development of automated measurement techniques. These techniques permit the measurement of puffing and inhalation both in the laboratory (Gust, Pickens, Peehacek 1983; Epstein, Dickson, Stiller et al. 1982; Creighten, Noble, Whewell 1978; Herning, Hunt, 151

Jones 1983; Henningfield and Griffiths 1979; Puustinen et al. 1987) and outside the laboratory (Henningfleld et al. 1980; Grabowski and Bell 1983). Puffing behavior is generally measured by having subjects smoke through cigarette holders that measure air flow by use of either temperature-sensitive thermistors (Gritz, Rose, Jarvik 1983; FagerstrSm and Bates 1981) or pressure-asnsing transducers (Henningfield and Griffiths 1979; Gust, Pickens, Pechaeek 1983a; Rawbone et al. 1978). Inhalation behavior has been measured by a variety of techniques, including mercury strain gauge pneumogra- phy (Rawbone et al. 1978; Herning et al. 1983), head- and arms-out whole-body plethysmography (Adams et al. 1983), and impedance (Nil, Buzzi, B~ittig 1986) and inductive plethysmography (Herning, Hunt, Jones 1983; Tobin and Sackner 1982; Tobin, Jenouri, Sackner 1982). Other methods include the use of inert gas radiotracers to determine the amount of smoke inhaled (Sheahan et al. 1980; Woodman et al. 1986) and a sensor for directly measuring the concentration of smoke particles in the holder before puffing (Jenkins and Gayle 1984). These procedures have proved to be valuable and reliable methods of measuring smoking behavior (Woodman et al. 1984; Herning, Hunt, Jones 1983). Comparisons of data obtained when simply observing smokers to data obtained when using the mechanical devices indicate that such automated measuring techniques are valid. Such comparisons reveal consistent findings on measures such as number and duration of puffs and even of patterns of puffing within cigarettes (Henningfield and Grifflths 1979; Griffitlis and Henningfleld 1982). However, other research suggests that the devices may alter certain characteristics of smoking such as intensi- ty of puffing (Tobin and Sackner 1982; Ashton, Stepney, Thompson 1978; Ossip-Klein, Martin et al. 1983). In addition, some smoking behaviors, such as blocking the ventilation holes of filters of low- yield cigarettes (which can markedly influence nicotine and tar intake from the cigarette) are thwarted by the use of a cigarette holder. Nonetheless, such measurements are useful and appear to provide valid means of evaluating the effects of specific experimental manipulations. Measurement of the intake of cigarette smoke constituents may also be obtained by analysis of various biological fluids (saliva, urine, or blood) and expired air. Chapter II reviewed the methods and practical issues of using such specimens to assess resulting levels of nicotine, cotinine (a nicotine metabolite), CO, and other tobacco- associated compounds (see also Jarvis et al. 1987; Benowitz 1993). Use of the methods described above has led to a much better understanding of how cigarettes are smoked and factors that affect intake of smoke constituents such as CO and nicotine. In addition, these methods permit conclusions regarding which aspects of smok- Q 152 •

ing are most robust across individuals, which aspects are strongly influenced by pharmacologic factors, and which aspects appear to be determined by other factors. Some of these findings are reviewed in subsequent sections. Characterization of Cigarette Smoking Behavior Although the process of smoking a cigarette may appear to be a simple behavior, it is actually a complex series of events; a full characterization requires the measurement of a variety of interde- pendent indices of frequency, duration, and volume. Even the act of taking a single puff is complex. Typically, a smoker puffs a volume of smoke into the mouth, where it is held for a short period of time (Guillerm and Radziszewski 1978; Medici, Unger, RCiegger 1985). The • puff itself can occur at any point during inhalation, although most commonly it occurs toward the beginning of an inhalation (McBride et al. 1984; Guillerm and Radziszewski 1978). During inhalation, the puff is diluted with ambient air which may be inhaled through the nose, the mouth, or both (Rodenstoin and Sttinescu 1985; McBride et el. 1984; Adams etal. 1983). The postpuff inhalation is generally longer and larger in volume than normal inspirations (Rodenstein and Sttinescu 1985; McBride et al. 1984). After a variable period of breath holding, the smoker exhales, usually through the mouth (Redenstoin and St~inescu 1985). All of the above-mentioned behavioral factors can alter nicotine absorption. The likely impact of some factors is obvious (e.g., number of puffs taken) (Kozlowski 1981); others are much more subtle (e.g., puff shape, which is a function of the air flow rate over time) (Croighton and Lewis 1978b). Analogous but distinct from puffing factors are inhalation factors (e.g., depth and duration, dilution of the puff with ambient air) which can also determine the amount of tobacco smoke constituents which are absorbed. Table 1 lists several measures of cigarette smoking that have been objectively defined and measured. The relationships among these behavioral measures have been studied. For instance, duration and volume of puffing are generally highly correlated although they vary ~omewhat from smoker to smoker (Gust and Pickens 1982; Epstein etal. 1982; Adams et al. 1983; NemethoCoslett and Griffiths 1985; Gust, Pickens, Pechacek 1983b; Gritz, Rose, Jarvik 1983). Peak smoke flow rate has been reported to be moderately correlated with puff volume and weakly correlated with puff duration (Gritz, Rose, Jarvik 1983). The relationship between puff volume and interpuff interval is much more variable (Adams et ah 1983; Gust, Pickens, Pechacek 1983b), and puffs per cigarette and puff duration have been found to be inversely related (Lichtenstein and Antonuccio 1981). 153

Q TABLE ].--Behavioral measures of cigarette smoking Puffing behavior POf fs/cigarptte In~tpuff interval Puff duration Sutt length 1weight} Puff volume Puff sha~ Puff now rate <puff intensity} Peak Sow rate (pressure/ I~tency to peak Now rate <pre~ure} Perccr=t puMng time Inhalation behavior Ir~halvtiorL volume Inhalation duration S~tbho]d duration Lung exposure d~r~tion Penni of puff inh~ed When the smoking of individual cigarettes is studied, the mea- sures of cigarette smoking behavior and the resulting levels of biochemical markers have also been found to be highly correlated. For example, four studies found positive correlations between one or more of the behavioral measures and plasma nicotine levels (Pomer- leau, Pomerleau, Majehrzak 1987; Sutton et ah 1982; Bridges et al. 1986; Herning et al. 1983). Using another approach, Zacny and associates (1987) independently varied three aspects of smoking-puff volume, inhalation volume, and lung exposure duration. They found that increases in puff volume (from 15 to 60 mL) produced proportional increases in plasma nicotine level, whereas increases in inhalation volume (from 10 or 20 to 60 percent of vital capacity) or lung exposure duration (from 5 to 21 sec) had no such effect. CO intake (measured either from expired air or blood samples) also tends to be positively related to measures of smoking behavior, including total puff volume (Gust and Pickens 1982; Guillerm and Radziszewski 1978; Nil, Buzzi, B~ittig 1984; Woodman et ah 1986) and mean puff volume (Zacny et al. 1987; Zecny and Stitzer 1986). McBride and coworkers (1984) found moderate correlations (r--0.36 to 0.45) between CO boost and other measures of ventilation (tidal volume, minute ventilation, and prepuff expiratory volume). These studies illustrate some of the ways that specific aspects of cigarette smoking can affect absorption of smoke constituents. These mea- sures have been used to scientifically describe many features of cigarette smoking. A summary of findings that have emerged from such studies is presented in the next Section. 154 •

Patterns of Puffing and Inhaling Several studies have characterized the behavior of cigarette smoking in and outside the laboratory. The values of the most frequently measured variables are shown in Table 2. Despite a wide range of variations among studies, including differences in subject population (age, gender, smoking history, type of cigarette smoked), experimental setting, method used to collect the measurements, apparatus calibration procedures, and operational definitions of the measured variables, the findings among studies are strikingly consistent. Over the course of smoking each cigarette there are striking consistencies from cigarette to cigarette, both within and between • individuals. For example, during the smoking of a single cigarette, the duration of each puff tends to decrease and/or the time between each puff (interpuff interval) tends to increase (Graham et al. 1963; Griffiths and Henningfield 1982; Nemeth-Coslett and Griffiths 1985; Herning et al. 1981; Gust, Pickens, Pechaesk 1983b~ Woodman et al. 1986; Buzzi, Nil, B/ittig 1985; Adams et al. 1988; McBride et al. 1984; Chalt and Griffiths 1982a). These trends were also found in nonlaboratory observations by Sehulz and Seehofer (1978). Although these observations reflect a tendency to decrease overall intensity of smoking over the course of the cigarette, the specific factors which produce such effects remain to be fully elucidated. The pattern has been hypothesized to be related to the nicotine dose per puff (Riokert et al. 1983; Russell et al. 1975; Chamberlain and Higenbottam 1985), because the nicotine concentration of smoke increases as the cigarette is smoked (Kozlowski 1981). However, experimental studies suggest that within-cigarette changes in puff intensity are not a simple function of the nicotine dose per puff (Nemeth-Coslett and Oriffitbs 1984a,b, 1985). Furthermore, puff volume may not be controlled by the same factors as puff duration (Nemeth-Coslett and Griffiths 1985). Thus, the orderliness of the behavior may be due to a variety of factors. Various other aspects of puffing and inhaling during the smoking of single cigarettes have been studied and provide further informa- tion that helps to characterize this complex behavioral process. For example, puff shape (puff intensity over time) (McBride et al. 1984), latency to peak puff pressure (Buzzi, Nil, B~ittig 1985), and inhala- tion volume and duration (Adams et al. 1983) did not change over the course of smoking single cigarettes. The volume expired from puff to puff during and immediately after puffing (before inhalation) was lower for early puffs than for later puffs (Adams et al. 1983). Woodman and colleagues (1988) reported that the amount of smoke actually inhaled (range, 46 to 88 percent of puff volume) decreased proportionately with puffvolume as cigarettes were smoked. Finally, significant changes from cigarette to cigarette in puff volume and 155

F~ cb~ TABLE 2.--Published values of common measures of smoking I~terp~ff Cigarette Puff Puff Peak Inhalation Number Puffsf in.oval duration duration volume flow ~[ume Study of subjects cigarette t t~c) tseo Isec) ~mL~ ImL/~ecl ~mL~ Rawbc~e et al fl~CqS) Rawbone et al. fl9789 Woodman et aL (1986p Nemeth~e~,ett et aL 11986a) Nerneth~osletl et al~ ~1956"bl Nil, Wccd~qn, BatIig I19851 Jarvlk eta[. 11978~ Runnel[ et al. (19~Ob~ Ashton, Stepney, Thompson (19781 Schu[z and Seehofer (1978b Schulz and Seehofer 11978~ Henning~teld and GrilTiths (1981) Stepney t1981) Battig, Buzzi, Nil ~1982~ Epstein et al. (19~32) Rtt~ell et aL (1982) Gritz. R~e, Javclk (19~,) (~zsip-Kleln, Martin et ol (1983) O,~*ip-Klein. Martin eta]. I19~31 Guillerm and Rad:vszewski tl978) Gust. Pickens. Pechacek 11983b) 12 10 41 9 10 35 9 13 18 254 8 8 64 414 8 8 47 362 132 13 28 9 10 10 11 35 14 24 IC~ 11 50 218 12 42 8 10 3~ 3,51 19 13 400 llO 13 26 63 13 12 15 26 324 8 9 47 9 8 , 3-51 9 12 339 8 12 41 390 8 9 48 393 L8 2.1 43 1.9 49 413 1.8 1.4 22 30 L~ 5,5~ 15 14 13 10 2,4 23 22 14 1.9 1.9 1.6 40 21 66 39 44 35 915

Interpufl" Cigarette Pu/l" Pu/l" Pe~k InhalaOon Number Puffs/ interval du~tlon durati<~ volume flow volume Study of sub~'t s cigarette (~c) (~) (see) (mLJ ImL/~l ImLl Adams et al. (19~3) I0 26 1.9 44 614 Mood)" (19~4) 517 9 26 ~ 21 44 Nil, Buzzl. Battlg I1964) 20 15 ~ 1.6 40 4O McBride et al. II~4~ 9 16 25 352 2.1 42 Me~icl, Unger, Rt~gger (198.5) 17 14 19 2-2 43 3] Burllng eL a]. I19~51 24 12 28 330 1.7 Nil, Bull. B~ttlg (1966) 117 J3 22 2.1 42 36 4~0 Hugh~ et aL {19~I 46 I! • 1 6 Bridges et eLL (19861 1~ II . 56 ~N~ttstlnen et al (I~) 11 13 22 2,3 44 Hildlng (I~o6~ 27 10 Mean i] 34 346 1-8 43 36 59! Median 11 28 351 1.9 4~5 35~5 560 :~,m~e 8-16 18-64 232-414 1.0-2.4 21~6 ~ 413-918 ~nd in some ~ ,~ere ~l~ted f~lx~ rst her ,~ris~ or e~tlrm~ted f~ dm~ pr~'~ted in F~'ui'e~ mi~in~ value; iedlmt e that the ,mrlable was nat ree~r~l or wa~ eo~ F~.~n ted in lhe pub~i~ study. .,1

inhalation volume, as well as their ratio, were reported for indlvldu- a] subjects over the course of a 4-hr smoking seselon (Hernlng, Hunt, Jones 1988). Dose-Related Determinants of Tobacco Intake As the preceding material shows, cigarette smoking is a complex but orderly behavior; it may be qualitatively and quantitatively described. Furthermore, the behavioral process of tobacco smoke self.administration substantially determines the amount of smoke that is actually consumed. Similarly, the behavior of smoking may change in response to factors related to the delivered smoke and/or nicotine dose. These interactions are described in the present section. Much of this research has addressed issues concerning the manipula- tion of some aspect of cigarette and/or nicotine dose level. Such data are relevant to comparing this form of drug self-administration with ,other forms of drug self-administration, because one of the basic findings in studies of drug-seeking behavior is that the dose may affect the behavior. For example, when the dose (quantity) of a psychoactive drug is high, fewer doses are generally taken compared to when the dose is very low (Griffiths, Bigelow, Henningfield 1980; Chapter V). With regard to cigarette smoking, the control and measurement of cigarette dose level is more complex than is the ease with most other ' forms of drug delivery. For example, in opioid and alcohol studies, ~he amount of the morphine injected and volume of alcohol consumed can be precisely measured, but cigarette snmke can vary in levels of CO, tar, nicotine, and many other potentially important constituents (see Figure 2). The total smoke dose is positively related to the number of puffs taken per cigarette, However. total smoke dose might be changed by diluting the smoke with air or changing the number of available cigarettes. Alternatively, the smoke concen- trations can be kept constant while changes are made in the concentration of nicotine delivered. This Section reviews these and several other strategies used to investigate some form of tebac- co/nicotine dose manipulation and the resultant effects on cigarette smoking. Control of Nicotine Intake Among the most robust findings in research on cigarette smoking is the stability of nicotine intake that occurs from day to day within cigarette smokers. Several studies have collected blood samples from cigarette smokers while they are smoking their own cigarettes (Russell, Jarvls et aL 1980; Benowitz et al. 1983; Gori and Lynch 1985). This research has shown that blood levels of nicotine and cotinine among different cigarette smokers are stable and are relatively independent of the machine-estimated nicotine yield of the 158 •

cigarettes. Similarly. there are generally only modest correlations between the number of cigarettes smoked per day and resultant blood nicotine levels. This finding occurs because smokers consume different amounts of nicotine from their cigarettes, according to how the cigarettes are smoked. Figure 2 presents data from one of these studies. To explain why nicotine intake is not simply determined by the machine-estimated nicotine yield of the cigarettes or the number of cigarettes smoked, many other aspects of smoking have been measured. This research is described in the remainder of this Section. Smoke Concentrati~)n T.he concentration of tobacco smoke delivered to the lung can be changed by dilution with air. Such dilution is an important means by which the low smoking-machino-estimated ratings (e.g., Federal Trade Commission ratings) of tar and nicotine are achieved in the so- called "light" or "ultra light" cigarettes (Kozloweki 1981, 1982, 1986, 1987). One way to study the possible effects of smoke dilution is to use the ventilated cigarette holders which have been marketed for persons who are trying to quit smoking. In principle, the smoker gradually reduces his or her level of dependence to nicotine by using holders of gradually increasing ventilation level. Three laboratory studies have evaluated the effects of such holders on cigarette smoking behavior (Henningfleld and Griffiths 1980; Sutton et al. 1978; Martin et al. 1980). The results of all three were consistent: smoking was more intense at lower smoke concentrations and less intense at the highest concentration. In fact, in one of the studies, expired air CO levels were similar at all four concentration levels, indicating that the changes in smoking intensity were suffieient to defeat the holders' intended purpose of reducing the dose taken (Henningfield and Griffiths 1980). Using a somewhat different strategy, Zacny, Stitesr, and Yingling (1986) studied cigarette smoking with commercially available ventilated cigarettes. When the experimenter systematieally blocked the filter vents of "ultra" low-yield cigarettes, there were decreases in puffs per cigarette, puff volume, and puff flow rate, and increases in interpuff interval. These laboratory findings are consistent with findings obtained outside the laboratory when the cigarette butts of vented cigarettes are examined following smoking. Koslowski, Riekert, Pope, and Robinson (1982) found that the eigarette butts taken from people who blocked the ventilation holes (often inadvertently) were more stained by tar and nicotine, reflecting loss effective dilution and hence greater amounts of smoke delivery to the smoker. Data from a laboratory study suggest that 40 percent or more of smokers may inadvertently block the holes (Kozlowski, Rickert, Pope, Robinson, 159

Q 1000 ..J 800 .o_ 6O0 8 Q 400 20(] o- 1 observation • - 2 observations • -3 observations a.4 observations O • o • ::o Oo = <o.ot I I I I I I r I I 10 20 30 40 50 60 70 80 90 100 Number of cigarettes/day I000I "~ N = 137 r. 0.15 8oo NS ._o ¢b C 8 Q) C -o _8 600~- % i ooo 400}- o o t 00 0,~ 0,4 0.6 0,B 101,2 1.4 1,b 18 2,0 FTC nicotine yield (mg) FIGURE 2.--Afternoon blood cotinine concentrations, c.ompared by regression analysis with number of cigarettes smoked/day (A) and with U.S. Federal Trade Commission (FTC).determined nicotine yield (B) NOTE: The grouped imokers' values (observatioas 2-41 were r,o ~imiLar l• individual value~ Khat plots overlapped Tolal humor of subj~ in B is Lower because da~a for a few ~ubjeets were ln~omplete Mot~i~g blo.~ ¢otinine ¢~ocent ration~ (~ot I~how~) w~re on I=ver~ ~li~htly lower, but had similar ¢orrelation~ with number of eigaretce~ (r.0451 and FTC yield (r=O.061. SOURCE: BenowLlz et ELI, {198ai 160 •

Frecker 1982). These findings imply that there is much greater . exposure to cigarette smoke in the general population than one would expect based solely on the market share of ventilated cigarettes (US DHHS 1981; Kozlowski 1987). Cigarette Length When cigarettes are shorter, people smoke more of them (Ashten, Stepney, Thompson 1978; Goldfarb and Jarvik 1972; Grits, Baer- Weiss, Jarvik 1976; Jarvik et al. 1978; Chait and Griffiths 1982b). Cigarette length may also affect how people smoke each cigarette. Asbton, Stepney, and Thompson (1978) found that smokers short- ened their intervals between puffs and spent a greater proportion of time' puffing on two-thirds-length cigarettes compared with fullo length cigarettes, Russell, Sutton, and associates (1980) reported that smokers took relatively more puffs and left shorter butts when smoking shortened cigarettes. In another study, subjects smoking half-length cigarettes shortened the interval between puffs, but did not spend more time puffing on these cigarettes relative to full- length cigarettes (Chait and Griffiths 1982b). Puff duration and puff volume were inversely proportional to the length of the tobacco rod, even for the first puff of the cigarette (Chait and Griffiths 1982a; Nemeth-Co~lett and Griffiths 1984a,b, 1985). Cigarette Brand Numerous studies have examined the effects of cigarette brand manipulations on cigarette smoking, and several reviews are avail- able (Gritz 1980; Moss and Prue 1982; McMorrow and Foxx 1983). Such studies are of practical importance because smokers often switch to lower tar/nicotine yielding cigarette brands in an effort to reduce this exposure to toxins and to reduce their level of nicotine dependence (see Chapter VII). One finding of these studies is that the number of cigarettes smoked per day is only slightly increased when lower nicotine-yield brands are used. For this reason, it has been suggested that smokers switch to lower yield cigarette brands (1) to reduce exposure to smoke constituents and (2) to help them gradually reduce their dependence on nicotine (see discussion of these issues in US DHHS 1981 and in Chapter VII (nicotine fading)). However, as discussed earlier, several other studies indicate that there is little correlation between the nicotine rating of a cigarette and the plasma nicotine level of the smoker (Russell, Jarvis et al. 1980; Benowlts et al. 1983; Gori and Lynch 1985). Kozlowski (1981, 1982) has observed that increases of only one or two puffs per cigarette and possibly other more subtle changes in cigarette smoking (e.g., blocking ventilation holes and taking deeper inhala- 161

tions) may defeat the intended purpose of the brand-switching procedure. Laboratory studies have provided information on the specific changes in smoking behavior that may reduce the intended impact of switching to lower yield brands of cigarettes. One confounding factor in such studies is that machine-estimated nicotine, tar, and CO yields do not necessarily change to the same degree or even in the same direction from one cigarette brand to the next (Tobacco Reporter 1985); thus. no definitive conclusions can be drawn about which specific smoke component was responsible for observed changes in smoking behavior. Nonetheless, some orderly and consistent findings emerge from a review of this literature. Several measures suggest that when tobacco smoke constituent ratings decline, smoking is more intense so that more smoke is delivered per cigarette; conversely, when tobacco smoke constituent ratings are higher, cigarette smoking becomes less intense (Frith 1971; Ashton, Stepney, Thompson 1979; Stepney 1981; Guillerm and Radziszewski 1978; Rawbene et al. 1978; Adams 1978; Creighton and Lewis 1978a; Ossip- Klein, Epstein et al. 1983; Russell et al. 1982; Ashten and Watson 1970; Epstein et al. 1981; Russell, Epstein, Dickson 1983; Tobin and Sackner 1982; Fagerstr6m and Bates 1981; Woodman et al. 1987). The consensus of the foregoing studies is that smokers tend to smoke in ways that minimize the effect of attempted reductions in nicotine intake; however, brand preferences can modulate nicotine intake. One study employing biochemical measures of smoke intake illustratedboth of these phenomena (Benowitz and Jacob 1984). Subjects were permitted to smoke under each of three cigarette conditions: using their regular cigarette, using a higher nicotine- yield brand, and using a lower nicotine-yield brand. Subjects maintained significant nicotine intake under all three conditions, but the highest intakes of nicotine were with the subject's preferred brand. Nicotine intake from the lower nicotine-yield brands was somewhat lower than intake from the higher yield brands. Taken together, these studies indicate that brand switching may result in somewhat decreased levels of intake of nicotine and other constitu- ents of tobacco smoke. However, because of compensatory changes in how cigarettes are smoked and in the number of cigarettes smoked, the decreases are substantially less than would have been predicted on the basis of the machine-estimated yield of the cigarettes. Cigarette Yield of Nicotine Research cigarettes which vary mainly in machine-estimated nicotine yield ratings but little in the yield of other constituents (e.g., tar, CO) have also been used in laboratory and nonlaberatory studies of cigarette smoking. This literature has been extensively reviewed (Russell 1971, 1976; Gritz 1980; Henningfield 1984; US DHEW 1979; Q 162 •

US DHHS 1981}. The consensus of the literature indicates that as nicotine yield increases, the number of cigarettes smoked per day tends to decrease, although the converse relationship is not as robust (Russell 1979). Because few of these studies employed measures of smoking other than number of cigarettes smoked per day, the degree to which overall cigarette smoking behavior actually varied as a function of such manipulations may have been underestimated (Henningfield 1984). Laboratory studies in which multiple behavioral measures of cigarette smoking were employed indicate that smoking is sensitive to nicotine dose manipulations. When cigarettes with higher nicotine yield ratings are smoked, there are decreases in measures such as puffs per cigarette, puff duration and puff volume, number of cigarettes, and expired air CO; and increases in interpuff and intercigaretto interval (the specific measures were not identical for the three studies summarized) (Herning et al. 1981; Gust and Pickens 1982; McBride et al. 1984). These changes in smoking are consistent with the interpretation that intensity of smoking is inversely related to nicotine dose, indicating that compensatory changes in smoking could be affected by nicotine itself. Urine pH Because some nicotine is normally eliminated in the urine, manipulations of the rate of nicotine excretion might be expected to change cigarette smoking behavior (see Chapter II). Rate of renal excretion is partially determinedby the acidity of the urine: lower pH values (higher acidity) increase the rate of nicotine excretion. One study showed that acidification of the urine of cigarette smokers resulted in small increases in cigarettes smoked per day, and alkalinization of urine was accompanied by only very small de- creases in smoking (Schachter, Kozlowski, Silverstein 1977). A subsequent study in which urine pH was varied showed no change in cigarette smoking measures (Cherek, Mauroner, Brauchi 1982); another showed small but significant effects on nicotine intake in the expected direction (Benowitz and Jacob 1985). The fact that there is a direct albeit weak relationship between rate of nicotine excretion and cigarette smoking has suggested to some that alkaline diets might be useful for persons trying to decrease their cigarette smoking (Fix and Daughton 1981; Fix et al. 1983; Grunberg and Kozlowski 1986). However, the relatively small amount of systemic nicotine which is eliminated by this route (approximately 2 percent in alkaline urine, 10 percent in urine without controlled pH) (Rosanberg et al. 1980; Benowitz and Jacob 1985; Chapter II) weakens its practical significance as a determinant of cigarette smoking behavior. The results of clinical studies suggest 163

that such therapies are not useful in the cessation of smoking (see also Grunberg and Kozlowski 1986; Schwartz 1987). Tobacco Administration and Deprivation When tobacco smoke itself is given or withheld, the tendency to smoke, as well as the way cigarettes are smoked, may be affected. Kumar and colleagues (1977) reported that pretreating smokers with a varying number of uniform puffs of tobacco smoke produced dose- related reductions in the subsequent number of puffs taken, volume per puff, and total puff volume during a 40-rain period of smoking ad libitum. In a study of similar design, Chair, Russ, and Griffiths (1988) found that an increasing number of uniform pretreatment puffs decreased subsequent puffs per cigarette, cigarette duration, and total puff duration. Analogously, when the number of puffs available during any period of smoking (smoking "bout") during a given day was varied by the experimenter from 1 to 12 while the smokers were free to vary the interbout interval, the intervals between each smoking bout were directly related to the number of puffs that had been given (Oriffiths, Henningfield, Bigelow 1982). These studies show that cigarette smoke intake is a function of time since the last cigarette or the smoke dose given at any smoking opportunity. Whereas smoke pretreatment decreases several measures of cigarette smoke intake, other studies have found that deprivation for just :~ hr increases the tendency to smoke and elevates several measures of tobacco smoke intake (Henningfield and Griffiths 1979); furthermore, these effects were not due to "anticipation" by the subjects of the periods of smoke deprivation (Griffiths and Henaing- field 1982). Several additional studies have confirmed that smoke deprivation increases one or more measures of cigarette smoking (Karanci 1985; Grifflths and Hennlngfield 1982; Zacny and Stitzer 1985; Epstein et al. 1981). Sutton and coworkers (1982) found a small, but statistically significant, positive correlation between time since the last cigarette and total puff volume on the subsequent cigarette. Simi]arily, when the interval between each smeking opportunity was varied from 7.5 to 120 rain and subjects were free to take as many puffs per smoking bout as they pleased, the number of puffs per bout was directly related to the duration of the preceding interbout interval (Griffiths, Henningfield, Bigelow 1982). Restricting the number of cigarettes that may be smoked is another way to study tobacco deprivation. When smokers who on average smoked 37 clgarettes/day were permitted to smoke only 5 cigarettes/day, they consumed three times as much nicotine per cigarette compared with unrestricted smoking (Benowitz et al. 1986). The results of studies of the effects of tobacco administration and deprivation on subsequent rates and patterns of cigarette smoking show that tobacco smoke can function as do other primary reinforc- 164 •

ers such as food, water, and dependence-producing drugs (Thompson and Schuster 1964). Such studies in themselves, however, do not reveal which of the many tobacco smoke constituents are critical. The next two sections will examine evidence that specific manipula- tions of nicotine and nicotine antagonists can produce analogous changes in cigarette smoking. Nicotine Pretreatments One of the basic ways to demonstrate that a psychoactive drug is serving as a reinforcer is to determine if pretreatment with the drug leads to decreases in the amount subsequently taken. Such findings have been obtained with. a variety of dependence-producing drugs (e.g., Griffiths, Bigelow, Henningfisld 1980; Chapter V), and .the strategy has been used to study the role of nicotine in cigarette smoking. These studies have shown that nicotine pretreatment by a variety of routes decreases the amount and/or intensity of subse- quent cigarette smoking although the specific measures that have been reportedly affected vary across studies. It is possible that differences across studies reflect variations in sensitivity of measure- ment techniques and in the measures used. Cigarette smokers may be pretreated with nicotine by giving them nicotine polaerilex gum to chew. The gum is available in similar tasting nicotine dose levels of 2 or 4 mg/piece. A similar tasting placebo preparation with no nicotine is also available. (In the United States, the placebo and d-rag dose are only available for research.) With various combinations of nicotine gum doses it is possible to provide a wide range of dose levels. In one study, the chewing of nicotine polacrilex gum produced a dose-related (dose range -- O to 8 mg nicotine) decrease in cigarette consumption during subsequent 90-rain cigarette smoking sessions: Total puffs, total cigarettes, and expired-air CO levels were inversely related to nicotine dose; desire to smoke was also inversely related to dose btit this effect varied considerably and was not statistically reliable (Nemeth-Coslett etal. 1987). Comparable findings have been obtained in several other studies, although dose manipulations were not as extensive as in the former study (Kozlowski, Jarvik, Grits 1975; Nemeth-Coslett and Henningfield 1986; Brantmark, Ohlin, Westling 1973; Russell et al. 1976; Herning, Jones, Fischman 1985). Another study showed that nicotine given in capsule form also reduced subsequent cigarette smoking (Jarvik, Gllck, Nakamura 1970), although the low dose and poor systemic absorption of nicotine given by this route (see Chapter IID required that much higher dose levels be given (1O mg). Two studies have also demonstrated that intravenous (i.e.) admin- istration of nicotine decreases cigarette smoking (Lucchesi, Schuster, Emley 1967; Henningfield, Miyasato, Jasinski 1983). Another study found no change in smoking following i.e. nicotine infusions (Kumar 165

eta]. 1977); however, the dose (equivalent to about 1.7 rag, given in 10 divided doses over 10 rain) was probably inadequate, as suggested by results of other studies (Nemeth-Coslett et al. 1987). The finding that even i,v.-delivered nicotine can reduce subsequent cigarette smoking confirms that neither the tobacco vehicle nor the oral/respiratory route are necessary for nicotine to control behavior. The overall consistency of findings using a variety of forms of nicotine pretreatment is evidence for a specific effect of nicotine as a determinant of cigarette smoking. Nicotine Antagonist Pretreatments Another way to evaluate the specific role of nicotine as a determinant of rate and pattern of cigarette smoking is to adminis- ter drugs that block the effects of nicotine on the nervous system. Nicotine antagonists (gengllbnie biockers) are available as drugs (e.g., pentelinium and bexamethonium) that do not readily enter the brain but are active in the peripheral nervous system, and as drugs (e.g., meeamylamine) that do enter the brain and thus work in both the peripheral and central nervous system (CNS) (Taylor et el. 1985b). In theory, such drug administration should produce effects that are analogous to those that would be expected if the nicotine dose of cigarettes was decreased: that is, smoke intake should increase. Moreover, if smoke intake increases, but only when the centrally acting antagonist is given, such data would suggest the critical involvement of the effects of nicotine in the brain. Three studies showed that pretreatmont of smokers with meeamy- lamine produced increases in cigarette smoking that resembled those expected if the nicotine dose of the cigarettes had been decreased (Stelerman et el. 1973; Nemeth-Coslett et al. 1986a; Pomerleau, Pomerleau, M~jchrzak 1987). In each of these studies, the short-term effect of the nicotine antagonists was studied. Similarly, mecamyla- mine pretreatment increased the preference for high nicotine-yield cigarette smoke (apparently by reducing its nicotinic effects) when subjects were tested with n device which blends smoke from high and low nicotine-yield cigarettes (Rose, Sampson, Henningfield 1985). The role of nicotine action in the brain was demonstrated in the study by Stelerman and colleagues (~973) in which n nicotine blocker (pentolinium) that does not readily enter the bruin produced no effects on cigarette smoking. Effects of Nonnieotinie Drugs on Cigarette Smoking In addition to nicotine and nicotine antagonists, the effects of other psychoactive drugs on cigarette smoking have been studied in the laboratory. Such studies are important insofar as they constitute drug-interaction studies whereby it may be determined if the 166 •

behavioral and physiological actions of nicotine are altered as a function of pretreatment with other drugs. In addition, studies of int~racticas of nicotine with other dependence-producing drugs are important because tobacco use generally precedes and accompanies use of many other dependence-producing drugs (Chapter V). Several classes of psychoactive drugs have been administered in studies in which cigarette smoking was specifically measured. In general, the results permit a categorization of these drugs into two groups: (1) those drugs that produce increases in smoking under standard test conditions, and (2) those drugs that produce little reliable effect on cigarette smoking under standard test conditions. Sedatives, opioid agonists, and psychomotor stimulants have been shown capable of producing robust and dose-related increases in cigarette smoking. Specifically, alcohol (ethanol) has been shown to increase cigarette smoke intake (Griffiths, Bigelow, Liebsen 1976; Henningfield, Chait, Griffltks 1984; Nil, Buzzi, B~ttig 1984; Mintz st al. 1985; Mello et al. 1980b). In a study in which alcohol was found to increase smoking in all of five alcoholic subjects tested, pentobarbitel (a depressant) was found to increase smoking in the two subjects with extensive histories of barbiturate use (Henningfield, Chait, Griffiths 1984). The effects of alcohol and pentebarbital were most robust in heavier drinkers and alcoholics (Henningfield, Chait, Griffiths 1983, 1984). The opioid agonists, heroin and methadone, -increase cigarette smoking in opioid users (Mello et al. 1980a; Chait and Griffiths 1984). Methadone produced dose-related increases in number of cigarettes and puffs, and in puff duration in methadone- maintained smokers (Chnit and Griffiths 1984). Analogously, num- ber of cigarettes smoked per day gradually decreased as methadone- maintained clients had their daily methadone doses decreased over several weeks (Bigelow et al. 1981). Finally, the psychomotor stimulant d-amphetamine increases a variety of measures of ciga- rette smoking (Henningfield and Oriffiths 1981; Chait and Griffitks 1983). Three other drugs have been studied and found to produce little reliable effect on cigarette smoking. Caffeine is of interest because it might be predicted to either increase smoking by its general stimulant (amphetamine-like) effects (Rall 1985) or to decrease smoking by serving as a substitute for some of nicotine's stimulant effects (Kozlowski 1976). Laboratory studies, however, have found the effects of caffeine administration on cigarette smoking to be weak and inconsistent: two studies showed no reliable effect (Chair and Grlffiths 1983; Nil, Buzzi, B~ttig 1984), another showed weak decreases in smoking (Kozlowski 1976), and a fourth showed weak increases in smoking following caffeine administration (Ossip and Epstein 1981). 167

The opioid antagonist naloxone (naloxone blocks effects of heroin- llke opioids) is another drug of interest because of the possible role of endogenous opioids as mediators of some of the effects of nicotine (Chapter ]II; Pomerleau and Pomerleau 1984). In a test paradigm in which several drugs have been shown to produce orderly effects on cigarette smoking (Griffiths and Henningfield 1982), naloxone produced no consistent changes in cigarette smoking over a wide range of dose levels (Nemeth-Coslett and Griffiths 1986). Another study of the effect of naloxone which employed a single dose found a reduction in smoking (Karras and Kane 1980). No clear reconcilia- tion of these disparate findings is evident. Finally, marijuana pretreatment was found to produce no reliable effect an tobacco intake (Mello et al. 1980b; Nemeth-Coslett et al. 1986b) or on the way cigarettes were smoked (Nemeth-Coslett et el. 1986b). Effects of Nonninotine Constituents of Tobacco Smoke and Citric Acid Aerosol Chemicals presumed to act primarily in the respiratory tract and not in the central nervous system may also affect smoking. The region of the trachea just below the larynx is assumed to be a site of some cigarette smoke related sensations (Cain 1980). This site corresponds to the region 2 cm below the narrow opening of the larynx where particles entering the trachea change direction (Chan and Sohreck 1980). The components of cigarette tar and volatile .gases in smoke contribute to the taste, olfactory, and tracheobronchial sensations elicited by cigarette smoke. In fact, minimal levels of tar are held by tobacco manufacturers to be important to maintain product satisfac- tion in smokers (Tobacco Reporter 1985; Gori 1980). Besides its causal role in lung cancer and other diseases (US DHHS 1982, 1983, 1984), tar may function to mask the harshness and irritation of nicotine (Herskovic, Rose, Jarvik 1986). Consistent with this hypoth- esis, nicotine aerosols delivering doses of nicotine similar to those in mainstream cigarette smoke are rated as extremely harsh and irritating by cigarette smokers (Russell 1986). Similarly, some gaseous components of smoke, such as acrolein and formaldehyde, are irritating and could also contribute to the tracheobronchial sensations elicited by smoke (Lundberg et al. 1983). Levels of tar and other constituents may also contribute to brand preferenceand, conversely, to the difficulty in finding readily acceptable substitutes for the cigarettes normally smoked by individ- uals. For example, a nonmentholated cigarette may not be a desirable substitute for a mentholated one. Moreover, when given cigarettes made of lettuce or cocoa leaves, smokers complain about the unpleasant smell and taste (Goldfarb, Jarvik, Glick 1970; Herskovio, Rose, darvik 1986). Tobacco research cigarettes are often Q 168 •

found to be less palatable than commercial brands (Benowitz, Kuyt, Jacob 1982), indicating the importance of specific tobacco blends and/or additives in determining taste and brand preferences. The precise nature of the sensations critical to smoking satisfac- tion has not been elucidated, and the relative roles of taste, olfaction, and tracheobronchial sensations are not clear. One way to assess the importance of local respiratory sensations in the subjective response to cigarette smoke is to block these sensations with a short-actlng topical anesthetic. Two studies have used inhalation of a 4-percent lidocaine aerosol and mouth rinses and gargling with lidocaine solutions to assess the importance of airway sensations to cigarette smokers (Rose et al. 1984, 1985). In both studies, the desirability of puffs was decreased by local anesthesia of the respiratory tract. Additionally, the decline in reported craving for cigarettes that usually occurs after smoking was diminished by local anesthesia. A study was also conducted in which smokers inhaled a refined tobacco smoke condensate (Rose and Behm, in press). The condensate produced a low overall nicotine yield (about 0.2 rag/10 puffs), while maintaining a higher ratio of nicotine to tar and a larger particle size than that of conventional cigarette smoke. Smoke generated in this fashion was rated as stronger and harsher than smoke of equivalent nicotine content delivered by smoking a conventional low-tar and low-nicotine cigarette (Rose and Behm 1987). The subjects also reported significantly greater satisfaction and dimin- ished desire to smoke additional cigarettes after inhaling puffs of refined smoke compared with conventional low-nicotine cigarette smoke (Rose and Behm 1987). These studies demonstrate that local sensory effects of smoke may influence the short-term subjective responses to smoking. The inhalation of aerosols containing citric acid is a standard method of eliciting coughing in human subjects (Pounsford and Saunders 1985). One study found that smokers inhaling puffs of a nebulized 15 percent aqueous solution of citric acid reported sensations of strength and harshness comparable to those produced by their own cigarette brand and considerably stronger than those elicited by an "ultra" low-tar, low-nicotine cigarette (Rose and Hickman 1987). Moreover, some pleasure was reported to be associated with these sensations, and desire for c!garettes was decreased, suggesting that mild irritation of the respiratory airways may be involved in satiation of smoking behavior and may have a role in smoking cessation efforts (Hennlngfield 1987c; Chapter VID. Nicotine: Psychoactlvlty, Reinforcing and Related Behavioral Mechanisms of Nicotine Dependence As the preceding sections have shown, cigarette smoking is an orderly behavioral and pharmacologic process clearly involving 169

maintenance of the desired levels of nicotine in the body. These data are sufficient to label tobacco use as a form of drug self-administra- tion in which the role of nicotine in controlling tobacco self- administration functions as do morphine, ethanol, and cocaine in the use of opium-derived products, alcoholic beverages, an([ eoca- derived products, respectively. However, the question may he asked whether the behavior-controlling pharmacologic properties of nic- otine are similar to those of prototypic dependence-preducing drugs when evaluated in standard laboratory tests. More specifically, the scientific question is whether nicotine itself shares critical depen- dence-producing properties with drugs such as morphine, cocaine, and alcohol. Standardized testing procedures can be used in both animal and human studies to obJectively determine if a drug is dependence producing: These procedures, as well as a review of how addicting drugs control behavior, is presented in Chapter V. Chapter V also presents data obtained when drugs such as morphine, cocaine, and alcohol are tested by identical procedures. In brief, four general kinds of behavior-modifying drug effects can be differentiated on the basis of the test procedure used. These drug effects are discussed in Chapter V and include the following: (l) Drugs may produce intereceptice stimulus effects; that is, they can produce effects that a person or animal can distinguish from the nondrug state. Although not identical in meaning, the following terms are often used to designate interoceptive drug effects: "psy- choactive," "discriminative," "subjective," "self-reported." (2) Drugs may serve as positive reinforcers or rewards, the presentation of which produces repetition and strengthening of the behaviors which led to their presentation, i.e., "drug self-administration" or "drug seeking." (3) Drugs can serve as unconditioned stimuli, in which case they may directly elicit various responses; these responses may subsequently be elicited by stimuli which are associated with the drug (i.e., conditioned stimuli), including the presence of environ- mental, or even internal, cues. (4) Drug administration or abstinence can also function as "punishers" or aesreive stimuli. This Section will present data from studies of nicotine with each of the four testing procedures mentioned above. The convergence of findings from several distinct approaches provides compelling evi- dence that nicotine is a drug that can effectively control behavior, including behavior leading to its own ingestion (i.e., dependence or addiction). Interoceptive, Discriminative, and Subjective Effects of Nicotine Ingested chemicals can serve as stimuli by actions on either peripheral or centrally located receptors or by indlrect affects mediated through the release of various blochemicals or neurohor- 170

rashes. In general, the term "psychoactive" is reserved for those drugs whose discriminative effects are known to result from their actions in the brain. As described by Lewin (1931) and others (T1~mpson and Unna 1977) it is, in part, the nature of the disdriminative stimulus effects of a drug within the body that set the dependence-producing drugs apart from other non-nutritive sub- stances. As shown in Chapter If, all commonly used forms of tobacco are effective means of delivering nicotine to the blood from which it is rapidly transported to the brain. Research with animals has shown that nicotine produces distinct effects in the central nervous system (CNS). In addition, nicotine has diverse peripheral and hormonal actions that could serve to intensify its CNS stimulus properties. The biochemical mechanisms of these effects are discussed in Chapter Ill, Three procedurally distinct methods have been used to character- ize the stimulu§ properties of nicotine and will be discussed in the following sequence: (1) discrimination testing in animals and hu- mans, (2) assessing subjective effects in humans, and (3) testing for state-dependent learning effects in humans. Each method has been used to help characterize the stimulus properties of a variety of drugs including nicotine (Chapter V). Drug Discrimination Testing in Animals Animal studies of nicotine discrimination show that nicotine produces reliable effects that are readily identified by the subjects. Such studies indicate that fundamental biobehavioral mechanisms mediate the psychoactive properties of nicotine in humans, and that such effects are not unique to human psychological processes. These date also have implications for understanding and treating tobacco dependence and are summarized below, Specificity of the Nicotit~e Stimulus Although dependence-producing drugs may overlap, to some degree, in the nature of their effects on mood and feeling, each drug class and sometimes drugs within a class produce unique effects. As this Section shows, nicotine also produces some effects that permit it to be distinguished from most other psychoactive drugs. These studies are also useful for testing new drugs that are thought to produce nicetine-like effects. Rats can learn to accurately discriminate nicotine from placebo regardless of the route of administration as long as the nicotine reaches the brain. Most researchers have utilized the subcutaneous (s.c.) route of administration (Rosecrans and Mcltser 1981); however, more recent studies have incorporated other routes of nicotine administration and have found that rats could learn to discriminate nicotine when given nicotine by gavage (oral tube) in a dose of 0.5 171

mg/kg (Howard and Craft 1987). Oral nicotine-trained rats general- ized to nicotine administered via either the s,c. or transdermal routes (nicotine solution was applied to a 1.5-cm circular area on the shaved back of the rat). There was little difference in dose potency between the oral and s.c. routes; however, the transdermal route was much less potent and required eight times the oral dose to establish equivalent response patterns. Taken together, the results of these studies showed that nicotine given by a variety of routes produces time- and dose-related discriminative effects. Several studies have compared nicotine with a variety of drugs by these drug discrimination testing procedures (Rosecrans and Meltser 1981; Stolerman et al. 1987). Early research involved testing a wide variety of chemicals. These studies showed that nlcotine-trained rats did not generalize to drugs of other classes such as the opioids, barbiturates, or hallucinogens (Rosecrans and Meltzer 1981). Of special interest was the protetypieal stimulant d-amphetamine, because nicotine also has a variety of stimulant-like actions (Rail 1985}. When nicotine-trained rats were tested with amphetamine, however, they only partially generalized to nicotine. In another study, Schechter (1981) observed higher levels of amphetamine generalization to nicotine in a group of rats trained to discriminate amphetamine from pentebarbital. Thus, nicotine may have some amphetamlne-like effects which are unmasked under certain condi- tions. Oxotremorine and arecoline are agonists of the cholinergic ner- vous system, but these drugs activate muscarinic, and not nicotinic, cholinergic receptors (Rail et al. 1985). Consistent with the mechan- isms of action of these cholinergic drugs are the findings that neither oxotremorine nor arecoline generalized to nicotine in nicotine- trained animals (Rosecrans and Meltzer 1981). Nicotine analogs and metabolites have also been studied with the discrimination paradigm (Rosecrans and Chance 1977; Stelerman et al, 1987). Such research can help reveal the extent, if any, of the role of these nicotine-related or nicotine-derived chemicals in determin- ing the nature of the discriminative effects that follow nicotine administration. In rats trained to discriminate 100 p,g/kg of nicotine, the analogs cytisine and anabasine generalized to nicotine. The alkaloid nornicotine generalized partially to nicotine. Cotinine, the major metabolite of nicotine, was observed to generalize to nicotine only when the cotinine was given intraventricularly in relatively high doses to rats trained to discriminate relatively low dose levels (10O ~tg/kg) of nicotine. These data show that although metabolites of nicotine may share some stimulus properties with nicotine, the degree of generalization is weak, suggesting that the discriminative stimulus effects of nicotine are mainly due to nicotine itself and not to the metabolites. 172 •

Synthetic analogs of nicotine have also been evaluated for their possible nicotine-like properties in discrimination studies (Rose- crans, Kallman, Glennon 1978; Roseeraas et al. 1978). Of the several compounds tested, only one, 3.methyl-pyridylpyrollidine, a chemical isomer of nicotine, was observed to generalize to the nicotine stimulus in nicotine-trained rats. This compound was observed to be 8 to 10 times less potent than nicotine. Its effects were significantly antagonized (reduced or blocked) by mecamylamine, which also antagonizes the stimulus generated by both S- and R-nicotine; the naturally occurring tobacco constituent, S-nicotine, is also 8 to l0 times more potent as a stimulus than R-nicotine. The results of these investigations indicate that the stimulus properties of nicotine am highly specific. A finding reich, ant to pharmacologic treatment efforts (see Chap- ter VII) involved discrimination studies with lobeline (a constituent in several over-the-counter aids for quitting smoking). Lobeline is an alkaloid with some nicotine-like ganglionic effects in the peripheral nervous system (Rail et al. 1985). Rosocrans and Chance (1977) found that lobeline was neither discriminated as nicotine nor did it block nicotine discrimination in nicotine-trained rats. These results do not support the use of lobeline-eontaining compounds as treatment aids for cigarette smoking (see also Schwartz 1987; Chapter VII). Peripheral Versus Central Discriminative Stimulus Effects of Nicotine The degree to which the stimulus is generated via peripheral rather than central nervous system (CNS or brain) actions is also important in understanding the nature of the nicotine stimulus. As discussed in Chapter III, nicotine has many peripheral autonomic nervous system (ANS) effects which might feed back to the CNS, thereby indirectly generating or contributing to stimulus effects. Thus, changes in blood pressure, heart rate, body temperature, and hormone release could be potential mediators of the effects. Several approaches have been utilized to address the role of peripheral actions of nicotine in the generation of the discriminative stimulus. One approach is to attempt to block nicotine with an antagonist not able to enter the CNS. In one study, animals were trained to discriminate a dose of nicotine (Rozecrans and Chance 1977). Then they were pretreated with a series of nicotinic cholinergie antagonists and with muscarin- iv cholinergie antagonists. ARer pretreatment with an antagonist, the animals were retosted with the training dose of nicotine. Meeamylamine, a centrally and peripherally acting nicotine antago- nist, was the only drug observed to completely block the nicotine stimulus. As the dose of this antagonist was increased, percent correct responses on the nicotine-correct lever, after the injection of 173

200 or 400 ~g/kg of nicotine, decreased to placebo response levels, indicating a complete antagonism of the nicotine stimulus. In a similar study, Stolerman, Pratt, and Garcha (1982) increased the nicotine dose in an attempt to overcome the actions of mecamyla- mine: the blockade was not overcome by any dose of nicotine. Thus, these data suggest that mecamylamine is not a competitive antago- nist (blocking at the receptor itself) but rather may functionally antagonize nicotine's effects through another mechanism (Stolerman etal. 1987). In other studies, a 331 ~g/kg dose of mecamylamine antagonized the stimulus effects of 200 }xg/kg of nicotine, while 835 ~g/kg was required for similar antagonism of the 400 ttg/kg dose of nicotine (Rosecrans and Meltzer 1981). All such studies found that the peripherally acting nicotinic antagonist, hcxamethonium, did not affect nicotine discriminations. The muscarinic antagonist, atropine, was also without effect. The possible relationships of the nicotine stimulus to brain norepinephrine and 5-hydroxytryptamine (sereto- nin or 5-HT) systems were also investigated through the use of the appropriate antagonists/agonists. Similarly, a quaternary analog of nicotine, which does not enter the brain, was evaluated and found to produce no evidence of generalization in nicotine-trained rats (Rosecrans etal. 1978). Such studies do not support the involvement of peripheral systems in the generation of the nicotine stimulus. Another strategy used to investigate the central nature of the nicotine stimulus compared concentrations of nicotine in the brain with the resulting stimulus effects of nicotine (Rosecrans and Chance 1977). It was assumed that if nicotine's stimulus effects are mediated in the brain, then such effects should he related to brain levels of nicotine. This hypothesis was confirmed, In fact, it was found that before nicotine functions as a stimulus, it must achieve a minimal drug level in the brain. In addition to relating drug level in the brain to the stimulus effect induced by nicotine, Rosecrane and Chance (1977) showed that systemically administered nicotine generalized to nicotine administered intraventricularly. Taken together, the fore- going studies show that the nicotine-generated discriminative stimu- lus is dependent on the actions of nicotine at central nicotine receptors in the brain. Drug discrimination research has also examined the stimulus properties of the muscarinie cholinergic agonist, arecoline. Arecoline is a constituent of the betel nut mixtures commonly chewed in the East Indies (Taylor 1985a). Three approaches have been utilized to investigate the stimulus properties of arecoline. In the first study, areseline served as a discriminative stimulus and thereby assumed control of behavior (Reseerans and Meltzer 1981). These effects of arecoline were blocked by pretreatment with the muscarinie antago- nist, atropine, while the quaternary compound, methyl atropine @ 174 •

(which does not readily cross the blood-brain barrier), was ineffec- tive. These results indicate that the stimulus can also be exerted via muscarinic stimulation and confirm that the discriminative stimulus properties of muscorinic agonists, like those of nicotinic agonists, are centrally mediated. Additional studies indicated that mecamylamlne was not able to antagonize the stimulus effects of arecoline (Rose- crans and Meltser 1981). Finally, it was found that rats could be trained to discriminate between the muecarinic and nicotinic agonists, areceline and nicotine. Thus, there appear to be two independent central cholinergic receptor systems (muscorinic and nicotinic), each of which can exert stimulus control over behavior when appropriately stimulated. These findings have been confirmed by Stolerman and colleagues (1987). Interactions with Noncholinergiv Neurvns In a preliminary study (Takada et al., in press) two nicotine- trained squirrel monkeys recognized beta-earboline as nicotine. Beta- carboline induces symptoms resembling anxiety in animals; these symptoms can be reduced by administration of the anxiolytic, diazepam (Shepherd 1986). In addition to this observation, Colpaert (1977) reported that nicotine can antagonize the diasepam cue, and Heath, Porter, and Rosecrans (1985) noted that nicotine a~tagonized the effects of diazepam on punished responding in rats. Mecamyla- mine was also found to attenuate the nicetine-induced antagonism of diazepam's antlanxiety effect~ Harris and coworkera (1986) found that metrazol (a convulsant) partially generalized (35 percent) to nicotine when tested in the discrimination paradigm in nicotine- trained animals. A greater degree of generalization of the metrasol cue to nicotine (50 percent) was observed 48 hr after the cessation of a 21-day chronic nicotine regimen in rats trained to discriminate metrazol (5 mg/kg) from saline; these generalizations were not antagonized by mecamylamine. Harris and colleagues (1986) suggest- ed that the generalization of metrazol to nicotine was a function of a nicotine abstinence-induced withdrawal syndrome resembling anxie- ty. These studies suggest that nicotine may act at central receptors capable of eliciting a stimulus cluster which induces anxiety (Chapter III). Subjective Effects of Nicotine in Humans The extensive amount of nicotine discrimination research using a variety of animal species and several routes of administration confirms that nicotine is a potent drug that can induce alterations in nervous system function that are distinct and readily identifiable. In addition, the similar findings observed in studies using different routes of nicotine administration are consistent with the hypothesis • 175

that the tobacco vehicle is not necessary to produce nicotine-assocl- ated changes of mood and feeling. The next Section examines date from analogous studies in which humans served as research subjects. Psychoactivity of Nicotine The animal research described above indicates that nicotine's psychoactivity is a result of basic biological actions. Human research on nicotine corroborates the validity of the animal research. Results from studies of the interoceptive effects of nicotine, in humans are analogous to those obtained in animal studies described above. One of the first human studies that used drug discrimination procedures, as had been developed with animal subjects, was a study of nicotine discrimination, The study involved the systematic n~anipulation of nicotine dose levels with research cigarettes which varied primarily in the amount of nicotine delivered (Kanman et al. 1982). This study demonstrated that nicotine, as delivered by the inhalation of tobacco smoke, produces discriminative stimulus effects. The degree and rate of acquisition of the discrimination appeared to be dose dependent. The ability of the subjects to make the discriminations did not appear to be related to either autonomic (e.g., heart rate) effects of nicotine or to nicotine's effects on other self-reported measures (e.g, taste of the cigarette). The data from Kallman and associates (1982) are consistent with those of several other studies which have found that human volunteers can differentiate among cigarettes which vary mainly in the amount of nicotine which they deliver (Goldfarb, Jarvik, Glick 1970; Goldfarb et al, 1976; Herskovic, Rose, Jarvik 1986; Rose 1984; Oriffiths. Bigelow, Henningfield 1980; Henningfield, Miyasato, John- son, Jasinski 1985). Furthermore, the conclusion that centrally mediated effects of nicotine are important in such responsivity is supported by findings that pretreatment with mecamylamine re- duced responsivity to nicotine dose levels of the cigarette (Stolerman et al. 1973; Nemeth-Coslett et al. 1986a; Pomerleau et al. 1987). The study by Stolerman and associates (1973) also showed that such antagonism of nicotine's effects was not obtained when peripherally acting pentolinium was given. Other research has confirmed that the tobacco vehicle is not necessary to enable the interoceptive effects of nicotine, Several studies involving i.v. administration of nicotine in human subjects have found that humans readily differentiate among nicotine dose levels given intravenously. In the earliest of these studies, i.v. injections of nicotine were given to 35 volunteers, most of whom were cigarette smokers (Johnston 1942), The conclusions of Johnston that are especially relevant to characterization of the psychoactivity of nicotine are shown in Table 3. @ 176 •

TABLE 3.---Summary of early observations regarding psychoactivity of intravenously delivered nicotine in humans 1 "Psychic" effects are directly related to nicotine dose; nonsmokerw are much more $enaitive to b~xic symptoms (d.S~ natlsea) than smoker~ 2 Effect of nicotine is ~'specific and readily distinguished from that of cocaine or codeine"' Nicotine injections are ~'plee~ant" to smokers, and are preferred by some over cigarette ~rnoking Orally given nicotine (dissolved in water) sluo had "psychi:" action, but ttppeared much ler~ potent than ir4ravermusly adm~nis~red nlcotir~e: delayed onset of affect ~ 1-3 mg doses aSpeare~ tolerable and equivMent to B~noktng single ¢igarette~ ~ 0.11 rag doses appeared Lo produce "subjectlve sensation"" equivalent to one 'tdeep" cigarette smoke lnhaletlen • Mo~ recent research indicates that h~gher d~ levell of nlCOtln~ Oa~ produce cocaine.like elfec~s fae~ninglield, Mix~Lgato~ JasLnskl 1985~ • Johnston's findings (Table 3) have been generally confirmed. Jones, Farrell, and Herning (1978) and Rceenberg and colleagues (1980) also found that human volunteers could differentiate i.e. nicotine at dose levels similar to those obtained by smoking • cigarettes. In another study which extended the findings of Johnsten (1942)~ both i.e. nicotine and nicotine inhaled from research ciga- rettes across a range of doses were administered to human volun- tcers with histories of using a variety of dependence-preduciug drugs (Henningfield, Miyasato, Jasinski 1985). Subjects clearly distin- guished nicotine from a placebo, and the dose strength estimates were directly related to the nicotine dose level. A subsequent study showed that the immediate subjective effects of nicotine were diminished by pretreatment of subjects with mecamylarnine (Hen- ningfield et el. 1983). In a study by Hemingfield, Miyasato, Jasiaski (1985), measures used to qualitatively describe the nature of the drug stimulus indicated that nicotine met criteria as a euphoriant. At higher doses nicotine was sometimes identified as a stimulant (cocaine or amphetamine); it elevated scores on the Morphine Benzedrine Group ("Euphoria" or "MBG") scale of the Addiction Research Center Inventory (ARCI) (Haertzen and Hiekey 1987); and it produced dose- related increases in scores on a drug-llking scale. The high-dese cocaine/amphetamine identifications found in the study by Hen- ningfield, Miyasate, and Jasinski (1985) were not observed by Johnston, but such similarities between nicotine and cocaine may 177

only be clearly identifiable by subjects experienced with both cocaine and nicotine. Nicotine given in the polecrilex gum form has been evaluated with similar measures as described above. These studies involved giving various combinations of 2-rag- and 4-rag-nicotine pieces of polacrilex gum and placebo to cigarette smokers. Human volunteers were given the polacrilex gum to chew in doses ranging from 0 to 4 mg in one study (Nemeth-Ccslett and HenningFleld 1986) and 0 to 8 mg in another study (Nemeth-Coslett et al. 1987). Both studies showed that subject ratings of several effects (including "dose strength") were directly related to the total dose of nicotine that was given. In addition, similarity of the stimulus effects to those produced by cigarettes was a direct function of dose level. In these studies "liking" or "positive" effect scores were inversely related to dose level, suggesting that this nicotine delivery system has low potential for causing dependence when compared with that of cigarettes (Chapter VII]. The role of centrally mediated nicotinic actions in the ability of humans to differentiate among polacrilex gum-delivered nicotine doses was confirmed in a study by Pickworth, Herning, and Henningfield (in press). These researchers found that mecamylamino pretreatment of human volunteers reduced both the EEG and subjective effects of nicotine polacrilex gum administra- tion. Like many other psychoactive drugs (Chapter V), nicotine can also produce unpleasant or dysphoric subjective effects that are related to the dose given and the route of administration. Such effects can be quantified by a psychological scale of the ARCI that is sometimes referred to as the "dysphoria" scale (Jasinski, Johnson, Henningfieid 1984) or the "LSD" scale because it was constructed from items found to be elevated when lysergic acid disthylamide (LSD) was given to volunteers (Haertzen 1966, 1974). In one study, Henningfield, Miyasato, and Jasinski (1985) found that beth inhaled (research cigarette smoke) and i.v. nicotine produced dose-related increases in LSD scale scores. In two other studies, nicotine polacrilex gum was tested (Nemeth-Coslett and Henningfield 1986; Nemeth-Ceslett et al. 1987). LSD scale scores were at least slightly increased in both studies and were significantly increased in the study by Nemeth-Coslett and Henningfield (1986). These results with nicotine polacrilex gum, combined with no increases in MBG scale scores, are consistent with the observations described earlier suggesting a low overall dependence potential for this formulation. Sensory Effects of Nicotine As discussed earlier in this Chapter, nonnicotine constituents of tobacco smoke can produce functional sensory effects. Nicotine, too, Q 178 •

can produce peripherally mediated sensory effects which could contribute to the taste of the cigarette. Although not generally termed "psychoactive" drug effects, such effects could contribute to the control over behavior as they provide discrete cues which may be associated with centrally mediated nicotinic effects. For example, nicotine has a bitter taste, elicits burning sensations when placed on the tongue, and is irritating to the oral and respiratory musosa (Windholz et al. 1976). Increasing the nicotine delivery of cigarettes while holding tar delivery constant leads to an increase in perceived strength and harshness. The possible effects of nicotine in the upper respiratory tract on subject ratings cannot be excluded in these studies. Nicotine also stimulates mechanoreceptors sensitive to pressure and stretch (Taylor 1985b), and this local action of nicotine may also contribute to the sensory characteristics of inhaled cigarette smoke. Hexamethonium (the nicotine receptor antagonist that only acts peripherally} has been shown to block cigarette smoke-induced edema in the tracheobronehial mucesa of rats (Lundberg, Saria, Martling 1982). Another study showed that mseamylamine produced dose-related decreases in harshness ratings of individual puffs of cigarette smoke (Rose, Sampson, Henningfield 1985). In this study, subjects were asked to rate their preference at different nicotine concentrations of the smoke: mecamylamino pretreatmcnt shifted preferences to higher smoke concentrations for individual puffs. Another method of producing at least some of the nicotine-related sensations of cigarette smoke is to present nicotine in vapor or aerosol form without any components of tar. Nicotine vapor is likely to be deposited mainly in the mouth and pharynx (Russell 1986); thus it would be difficult to administer a pharmacologically effective dose of nicotine without producing excessive local irritation and bad taste. However, a low dose of nicotine delivered in this fashion might simulate the sensory effects of smoking, even if the pharmacologic effects are minimal. A low-dose nicotine aerosol delivering droplets 1 to 5 ttm in size would be expected to provide respiratory sensations even more similar to cigarette smoking, as particles of this size would impact mainly in the tracheobronehial region. Three studies have evaluated the effects of a commercially marketed nicotine vapor delivery system in human subjects. The delivery system was a version of that originally described by Jacobsen, Jacobsen, and Ray (1979); it was marketed as a "tobacco product" through February 1987, when the Food and Drug Adminis- tration (FDA) required verification of "safety and efficacy" for continued marketing as a "nicotine delivery system" (see Chapter VII). It consisted of a cigarette-size plastic tube with a nicotine- containing polymer in the end distal from the user's mouth. It was used by sucking air through the tube and inhaling in a manner 179

similar to that when smoking cigarettes. When the system was used in this fashion, two studies found that plasma nicotine levels were not significantly elevated (Sepkovic et al. 1986; Henningfield 1986b), A third study found significant elevations in plasma nicotine following use of the nicotine tube (Russell et al. 1987). However, in the latter study subjects used what may be described as a heroic puffing procedure: they were instructed to puff 1 nicotine tube 10 times, at intervals of 40 sec; after a 4-rain pause, subjects then "puffed and inhaled as hard and as frequently as possible, continous- ly for the next 20 rain, with changes every 5 min to fresh cigarette [nicotine tube]." Symptoms typical of those associated with higher levels of nicotine administration were observed, i.e., dizziness, lightbeadedness, and in a few subjects, nausea (Russell et al. 1987). In another study of the nicotine vapor inhaler, four tubes in which none, one, two, or four contained nicotine (the others being denico- tinized) were simultaneously puffed on by volunteers through a specially designed cigarette holder (Henningfield 1986b, 1987a). In this study, despite the fact that measurable changes in plasma nicotine levels did not occur, several responses often associated with nicotine delivery were observed: (1) subject ratings of "harshness" were directly related to dose (number of nicotine-containing tubes); (2) post-puffing increases in heart rate occurred as a function of dose; (3) subjective effects were directly related to dose; and (4) desire to smoke tobacco cigarettes was inversely related to nicotine dose level. Taken together, these results show than even with negligible systemic levels, nicotine can induce feelings of satisfaction and can reduce urges to smoke when it produces tobacco-like sensations of throat burn and harshness (Chapter VII). Some of the short-term satisfaction det:ivcd from inhaling nicotine may explain the apparent short-term efficacy of the vapor inhaler in reducing desire to smoke despite negligible plasma nicotine levels. This is in contrast to findings obtained when nicotine is given either intravenously or in the polacrilex gum (Henningfield, Miyasato, Jasinski 1983; Nemeth-Coslett et al. 1987). Whether the effects of the nicotine vapor inhaler are conditioned responses, peripheral nicotin- ic actions, or both, it remains to be determined if such effects would provide long-term efficacy as tobacco replacement in the nicotine- dependent tobacco user (Chapter VII). Such effects may not be satisfactory for long-term treatment (i.e., they may not satisfactorily alleviate tobacco withdrawal), although they may prove important in providing sources of pleasure and reduction of urges in people trying to quit smoking (Henningfield 1987b). State-Dependent Learning The potential of nicotine to induce state-dependent learning effects as well as how such effects are studied are discussed in i 180 •

Chapter VL In the present Section, findings are summarized in so far as they are relevant to assessing the dependence potential of nicotine. In brief, state-dependent learning refers to the phenome- non whereby behavior learned in one set of cues or stimulus conditions (context) is mast reliably performed when subsequently attempted in the same context and/or is adversely affected when attempted in a novel context (Chapter VI). Psychoactive drugs can produce state-dependent learning effects, apparently by providing a recognizable context based on the interoceptive stimulus cues provided by the drug (see also Chapter V). Several studies have shown that nicotine exposure can lead to state-dependent learning effects. For example, a series of studies conducted by Andersson and colleagues (Andersson 1975; Andersson and Hockey 1977; Andersson and Post 1974) and by others (Peters and McGee 1982; Warburten et al. 1986) showed that nicotine exposure in the form of tobacco smoke could induce state-dependent learning effects in humans. In a study by Lowe (1985), nicotine's part in the state complex produced by alcohol and nicotine together was also evaluated. There are two implications of the above findings regarding the dependence potential of nicotine. The first is that state-dependent learning could contribute to the dependence potential of cigarettes, in that optimal cognitive/behavioral performance may come to depend upon the continued self-administration of tobacco. These actions might also contribute to the strength of the reinforcing effects of nicotine by producing effects on learning and/or peffor- rnanee (see also Chapter VI). Nicotine as a Positive Reinforcer The primary biobehavioral mechanism by which dependence-pro- ducing drugs maintain drug seeking is by functioning as positive reinforcers (Thompson and Unna 1977; Thompson and Schuster 1968). That is, drugs can serve as stimuli that strengthen behavior leading to their own presentation (Skinner 1953; Thompson and Schuster 1968). As discussed in Chapter V, studios in the 1960s used the drug self.administration techniques developed to study morphine and other dependence-preducing drugs in animals (Weeks 1962; Thompson and Schuster 1964; Chapter V). In the first such study with nicotine, Deneau and Inoki (1967) found that monkeys would also self-administer nicotine intravenously. However, some investi- gators considered these findings equivocal (Russell 1979; Griffiths, Brady, Bradford 1979). In 1981, Goldberg, Spealman, and Goldberg showed conclusively that nicotine itself could function as an efficacious positive reinforcer for animals, although the range of conditions under which it was effective was somewhat more limited than for drugs such as cocaine and amphetamine. Analagous studies with humans in the 1980s (e.g., Henningfield, Miyasato, Jasinski 181

1983) demonstrated that intravenously administered nicotine is a reinforcer. The results leading to the foregoing conclusions arc summarized in the present Section. Animal Studies of Nicotine as a Reinforcer Whether a drug functions as a reinforcer can depend critically on the dose of drug, the previous exposure of the subject to that or other drugs, the behavioral history of the subject, and perhaps most importantly, the immediate contingencies relating responses and subsequent injections of drug (contingencies are often referred to as schedules of reinforcement) (Barrett and Witkin 1986; Chapter V). Nicotine differs from some dependence.prcducing drags (e.g., co- caine) (Griffitbe, Brady, Bradford 1979) in that for animals, the conditions under which it maintains high rates of self-administration behavior appear to be more limited; however, there are other dependence-producing drugs which also serve as reinforcers under a fairly limited range of conditions (e.g., alcohol) (Mello 1973; Meisch 1977). Table 4 (modified from Henniugfield and Goldberg 1983b) is a summary of the early studies that found i.v. nicotine injection to be ineffective or marginally effective as a reinforcer as well as more recent studies that conclusively demonstrated the capacity of nicotine to function as a positive reinforcer. The studies listed in this Table employed a variety of species (ranging from rats to human volunteers), different types and parameters of drug injection sched- ules, a variety of training histories, and a wide range of nicotine doses. Much of the research has been reviewed in greater detail elsewhere (Goldberg and Henningfield, in press; Swedberg, Henning- field, Goldberg, in press). The present Section only reviews some of the more recent studies that have experimentally evaluated nic- otine's reinforcing effects. Until 1981, most experiments of nicotine self-edministration involved continuous reinforcement schedules in which each response by an individual subject resulted in the i.v, injection of nicotine (Table 4). Under these continuous reinforcement schedules, (1) rates of responding were very low, ranging from about 0.008 to 0.0005 rasponses/sec in different studies; (2) changes in nicotine dose produced only small and inconsistent changes in rates of responding; (3) the differences in rates of responding maintained by nicotine compared with saline were generally small; and (4) marked intersub- jset differences in self-administration of nicotine were often report- ed. In one series of studies (Lang et al. 1977; Singer, Simpson, Lang 1978; Latiff, Smith, Long 1930; Smith and Long 1980) a concurrent schedule of periodic deliveries of food pellets to food-deprived rats was found to increase rates of nicotine self-administration respond- ing (Chapter V). The concurrent food reinforcement schedule ap Q 182 •

TABLE 4c--Summary of reports in which nicotine was available under intravenous drug self- administration (S-A) procedures Study Species Reinforcement ~hedt~la Main fiedin~ Comment~ Dene~u and lnoki Rhesus monkey FR 1: ~eral nicotine doses Two monkeys initiated S-A; Currently accepted reinforcing q19671 tested others required priming olTieacy ~.~e~mem criteria ,ol procedure achie~-ed Clark Hooded rat FR l: ~erol nicotine doses and Nicotine a reinforcer relative to No quantitative data (19~1 saline tested salla*. Lfvom study ab~racu Yanagita Rhesus monkey Experlment 1: F]~ 1: severn] Nicotine and caffeine not (pre]iminary report. Yanaglta et 119771 nicotine, caffeine, and soline reinforcers, com][xired wilh al LI9741 studle.I deles substituted for SPA ~line or SPA E~tperlr~nt 2: FR |; several Nicotine SA tatt~ stabla in No d~rect reinforcing effica¢) nicotine deses o~ntlnu~ly most subject& but net clearly test availabla dose related Experiment 3: PR ~ure~ 0~2 mg/kg nicotine and lowest two nic~lae doses, sa~i~, and cocaine dose I00~ mg~tg) • thr~ cccalne doses tested maintaiaed similar response rate~ which slightly exceeded rates maln~ined by ~line Nicotine marginally reinforcing c~m~red with ~aline and higher ~ine dc~ L~ng, Latiff. McQ~e~n. Hooded rat FR I; nicotine and ~aline tatd In foed~leptlved Inet food~ttedl Singer in f~ted and food-deprived ra~s, nicotine a relnfor~er, ~1977~ rats compared with solid. Singer, Simpson. l~ng Hooded rat CONC [(FR I:r&,otinexFT 1 Food ~tlatiev decreased nkotln* Results ~milar to ethanol (197~1 min:foed p~]latlI ~n fccd-deprlved S-A t~e. bet nicotine a testing r~u[ts ~at~ rats subsequently f~ted relafcrcer in'beth ¢ondltlovs

" TABLE 4.~ntinued Study Species Reinforcement ~hedule ~,lain findings ('ovnment~ Griffiths Brady P.abc~n FR ]60 followecl by .~hr " Number Qf nicc~line ('~lrf~ine. ephedrine. ~lnd ~ari~lu~ Hrud[ord timeout; several nlcollr~e d~¢~ injections/day did not exc~l olhel ~imil~lrly l~ted ,tlmu]~llll~ (]979~ and ~.~]in~ ~ub~it~ed [or ~]ine w~re rein~rc~er~ rel~liv~ lo cocalne ~]ine l~r~en~ Ivc~tc~ ~'ioreton Albino, ra~ F~ I: ~veral nlcc41ne d~e~ ~nd ~,~my[amlne q~en~ral]y ~¢ling Gl~u~ d~tI~ ~ugge~l nl~Iine ~ i]9791 ~.rt]irte ~e~ted ant~oni~II, nol ~nto]iniunl :~ r~nf~lrce~ no cl~r ~.t~.[]et'~ tperip~raltv aclin~ an~agcni~ ! c~rve altered S-A behavior l~ti~L Smith, I~ng H~eded rat CONC [IFR l:injec~ion~ ] NiCOtine ~ relnforce~ re~ali~e 1o ~A r~le i~verse[y dc~e rel~led I]9~}1 mln:food pellel~]; several niCOtine sa~ine; miLc~ effect~ of urine p~t during inili~l nlc~tine ~-A d~ ~z~d ~llne ~e~te~ m~nipll]atlol~ o~ S-~ ~'al(. only behavior ~cqui~iliiin n~t ~l~*r duri~¢ inltla] nlc~ine exposure ~tablishrnenl Smith and L~ng Hooded rat FR h one nlcoti~e d~e aed Ni¢ollne a r~in~er wilh and 119~01 ~[ive reded wlthout CONC food delivery s~hedule in ~oed~epri~L~, bul not food~.~ted. ~ats Go]dberg, Spea]mvn, Squirrel monkey Second-order scheduk. FI 1 or 2 ~icotlne m~inl,~ined high rvles Demon~raled impor~an~ o1" C, oldber~ rain (FR 10:~tlmulus~. I'ollowed of r~ponding: ral~ ~ievrea~ anci]L~ envi~nmen~:d ~inm]i 119811 by 3-mln timec~t one nlcvClne n'~rked~y when I~J svllne in n~in~ainin~ high n~l~ ¢1¸ clc~e and ~lir~ t~ted replaced n~tine, ~2) briel¸ responding ~imu~i omitted, q~l ~u~F~ct~ mecamv[arnlne pret re~te~ @ • • • • • • • • @ •

TABLE 4.--Continued Study Species I~ugherty, Milfer, To~d, Rhesus monkey K~enbeuder (I~D Reinforcement schedule F1 16 and sevond~Mer F] I rain ~FR 4~imulusr. severat nleotine deles and saline ~s~d Main findings Comments Nicotine maintained higher ~A rat~s than saline under FI ond ~t'td-t:cder schedule, but only a rr.~ginal[y effective reinfcccer wh~ c0etinuo~ly available Estabhshing nicotine as reinforcer ,'~it~d ~¢vera[ months, using procedures that ~stablish cocaine or codeine as reinforcers in few days Goldberg Bnd Spealman SqulrreJ monkey FI 5 rain follewed by lrain Nicotine and cosine Showed mco6ne can be (19~2) t[mc~u~ several nicotine and quEdit~tively siv~ilar reinfercers, punisher, similar to efectnc o~aine doses and s~line ~ compared with salin~ cvcai~e shock maintained higher rates of" responding in I of 2 monkeyS; mec~rnylamlne pret reatlylent r~uced nicotine S-A rates Si~[~er. Wa[tace, Hall L~ng-Evans rat CONC [~FR lmwotir, e~r 1 L~y~er nicotine S-A rates in rat Range ~( b~iowinhihited 11982~ rain:food pe~let~ one nicotine group with 6OHDA lesfens in schede[ed.i~duced behaviors tested n~fet~ ~t~.umbem; th~n in e~lende~ sh~m Jesloos group Spealma~ aod Gobtberg S~mrrel r~key Second-order FI L 2, or 5 rain Niec~ne ~ cocaine rv~int~ined Under beth scb~ules. ~e {15~2) (FR 10:stimt~l~l and FI ~-mln similar rates of ~pondlng ~nd and cocaine reinforcing efficacy schedules tesL~i; several nicotine patterr~ nicotine, not c~ai.e, comparable and cocaine dries and ~aline S-A decre~ to saline-like t~sted rates when mecamy[amlne pretreated Oo

o~ TABLE 4.-~Continued Study Species ~iafo~m schedute Main flnding~ CommeN~ Ater and Grifflth~ Baboon c19~3~ Expenre~nt 1: FR 2 follow~t by 15~e~ timeout; ~ve~l utcotine doses, cocaine, and saline tested Experiment ~ FI 5 mln followed by l~n ti~ut; ~veral nin~ive and cc~line ~ and saline tested; FI duratlo~ varied 1-11 rain Nieotiae marginally reinforcing. ¢ompare~ with ~allne acr~ narrow dose range Nicotine maintained higher rates of rasponding than saline, but milch lower than cocaine Or f~ in,~r~ed U-~bup~l init~l response c~rve; fiat tina~ curve ~earlier ai~tracL Ator and Griffiths ~1~1;~ Nicotine aad il~;ectlonst¢~ion responding rat~ little chaagt~ with varied FI duration Goldbe~ mad Human and FR lO followed by l-rain Monkey and httr~mtt pattorns of In both hun~qu~ and monkeys. HenningF~ld Squirrel monkey timeou~ sevtral nicotine dt:6~ t~ponding qualitatively similar: evidence of nicotine having both tlg@3a, bl and saline t~tocl nicotine injectloi~ number r~inforclng and punishing efft~ts exceeded ~line i~F.etina number tfrom study abstracts1 in 3 of 4 of both human~ arm monkey~ Hvn~ingt'~eld, Miy~ato. Hum:m FR 10 followed by l-rain Niemme injection n~mbur Nicotine and intravtaous Ja~inskl timormt; several nicotine doses generally ezceeded saline cocaine su~;eetlw effect~ similar: (1983) ancl saline tested injectinn number., uinatln¢., t~ieotine ha~ both r~inforcing ir~j~'tioa n~mber inversely effects arm punishing effects related to nin0tiw dose: rfieotlne suporessed pcstsession cigarette smoking • • @ • • • • • @ @ •

TABLE 4.~ntinued Study Species Reinforcevaent ~hudule Main findings Comments Ri~,~er and Coldberg ]~z~le dog FR 15 followed by 4-rain N~c41ne and cocaine maintained Substantially greater response ~1983~ time.t; ~veral nio~in¢, qulltatively similar patterns of tales maintained with c'acaine cocaine, and ~Hne des~ t~'~'~; responding and were ~laforeers than nio~tine PR schedule also ttsed relative to ~aline; meeamylamine pretreatment reduced nicotine, not oacalae, S-A Cox. Goldsteln. Nelson Wistar rat FR 1; several nicotine doses and Nicotine S-A rates higher than Active lever responding rates {I9841 saline tr~tad; a seeaud inactive saline, but result in part of low ~±40 re~pan~/12 hrsk only lever available ~ as~ss aonspeclfu" activity increases about twice as high ~ inactive ~lF~:il-~ activlty-mc~ng lever rates nicotine effects Prada and Goldberg Squirrel monkey FR 30 followed by 4rain or 10- At 4-mla tlme~t, ~rall Nicotine iv inj~ti~ and food {195.51 see tim~ut; one nicotine d~e nR.~tir~-main~laud response !~ll~ ~1i~1~' maintained tested rate range 0..~2.4 r,~seslser; similar high respoa~- rates at lOsec tiraeo~ r~pc~ding (from study abstraetl poorly maintained Slifer and Ralster Rhesus menkey Experiment 1: FR I and CONC At CONC condition, nicotine S-A At some doses, nicotine {19~51 [~FR l:nlcotlne}(FT 5-min~foud at rate higher than saline; at maintained higher S-A rates pelk~D]; se~ral nicotine doses FR I condition, nicotine S-A than at FR 1 couditlon saline and saliav tested wlthoat CONC foud (preliminary report, Slifer q1983pp ~x~erlm~nt 2: FR 1~ saline and Nicotine a reinforcer relative ~ Nicotine dose changes produced several nleotine dese~ saline, but response rates low only ~ll r~pon~ rate ~ubsthutud for co~lae relative ~ single vaoine dose changes tested .4

TABLE 4.~Continued GO O~ Study Species Reinforcement ~:hedule Main I~ndings ('~mlment~ Goldberg and Htlm:t~ ~nd Mo;tkey~: ~ l(~;,~f~3, with 1.. 2.. ~icollne n~llnlained aboul ~l~onl lexl ~f I~lkp Hennlng;-t~d s(~uirre[ monkey or 4-rain limeoui~ l~/s~" overall r~ate ~ FR ~l~b ltuma~: FR I~X}. wilh 1.5-. rt~c~ond~ng al high FR ~nd timcc~i. 1(~. o~- 20-mln tlmeout$ in both ht]mat~ and nlc~tk~, Naruse~ A~arni~ I~eda, Rat FR L FR 4. FR 8: ~!ve~[ Higher nicotine inj~cli~n dries Ni~tine a relatively weak Ohmu~ ni¢oline du-~e~ ~nd ~l[ine feted Ilo ~nd 30 it~ikg~ rnaint~[ne~ relnl~rcer after l~ly I1~ responding above saline ~nt~[ avai[ubi[ity {evel~ De I~ Garza and Rhesus monkey~ FR IC~ ~.~li~e ~nd ~e~rer~l Ni~'~ine a reinforcer re~tlve I~ F~i deprlw~ion ~ni~ican!l~ J~han~3n nlcotlne~ d~rnphet~mine, ~tllrt~ but s'e'~potl~e rale~ ~ery i~cre:~-,ed response r~e ~*r I~ 119~71 dlazep~m, and perph~na~i~ I~' telatlve to cocaine and (~. nicotine d~ in only I o~¸ :l dc~s ~ubs~itu~vd for cocaine ~mphetamine monkeys ~(Y~: FR. fixed ~tio: S{~A. ].~ d~ph~ [ ] <lin~lh yl a nlilu:et bane {~CI: ~)R prog~.~lvt. ~lio: ~'~ tixe~ t in~.~ FI. [iv.err nuvr ~al~ (X~(' ~n~t~rrerll .

peared to hasten acquisition of the nicotine self-administration (Smith and Lang 1980). Since 1981, methodology for studying the reinforcing effects of nicotine has shifted away from continuous reinforcement schedules and toward schedules of self-administration in which responses are only intermittently reinforced by nicotine injection (Goldberg et al. 1988). Such intermittent schedules appear to more closely approxi- mate the patterns of human cigarette smoking behavior in which nicotine is taken in intermittent small doses (puffs) and with even greater intervals between dosing resulting from periods of time between cigarettes (Henningfield 1984). On a variety of intermittent schedules, i.v. nicotine was shown to function as an effective reinforcer, maintaining overall rates of responding ranging from 0.I to more than 1 response/sec (Tab!e 4). These increases in behavioral responses maintained by nicotine were obtained without the use of food deprivation or concurrent inducing schedules of food delivery. In one series of experiments with squirrel monkeys, Goldberg and Spealmnn (1982) and Speaiman and Goldberg (1982) utilized a fixed- interval schedule in which the first response to occur after a 5-rain interval elapsed produced an i.v. injection of nicotine followed by a l- rain period of drug nonavailability Ctimeout"). Responses during the 5-rain intervals had no specified consequences, and daily sessions ended after 10 intervals or 2 hr. Under these conditions, nicotine functioned as an effective reinforcer: (1) peak rates of responding maintained by nicotine ranged from 0.1 to 0.8 respense/sec and were similar to those maintained by cocaine; (2) as nicotine dose per injection was increased from 3 to 300 mg/kg, rates of responding first increased and then decreased; (3) rates of responding maintained by nicotine were about fourfold to eightfold higher than those main- tainod during saline substitution; and (4) daily intramuscular treatment with I mg/kg of mecamylamine reduced rates of respond- ing maintained by nicotine to saline-control levels but had no effect on responding maintained by cocaine. Thus, nicotine satisfied all the criteria discussed in Chapter V as an effective reinforcer. Particular- ly striking was the finding that although injection doses of nicotine above 30 mg/kg produced vomiting during the session, one or more of these higher doses continued to be maintained near maximal rates of responding in four of the six monkeys studied. The results of Goldberg, Spealman, and Goldberg (1981) showing nicotine to be an effective reinforcer have been extended in subsequent studies. For example, high rates of responding were maintained on reinforcement schedules of nicotine injection in which the number of responses per injection was fixed at some intermediate level (e.g., 1 injection/15 responses; such contingencies are termed fLxed-ratio schedules). Risner and Goldberg (1983) used a 15-response fixed-ratio schedule of nicotine injection with 4-rain 189

timeout periods following each injection in beagle dog~. Nicotine was an effective reinforcer in all dogs: (1) peak rates of responding were about 0.3 response/see, but higher rates of responding were main- tained by cocaine; (2) as the injection dose of nicotine increased from 10 to 100 mg/kg, response rates first increased and then decreased at the highest dose; (3) peak rates of responding maintained by nicotine were about fifteenfold greater than those maintained by saline; and (4) rates of responding maintained by nicotine but not by cocaine were reduced to saline levels by presession treatment with mecamy- lamine. Although cocaine maintained higher rates of responding than nicotine in the dog, fixed-ratio patterns of responding main- tained by nicotine and cocaine were similar: a pause in responding at the start of each fixed ratio was followed by a change to steady • responding at. a high rate until nicotine or cocaine was injected. In other studies Goldherg and Henningfield (1983a,b, 1986) used 10- to 30-response fixed-ratio schedules of i.v. nicotine injection in squirrel monkeys. When a l-rain timeout followed each injection, nicotine maintained rates of responding higher than did saline, although overall rates of responding were very low. When the timeout value was increased to 4 min (Prada and Goldberg 1985; Goldberg and Henningfield 1986) making maximum frequency of nicotine injection comparable to that of earlier studies by Goldberg and colleagues, nicotine maintained high rates of responding that ranged from 0.3 to 2.4 responess/sec in different monkeys. Differences between nicotine and cocaine in their overall efficacy as intravenously delivered reinforcers have been found when the drugs are compared on progressive-ratio schedules. Risner and Goidberg (1983) studied beagles under a schedule in which the fixed- ratio requirement was increased daily until responding was no longer maintained. Cocaine maintained higher fixed-ratio values than did nicotine on this progressive-ratio schedule, although maximal fixed-ratio values for nicotine were well above those for saline. Yanagita (1977) obtained similar findings on a progressive- ratio schedule of i.v. nicotine or cocaine injection in rhesus monkeys (Chapter V). Nicotine was also studied in the baboon using an intermittant schedule of reinforcement and was found to be a weak reinforcer. Ater and Griffiths (1983) used a 5-min fixed-interval schedule of i.v. nicotine injection in baboons with l-rain timcout periods. Peak rates of responding were higher than rates maintained during saline substitution. However, rates of responding maintained by nicotine were much lower than those maintained by i.v. injection of cocaine. In addition, as the injection dose of nicotine was increased from 10 to 560 mg/kg, rates of responding first increased and then decreased at the highest doses in one baboon. With the other two baboons, rates of responding either showed little change or decreased as injection dose 190 •

was increased. Those variable dose-response data were consistent with the conclusion that nicotine was only a weak reinforcer in the baboons. When cigarettes are smoked, a variety of environmental stimuli arc intermittently associated with the pharmacologic actions of nicotine (e.g., pleasure and relief from withdrawal). These stimuli themselves appear important in controlling and strengthening repetitive cigarette smoking (e.g., removal of the sight and smell of cigarette smoking) ((}ritz 1978). An experimental model for investi- gating the role of drug-associated stimuli is the second-order schedule of drug reinforcement. Second-order schedules of reinforce- ment involve the intermittent pairing Or association of an environ- mental stimulus with the primary reinforcer; these stimuli are used as "secondary" or "conditioned" reinforcers to maintain chains of behavior leading eventually to the delivery of the primary reinforcer (Goldberg, Kelleher, Morse 1975; Katz and Goldberg, in press). These schedules add an additional component of relevance to the study of cigarette smoking: cigarette smoking involves the pairing of many such environmental stimuli (visual, olfactory, taste, and tactile) with the effects of nicotine Administration. Studies of i.v. nicotine on second-order schedules of reinforcement have shown that (1) nicotine can establish previously neutral stimuli (e.g., colored lights) as conditioned reinforcers when injections are paired with light presentations, (2) such schedules can result in high and persistent rates of drng.seeking behavior, and (3) the presenta- tion of the stimuli themselves (in the absence of nicotine injections) could sustain substantial amounts of drug.seeking behavior. Gold- berg, Spoalman, and Goldborg (1981) and Spealmun and Goldborg (1982) used n second-order schedule of nicotine injection in which completion of each 10-response fixed ratio during a 2-, 3-, or 5-rain interval produced a brief visual stimulus; the first fixed ratio completed after the specified fixed interval elapsed produced both the visual stimulus and i.v. injection of drug. In these studies, nicotine functioned as n powerful reinforcer: (1) peak rates of responding maintained by nicotine ranged from 0.8 to 1.7 respons- es/see and were similar to those maintained by cocaine; (2) as nicotine dose increased from 3 to 1OO mg/kg, rates of responding first increased and then decreased; (3) rates of responding maintained by nicotine were twofold to eightfold greater than those maintained during saline substitution; and (4) rates of responding maintained by nicotine, but not by cocaine, were reduced to saline control levels by presession administration of i mg/k~ of mecamylamine; (5) the brief visual stimuli functioned as conditioned reinforcers, as demonstrated by the finding that rates of responding fell markedly when they were omitted during the intervals. 191

Taken together, the results of the studies described in this Section confirm that nicotine is self-adminlstered in several animal species and in the absence of either tobacco or unique human cultural factors. It appears to be most effective as a reinforcer when intermittently available and when environmental stimuli are paired with nicotine delivery. Under these conditions, nicotine injections functioned to motivate behavior as did cocaine injections; however, cocaine injections maintained more total work output than did nicotine. Finally, studies wit~ nicotine antugonlsts further con- firmed that effects of nicotine in the brain were necessary to maintain its reinforcing actions. Human Studies of Nicotine as a Reinforcer The methods developed in animal studies have also been used to demonstrate the reinforcing effects of i.v. nicotine injections in human volunteers (Henningfield, Miyasato, Jasinski 1983; Henning- field and Goldberg 1983a; Goldberg and Henningfield 1983a,b, 1986). In these studies all subjects had histories of tobacco use and subjects were not allowed to smoke 1 hr before or during 3-hr sessions: During test sessions every 10th lever press produced an i.v. injection of either nicotine or saline followed by a 1-min timeont. In one study • (Honningfleld, Miyasato, Jasiaski 1983), nicotine was available on some days, while saline was available on ether days. In other studies (Henningfield and Goldberg 1983a; Goldberg and Henningfield 1983a,b), nicotine and saline were concurrently available for re- sponding on alternate levers. With both approaches, all of the subjects initiated self-administratlon of nicotine. Nicotine injections were regularly spaced throughout each session, and the rate of self- administration was inversely related to dose. When saline was substituted for nicotine, rates of responding usually decreased; responding that did occur for saline occurred predominantly at the start of each session and was erratic in temporal patterns. In another study, the fixed-ratio value was then increased to 100; following each injection, subjects then had to wait 20 mJ~ before another injection could be obtained (Swedburg, Henningfield, Gold- berg, in press). Under these conditions rates of responding increased and ranged from 0.4 to 2 respanses/sec, similar to those seen with squirrel monkeys and dogs in the studies previously described. These studies of i.v. nicotine self-administratlon demonstrated conclusively that nicotine itself can serve as an effective reinforcer in humans. Nicotine as an Aversive Stimulus Even dependence-preducing drugs do not have invariant positive reinforcing effects; they may be aversive under some conditions (see Chapter V). Furthermore, averslve effects are an additional mechan- $ 192 •

ism by which drugs can modify behavior and may be important in gradually increasing the total amount of control which is exerted by the drug over the individual. Such effects of nicotine could be important in limiting the total amount of cigarette smoking or even in determining when the cigarette is discarded. The potential effects of nicotine to produce severe discomfort and thereby limit further intake have been part of the history of nicotine which has developed over the centuries (Lewin 1931; Dixon and Lee 1912). Two types of laboratory studios have [men conducted to assess possible aversive effects of nicotine. The studies, involving animals and/or humans, showed that nicotine (at high levels) can serve as a punisher to suppress behavior leading to the delivery of another • reinforcer, and as an aversive stimulus or negative reinforcer to maintain behavior that either terminates or prevents injections of nicotine. In one series of studies (Goldbsrg and Spealman 1982, 1983), squirrel monkeys responded on a two-component fixed-ratio schedule of food presentation. In both components, every 3Oth lever press produced a food pellet. In the punishment component, which was signaled by a red light, the first response in each fixed ratio produced an i.e. injection of nicotine. When responding produced 10- or 30- mg/kg injections of nicotine during the punishment component, responding was selectively suppressed in that component in a dose- related manner. When saline was injected, however, rates of responding for food were no longer suppressed. Similar findings were obtained when electric shock was compared with nicotine in the same studies. Administration of mocamylamine, but not hexatrietho- nium, reduced the punishing effects of the nicotine, showing that the effects were centrally mediated. Futhermoro, these antagonists did not reduce the aversivo effects of the electric shock, confirming that the effects of nicotine were due to nicotine actions at nicotinic receptors and not to more general possible effects of nicotine. The potential aversive effects of nicotine have been experimental- ly demonstrated in human subjects in a preliminary experiment by Hsnningfield and Goldberg (1983a). Human volunteers who had been recruited for studies of i.e. nicotine self-administration and who did not self-administer nicotine during initial sessions were tested under a concurrent schedule of nicotine avoidance and nicotine self- administration. Two levers were present, and injections of nicotine were programmed to occur every 15 or 30 rain. Pressing the left lever 10 times avoided the impending injection, while pressing the right lever 10 times produced an injection. Higher doses of nicotine (1.5 to 4 rag/injection given over 10 sec) resulted in increased rates of pressing on the left lever, and fewer injections occurred. Subjects never completed the 10 responses on the alternate lever required to produce an injection. When saline was substituted for nicotine, 193

responding desreascd and the number of injections received marked- ly increased. Analogously, in these same subjects scores on a visual line analog scale for rating "negative or undesirable" effects were directly related to nicotine dose, and declined to zero when saline was substituted for nicotine. Nicotine as an Unconditioned Stimulus The preceding studies have largely evaluated the effects of nicotine administration on some behavior which was associated with the drug by a specific behavioral contingency. But drugs can also directly elicit responses which then might become conditioned to occur in the presence of whatever stimuli were associated with those effects. The effects may be seen as positive or negative and may be s~sociated with either increasing or declining drug levels in the body (i.e., drug taking or drug withdrawal). Two general conditioning paradigms are used to evaluate the unconditioned stimulus effects of drugs and have been used to test nicotine: the conditioned place preference and aversion paradigm, and the conditioned taste aversion paradigm. In addition to a discussion of these paradigms, data obtained from the practical application of such findings in the treatment of tobacco dependence will be summarized. Conditioned Place Preference and Aversion The place preference and aversion paradigm has been increasingly used to evaluate the potential of drugs to produce dependence (Bozarth 1983). It may be used to assess the positive and negative subjective states induced by drugs and other chemicals. In the place- conditioning procedure, an animal is exposed to the effects of a drug in a novel, distinctive environment. Another environment is paired with the administration of the drug vehicle (e.g., saline). Subsequent- ly, the subject is given a free choice of both environments while not under the influence of the drug. It is currently hypothesized that the formation of place preferences or place aversions depends on the association of the interoceptive drug effect with an external stimulus (e.g., the particular environmental context of the place-conditioning apparatus). Nicotine has been shown to condition both positive and negative effects in this paradigm. The first published study of the place-conditioning effects of nicotine (Fudala, Teoh, lwamoto 1985) indicated that nicotine, at doses from 0.1 to 1.2 mg/kg administered s.c. to rats, produced beth a place preference and place aversion depending upon the dose. As discussed in Chapter V, the ability to condition both place prefer- ences as well as place aversions is characteristic of several depen- dence-producing drugs. A dose of 0.8 mg/k~ was found to condition a I @ 194 •

pi~ce preference for previously nlcotine-paired environmental cues in the greatest proportion of animals. At the lowest effective place- conditioning dose of nicotine, 0.1 mg/kg, an almost equal proportion of animals exhibited place preferences and place aversions. This investigation also indicated that mecamylamine, but not hexametho- nium, blocked the place preference-producing effects of nicotine, suggesting that this nicotine-induced effect was centrally mediated. Subsequent studies have extended the findings of Fudala, Teoh, and lwamoto (1985) discussed above. Using a more conservative classification method in categorizing their subjects, Fudala and lwamoto (1986) observed that nicotine produced a conditioned place preference only within the dose range previously tested. Further- more, nicotine conditioned a place preference when the drug was administered immediately prior to conditioning sessions, but not when administered from 20 to 120 rain prior to conditioning. Depending on the timing of nicotine administration, either place preferences or place aversions may be produced. For example, at doses between 0.2 and 0.8 mg/kg, a dose-dependent place aversion was induced when nicotine was administered 5 rain or less following an animal's exposure to the conditioning environment (Fudala and lwamoto 1987). One other group of investigators, Clarke and Fibiger (1987), using the same dose range of nicotine as in the two aforementioned studios, found no nicotine-inducod conditioned place preference in rats. However, the two investigative groups used experimental methods that differed considerably, including differ- ences in apparatus design, olfactory cues, number of conditioning trials performed, and time of conditioning relative to nicotine administration. The finding that nicotine administration can lead to conditioned responses in animals provides additional evidence of nicotine's potential to control behavior by this basic learning process (i.e., Pavlovian or classical conditioning, see Chapter V). Conditioned Taste Aversion and Rapid Smoking During conditioned taste aversion experiments, the presentation of an aversive stimulus after the consumption of a distinctively flavored solution causes rejection of the solution when it is presented at a later time (Palmerino, Rusiniak, Gareia 1980; Chapter V). A variety of dependence-producing drugs have been found to be effective at inducing taste aversions (for example, Wise, Yokel, DeWit 1976; Suzuki et al. 1983; Hunt and Amit 1987; Chapter V). Findings specific to nicotine are presented here. Etscorn (1980) reported that a large intraperitoneal (i.p.) close of nicotine, 2 mg/kg, conditioned taste aversions to 20 percent (weight per volume) sucrose in Swiss-Webster mice with the tw~bottle choice test paradigm. Etscorn and colleagues (1986) also reported that i.p. injections of 1, 3, and 9 mg/kg of nicotine in golden Syrian hamsters 195

induced dose-related conditioned taste aversions to 0.1 percent sodium saccharin solutions with a single.bottle choice paradigm. Kumar, Pratt, and Stelerman (1983) reported that s.c. injections of nicotine bitartrate could condition taste aversions to either 0.1 percent sodium saccharin or 0.9 percent sodium chloride solutions at doses as low as 0.08 mg/kg in Lister hooded rats with a two-bottle choice paradigm. The conditioned taste aversion was induced by nicotine in a dose-related manner; stronger taste aversions were induced by nicotine after four conditioning trials than after one or two trials. The S-nicotine (the nicotine form normally delivered in cigarette smoke) was approximately five times as potent as its stereoisomer in conditioning taste aversions. Mecamylamine, 0.I to 2 mg/kg administered before each conditioning trial, blocked the ' development of taste aversions produced by 0.4 mg/kg of nicotine; hexamethonium, 1 to 10 mg/kg, had no effect. Other studies have confirmed the pharmacologic specificity of nicotine-induced taste aversions; that is, Iwamoto and Williamson (1984) also found that the development of nicotine-conditioned taste aversions could be prevented in rats by pretreatment with mecamy- lamina, 3 mg/kg, but not wlth 1 mg/kg of hexamethonium. In an analogous study, the pharmacologic specificity of apomorphine- (dopamine agonist chemically derived from morphine) conditioned taste aversions was investigated in rats by establishing the response • to both apomorphine and nicotine following pretreatment of the animals with pimozide (Kumar, Pratt, Stolerman 1983). Pimozide is a dopnmlne antagonist that blocks many of the effects of apomor- phine. Pimozide pcetreatment reduced the strength of the condi- tioned test aversions to apomorphine but not to nicotine, confirming a certain degree of pharmacologic specificity of the conditioning effects of these two chemicals. Finally, an intraventricular microin- jetties of 5 mg/kg of the quaternary nicotinic eholinergic ganglionic antagonist, ehlorisondamine, in hooded Lister rats blocked the development of conditioned taste aversions to 0,1 percent sodium saccharin or 0.9 percent sodium chloride induced by nicotine injected 9 to 16 days after the chlerisondamine (Reavill et al. 1986). These data indicate that nicotine, like some other drugs, is capable of conditioning taste aversions in a dose-related manner in rodents (see Chapter V). Because mecamylamine, but not hexamethonium, blocks nicotine-conditioned taste aversions, the mechanism by which nicotine conditions taste.aversions appears to be centrally mediated. Conditioned taste aversion studies in which various combinations of nicotinic agonists and antagonists are given have also been useful in helping to identify specific brain mechanisms of nicotine's behavior modifying properties (see review by Stolerman, in press; also see Chapters HI and V). 196 •

The fact that nicotine can be used to elicit aversive effects has been put to practical application in the treatment of cigarette smoking (Chapter V), generally to associate aversive effects of high doses of nicotine with the taste, smell, and inhalation of cigarette smoke. Variations on this procedure have been termed "rapid" smoking or "aversive" smoking procedures; the clinical results of these procedures have been mixed (see Chapter VII). iw . Nicotine: Withdrawal Reactions (Physical Dependence) The preceding Sections have shown that cigarette smoking is an orderly form of drug self-administration. The role of nicotine in controlling this behavior is similar to the role of other psychoactive drugs in the determination of other forms of drug dependence (see Chapter V). Nicotine can serve as a highly effective positive reinforcer, and deprivation of cigarette smoking and presumably of nicotine itself can increase the reinforcing efficacy of cigarettes (Henningfield and Griffiths 1979). If longer periods of deprivation are associated with a discomforting withdrawal syndrome, this would constitute an additional mechanism by which the reinforcing efficacy of nicotine would be further increased. The drug effect which enables such discomforting withdrawal is physical depen- dence. Physical dependence refers to physiological and behavioral alterations that become increasingly manifest after repeated expo- sure to a pharmacologic agent. The primary indication of physical dependence is an abstlnence-associated withdrawal syndrome, al- though tolerance is a frequent concomitant (Kalant 1978; Cochin 1970; Kalant, LeBlane, Gibbons 1971; Eddy 1973; Clouet and lwatsubo 1975; Yanagita 1977). Physical dependence and tolerance are discussed in greater detail in Chapter V. Tolerance to nicotine has been studied since the 19th century and is well documented (Langley 1905; Dixon and Lee 1912; Gfllman et al. 1985). As reviewed in Chapters II and V, nicotine produces tolerance to a variety of behavioral and physiological responses. Until the 1970si however, physical dependence on tobacco was not rigorously studied, although there was evidence for a syndrome of withdrawal that could accompany abstinence from chronic cigarette smoking (Lewin 1931; Weybrew and Stark 1967) and that was significantly involved in attempts to quit smoking (Dorsey 1936). The clinical significance of the tobacco withdrawal syndrome has also been formally recognized by professional organizations such as the American Psychiatric Association (APA) (1980, 1987) and the American College of Physicians (1986). These observations, along with the evidence that nicotine produces tolerance (Chapter II), led to the conclusion that nicotine exposure produced physical depen- 197

dence {Jaffe 1985; Jaffe and Jarvik 1978; US DHHS 1986b; APA 1980). Conclusions that nicotine exposure produced physical dependence were also consistent with early data which suggested that i.e. nicotine delivery seemed to relieve withdrawal from cigarettes and may have produced physical dependence in a nonsmoker (Johnston 1942). Other supporting observations included the finding that abrupt reduction of the nicotine in cigarettes (i.e., low nicotine.yield cigarettes) resulted in behavioral and physiological withdrawal signs including discomfort and the seeking of regular cigarettes (Finnegan. Larson, Hang 1946; Knapp, Bliss, Wells 1963). However, the rigorous scientific methods of the kind that were developed to evaluate withdrawal from opioids and sedatives (Himmelsbach 1942; Isbell 1948; Isbell et ah 1955; Chapter V) were not applied to the study of the tobacco withdrawal syndrome until the late 1970s. Therefore, the data available at the time of the 1964 Report of the Surgeon General's Advisory Committee on Smoking and Health were not considered conclusive (US DHEW 1964). The present Section reviews characteristics of physical dependence on nicotine, including the relationship of nicotine intake to withdrawal magnitude and the role of both environmental and pharmacologic factors which influence the course of withdrawal. Criteria for Physical Dependence on Nicotine and Clinical Characteristics of the Withdrawal Syndrome Similar kinds of phenomena characterize withdrawal syndromes from all drugs that produce physical dependence. If physical dependence on nicotine occurs, these same phenomena should be observed (see Chapter V; Martin 1977; Thompson and Unna 1977; Woods, Katz, Winger 1987). Based on these phenomena, criteria for establishing that physical dependence on nicotine occurs include the following: (1) Termination of cigarette smoking should be accompa- nied by changes in mood, behavior, and physical functioning. (2) Some of these changes should be in a direction which is opposite to those produced by cigarette smoking and should return to the baseline levels observed during chronic tobacco administration ("rebound effects"). (3) Physiological withdrawal effects should be reversible by nicotine administration. The tobacco withdrawal syndrome as described by the APA in the revised Diagnostic and Statistical Manual (DSM III-R) (APA 1987), provides a clinical description (Table 5). Several of the symptoms of the nicotine withdrawal syndrome carrespond to effects of nicotine that are either known or suspected to promote tobacco dependence as discussed in Chapter VI. It should be noted that the sequelae of tobacco abstinence include a range of responses which do not share the same underlying mechanisms. For example, some 198 •

sFmptoms are transient responses which are opposite those produced when nicotine is given and which subside within a few days or weeks of nicotine abstinence; such responses are presumed to reflect a physiologic rebound occurring in the absence of chronic drug exposure. Other responses are also opposite those produced by nicotine administration but appear to primarily reflect the removal of nicotine exposure, and which may occur whether or not sufficient nicotine had been taken to produce physical dependence. An example of the latter type of response is body weight. Nicotine can directly suppress appetite and body weight, often below the value at which it would have been had nicotine not been taken; removal of nicotine is then accompanied by a stable increase in body weight. Various lines of scientific evidence are available to characterize physical dependence on tobacco and to evaluate the specific role of nicotine. These data include surveys, treatment studies, and experi- mental laboratory studies and are briefly reviewed in this Section. Retrospective Survey Data Retrospective studies have been conducted with ex-smokers who were participating in major surveys (Wynder, Knufman, Lesser 1967; Hughes, Gust, Pechacek 1987) or who were patients with chronic r~piratory problems (Bums 1969; Mausner 1970). Other studies were conducted using subjects who responded to advertisements in newspapers (Pedersen and Lefcoe 1976) or were contacted by word of mouth (Trahir 1967). The subjects in these studies had either quit smoking recently, had quit smoking for more than 1 year, or had at least one episode of remaining abstinent for 24 hr. Although the reliability of these data are limited because they are from retrospec- tive self-reports, they provide information on the prevalence and nature of symptoms which may be experienced by smoke-deprived persons and acutely abstinent smokers. Symptoms reported by significant numbers of ex-smokers includ- ed: ~'crnviug" for tobacco (Hughes, Gust, Pechncek 1987; Trahir 1987; Burns 1989; Mausner 1970; Pederson and Lefcoe 1976); restlessness, nervousness, or irritability (Trahir 1967; Wynder, Knufman, Lesser 1967; Burns 1989; Mausner 1970; Hughes, Gust, Pechacek 1987); anxiety (Hughes, Gust, Pechacok 1987); impatience (Hughes, Gust, Pechacek 1987); difficulty concentrating (Trahir 1967; Wynder, Kuufman, Lesser 1967; Hughes, Gust, Pechacok 1987); somatic or physical complaints (Hughes, Gust, Pechacek 1987; Pederson and Lefcoe 1976); increased appetite (Wynder, Kaufman, Lesser 1967; Hughes, Gust, Pechacek 1987); increased food intake C~Vynder, Kanfman, Lesser 1967); and weight gain (Trahir 1967; Wynder, Kaufman, Lesser 1967; Mausner 1970; Pederson and Lefcoe 1976). Measures of the incidence and magnitude of signs and symptoms vary across studies, at least partly because of the diversity of the 199

TABLE 5.--Diagnostic categorization and criteria for nicotine withdrawal Nicotine-induced organic mentaL disorder 29200 Nicotine Withdrawal The essential feature of this dis0~der is a characteristic withdrawal syndrome ~ue to the ahrupl cessat~n of or redtlcti~il in (he Iase of nicot(he- contvintog substances leg,, cigarettel, cigars, and pipes, chewlng tobacco, or nicotine gum) that has been at least medera~e in dttration arid amount. The eyndrome includes craving for nicotine; irritability, eustration, or anger: anxle~y; difficuLty concetttrating; regtle~sness~ decreased heart rate; /~nd increased appetite or weight gain. In many heavy cigarette Jmokerll, chalages in mood and perfe~rmartce that are related to withdrawal e~n he detected within 2 hours after the last tobacco use. The ~nse of craving appears to reach u peak within the first 24 hours after cessation of tobacco use, and Srndually declines thereafter over a few days to several weeks¸ In s~y given case it is difflcu[t to* distinguish a withdrawal effect from the emergence of psychological trMt~ that were st~ppressedl controlled, or altered by the effects of nicotine or from s heh&vioral reaction le~., frustration) tv the to~s of a reJbforeer~ MiLd symptoms of withdrawal may ot~tlr aeei" 6wftching to low tar/nicotine cigarettes ned sfter stopping the use of smnhe]ess (chewJngl tobacco or ni¢otlne gum The dlasr~eLq d Nfeoti~e Withdrawal ia u~uaJJy se)f-ev$~em from the person's history, and disappearance of the symptoms if smokJ~g Js resurned is confirmatory. However, withdrawal acre other l~ycSoactive st~bgt~ne*s m~ly take place simultaneously, and produce similar sympt~rnS. Di~guc~tfo Criteria for Nicotine Withdrawal A. Daily use of nicotine for at lealt *everaJ weel~ e Abrupt ¢e~d, ation of nicotine use, or redu~tlon in the amount of nicotine used. followed w~thla 24 hours by at le~t fo~r of the following si~s: (I) Craving for nicotine (2) Irritability, frustration, or anger Anxiety (4) I~ffficuity concentrating (5) Restiessness (6) Decreased heart rate (7) Increased ap~tit* or weight gain SOURCe: Condense~ from the Ar~ericBn i~¥¢hlatric Ass~i~t~on (19~71 measuring instruments and techniques used, questions asked, and populations examined. Collectively, the results of many such studies suggest that most nicotme.deprlved cigarette smokers experience at least one symptom of the tobacco withdrawal syndrome, that between one-fourth and one-half show significant withdrawal, and that about one-fourth report no withdrawal at all (Pederson and Lefcoe 1976; Wynder, Kaufman, Lesser 1967; Hughes, Gust, Pecha- cek 1987; Gritz 1980; Henningfield 1984). Of those persons who retrospectively report experiencing no withdrawal symptoms, it is unclear whether they were not physically dependent, whether the assessment instruments were not sufficiently sensitive, or whether 2OO •

some persons are less impaired or discomforted by withdrawal symptoms. Prospective Data from Laboratory and Nonlaboratory Studies Cigarette smokers have been studied both in laboratory and nonlaboratory settings using a variety of self- and observer.adminis. tered tests measuring subjective, behavioral, and physiological signs and symptoms that accompany tobacco deprivation. The studies have examined changes in functioning resulting after periods of tobacco deprivation ranging from 1 hr to 21 days. Most studies have obtained both baseline and deprivation measures; a few studies have incorpo- rated a control group of continuing smokers or nonsmokers; and a few have obtained data after smokers resumed smoking or were given nicotine pelacrilex gum. The studies included ones which were conducted while the subjects were residing on a research ward, were living in their usual environment, or were paying occasional visits to a clinic for smoking cessation treatment. The symptoms reported in these studies were similar to those obtained from the retrospective studies, demonstrating generality across method and setting. These symptoms included the following: "craving" for tobacco (Gritz and Jarvik 1973; Hatsukami et al. 1984; Gilbert and Pope 1982; Shiffman and Jarvik 1976; Cummings et al. 1985; Hughes and Hatsukami 1986), irritability or anger (Myrsten, Elgerot, Edgren 1977; Elgeret 1978; Weybrew and Stark 1967; Hughes and Hatsukami 1986), anxiety and tension (Mrysten, Elgerot, Edgren 1977; Hughes and Hatsukami 1986), restlessness (Hughes and Hatsukami 1986), impa- tience (Hughes and Hatsukami 1986), depression (Hatsukami at al. 1984), problems with concentration (Hatsukami et el. 1984; Weybrew and Stark 1967; Myrsten, Elgerot, Edgren 1977; Frankenhaeuser et el. 1971; Hughes and Hatsukami 1986), drowsiness or fatigue (Weybrew and Stark 1957), sleep disturbances (Hatsukami et al. 1984; Larson, Haag, Silvette 1981; Weybrew and Stark 1967; Myrsten, Elgerot, Edgren 1977; Hughes and Hatsukami 1986), and increased hunger or appetite (Myrsten, Elgeret, Edgren 1977; Hughes and Hatsukami 1985). In one study (Hughes and Hatsukami 1986), each subject had a spouse, relative, or friend rate some of the symptoms of withdrawal to verify self-report. These observer ratings of irritability, anxiety, restlessness, drowsiness, fatigue, impatience, and somatic complaints were all significantly related to their respective subject's ratings, thus adding to the validity of reports of these symptoms. These researchers found that the most common self-repert symptoms were increased irritability (80 percent), anxiety (87 percent), difficulty concentrating (73 percent), restlessness (71 percent), impatience (76 percent), insomnia (84 percent), and craving for tobacco (82 percent). 201

Seventy-eight percent of the subjects reported four or more DSM-III criteria. This degree of prevalence was higher than that found in a retrospective study conducted by Hughes, Gust, and Pechacek (1987), possibly reflecting differences in the measuring instruments or the populations themselves. The physiological changes which have been found to occur after • cigarette deprivation include decreased heart rate (Knapp, Bliss, Wells 1963; Murpbee and Schultz 1968; Parsons, Avery etal. 1975; Benowitz, Kuyt, Jacob 1984; Hatsukami et al. 1984; Weybrcw and Stark 1967; Gilbert and Pope 1982; Hughes and Hatsukami 1986; West and Russell 1987; Elgerot 1978; West, Jarvis et al. 1984; Henningfield 1987a) and decreased cortical arousal as evidenced by decreases in peak alpha frequency and increases in low frequency activity which appear to be associated with drowsiness and decreased vigilance (Knott and Venables 1977, 1979; Ulett and Itil 1969; Hernlng, Jones, Bachman 1988; Herning 1987). Knott and Venables (1978) hsve also found that the visual evoked response in tobacco- deprived smokers showed faster lateneies and larger amplitudes for low-stimulus intensities than among nondeprived smokers and nonsmokers. They concluded that deprived smokers experience CNS hypersensitivity and, as a result, may experience visual stimulus input more easily and strongly. Hall and colleagues (1973) reported reduced auditory evoked response (AER) amplitudes during tobacco withdrawal. Blood pressure (Benowitz, Kuyt, Jacob 1984; Murphee and Sehultz 1968; Knapp, Bliss, Wells 1963) and respiratory rate (Parsons etal. 1976) have also been found to decrease during abstinence. Studies have also reported an increase in skin tempera- ture among tobacco-deprived smokers (Gilbert and Pope 1982; Myrsten, Elgerot, Edgcen 1977) or no change (West and Russell 1987), and either a decrease (FagerstrSm 1978) or no significant change (Hateukami et al. 1984) in body temperature among those who are classified as more dependent. Although some studies have reported insomnia and sleep disturbance following tobacco depriva- tion, tobacco.deprived smokers' total sleep time may be longer during withdrawal (Soldatos et el. 1980). Reported changes in sleep pattern include decreased latency to rapid-eye-movement (REM) sleep (Kales etal. 1970), decreased latency to light (delta electroen- cephalogram (EEG) wave) sleep onset (Parsons, Luttrell et al. 1975; Parsons and Hamme 1976), and increased total REM sleep time (Soldatos et al. 1980; Kales et al. 1970; Parsons, Avery et al. 1975). Another physical change found among tebacco-deprived smokers is an increase in weight (Grunberg 1986; see also Chapter VI). Weight increase has also been found among those who quit smoking in a number of longitudinal survey studies (Bosso, Garvey, Costa 1980). This increase in weight has been attributed to increased calorie intake (Hateukami et al. 1984; Grunberg 1982; Myrsten, Elgerot, 202 •

F~dgren 1977; Bursa et al. 1975; Gilbert and Pope 1982; Wack and Rodin 1982), decreased basal metabolism (Glanser et aL 1970; Wack and Rodin 1982), decreased energy expenditure (Hofstetter et el. 1986), or increased activity of lipepretain lipase (Carney and Goldberg 1984) (see also Chapter VI). Several studies have examined the effects of cigarette deprivation and administration on reaction time and psychomotor performance. These are reviewed in detail in Chapter V! and are only briefly summarized here. Two early studies each found considerable across- subject variability, with some subjects showing distinct deprivation- induced performance impairments which were reversed by tobacco administration, and other subjects showing impairments under the tobacco administration conditions (Bates 1922; Carver 1922). Since the studies by Bates and Carver, investigators have developed increasingly sophisticated methods of performance assessment which have led to a clearer understanding of the performance- related affects of nicotine administration and deprivation (see details in Chapter VI). For example, Heimstra, Bancroft, end DeKock (1967) used a simulated driving task and found that deprived smokers made significantly more errors on tracking and vigilance tasks than did nondeprived smokers or nonsmokers, who did not significantly differ from each other. Other research has demonstrated that smokers who were allowed to smoke cigarettes during the experimental session exhibited either no decrease or an improvement in speed and accuracy in reaction time, cognitive tests, and/or vigilance perfor- mance tasks, whereas deprived smokers most frequently show some impairment in performance tasks (Myrsten et aL 1972; Franken- haeuser et el. 1971; Elgecet 1978; Kleinman, Vanghn, Christ 1978; Anderssan 1975; Washes and Warburton 1984; Edwards et el. 1985; Snyder and Henningfield, in press; Henningfield 1986a, 1987a). A recent study using a computerized battery of such tasks found clear impairments beginning within 8 hr of the last cigarette and improving only somewhat across 10 consecutive days of tobacco deprivation; resumption of smoking was accompanied by complete restoration of performance (Henningfield 1987a). The specificity of these performance effects of nicotine was confirmed by the findings that administration of nicotine in the polasrilex gum form produced a dose-relatad reversal of all performance impairments (Snyder and Henningfield, in press; Henningfield 1987a); this effect was not related to satisfaction or reduction of "craving" because the gum produced dose-related decreases in "liking" scores and produced no reliable decrease in "desire to smoke" (Henningfield 1987a). Other changes occurring in tobacco-deprived cigarette smokers include increases in aggression scores on the Buss aggression machine (Schechtar and Rand 1974) and increases in frequency of spontaneous jaw contractions (a putative analog of aggression) 203

(Hutchinson and I~mley 1973). Analogously, monkeys withdrawn from chronic oral nicotine exposure (nicotine was placed in their drinking water) exhibited an increase in frequency of post-shcok biting (Hutchinson and Emiey 1973), The magnitude of tobacco withdrawal is related to the environ- mental context (see Chapter V for a comparison to other dependence- producing drugs). For example, Hatsukami, Hughes, and Pickens (1985) reported that smokers who were deprived of cigarettes on an outpatient basis experienced more withdrawal symptoms than those who underwent withdrawal on a clinical research ward. These findings are consistent with those of Suedfsld and Ikard (1974), who found that deprivation of normal sensory stimulation reduced • tobacco abstinence*asscoiated discomfort. It has also been observed that the diurnal variation of withdrawal discomfort found among abstinent smokers (greater discomfort in the evenings) appears to be associated with diurnal variation in the social environment (e.g., meals, departure from work, or social contact) (Shiffman 1979). Time Course of Responses to Nicotine Abstinence Drug withdrawal syndromes generally include some signs and symptoms which are opposite those produced by administration of the drug.and which then return to approximately the same values observed when drug intake was stable (rebound phenomena). The time course of different responses varies (Chapter V). The most recent studies show that several signs and symptoms df withdrawal appear to rebound within the first few days following cigarette abstinence; these signs and symptoms include increases in the urge to use tobacco, anxiety, problems with concentration, increased calorie intake, sleep disturbance, performance impairment, and general subjective distress (Hatsukami et al. 1984; Hughes and Hatsukami 1986; Schneider and Jarvik 1984; Cummings et el. 1985; Henningfield 1987a). Heart rate has been found to decrease to levels found among nonsmokem (Weybrew and Stark 1967) and may include some rebound, returning to stable ]~els between those maintained during normal cigarette smoking and those recorded during the first week of abstinence (Henningfield 1987al. The P300 response, a cognitive evoked potential component which is related to the ability to evaluate auditory stimuli (i.e., differentiate one sound from another by counting only certain sounds), showed n rebound (decrease in amplitude), with values returning to preabstinence (cigarette smoking) levels after about 3 to 5 days (Herning 1987). West, Runnel, Jarvis, Pizzey, and Kadam (1984) reported that urinary epinephrine concentrations rebounded with a significant decrease during the first 3 days of abstinence followed by a significant increase, Finally, in the squirrel monkey study of nicotine absti, nence-asseeiated biting, Hutchinson and Emley (1973) found a 204 •

distinct rebound pattern in some subjects with biting levels sharply increasing and then returning to the levels observed during chronic oral nicotine administration. Other signs and symptoms associated with tobacco abstinence do not return to levels observed during cigarette smoking. For example, weight gain has persisted for long periods of time (Blltzer, Rimm, Giefer 1977) and has also been reported to approach levels of nonsmokers (Khosla and Lowe 1971; Lincoln 1969; Chapter VI), In addition, some levels of performance impairment and associated reduction of a cognitive evoked cortical potential (N10O), which is related to attention, persists at least l0 days and may last longer (Henningfield 1987a; Herning 1987). As the preceding studies suggest, the duration of withdrawal varies among studies and as a function of the measure (Shiffman 1978; West 1984). Urges to smoke cigarettes among ex-smokers has been reported to occur intermittently, although sometimes with great intensity, for up to 9 years after cessation of cigarette smoking. These reported symptoms may represent conditioned responses to environmental stimuli associated with either cigarette smoking or deprivation, may represent a protracted physiological phase of withdrawal, or both (e.g., Wikler 1965; Jasinski 1981; Chapter V). Alleviation of Withdrawal Symptoms by Cigarette Smoking Several studies have demonstrated that the signs and symptoms resulting from cigarette deprivation are alleviated by the resump- tion of cigarette smoking. These signs and symptoms include heart rate OVIarpboe and Schultz 1968; Weybrew and Stark 1967; Henning- field lg87a), blood pressure (Murphee and Sehultz 1968), skin temperature (Myrsten, Elgerot, Edgren 1977), epinephrine and norepinephrine levels (Myrsten, Elgerot, Edgren 1977), EEG changes (Ulett and Itil 1969; Herning 1987), weight (Noppa and Bengtsson 1986), desire for food (Bursa et al. 1975), hand tremor (Myrsten, Elgerot, Edgren 1977), desire to smoke (Gritz and Jarvik 1973), and fatigue, irritation, sleeplessness, problems with alertness and con- centration (Weybrew and Stark 1967), and performance (Henning- field 1987a). Hughes, Hatsukami, Pickens, and Svikis (1984) examined the consistency of tobacco withdrawal signs and symptoms using an experimental design in which periods of cigarette smoking and abstinence were alternated in the same subjects. This study demon- strated both the consistency of the withdrawal symptomology within subjects as well as the efficacy of resumed smoking in reversing it, The most consistent withdrawal effects across subjects were supine heart rate changes, insomnia, caloric intake, irritability, rest- lessness, drowsiness, general mood disturbance (measured by the Profile of Mood States), and withdrawal discomfort. Furthermore, 205

the intensities of the withdrawal discomfort of subjects during the two deprivation periods were similar. Similarly, a study at the Addiction Research Center (Baltimore, Maryland) showed that resumption ef cigarette smoking after 10 days of tobacco abstinence was accompanied by a return to preabstinence levels of all measures including EEG, evoked cortical electrical potentials, heart rate, behavioral performance, and measures of meed (Henningfield 1987a; Herning 1987). Relationship Between Preabstlnence Nicotine Intake and Magnitude of Withdrawal Syndrome The observation that the magnitude of tobacco withdrawal reac- tions is directly related te preabstinenee levels of nicotine intake prbvides specific evidence that nicotine is the pharmacologic cause of the physical dependence. The clinical significance of these relation- ships is that both the magnitude efthe tobacco withdrawal syndreme and difficulty in quitting smoking are directly related to the daily levels of nicotine that were being ingested. The relatienship has not always been observed, however, when only crude indices of nicotine desing were used. For example, correlations between number of cigarettes smeked per day (a poor marker ef nicotine intake) (Benowitz 1983; Abrams et ah 1987; Chapter II) and withdrawal severity are mixed across studios. Some investigators have ebserved a positive correlation between the number of cigarettes smoked per day and Withdrawal severity (Wynder, Kaufman, Lesser 1967; Shiffman 1979; Burns 1969; Hall, Ginsburg, Jones 1986). Others have reported ne differences in severity of craving or other measures of withdrawal between light and heavy smokers er as a function of number of cigarettes smoked (Grits and Jarvik 1973; Shiffman and Jarvik 1976; Myrsten, Elgerot, Edgren 1977; Mausner 1970). Cum- mings and coworkers (i985) reported that although heavy smokers reported more withdrawal symptoms than light smokers, differences between heavy and light smokers were statistically significant only with respect to irritability, The most reliable measure of day-to-day nicotine exposure appears to be cotinine in biological specimens or nicotine itself (Benowitz 1983; Chapter II). Recent studies using such measures haw found significant relationships between either nicotine or cotinine levels and severity of withdrawal. Pomerleau, Fertig, and Shanhan (1983) divided subjects by their baseline plasma cotinlne levels (high or low quartiles). They found that subjects in the low-cotinine quartile exhibited less withdrawal change en the Shiffman Craving and Perception of Physlcal Signs subscales compared with subjects in the high-cotinine quartile. They also found a significant correlation between preabstinence baseline plasma cotinine levels and absti- nenco.asseclated cravlng for cigarettes, Hatsukami, Hughes, and e 2O6 •

Q Plckens (1985) established a similar significant correlation between craving for tobacco and plasma nicotine level, as well as nicotine boost. Zeldenberg and associates (1977) found that preabstinense serum cotinine was correlated significantly with the degree of difficulty in smoking cessation among males but not females. Finally, West and Russell (1985b) determined that whereas preabsti- nonce plasma nicotine levels significantly predicted craving, hunger, restlessness, inability to concentrate, and overall withdrawal severi- ty, preabstinence rates of daily cigarette consumption did not significantly predict any withdrawal effects. Smokeless Tobacco Withdrawal Syndrome A study of withdrawal reactions accompanying abstinence from smokeless tobacco products helped to determine .that the syndrome did not require inhalation of smoke and its constituents, 'which are not present in smokeless tobacco (e,g., tar and CO.), This study showed that signs and symptoms of smokeless tobacco deprivation are similar to those occurring Jn smokers after cigarette deprivation (Hatsukami, Gust, Keenan 1987). In persons who had been using a high nicotine containing brand of chewing tobacco, Hatsukami, Gust, and Keenan (1987) measured a number of potential withdrawal signs and symptoms over a 6*day period. Baseline data were collected during 3 days of regular smokeless tobaco use. The significant changes which occurred during smokeless tobacco deprivation rela- tive to the baseline included decreased heart rate and an increase in craving for tobacco, confusion, eating, number of awakenings, and total scores on a withdrawal symptom checklist for beth self-rated and observer-rated measures, These changes were simi]ar to those found among cigarette smokers who underwent a similar experimen- tal protocol, although smokeless tobacco withdrawal appeared to be less severe than cigarette withdrawal (Hatsukami, Gust, Keanan 1987). Nicotine Polacrilex Gum: Treatment and Physical Dependence Nicotine pelaerilex gum has been used to evaluate the specific role of nicotine in tobacco dependence. Experimental research and clinical observations of the ability of nicotine in the polaorilex gum form to alleviate tobacco withdrawal symptomatology provide Con- clusive evidence that the tobacco withdrawal syndrome is pharmaco- logically determined by physical dependence on nicotine. To the extent that the tobacco withdrawal phenomena described above are specific to nicotine and not characteristic of the delivery system (e.g., cigarette smoke), alternate forms of nicotine delivery should be able to sustain the physical dependence. This would be evidenced by (i) blockade of signs and symptoms of withdrawal by nicotine delivery 207

and (2) subsequent emergence of a tobacco withdrawal-like syndrome upon abrupt abstinence from nontobacco-delivered nicotine. Treatment of Withdrawal Symptoms Clinical trials and experimental studies in which nicotine polacri- lex gum is evaluated as a means to alleviate signs and symptoms of tobacco withdrawal are of relevance to the treatment of tobacco dependence (Chapter VII). In addition, however, such data are analogous to data from the classic "substitution" study methodology used to help determine the pharmacologic specificity of withdrawal reactions following use of opioids, sedatives, and alcohol (described in Chapter V). In brief, however, the objective is to determine if the withdrawal reaction from the primary substance upon which the person is dependent can be alleviated by administration of a test. drug. Several studies have examined the effects of nicotine polacrilex gum on tobacco withdrawal (Jarvis et al. 1982; Schneider, Jarvik, Forsythe 1984; West, Jarvis et al. 1984; Hughes, Hatsukami, Pickens, Krahn et al. 1984; Snyder and Henningfield, in press; Henningfield 1987a). These studies have examined two groups of cigarette smokers who were assigned in a double-blind fashion (with the exception of West, Jarvis and colleagues (1984), who used a single-blind design) to receive 2-rag polaerilex gum or placebo. The duration of cigarette deprivation during which the polacrilex gum (or. placebo) was used varied from 24 hr to 6 weeks. In general, the results consistently showed an attenuation of withdrawal signs and symptoms. For example, nicotine polacrilex gum significantly z;e" duced irritability (Jarvis et al. 1982; Hughes, Hatsukami, Pickens, Krahn et al. 1984; West, Jarvis et al. 1984), total withdrawal discomfort (Schneider, Jarvik, Forsythe 1984; Hughes, Hatsukami, Pickens, Krahn et al. 1984), somatic complaints (Hughes, Hatsuka- mi, Pickens, Krahn et al. 1984), sleepiness (Jarvis et al. 1982), unsociability (West, Jarvis et al. 1984), cognitive performance deficits (Snyder and Henningfield, in press; Henningfield 1987a), heart rate decreases (Schneider, Jarvik, Forsythe 1984; West, Jarvis et al. 1984; Henningfield 1987a), and EEG effects including changes in cortical evoked potentials (Herning 1987; Pickworth, Herning, Henningfield, in press). Other measures were less reliably alleviated; these included depression (Jarvis et al. 1982; West, Jarvis et al. 1984), anxie- ty/tension (Jarvis et al. 1982; Hughes, Hatsukami, Piekens, Krahn at al. 1984), difficulty concentrating (Hughes, Hatsukami, Pickens, Krahn et al. 1984; West, Jarvis et al. 1984), and restlessness (Hughes, Hatsukami, Piekens, Krahn et al. 1984; West, Jarvis et al. 1984). The urge to smoke cigarettes has not been found to be reliably alleviated by nicotine polacrilex gum administration (West and Schneider 208 •

1087; West 1984; Henningfleld 1987a; Hughes, Hatsukami. Pickens, Svikis 1984) except possibly at high dose levels (Nemeth-Coslett, Henningfield, O'Ksefe, Griffiths 1987). Interpretation of such data is complicated by the diverse strategies used to measure the urge to smoke or "craving" as discussed further in this Section. Of these studies, two showed nonsignificant effects of nicotine polacrilex gum on hunger (Hughes, Hatsukami, Pickens, Krahn et el. 1984; West, Jarvis et at. 1984) and one showed significant effects in decreasing hunger (Jarvis et el. 1982). More recent research shows that the anorastic effect of nicotine polaerilex gum during tobacco abstinence is directly related to the dose level (i.e., number of doses taken per day) (Stitzer and Gross 1988; Fagerstrdm 1987; Chapter VI). The dose-response relationship may explain the diversity in results when studios are compared; in some of these studies, dosing was. either poorly: controlled or not reported, or there was no verification of subject compliance with a dose regimen: As would be expected, depending on the dose administered, the efficacy of nicotine polaerilex gum for most measures of withdrawal ranges from complete reversal of withdrawal to no effect. In a study in which periods of tobacco abstinence (3 days) were alternated with periods of cigarette smoking (4 days), subjasts were given either 0", 2-, or 4-rag-nicotine-containing pieces of the pelacrilex gum (Henning- field 1987a). The subjects were given the polasrilex gum at 1 hr intervals (for 12 hr), and they chewed under the direction of research • staff. Blood nicotine and cotinine levels confirmed that this proce- dure resulted in dose-related nicotine administration; plasma coti- nine and nicotine levels at 4 mg were similar to those obtained during cig'aret te smoking (ad libltum smoking); plasma levels at 2 mg were between those at 4 and 0 rag. Measures included cognitive performance, heart rate, EEG, and self-reported symptomology. At 4 rag, all signs and symptoms of withdrawal were reduced or complete- ly reversed except the desire to smoke. The 2-rag dose produced partial reversal of withdrawal effects. Maintenance of Physical Dependence Two studies have examined withdrawal effects after deprivation of nicotine polacrilex gum. West and Russell (1985a) conducted a study in which they examined withdrawal symptoms in six people who used nicotine polacrilex gum for at least 1 year. Baseline measures of possible withdrawal effects were collected during days that the subjects were chewing 2-rag pieces of nicotine polasrilex gum. These days were the first and third days of a 4-day experiment. On the second and fourth days, subjects were given either 0.5 rng unbuffered polaorilex gum (nicotine absorption is negligible in the unbuffered formulation) to chew or no polacrilex gum. West and Russell (1985a) found significant changes for measures of withdrawal including 209

irritability, ability to concentrate, and heart rate and for composite subjective withdrawal scores. Withdrawal magnitude was slightly, but not significantly, less in the unbuffered gum than in the no gum condition. Hughes, Hatsukami, and Skoog (1986) extended the findings of West and Russell (1985a) with a longer period of observation (1 week) and a double-blind, placebo-controlled design. In the study by Hughes, Hatsukami, and Skoog (1986), eight former smokers who had been using nicotine polaerilex gum for at least 1 month participated+ The m~dn finding was that when the maintenance dose levels (2-rag polacrilex gum) were replaced with placebo, reliable symptoms of withdrawal were produced. The effects included "craving" for tobacco, irritability/hestility, anxiety, depression, restlessness, impatience, difficulty concentrating, hunger, and total withdrawal discomfort; reports from observers verified several of the effects (i.e., observer estimates of irritability, anxiety, restlessness, impatience, and total withdrawal discomfort). The scales used to measure withdrawal discomfort in the study by Hughes and c01- leagues were similar to those used in a previous study of cigarette withdrawal conducted by the same investigators (Hughes and Hatsukami 1986), thus enabling an across-study comparison between abstinence from cigarettes and abstinence from nicotine in the polacrilex gum form. Intensities and numbers of withdrawal symp- toms, except heart rate and insomnia, were similar. Taken together, the results of the abeve-deseribed studies with nicotine pelaerilex gum have helped to confirm that tobacco withdrawal is pharmacologically caused by physical dependence on nicotine. Furthermore, the results of such work are of clinical significance because they indicate that much of tobacco withdrawal symptemology can be treated with nicotine polaerilex gum. Two studies show that nicotine polaerilex gum can maintain physical dependence; this emphasizes the importance of gradually giving up use of the gum to minimize the abruptness and severity of withdrawal symptoms (see Chapter VII). Tobacco Craving The measurement of self-reported craving for tobacco and inter- pretation of resulting data are among the more complicated issues in tobacco research. Findings discussed in this Chapter that nicotine polacrilex gum administration can suppress cigarette smoking and alleviate physical signs of tobacco withdrawal while having little effect on the urge to smoke indicate that such urges are not solely determined by nicotine deprivation. Similar observations regarding urges to use other dependence-producing drugs are discussed in Chapter V (see also Childress et ak, in press). The eticitation and alleviation of the urge to use tobacco, as for other dependence- 210 •

producing substances, can be effected by a variety of pharmacologic and other environmental stimuli as well as changes in the physiolog- ical and/or behavioral state of the person (Chapter V). Conclusions regarding the measurement and treatment of urges to use drugs are complicated because the questions about urges have been worded differently among studies. For example, subjects are semtimes asked to report their "craving." Unfortunately, subjects very widely in their interpretations of the word"craving" and in their answers to questions about it (Kozlowski and Wilkinson 1987; Ludwig and Stark 1974). In addition, results concerning "craving" are sometimes discussed when the word was not even used in study questionnaires, and sometimes craving was inferred from other observations (e.g., self-reported discomfort or drug abstinence) (Koz- lowski and Wilkinson 1987). These and other problematic issues have been discussed in several recent papers (Kozlowski and Wilkinson 1987; Shiffman 1987; West 1987; Hughes 1987; Marlatt 1987; Steckwell 1987; Henalngfield 1987b; Henalngfield and Brown 1987; West and Schneider 1987). One consensus that seems to emerge is that the term "craving" be replaced with "urge" or "desire" to smoke, and that subjects be asked to report the "strength" of such responses and not simply whether or not the re,pease occurred (Kozlowski and Wilkinson 1987; Hennlngfield 1987b). In consideration of the above reports and commentaries and the data reviewed in the present Chapter, the following conclusions may be drawn regarding the urge to smoke. Many means of measuring urges are reliably associated with early abstinence from tobacco; however, urges can also be elicited by a variety of other stimuli including cigarette smoking itself, tebaoco-associated stimuli (e.g., sight, smell, advertisements), consumption of other psychoactive drugs, food deprivation, and mood changes. Furthermore, although urges are reliably associated with tobacco abstinence, the levels to which plasma nicotine must fall to produce it are unclear; for example, West, Russell, Jarvis, and Feyerbond (1984) found that smokers who switched to a low-nicotins cigarette reported only slight craving for their usual brand in spite of a drop in nicotine intake of around 60 percent. In addition, as discussed earlier, some sensory stimuli are effective at eliciting urges, whereas other sensory cues accompanying the inhalation of cigarette smoke may be effective at diminishing such urges (Rose et al. 1985). Chapter V provides a discussion of these issues in the context of analogous observations which have been made with other dependence-producing drugs and Chapter VII discusses the implications for replacement therapy used in treating tobacco dependence. 211

Alternate NicoUne Delivery Systems Certain effects of nicotine depend little upon the specific type of delivery system that is used (see also Chapters, II, III, and VI). For instance, it appears likely that all forms of nicotine delivery resulting in systemic absorption are capable of producing tolerance and maintaining physical dependence (see also Chapter II). Similar- ly, it follows that a variety of nicotine delivery systems have potential utility in the treatment of cigarette smoking by the alleviation of withdrawal symptoms. However, the safety, including the potential to produce dependence, may vary considerably as a function of characteristics of the nicotine delivery system itself. Kinds of Nicotine Delivery Systems Because nicotine is well absorbed through the common routes of drug delivery and because the commonly used tobacco vehicle is not necessary to efficaciously deliver nicotine, nicotine can potentially be placed in a variety of vehicles and administered via a variety of delivery systems (Chapter II; Benowitz 1986; Jarvik and Henning- field, in press). The nicotine delivery systems thus far discussed in this Chapter are tobacco smoke, nicotine polacrilex gum, i.v. nicotine, transdermal nicotine, and a nicotine vapor inhaler. Other potential therapeutic nicotine delivering systems under development include a nasal spray (Perkins et al. 1986) and nasal nicotine solutions given in droplet form (Russell, Jarvis, Feyerabend, Ferno 1983), both of which have been discussed by Russell (1988). Two other nicotine delivery systems are a chewable food product (Tobacco International 1987) and a "toothpaste" formulation which contains ground tobacco. Other nicotine delivering systems (in which the tobacco may be incidental and not necessary for nicotine delivery) are under development or consideration for over-the-counter retail marketing (R.J, Reynolds "Smokeless Cigarette" European Patent Application 1985, 1986; Cleghorn 1987; Mints 1987). As noted earlier, the nicotine vapor inhaler was removed from the retail market in February of 1987 by the FDA because it was a "nicotine delivery system intended to satisfy nicotine dependence" which had not been tested for safety and efficacy (Slade and Connelly 1987). At least through the end of 1987, the toothpaste-like formula- tion was available as an ever-the-oounter product but was under review by the FDA (FDA letter to Congressman Waxman); this formulation is distributed in Indian food stores. The chewable nicotine delivering product marketed by Pinkerten Inc. was test- marketed as a "tobacco product" for approximately 6 months during 1987. The FDA removed it from the market ruling that it was a "food product" ["chewing gum"] which was "unlike traditional smokeless tobacco products," and contained a "food additive [tobacco] deemed 212 •

unsafe" for human consumption (FDA letter to Congressman Waxman). Safety of Alternate Nicotine Delivery Systems Alternate nicotine delivery systems may be evaluated with respect to at least three categories of safety issues. These are: (I) short- and long-term toxic effects resulting from use of the system; (2) the ease and convenience of using the system; and (3) the dependence potential of the system. All of these factors can affect initiation and mainte- nance of nicotine dependence. The first safety issue is related to the direct behavioral and physioiogica] toxicity of the preparation itself. In the moderate nicotine doses that each of these and previously marketed systems deliver, acute nicotine toxicity would not appear to be a significant health risk. However, adverse health effects from chronic exposure to nicotine may occur (see Appendix B), and other potentially absorbed constituents of the system (e.g., tar) are markedly toxic. Existing nicotine delivery systems vary widely in their potential overall toxicity. One product was found to meet FDA criteria for safety as well as efficacy (i.e., nicotine polaerilex gum). On the other hand, cigarette smoking is a cause of lung cancer and other cancers, emphysema, heart disease, and a variety of other diseases; smokeless tobacco use causes oral cancer and other forms of gum and mouth disease (US DHEW 1979; US DHHS 1982, 1983, 1984; US DHHS 1986b). Traditional tobacco products have historically been considered by the FDA to be outside its regulatory purview (Action on Smoking and Health vs. Harris 1980). New products, which contain either small amounts of tobacco (e.g., tobaeeo-containing food products) or which appear to contain possibly nonessential amounts of tobacco (e.g., possibly the case with the R.J. Reynolds smokeless cigarette (European Patent Application 1985, 1986)) and which are not regarded as traditional tobacco products, may not be exempt from such review. The second safety issue is the potential for the product to actually sustain tobacco use by alternating use of the substitute with use of the traditional tobacco product. This is analogous to the nonmedicai- ly approved use of methadone by opioid-depaudent individuals when their drug of choice (e.g., heroin) is not available, and they are not involved in treatment for opioid dependence. The use of non-tebaeeo nicotine products to sustain tobacco use is, similarly, medically contraindicated and hence a form of nicotine abuse (Slade 1986; Richards 1987). While any alternative nicotine delivery system can theoretically be used for this purpose, two commercial products (the chewable nicotine-delivering "food" product and the nicotine vapor inhaler) were marketed specifically as temporary substitutes for 213

cigarettes when it was inconvenient to smoke (Bosy 1986; Tobacco International 1987). In contrast, the instructions for use of nicotine polacrilex gum clearly specify that this preparation should not be used along with cigarettes {Physicians' Desk Reference 1988). In addition to product design and formulation, factors such as labeling, packaging, marketing, retail distribution, and regulatory oversight might influence the degree to which any particular preparation is associated with an individual's continued use of the nicotine delivery system. The third potential safety concern is related to the dependence potential of the system. As shown in Chapter V, the potential of a drug to addict users is associated with its effects on mood, feeling, and behavior; such effects are related to the bioavailability of the drug. Systems with a controlled rate of bloavailability or a lesser rate of absorption than is obtained from conventional tobacco products may have a 'lesser dependence potential than tobacco products. Other factors related to availability of the preparation and cost (both economic and behavioral) may also affect the likelihood that dependence will develop in users. For example, nicotine polacrilex gum is available by prescription only, and use of' the gum is recommended as a temporary treatment aid. Active chewing is required to extract the nicotine, and swallowing the nicotine too quickly reduces the amount absorbed. These factors appear relevant to the observation that less than 10 percent of all subjects entering smoking'treatment trials continue to use nicotine polaerilex gum after 1 year (Tonnesen et al. 1988; Jarvis et al. 1982). Among people who have used the polacrilex gum to quit smoking and who have maintained their tobacco abstinence for 1 year or more, a higher percentage of polacrilex gum use has been reported (13 to 38 percent); however, it is not clear to what degree such use may be necessary for some people to avoid relapse to tobacco use (see further discussion of these issues in Hughes 1988; Jasinski and Henningfield 1988; Hall et al. 1985; Tonnseen et al. 1988; Chapter VII). In contrast to nicotine pelacrilex gum, smokeless tobacco products (particularly one in which finely ground snuff is placed in a small tea bag-like pouch) readily lend themselves to initiating as well as to maintaining nicotine dependence (US DHHS 1986b). Table 6 compares nicotine pelacrilex gum and cigarettes on a number of dimensions, most of which have been reviewed in either Chapters II, V, or VII. As shown in the Table, there is considerable disparity between these two delivery systems: the polacrilex gum provides a generally safe and medically beneficial form of nicotine delivery; cigarettes are a known cause of substantial amounts of death and disease each year (Chapter I; US DHEW 1979; US DHHS 1981, 1982, 1983, 1984, 1985). Such a disparity in potential safety 214

TABLE 6.---Compartson of tobacco cigarettes and nicotine polacrilex gum on indices related to safety, including potential to cause dependence CbarvcterisLic Tobacco eigaret~$ Nicotine polaerilex gum Proven carcinogen YeS No Availability Widely available consumer Prescription only product, including veodi~g machine availability Taste Carefully formulated with Not formulated to provide flavor enhancers desirable ~ste of nicotine extraction Readily arguable with little Much effort required effort Nicotine kinetics Rapid uptake Slow uptake Initlation Of dependence Highly effective No reported problem Psychoactivity Dec, e-related "liking" Dose-related "disliking" Reinforcing effe¢~ Powerful Weak Withdrawal symptoms Yes Yes a~o~iated with al:~tinence So~ial factors Used for specific therapeutic benefit Primary re~latory U~. Food and Drug oversight Adminlst ration Olin u~ in ~lal Bettingsa~ part Of6ocial interactions U,S, Bureau of Alcohol, Toby, and Fi~rms across systems would suggest that any new system be submitted to evaluations of safety including dependence-potential testing. Conclusions 1. Cigarettes and other forms of tobacco are addicting. Patterns of tobacco use are regular and compulsive, and a withdrawal syndrome usually accompanies tobacco abstinence. 2. Nicotine is the drug in tobacco that causes addiction. Specifi- cally, nicotine is psychoactive ("mood altering") and can provide pleasurable effects. Nicotine can serve as a reinforcer to motivate tobacco-seeking and tobaccc~using behavior. Toler- ance develops to actions of nicotine such that repeated use results in diminished effects and can be accompanied by increased intake. Nicotine also causes physical dependence characterized by a withdrawal syndrome that usually accompa- nies nicotine abstinence. 215

3. The physical characteristics of nicotine delivery systems can affect their toxicity and addictiveness. Therefore, new nicotine delivery systems should be evaluated for their toxic and addictive effects. 216 •

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CHAPTER V TOBACCO USE COMPARED TO OTHER DRUG DEPENDENCIES 241

CONTENTS Introduction Clinical Characteristics of Drug Dependence Drug Dependence Defined Diagnostic Criteria for Drug Dependence Features of Drug Dependence Highly Controlled or Compulsive Drug Use Physical Dependence and Tolerance Harmful Effects Course of Drug Dependence Polydrug Dependence and Multiple Psychiatric Diagnosis SpontE/neous Remission Chemical Detection Measures Patterns in the Development of Drug Dependence Current Use of Cigarettes and Other Drugs Epidemiological Studies of the Progression of.Drug Use Tobacco Use as a Predictor of Other Drug Use Frequency of Use of Cigarettes and Other Drugs Initiation of Drug Use Vulnerability to Drug Dependence: Individual and Environmental Factors Pharmacologic Determinants of Drug Dependence How Drugs Control Behavior Dependence Potential Testing,: Psychoactive, Reinforc- ing, and Related Effects Effects of Drugs on Mood and Feeling (Psy- ehoactivity) Methods and Results ' Drug Discrimination Testing Methods and Results Drug Self-Administration Initiation of Drug Self-Administration Evaluation of Reinforcing Effects Results from Drug Self-Administration Studies Drug Dose as a Determinant of Drug Intake 243

Cost of the Drug as a Determinant of Intake Place Conditioning Studies Constraints on Dependence Potential Testing Dependence Potential Testing: Tolerance and Wii:h- drawal Tolerance Cross-Tolerance Mechanisms of Tolerance Constitutional Tolerance Withdrawal Syndromes Spontaneous Withdrawal Syndromes Precipitated Withdrawal Syndromes Variability in Withdrawal Syndromes Cravings or Urges Constraints on Physical Dependence Potential Testing Therapeutic or Useful Effects of Dependence-Produc- ing Drugs Adverse and Toxic Drug Effects Identification of Dependence-Producing Drugs Comparisons Among Drugs Environmental Determinants of Drug Dependence Includ- ing Behavioral Conditioning ' Drug Taking as a Learned Behavior Drug-Associated Stimuli Modulate Drug Seeking Conditioned Withdrawal Symptoms May Precipitate Drug Seeking Relapse to Drug Dependence Definition of Relapse Measurement of Relapse Rates of Relapse Correlates of Relapse Pretreatment Correlates of Relapse Severity of Drug Dependence Psychiatric Impairment Demographic Factors Treatment Correlates of Relapse Posttreatment Correlates of Relapse Family Support Factors Drug Use Among Peers Involvement in Work and Leisure Activities Negative Emotional States Treatment of Drug Dependence O i i •

Goals of Treatment Types of Treatment for Drug Dependence Pharmacologic Treatment of Drug Dependence Replacement Therapy Blockade Therapy Nonspecific Pharmaeotherapy or Symptomatic Treatment Pharmacologic Deterrents Behavioral Treatment Strategies Relapse Prevention Skills Leisure Activity Skills Stress Management Skills Motivation Enhancing Treatments Conclusions References 245

[ntroduntion The present Chapter compares cigarette smoking end nicotine with other forms of drug dependence and addicting drugs. Other chapters in this Report describe the behavior of cigarette smoking, the known biobehavioral mechanisms and modulators of nicotine's actions, and techniques for achieving abstinence from smoking. As is evident from this Report, cigarette smoking is most usefully ex- plained and characterized as a drug dependence process in which nicotine is the identified drug of dependence. It is also evident that by either the World Health Organization (WHO) definition of "drug addiction" that was issued in the 1950s (WHO 1952) or by the definitions of "drug dependence" issued since the 1960s (WHO 1964, 1969, 1981), nicotine is appropriately catogorized as an addicting or dependence-producing drug. Its designation as a drug is also consis- tent with the definitions provided by the WHO (1981) and the Food and Drug Administration (FDA) (1987). Nicotine~lefivering tobacco preparations (which include all currently marketed tobacco prepara- tions) could, therefore, be appropriately categorized as addicting or dependence-producing drugs. In addition to evaluating nicotine with respect to definitions of dependence-producing drugs, it is also useful to compare features of tobacco dependence and the pharmacologic properties of nicotine to other drug addictions and addicting drugs, respectively. This comparison is the purpose of the present Chapter. Two of the most widely studied drug addictions provide standards to which other addictions may be compared, They are the addictions to {,he opium-derived or related substances ("opioids," e.g., morphine, heroin, methadone, codeine) and to alcohol. For nearly a century, it has been widely accepted that use of these substances could lead to addictive behavior and to adverse effects. Moreover, such conse- quences of use develop in a sufficient number of persons that there have been recurrent regulatory efforts to restrict access and conditions of use. Cocaine and related psychomotor stimulants (e.g., amphetamine) provide an additional important standard by which to judge suspected and known addicting chemicals. These stimulants have been accepted as standards by which to evaluate the addicting potential of other stimulants since the 1950s. It is beyond the scope of the present Chapter to review all aspects of drug dependence in detail. Rather, this Chapter summarizes primarily the pharmacologic aspects of drug dependence. In particu- lar, the Chapter provides information that permits a comparison of the pharmacologic basis of tobacco dependence, as described in the other Chapters, with the pharmacologic basis of ether forms of drug dependence. More extensive reviews of the topics to be discussed have emerged from various review panels sponsored by the National Institute on Drug Abuse (NIDA) (Krasnegor 1978, 1979a,b,c; Thomp- son and Johanson 1981; Grabowski, Stitzer, Henningfield 1984; 247

Sharp 1984), the National Academy of Sciences (Levisen, Gerstein, Maloff 1983); other reviews have been held under the auspices of professional scientific societies (Goldberg and Hoffmeister 1973; Thompson and Unna 1977; Balster and Harris 1982; Taylor and Taylor 1984; Ssiden and Balster 1985). Other important determi- nants and consequences of drug dependence are more thoroughly described elsewhere (Blaine and Julius 1977; Manatt 1983; Tims and Ludford 1984; Petersen 1978; Bell and Battjes 1985; Richards and Blevens 1977; Levisen, Gerstein, Maloff 1983; Dupont, Goldstein, O'Donnell, Brown 1979; Lettieri, Sayers, Pearson 1980; Crowley and Rhine 1985). Q Clinical Characteristics of Drug Dependence Drug Dependence Def'med Before the 1960s it was fairly common to invoke factors such as "criminality," "character deficit," "immorality," and "weakness of will" in the clinical diagnosis of "drug addiction." In addition, these factors often included various social connotations. In part, it was because these attributes were not objective or scientifically based that t~he WHO in 1964 recommended that the term "addiction" be replaced with "drug dependence" in an effort to be more precise and descriptive in definition (WHO 1964, 1981). According to current conceptualizations, the central and common element across all forms of drug dependence is that a psychoactive drug has come to control behavior to an extent that is considered detrimental to the individual or society (WHO 1981; APA 1987). Although the precise wording varies, the central concept of drug- dependence definitions refers to the behavior of the individual who has come under the control of a psychoactive drug, and this concept has provided the cornerstone of most definitions of depen- dence/addiction for at least a century (Berridge 1985) and arguably for several centuries (Murray et al. 1933; Austin 1979; Levine 1978). The involvement of a psychoactive drug is the critical feature that distinguishes drug addictions from other habitual behaviors. In principle, the term "drug dependance" might be used to characterize any form of drug ingestion; however, the term is generally reserved for use when the chemical meets criteria as a "psychoactive" drug. These criteria are based on drug-induced changes in brain function; such changes may involve alterations in mood, feeling, thinking, perception, and other behavior. In this Chapter the term "drug dependence" or "drug addiction" refers to self-administration of a psychoactive drug in a manner that demon- strates that the drug controls or strongly influences behavior. In other words, the individual is no longer entirely free to use or not use the substance. Often times, this reduction in the degree to which use 248 •

TABLE L--Diagnostic criteria for psychoactive substance dependence A At least three of the following: (I) subs~nce often taken in larger amountll Or over a loilser PeriOd thtln the p~h intended {2) Persisteht desire or one or more uBsu~-'-~l efforts to cut down or control ~ltll~tanCe use {s) A great deal of time spent in activities nvce~ry to get the sul~tance {es., theft), to take the sut~lance (e~g.. chain smoking}, or to recover from its effe¢~ (41 F~Kluent intoxication or withdrawal symptoms when expected t¢ fulsll major role obligations at work, Ilcho~], or home (e.g., (Ic~@ llqt go t~ work b~tlle of hahgover. goes to sch¢¢l or work "high," Int~xlcated whilo taking care of ~wn children}, or when lubstance ~ is physi~lly hazardous (e.g.. drlv~ when intoxicated) Important Bovial, occupational, or recmBtiona] ~ctiviti~ givel~ up or reduced because of Continued ~u~t~n~e u~e d~pite knowledge of h~vi~g a persistent or recurrent s~cial. psychol~gl¢~l, or physical problem that is ~u~ed or exacerbated by the use of the substance (e.g.. ¢o~linuin~ he~in use despite family a;'guments ~bout it. c~rine-ind~ced depression, or ulcer made worse by drinking {71 Marked tolera~: ~eed for nmrkvdly i,cre~ 8mo,nt~ of the 8,b~ta~ (i.¢.. it le~t a 50 percent increase) to achieve i~toxic~tion or de$[r~i effect, or markedly dimini~h~ effect With continued use of the same ~mount (Note: The f¢l~owln~ i~ms may ~ot ~pply to ~nn~bis. hall~ino@ns, or PCP) (s) Characteristic withdrawal ~ympt~ms {~ee specific withdrawal ~ynd~mes under Psychoactive substance-Induced Organic Mental Di~o~r~) {9) Sul~tance of~n "t~ken to relieve or Bvo[d withdrawal lymptomu Some symptoms of the disturbance persistant for ~t l~a~t 1 month, or occurl~nt repeatedly over longer period of time sOURCE~ American Psychiatric Ate.~ctation (1987). is considered "voluntary" is described as "habitual" or "compulsive" drug use. Diagnostic Criteria for Drug Dependence The Diagnostic and Statistical Manual (DSM-III-R) of the Ameri- can Psychiatric Association (APA 1987) provides a useful example of the objective criteria currently used to define drug dependence. As stated in DSM III-Revised: "The essential feature of this disorder is a cluster of cognitive, behavioral, and physiological symptoms that indicate that the person has impaired control of psychoactive substance use and continues use of the substance despite adverse consequences." Specific diagnostic criteria for psychoactive sub- stance dependence are shown in Table 1. The APA designated 10 classes of psychoactive substance for which use may lead to dependence: alcohol; amphetamine or similarly acting sympathomimeties; cannabis; cocaine; haUucino- 249

gens; inhalants; nicotine; opioids; phencyclidine (PCP) or similarly acting arylcyclohexylamines; and sedatives, hypnotics, or anxiolyt- ics. The fact that dependence criteria are the same for all classes of drug use highlights the assumption that dependence processes are functionally similar across substances with different pharmacologic profiles. Features of Drug Dependence Behavior that leads to drug ingestion, as well as the various behavioral and physiological sequelae resulting from the ingestion, are determined by both drug (pharmacologic or agent) and nondrug (behavioral or environmental) factors which will be discussed in this Chapter. The nondrug determinants include characteristics of the individual ("host" characteristics) such as age, genotype, and person- ality. Highly Controlled or Compulsive Drug Use Highly controlled or compulsive drug usa indicates that drug- seeking and drug-taking behavior is driven by strong, often irresisti- ble urges. It can persist despite a desire to quit or even repeated attempts to quit. Compulsive drug use may take precedence over other important priorities. The extent to which compulsive bahavigr is apparent varies across individuals and is most easily detected in extreme cases. For example, to maintain daily drug intake laryngoctomized patients may smoke cigarettes through their trachesstemy hole, cocaine users may take cocaine at the risk of loss of family and job, and prostitution has been observed to occur in exchange for a variety of drag~ for which availability was low or price was high. The drag-soekiag behavior itself ranges from the routine and licit procurement of cigarettes or alcohol, to the possibly more extensive behavioral repertoire necessary to obtain prescriptions for certain drugs, to the highly intricate chains of behavior required to procure many illicit drugs. Drug-seeking behavior is not determined entirely by the specific pharmacologic properties of a particular drug, however. For instance, when alcohol or tobacco has been prohibited, procurement has at times involved as much risk and involvement as the procurement of illicit drugs in the 1980s (Austin 1979; Brecher 1972). A drug may be taken ~to avoid withdrawal symptoms and other undesirable sequelae of drug abstinence. This factor may contribute to the level of compulsivity which develops. Addicting drugs often provide some therapeutic benefit or otherwise useful effect (Chapter V]); these effects may also contribute to the compulsive nature of drug use. Whether or not such benefits are considered to be more Q 250 •

important than the adverse effects of drug taking, this factor is important because it may have been prominent in initial exposure to the drug, it may have strengthened the control of the drug over behavior, and it may constitute a potential cause for relapse. Physical Dependence and Tolenance The observation of a withdrawal syndrome that accompanies abstinence from chronic drug exposure is the primary index of physical dependence induced by the drug (Martin 1965; Knlant 1978). Drug withdrawal syndromes are behavioral and physiological sequelae of abstinence from chronic drug administration. Tolerance refers to the diminished responsiveness to successive administration of a drag; it may occur independently of physical dependence but is a frequent concomitant (Kalant 1978). The magnitude of tolerance and physical dependence is directly related to the frequency and • magnitude of the drug-dosing regimen; thus, low or infrequent drug dosing may not produce measurable levels of tolerance or physical dependence. Tolerance may develop in the absence of physical dependence; for example, infrequent dose administration may result in decreased responsiveness even though no measurable withdrawal reaction accompanies drug abstinence• Whereas initial drug exposure may have caused marked behavior- al and physiological disruption, the development of physical depen- dence implies that a relatively normal appearing behavioral and physiological functioning requires continued drug administration and that disrtiption will occur when the drug is withdrawn. For example, at certain doses, opioids, sedatives (including alcohol), and nicotine can produce marked intoxication in nontelerant individuals. As tolerance develops, these same dose levels may produce no readily observable signs of intoxication, and in the case of opioids and nicotine only extremely high doses or sudden abstinence are accompanied by disruption of ongoing behavior. The development of tolerance to repeated drug exposure and of the onset of a withdrawal syndrome may be observed following a period of repeated drug exposure and drug abstinence, respectively, but these factors do not in themselves define a drug dependence syndrome requiring intervention to prevent relapse to drug use. It is possible to establish tolerance and physical dependence by repeated drug administration even when the animal or human never actually self-administered the drug. In animals, this is often done in experimental studies; human patients requiring pain relief may become tolerant to and physically dependent on opioid analgesics in hospital settings. Such animals and humans do not necessarily exhibit drug-seeking behavior when drug administration is terminat- ed. Another such instance is the fetal opioid syndrome, in which treatment of the withdrawal reaction might be indicated but no 251

drug-seeking behavior would be present for which an intervention would be needed (Weinberger et al. 1986~. Although not always essential for the occurrence of addictive drug-seeking behavior, tolerance and withdrawal phenomena are important in principle because they can serve to strengthen the control of the drug over behavior. Specifically, tolerance development can result in increased drug intake in an attempt to maintain the desired drag effects, and the onset of a drug withdrawal syndrome may constitute an aversive state which is alleviated by drug taking. Harmful Effects The concept that some sort of harm or disadvantage to the individual or society is a consequence of drug.use is another element in most definitions of drug dependence. This concept is complex and socially determined, however. For example, drag seeking may result in illicit production and trafficking as currently ascurs,for illicit drugs (Drug Abuse Policy Office 1984), and had occurred for tobacco at various times when it was banned (Austin 1979; see also Warner 1982 for a discussion of recent cigarette-smuggling issues). Adminis- tration of drugs, or abstinence in the physically dependent person, may directly produce adverse behavioral and psychiatric effects ("psychotoxicity'). Finally, toxicity may also be a direct physiological effect of the addicting drug. itself (e.g., liver damage caused by alcohol) or to associated toxins (e.g., transmission of the human immunodeficiency virus by needle sharing among i.v. drug users, or carcinogens delivered by tobacco smoke). These forms of drug-asseciated damage can result in a variety of societal costs such as health care of drug users (including cigarette smokers)~ lost productivity of the work force (including tobacco-use- associated losses in productivity), and criminal justice system burdens associated with illicit drug use. Such adverse effects of drug use constitute the "liability" of drug use and may also be factors in the determination that drug use constituted "drag abuse" (Yanagita 1987). These societal aspects of drug dependence frequently invoke debates which pit the ~'right" to self-damage against the "right" of society to protect itself from the direct damage or costs incurred as a consequence of the individual's behavior. A historical appraisal of psychoactive substance use reveals that societies have often moved cautiously to restrict the use of drugs when there was little assumption of drug-use-associated damage. Course of Drug Dependence The chronic nature of drug ingestion in the severely dependent individual suggests that drug dependence processes themselves may be long lasting and resistant to termination. In contrast, the direct 252 •

effects of psychoactive drugs are generally limited to a few hours or days at most. Peak physical withdrawal signs and symptoms from opioids, sedatives, alcohol, and tobacco appear to last for about i to 2 weeks. However, at least for the opioids, a secondary stage of withdrawal may last for I year or more', this has been termed protracted withdrawal (Martin 1965; Jasinski 1981). As discussed in Chapters Ill and VI, an analogous protracted abstinence syndrome appears to exist in tobacco dependence and to be of importance for treatment efforts. Therefore, despite the relatively short-term dura- tion of the effects of drug administration or withdrawal, the clinically relevant duration of drug dependence is much longer. A major implication of post-1960s definitions of drug dependence is that drug dependence is not an absolute phenomenon, but rather may vary in degree (Jaffa 1965, 1985; Miller 1979). Often, within an individual the level of severity increases over time ("progressive" characteristic). The course may be quite variable, however. For example, an initially rapidly developed high level of use may be followed by long-term or transient remissions, while some individu- als never progress at nll beyond levels of use of a given drug that are sometimes considered safe and acceptable (Valllant 1970, 1982). Such low or intermittent levels of drug use are sometimes referred to as "occasional," "controlled," "recreational" or "social" drug use or "chipping"; such use may still be problematic because there may be acute adverse consequences (e.g., auto accidents following drinking), as well as a' transition to chronic drug use (as is characteristic followirig occasional tobacco use) end the possibility that any use involves illicit behavior (e.g., procurement of alcohol and tobacco by minors or possession of marijuana). There are differences among drugs in the relative incidence of occasional users compared to regular daily users who meet criteria for dependence. For example, it is generally estimated that less than 15 percent of those who consume alcoholic beverages are dependent (Miller 1979). Analysis of opioid data are more problematic (Zinberg and Jacobsen 1976); however, observations such as those made of Vietnam veterans show that opioid chipping is not only n well- documented phenomenon but may also be common in some social and environmental settings. Robins and colleagues found (1) that opioid chipping was a common occurrence among enlisted men in Vietnam, (2) that 88 percent of heroin-addicted Vietnam veterans used heroin occasionally upon their return to the United States, and (3) that most (approximately 90 percent) were able to avoid readdic- tion (Robins et el. 1977; Robins and Helzer 1975; Robins, Helzer, Davis 1975; Robins, Davis, Goodwin 1974; Robins, Davis, Nurco 1974; see also Zinberg 1972, 1980). In contrast, however, chipping appears relatively rare among tobacco users: the 1985 National Health Interview Survey showed that 10.6 percent of current smokers 253 J

smoke 5 or fewer cigarettes/day (unpublished data; Office on Smoking and Health; see also Russell 1976 and US DHHS 1987). Polydrug Dependence and Multiple Psychiatric Diagnosis Another feature of drug dependence is the common use of multiple substances, including tobacco, by dependent individuals. In fact, the most consistent feature of such multiple drug use is the high rate of co-occurrence of tobacco dependence along with dependence on opioids, alcohol, stimulants, and even gambling (Taylor and Taylor 1984). In addition, drugs used by individuals may sometimes vary end be interchanged as price and availability vary (e.g., cocaine is preferred by many but individuals may use opioids, or even sedatives, when cocaine is unavailable) (Kliner and Piokens 1982). Several drugs may also be taken simultaneously; for irlstance, heavy consumption of nicotine, alcohol, and marijuana is common. Finally, most surveys indicate that use of drugs such as cocaine, alcohol, epioids, and marijuana is accompanied (and usually preceded) by use of nicotine (US DHHS 1987). Tobacco use concurrent with other drug dependencies is so prevalent that it is not generally considered to be of diagnostic significance or considered as a basis of multiple drug dependence diagnosis. Recently, the possible interactive nature of co<lependen. cies to nicotine and other drugs has been given increosing attention in drug treatment programs (Taylor and Taylor 1984; Koslowski et al. 1984). These data are discussed later in this Chapter, as well as the issue of whether nicotine serves as a "gateway" to the use of illicit drugs. Also of clinical significance is the concurrence of drug dependence and some other p6ychiatrie disorder. This phenomenon is termed multiple or dual diagnosis (Meyer 1986; McLellan, Woody, O'Brian 1979; Allen and Frances 1986; Rounsaville and Kleber 1986; Jaffe and Cicaulo 1986). In general, dependence on epioids, alcohol, cocaine, and nicotine is often associated with elevated rates and levels of antisocial tendencies end extraversion, but such trends are not generally regarded as multiple diagnoses (for a review of several forms of multiple diagnosis, see Taylor and Taylor 1984). The designation of multiple diagnosis is reserved for the concurrent appearance of a clinically significant psychiatric disorder and drug dependence; the most common of such disorders would appear to be depression, anxiety, and antisocial personality (McLellan, Woody, O'Brien 1979; Rounsaville et al. 1982; Woody, MeLellan, O'Brien 1984). 254

Spontaneous Remission It is characteristic of drug dependence that some persons discon- tinue use of the drug while not engaged in a formal treatment program (i.e., "on their own"/ although they may have participated in a treatment program at some earlier point in time (Stall and Biernacki 1986). Spontaneous remission refers to intentional and unintentional cessation of drug use, variously referred to as "natural recovery," "maturing out," "burning out," or "self-quitting," but most frequently in current literature as "spontaneous remission." Such quitting is sometimes reported to be due to "will power" or "just deciding to quit." However, follow-up studies have revealed that significant environmental events are often associated with such quitting (for example, Vaillant 1970, 1982). Such data have suggested to some that the terms such as "self-quitting," "self-help," and "spontaneous remission" are misnomers (Fisher 1986; Fisher et al. 1988); nonetheless, because the term spontaneous remission is extant in the scientific literature, it will be used here. This Section provides a brief summary of available information comparing alcohol, opioids and tobacco with regard to their rates of spontaneous remission and of factors associated with remission from drug use. In studies of spontaneous remission, a minimum criterion for abstinence, such as 1 year, is often imposed. Although the recorded history of drug dependence acknowledges that some people can achieve abstinence with~)ut benefit of formal intervention programs, there was little systematic study of spontaneous remission until the 1970s. Major motivations for the current interest in this pbenome- non are to determine if the so-called spontaneous remitters differ in behavioral or physiological parameters from other drug-dependent persons, to identify factors which may be systematically applied in treatment settings, and to better understand the process of drug dependence itself. The percentage of such spontaneous remitters reported in any given study appears to vary more as a function of population and study variables than as a function of drug class. For instance, data averaged across 10 studies show that approximately 30 percent of opioid-dependent persons spontaneously remit (Angiin, Brecht, Bonett 1986) although estimates of remission rates vary from 2 percent to 65 percent (Harrington and Cox 1979; Winick 1962). On the other hand, approximately 90 percent of.people who have quit smoking report that they quit without the aid of formal treatment programs or smoking cessation devices (Fiore et ai., in press; see discussion of related issues in Fisher et al. 1988). Deriving precise quantitative comparisons of rates of spontaneous remission across the various drug dependencies is problematic due to the differing criteria used to identify those who are spontaneous remitters. For example, in tobacco surveys, rates of spontaneous 255

remission are often estimated by retrospective self-reports from a sample of former smokers, whereas surveys of opioid and alcohol users generally include only those who were dependent enough to be involved in formal treatment programs at some time. The factors which are associated with spontaneous remission appear to be similar across dependencies on alcohol, opioids, and tobacco (Stall and Biernaeki 1986). Table 2 is a summary of findings which have been reported on factors related to spontaneous remis- sion. As shown in the Table, influences such as health problems associated with use of the drug and social pressures are frequent presipitants of spontaneous remission among persons who were dependent on alcohol, opioids, or tobacco. Similarly, spontaneous remitters have often learned to better manage their drug "cravings" and to provide contingent reinforcement for quitting to themselves, and may even undergo significant lifestyle changes (Stall and Biernacki 1986). These data regarding spontaneous remission support the conclu- sion, discussed earlier, that it is somewhat misleading to infer that spontaneous remitters are truly spontaneous or that they were not "really dependent" as is sometimes assumed (Fisher 1986; Fisher et a]. 1988; US DHHS 1982). Rather, it seems more plausible that spontaneous remitters ere largely thee who have either learned to deliver effeotive treatments to themselves or for whom environmen- tal circumstances have fortuitously changed in such a way as to provide a therapeutic situation (Fisher 1986; Stall and Biernacki 1986; VaiUant 1982, 1970). In addition, persons most likely to quit use of tobacco and opioids without benefit of formal intervention do tend to have shorter histories of use and/or be at lower levels of dependence (US DHHS 1987). Such issues, relating specifically to cigarette smoking, have been reviewed in considerable detail in a previous report of the Surgeon General (US DHHS 1982). Chemical Detection Measures Although drug dependence is not reliably diagnosed simply on the basis of amount of drug intake (Crowley and Rhine 1985; Jaffe 1985), it can be useful to determine whether or not a person has ingested a significant amount of a drug. For example, as is discussed later in this Chapter, many treatment programs require objective verifica. tion of drug-frse patient status. A potentially useful adjunct for objectively assessing exposure to drugs is to test for the presence of the drug in biological specimens (Walsh and Yohay 1987; Hawks and Chiang 1986). For instance, blood, urine, saliva, expired air, and other biological samples can be assayed for residual drug or drug-specific markers (e.g., metabolites). Such testing aids in determining that presumed drug-feinted effects were nnt actually symptoms of some other organic or mental 256 •

• • • • • • 0 • • • • TABLE 2.---Studies Concerning spontaneous remission behavior, by drug and commonly mentioned factors important to remission Factor Alcohol Tobacco Heroin Health probIems Cahalan (1970~. Goodwin et al. Hecaht 11978). ~ederson and I~fe~ Biernaekl (19~3D [1971), Knupfer [l~e/2~. Lemere (1953), {1978) Saunders et al. ¢1979). Stall 11983). Tuchfeld 1198D Caha[an 11970k Edwards et aL (1977). Goodwln et al. (1971k Knupfer (1972). Stall 11983). Thorpe and Pert.~ (1~). Tuchfeld (1~1}. Vailhant (1983) Edwards et al. (1977)* Goodwin et al (197D. Knupfer 11972). Saunders et aL (1979). Stall (1~. Tuchfetd (l~lk Vaillant (19~3} Cahalan (1970k Saenders et al. q1979]. Stall (19~1~. Thorpe and Ptrr~ (1%9}. Tuchfeld II~l) Kn,pfer (1972}* Stall (1~ Tuchfeld (19~11 to Soc~I san~ion~ Significant ethe~ Financial ¢¢oblems $~gnif'mant accidents MBnagen~nt of ceavings Stall (l~) Perrl et al. {19771 DiClemente and Prochaslm (1979k Hecht {1978}. 1~ and Lefcoe {1976}. Perriet al. (19"/7) Biernacki ~19831. Schasre q 19661 Vai]tant c1964. 1970J Biern~ki tlS~3k Waldor~ and Bieraacki {l~l. Vaillant 41~¢1. 1~70~ It¢~ht 0978) Bierna~ki ;i~3) Perrl et al. (19771 Iker et el. 119"/7). I~nte and Prochad~ (19791. Heeht (19781. Pecle~ and Lefe~e (1976]. I[~¢d et a[. 119771 Bieraaekl ( I~3~. Jorquez I I~3,. Walde.cf and B~ernacki I19~II Biernacki q9~3~. Jorqu~ 11983~

TABLE 2.---Continued oo Factor Alcohol Tobacco Heroin Poslti.~. ~in~oroer@t.o~ for quitting Internal psychic changel motlvaflon Change in lifestyle Edwards et aL 11977). Stall 11993~ Edwards et aL i1977L Knupfer (1972t. Saunders et aL {1979L Tuch feld (198D Edwards et al. (1977L Knupfer q1972~ Saunders et al. (1979k Tuchfeld (ig~ll B~er et al I1977L DiCleraente and pr~chaska (19791. Pederson and Lefcae 119761 Baer el al. i1977L Hecht t1978P t~Clemente aM Prochaska ~19791, Hecht (19781 Blernacki q 198,3 t fhe~nacki tlS83L Schasre ~19¢~3L Waldorf and Bierr~acki 119811 Biernackl ~19~1, Jorquez 119831, Schasre t196G). Waldorf and BiPrnacki q19~l) SOURC~ Modified from Slat] and Biemaeki t1981;t • • • • • • • • • • •

disorder. One problem with such verification is that the drug level measured reflects recency as well as amount of drug use and thus may lead to either underestimation or overestimation of the typical level of drug use. Furthermore, absolute level of use does not necessarily determine whether use is pathological or detrimental. Another problem is that biochemical drug tests vary widely in both their specificity (correct drug identification) and sensitivity (mini- mum amount of drug detected) (see Grabowski and Lasagna 1987 and Waish and Yohay 1987 for general reviews of such issues; and Benowitz 1983 and Muranaka et al. 1983 for a tebacco-related review; also see Chapter If). Presently, verification of drug dependence is based largely on the behavioral factors as described below. The most useful application of testing for drug levels in the body remains the verification of compliance with treatment regimens in which drug abstinence is the goal. These and other issues regarding the methodologies and applications of chemical detection measures have been reviewed by a committee of the American Society for Clinical Pharmacology and Therapeutics (1988). Patterns In the Development of Drug Dependence When the relationships among drug dependencies have been studied in major epidemiological surveys (e.g., NIDA's National Household Survey (NHS) (US DHHS 1987)), two findings consistent- ly emerge: persons who use dependence-producing drugs are often cigarette smokers, and cigarette smoking precedes and may be predictive of illicit drug use. Some of the data which have led to these conclusions are summarized in this Section. Current Use of Cigarettes and Other Drugs The association of current use of one drug with current use of other drugs has been studied extensively. One such study is the NHS conducted by NIDA (US DHHS 1987). The Eighth NHS, conducted in 1985, involved personal interviews with 8,038 persons 12 years of age and older, representative of the household population of the conti- nental United States. Questions were asked about the age of respondents when they first tried a cigarette and age when they first started smoking daily. This distinction may be important when comparing cigarette use with the use of other drugs. Persons who do not make the transition from trying cigarettes to daily use may be less likely to use other drugs than those who do make this transition. A similar format was used with alcohol (i.e., age at which respondent first tried alcohol, not including childhood sips, and age of first using alcohol once a month or more). Questions about age at the onset of other drug use were limited to age at first use. In the NHS studies, 259

TABLE 3.--Current use of alcohol, marijuana, and cocaine among "current" cigarette smokers and nonsmokers by age group (percentages) "Currci~" cigarette use Age group, current drug use No Yes Alcohol 12-17 23.5 742 {~2,~ 647 82,6 26-34 62.5 81.0 ~35 52,5 68.6 Marijuana {2-17 ~8 47.3 18-25 137 35.4 26~4 10,6 260 ~35 L7 3.5 12-17 04 88 18-25 3,9 139 ~SS 0.4 0.6 NOTE: Current ume Im i~¥ u~e reported in zhe 30 days prior to the interview, ~URCE~ National HouJehold Sur~e¥ on Drug F.bume. 1~ (in prel~Ta~io~ current drug use is defined as any use of the drug during the 30 days preceding the interview. Based on data from the 1985 NHS on Drug Abuse, Table 3 shows associations among use of various psychoactive substances. As shown in the table, rates of current use (i.e., during the past 30 days) of marijuana, alcohol, and cocaine are much higher among "current" cigarette smokers than among others. For example, among 12- to 17- year-olds, almost three-fourths of "current" smokers were current alcohol users compared with less than one-fourth of the youths who were not '~current" smokers. Approximately 47 percent of the "current" cigarette smokers report being current marijuana users compared with 5.8 percent of the youths who were not "current" smokers. Differences as large as these shown in Table 8 represent very strong correlations between use of cigarettes and use of other drugs. The strength of the correlation between use of cigarettes and use of other drugs, licit and illicit, suggests the potential importance of directing prevention efforts to the early gateway drugs: cigarettes and alcohol (Kandel and Yamaguchi 1985; Clayton 1986; Clayton and Bitter 1985). Q 26O •

Epidemiological Studies of the Progression of Drug Use Tobacco use has been found to play a pivotal role in the development of other drug dependencies. The classic descriptive model for initiation patterns of drug use was developed by Kandel (1975), who first divided drugs into two groups of availability: licit and illicit. Kandel concluded that virtually all persons who ever used illicit drugs such as marijuana and cocaine had previously used licit drugs such as cigarettes and alcohol. Kanders developmental stages model is based on the assumption that there are relatively invariant patterns of onset of use. The stages are: (1) No Use of Any Drugs (2) Use of Beer or Wine (3) Use of Cigarettes and/or Hard Liquor (4) Use of Marijuana (5) Use of Other Illicit Drugs Although Kandel's model addresses the initiation or onset of drug use, it does not account for patterns of early use (e.g., frequencY of occasions or quantity per occasion). Nonetheless, there is general agreement that the model accurately characterizes the drug initia- tion process in the United States as one that begins with use of licit drugs (tobacco and alcohol) and, if progression occurs, involves greater use of these substances (Kandol, Marguilies, Davies 1978; Huba, Wingard, Bentler 1981; O'Donnell and Clayton 1982). This pattern has also been obseri, ed in France and Israel (Adler and Kandel 1981). In a longitudinal study of the progression of drug use, Yamaguchi and Handel (1984a) gathered baseline data in 1971 from subjects in the 10th and llth grade in New York State. This representative sample was followed up in 1981 when the average age was 24.7 years. The order of onset identified by Yamaguchi and Kandel (1984a) was alcohol, cigarettes, marijuana, illicit use of psychoactive or prescrip- tive drugs, and other illicit drugs. Among persons who had used both alcohol and cigarettes 10 times or more, alcohol use preceded cigarette use in 70 percent of the cases for males and 55 percent of the cases for females. Among persons who had used cigarettes and marijuana 10 or more times, 67 percent of the males and 72 percent Of the females reported using cigarettes first. Using a sophisticated statistical analysis, Yamaguchi and Kandel (1984a) derived several additional conclusions including the follow- ing: (1) For men, the pattern of progression was one in which the use of alcohol preceded marijuana; alcohol and marijuana preced- ed other illicit drugs; and alcohol, cigarettes, and marijuana preceded the illicit use of other psychoactive drugs. Eighty- seven percent of the men were characterized by this pattern. 261

(2) For women, the pattern of progression was one in which either alcohol or cigarettes preceded marijuana; alcohol, cigarettes, and marijuana preceded other illicit drugs; and alcohol and either cigarettes or marijuana preceded the illicit use of psychoactive drugs. Eighty-six percent of women shared this pattern. Tobacco Use as n Predictor of Other Drug Use In an analysis of nationwide data from the high school senior class of 1980, Clayton and Ritter (1985) found that alcohol drinking and cigarette smoking were the most powerful predictors of the extent of marijuana use for both males and females. Cigarette use was a stronger predictor of marijuana use among females, Moreover, this role of cigarette smoking was especially pronounced when it had been initiated at age 17 or earlier. Similarly, data from the longitudinal study by Yamaguchi and Kandel (1984a,b) revealed that, among persons with some history of alcohol use, cigarette smoking was a powerful predictor of mari~uana use. Consistent with the above described findings regarding cigarette smoking, smokeless tobacco use has also been shown to be a predictor of other drug use, including cigarette smoking (Ary, Lichtenstein, Severson 1987). More then 3000 male adolescents were interviewed twice, at an approximately 9-month interval, to determine their rates and levels of use of various psychoactive substances. The main findings were that (1) users of smokeless tobacco were significantly more likely to use cigarettes, marijuana, or alcohol than nonusers; (2) users of smokeless tobacco were significantly more likely to take up use of cigarettes, marijuana, or alcohol than nonusers; (3) smokeless tobacco users who were using these other substances st the time of the first interview showed substantially greater increases in levels of use of these other substances over the 6-month interval than did nonusers of smokeless tobacco; and (4) 71 percent of thas~ who had been using smokeless tobacco at the first interview remained users at the second interview. Cigarette smoking is also a predictor of cocaine use. White and colleagues (US DHHS 1987) began with a large sample of 12-, 15-, end 18-year-old adolescents in New Jersey and reinterviewed them at 3-year intervals. As reported in NIDA's Triennial Report to Congress (US DHHS 1987), White and coworkers found that there were several predictors of cocaine use in 18.ycar~ids who had been interviewed 3 years earlier: prior use of cigarettes, alcohol, and marijuana. Furthermore, at the time of the second interview (of the 18.year-olds), the ceca/ne users used cigarettes, alcohol, marijuana, and other drugs more often than did nonusers of cocaine. Although alcohol use frequently precedes tobacco use, the use of alcohol only progresses to dependence (alcoholism in about 10 to 15 Q 262 •

percent of all drinkers (Miller 1979). Use of cigarettes, by contrast, almost inevitably escalates to a level characterized as dependent use (Russell 1976; US DHHS 1987). This is consistent with the observa- tion that although some use of alcohol may precede tobacco use, it is prior use of tobacco and not alcohol that emerges in the above-cited studies as the stronger predictor of illict drug use. The 1985 High School Senior Survey by NIDA (US DHHS 1987) showed that the first dependence-producing drug tried among users of alcohol and illicit drugs was often tobacco. For example, among all respondents 12 years of age and older, first use of tobacco and alcohol occurred in the same year for 18 percent of the sample; cigarettes were used first by 62 percent of the sample, and alcohol was used first by 20 percent. Among those who tried both cigarettes and marijuana, 14 percent first tried these drugs in the same year, 75 percent tried cigarettes first, and 11 percent tried marijuana first. Among those who tried both cigarettes and cocaine, 95 percent used cigarettes first, 3 percent used them first the same year, and only 2 percent used cocaine before cigarettes. These observations show that when cigarettes and another of these dependence-producing drugs have been used by the same individual, cigarette use usually is the first of the two drugs used. One difference between cigarette smoking an~i the use of other common substances (e.g., milk, sugar, or aspirin) that may also precede the use of illicit drugs is that nicotine itself is a drug that produces the tolerance, physical dependence, and drug- seeking behavior that meet the criteria of a drug-dependence syndrome.' Frequency of Use of Cigarettes and Other Drugs Measures of frequency of drug use also yield important findings. The data presented in Table 4 show the percentage of persons in three groups (never smoked, tried cigarettes but never used them daily, used cigarettes on a daily basis) who report use of alcohol, marijuana, and cocaine. The criterion for alcohol usa is 5 or more consecutive drinks during at least 1 day in the past 30 days; criteria for marijuana and cocaine use involve previous usa of these drugs more than 10 times during the respondent's lifetime. These criteria were used to eliminate those who merely tried the drug on a few occasions ("experimental" use). The percentages are presented separately for four age groups. The main finding shown in Table 4 is that those who become daily cigarette smokers are considerably more likely than others to report use of these other drugs, regardless of age group. For example, among the 12- to 17-year-olds, less than 0.5 percent of the never smokers report using marijuana more than 10 times compared with 3.3 percent of those who tried but never used cigarettes daily and 22.7 percent of those who have used cigarettes daily. These data 263

TABLE 4.--Use of alcohol, marijuana, and cocaine among "never" cigarette smokers, "occasional" cigarette smokers, and daily cigarette smokers, by age group (percentages) Cigarette use pat~rn Age group. Never Tried. never Smoked drug use smoked used daily daffy Atcoho] ' 12-17 g6~4 ~35 Marijuana~ 12-17 26-34 ~35 Cocaine~ 12-17 26-34 ~35 2,7 15.9 38.6 12.3 31,9 49.6 9.8 23.0 41.3 5.6 9.2 20.1 0.2 3,3 22,7 3.3 8.3 37.4 2~ 12.9 30.3 0.6 Lg 3.8 0.2 0.8 6.4 1.3 4,5 14,2 0~ 0~ 1.9 'Drank five or more drinks in s row on at ]east I day in p~t 30 day~ JU/.~ maruuana more thsa IU time~. • U~d cocaine more th~n I0 timeG SOURCE: Natlonal Household Survey on Drug AbuSe, 1985¸ (in preparstion, extend those presented in Table 3: associations exist between cigarette smoking and other drug use when considering "current" use (any use in the past 30 days) (Table 3) or measures of frequency of drug use (Table 4). Similarly, a study of alcohol drinking and cigarette smoking among student in grades 7 to 12 in New York State showed a positive correlation between the frequency of consuming alcoholic beverages and both the likelihood of smoking cigarettes and daily cigarette consumption (Welte and Barnes 1987). Initiation of Drug Use Initiation of drug use often occurs through social contacts, independent of the pharmacologic actions of the drug. Drug seeking is then sustained and modulated through combined social and pharmacologic factors. With the possible exception of the stimulants such as cocaine and amphetamine, initial exposure to many psy- choactive drugs (including opioids, alcohol, and nicotine) is often associated with aversive consequences (Haertsen, Hooks, Ross 1981; Hsertzen, Kochsr, Miyasato 1983). For example, opioids may pro- duce nausea; alcohol and nicotine not only produce nausea but may 0 @ Q 264 •

produce initially aversive sensory effects in some preparations (e.g., high-concentration alcoholic beverages may taste "bad" and ciga- rette smoke may be "harsh"). As a consequence, lengthy periods of occassional ("experimental" or "sseial") drug use frequently precede the development of daily drug use. These observations imply that nondrug factors are important in the initiation and maintenance of drug intake until dependence upon the drug itself develops (Crowley and Rhine 1985; Vaillant 1970, 1983; Marlatt and Baer 1988; Brown and Mills 1987). As discussed elsewhere in this Chapter, such factors can also modulate level of drug use as well as influence the frequency of quitting attempts and their likelihood of success (see also Chapters IV and VII in this volume and earlier Reports of the Surgeon General). The specific factors that have been identified and accepted as prominent in helping to establish initial exposure to drugs (Crowley and Rhine 1985) include: availability of the drug, cost of the drug, social acceptability of the drug, and other environmental sources of pressure to use drugs. The acceptability of the drug preparation itself can be manipulat- ed by controlling the dose of the drug and increasing its sensory palatability. For example, the utility of some of the newer smokeless tobacco formulations as "starter" products for youth is held to be due in part to the lower concentrations of nicotine, formulations that facilitate use (e.g., snuff in pouches), as well as nontobacco flavorings (e.g., mint or cinnamon) ~Henningfield and Nemeth-Coslett 1988; US DHHS 1986, 1987; Connolly et al. 1986). Such strategies of "starter product" manipulation are analogous to those used to initiate drug seeking in laboratory animals, described later in this Chapter. Such product acceptability factors, combined with the ready availability, peer pressure to use, perceptions that the products were safe, and marketing strategies aimed at increasing the social desirability of smokeless tobacco use, appear to have been largely responsible for the marked rise in use of smokeless tobacco by youth' in the 1970s (Ary, Lichtenstein, Seversen 1987; Christen and Glover 1987; Con- nelly et al. 1986; Connolly, Blum, Richards 1987; Olover et al. 1986; Ouggenheimer et al. 1987; JAMA 1987; Kozlowski et al. 1982; Marty et al. 1986; Negin 1985; Silvls and Perry 1987; US DHHS 1979). Vulnerability to Drug Dependence: Individual and Environmental Factors Despite the complexity of the issues, it is useful to identify factors that differentiate individuals who appear more susceptible to drug dependence. These factors may collectively be termed vulnerability factors. Vulnerability factors are diverse, varying among individuals and within individuals at different times (Radoucc-Thomas et ai.1980; Marlatt and Baer 1988; Brown and Mills 1987). Vulnerability may 265

arise from genetic variation or from environmental sources includ- ing learning (Jones and Battjes 1985). Vulnerability factors are such that they do not necessarily compel a persen to use a drug; in fact, they might be undetecLed in a person never exposed to a dependence- producing drug. Nonetheless, the presence of several vulnerability factors can increase the likelihood of the development of drug dependence, including cigarette smoking. The concept of a predisposition to drug dependence arose from the observation that not all people are equally prone to becoming behaviorally dependent upon drugs (Mann et el, 1985; Redouee- Thomas et al. 1980; Jaffe 1985; M,N. Hesselbrock 1986; V.M. Hesselbreck 1986; Mirin, Weiss, Michael 1986). The multiple sources of differences in predisposition or vulnerability to drug dependence are net mutually exclusive..One is a genetic predisposition, shared by family members by virtue of their common biological heritage. Another is an experiential predisposition, shared by family members by virtue of their shared life experiences. For instance, children with parents who are dependent on drugs are at elevated risk of becoming dependent (Hawkins, Lisbner, Cata]ano 1986; Begletier et al, 1984; Kumpfer 1987). For tobacco, the magnitude of the effect is greater when both parents smoke than when only erie parent smokes (Borland and Rudolf 1975; Green 1979). Other typos of vulnerability factors are physiologic (e.g., pain, sleep deprivation) and psychiatric (e.g., anxiety, depression) conditions that may constitute undesirable states for which relief is sotlght by use of a drug (Crowley and Rhine 1985). Finally, as discussed earlier in this Chapter, a variety of nonpharmaeologie factors are important in the initiation and development of drug dependence (e.g., price, availability); such factors may be considered vulnerability factor8 in their own right. A recent area under active investigation is the identification of specific vulnerability factors in youth (Brown and Mills 1987). For example, cigarette smoking has long been associated with juvenile behavior problems (Armstrong-Jones 1927; Welte and Barnes 1987; Kumpfer 1987); more recently, scientific data have confirmed the statistical association of increased rates of cigarette smoking among juveniles with a conduct disorder diagnosis (i.e., adolescent deviance) (Sutker 1984). A related observation is that children with conduct disorders are at elevated risk of using opioids, cocaine, alcohol, tobacco, and other psychoactive drugs (Baumrind 1985). In fact, Kellam, Ensminger, and Simon (1980) found that certain indices of mental health identified in first graders were highly predictive of the use of various psychoactive drugs (including alcohol, opioids, marijuana, and nicotine) when the children were restudied in their teenage years. These studies do not directly address the degree to which juvenile behavior problems are causes or consequences of drug use. It is plausible that either drug use or other behavior problems @ @ @ 266 •

can exacerbate each other, possibly alternately contributing to a gradual escalation of drug use, behavior problems, or both. These observations suggest that it is especially important to prevent initiation of drug use among individuals who appear to be at increased risk (vulnerability) to developing drug dependencies. Pharmacolog{c Determinants of Drug Dependence As discussed earlier in this Chapter and-in Chapter I, it is the involvement of a dependence-producing drug that sets drug addic- tions apart from the so-called "addictions" to other substances (e.g., food) and activities (e.g., gambling). There are scientific methods to determine if use of a substance involves a dependence-producing drug. These methods, how they are applied to study drugs such as morphine, cocaine, and nicotine, and some of the main findings from such work are reviewed in this Section. A wide range of drugs can be used to modify behavior (e.g., as used in psychiatric treatment); however, the term drug dependence is generally reserved for dependencies which involve drugs that can' sustain repetitive drug self-administtyation by virtue of their tran- sient effects on mood, feeling, and behavior. Drugs that exert such effects via alteration of functioning of the brain or central nervous system (CNS) are generally termed "psychoactive" (WHO 1981). When the psychoaetivity of a given drug is frequently pleasant, it is referred to as a "euphoriant," as '~ceinforeing," or as an "abusable" drug, although these terms are not precisely interchangeable. This "framework is consistent with that described by Lewin (1931); namely, that these drugs are chemicals which are "taken for the sole purpose of producing for a certain time a feeling of contentment, ease, and comfort." Drugs which produce such effects effectively control the behavior of a wide range of species, including humans. How Drugs Control Behavior Drugs cause addiction by controlling the behavior of users; that is, addicting dl:ugs come to influence behavior leading to their own ingestion. The behavioral and pharmacologic mechanisms of such control have been reviewed elsewhere (Thompson 1984) and will only be briefly summarized in this Section. Behavior, including drug taking, is biologically mediated by the electrical anfl chemical stimuli which arise from the nervous system. These stimuli may originate within the body and brain of the individual, but they may also arise from environmental events and be detected by sensory processes such as vision and audition. Dependence-producing drugs control behavior by activating, inhibiting, or mimicking the existing chemical circuits of the nervous system. Dependence-producing drugs are those that readily exert control over behavior by virtue of 267

their stimulus propertie~. It is useful to distinguish among four kinds of stimulus effects produced by dependence-preducing drugs. (1) Drugs can produce interoceptive or discriminative effects that a person or animal can distinguish from the nondrug state. These effects may set the occasion for the occurrence of particular behaviors. For example, the taste of alcohol or the smell of tobacco smoke can set the occasion for social interactions, and the "priming" effects of a single dose of a drug can lead to subsequent drug seeking and relapse in animals or humans with a history of use (Griffiths, Bigelow, Henningfield 1980; Colpaert 1986). (2) Drugs may serve as positive reinforcers or rewards which directly strengthen behavior leading to their administration. The reinforcing efficacy may be related to effects termed either "stimu- lating," "relaxing," "pleasant," "useful," "therapeutic," or "euphori- ant" or may be related to providing relief of withdrawal symptoms or other undesirable states. (3) Drug administration or abstinence can also function as "punishers" or aversive stimuli. For example, high dose levels of most psychoactive drugs serve as an upper boundary level of intake; analogously, decreasing drug levels can also function as aversive stimuli contributing to the strength of drug taking as a means to avoid such aversive effects (Downs and Woods 1974; Goldberg et al. 1971; Henningfield and Goldberg 1983b; Kozlowski and Herman 1984). Aversive stimuli may function as negative reinforcers by strengthening behavior that removes the stimuli (Skinner 1953). Thus, drug withdrawal symptoms are sometimes 'referred to as negative reinforcers that increase drug seeking. (4) Drug administration, or abstinence following a period of chronic administration, can serve as unconditioned stimuli, in which case they may directly elicit various responses, e.g., vomiting at high- dose levels of opioid administration or during opioid withdrawal, light-headedness produced by rapid smoking, and a strong urge to use a drug. As will be discussed later in this Chapter, repetition of such phenomena can lead to their elicitation by drug-esseciated stimuli, e.g., the sight or smell of drug-associated stimuli (O'Brien, Ehrman, Ternes 1986; Wikler 1965; Wikler and Pescor 1967). All of these processes may occur whether or not the person has correctly identified their source, i.e., is "aware" of how the drug led to the behavior (Fisher 1986). Furthermore, the biologic power and generality of these processes is evidenced by the findings that they also occur in animals (Young and Herling 1986; Spealman and Goldberg 1978; Johanson and Schuster 1981). Drugs differ widely in their potential to control behavior via such mechanisms. Depondence-preducing drugs usually readily control behavior in all of the above capacities. Quantification of such characteristics is the cornerstone of testing for the likelihood that @ 268 @

O use of a drug will lead to addiction. Observers in the ]gth and early 20tb centuries (e.g., Lowin 1931) had correctly determined that it was the psychological (behavioral) effects (sometimes termed "psych- ic" or "mental" effects) of substances that led to their habitual use. Practical methods for evaluating the behavior-modifying properties of drugs did not emerge until the behavioral sciences themselves had become sufficiently sophisticated in the 1930s and 1940s. Prior to this time, dependence-producing drugs were identified on the basis of retrospective observations of their effects. Since the 1940s, however, drug testing has grown increasingly reliable at identifying Csereen- ing") drugs for their potential to produce dependence prior to observations of dependence outside the laboratory. In fact, highly reliable information can now be obtained on the basis of animal testing alone (Martin 1971; Thompson and Unna 1977; Brady and Lukas 1984; Bozarth 1987b). Methods for evaluating the behavior-modifying properties of drugs were largely developed beginning in the 1940s in studies with morphine-like opioids, and cocaine-like stimulants, and have only recently been systematically used to evaluate nicotine. The methods will be described in the remainder of this Section, along with a comparison between the behavioral-pharmacologic actions of nic- otine and those of other drugs. Dependence Potential Testing: Psychoactive, Reinforcing, and Rete, ted Effects To scientifically determine if a chemical is dependence producing, a series of sclentifie tests may be done. These testsare jointly termed dependence potential tests, In this Chapter, Depen- dence Potential Testing refers to laboratory tests which measure the behavioral and physiological responses of animals and humans to drug administration and to termination of chronic drug administra- tion, Taken together, the results of these tests can he used to objectively predict whether a drug lends itself to self-administration by persons who are exposed. The focus of the present Section is on how the methods are applied to evaluate the potential of drugs to control behavior and to produce transient alterations in mood or feeling that are predictive of self-administration. Such effects have essentially defined the dependence-produelng drugs and have set them apart from other medielnals and food; drugs with such effects are sometimes termed "psychotropic" or "behaviorally active" but most commonly as "psychoactive" (President's Advisory Commission 1963; WHO 1981). Not all psychoactive drugs lead to dependence; many drugs used to treat behavioral and psychiatric disorders are considered to have minimal dependence potential (for example, tricyclic antidepres- sants) or may actually produce effects that substantially impair long- 269

term compliance with therapeutic regimens (for example, major tranquilizers). How dependance-producing drugs are distinguished from other psychoactive drugs will be described in this Section. The next Section will discuss methods used to measure test drugs for their potential to produce tolerance and physical dependence, In revle~ and proceedings from various expert committees, the procedures to be described have been referred to as testing for "Abuse Liability," "Psychic Dependence," "Abuse Potential," "Ad- diction Liability," "Behavioral Dependence," and "Dependence Po- tential" (Brady and Lukas 1984; Goldberg and Hoffmeister 1973; Thompson and Unna 1977; Selden and Balster 1985; Thompson and Johanson 1981; Bozarth 1987b; WHO 1981). Whereas there are differences in focus that are evident when these methods are compared, the general goals and strategies are consistent. These will be briefly described in this Section. Detailed descriptions of these methods have been provided by an expert subcommittee of the Committee on Problems of Drug Dependence (Brady and Lukas 1984) and in numerous conferences involving world experts on such procedures (Goldberg and Hoffmeister 1973; Thompson and Unna 1977; Selden and Balstsr 1985; Thompson and gohanson 1981; Bozarth 1987b), The results of the methods are also considered in the process of reviewing the national and international regulatory status of various drugs either known or suspected to be addicting by the FDA, the Drug Enforcement Agency (DEA), and the WHO (WHO 1981, 1987). Effects of Drugs on Mood and Feeling (Psychoactivity) Dependence-preducing drugs can change the way a person thinks, feels and behaves. The effects may be very subtle (e.g., feelings of relaxation), or they may be profound (e.g., intoxication and impaired cognitive abilities). The scientific assessment of the effects of drugs on mood and feeling (also referred to as "psychoactive," "psychologi- cal," "interocept, ive," "subjective," "psychic," or "self-reported" effects) was essentially an extension of the methods developed to assess physiological actions of drugs. By the late 1940s, several drug dependance researchers had concluded that physical dependence potential testing was of limited value in predicting whether drug- seeking behavior would develop following exposure to a given drug (|sbell 1948; fsbel! and Vogel 1948). These researchers used observa- tional techniques to measure intereeeptive drug effects. Later, the reliability and general applicability of the techniques were substan- tially enhanced by incorporation of the methods developed by Rao (1952) for assessing changes in subjective state and the methods developed by Beeeher (1959) for the measurement of pain and analgesia in humans. I 27O •

O 8 These methods contributed to the development of what are generally considered the first objective questionnaires for assessing addictive drug effects by Fraser and his colleagues (Fraser and lsbell 1960; Fraser et al. 1961). A prominent feature of the questionnaires was a series of scales to evaluate the ability to feel or discriminate a drug effect, to rate the liking of the drug effect, and to identify the drug that was given from a llst of widely used and abused drugs. The next major advance in the quantification of subjective drug effects was the development of the Addiction Research Center Inventory (ARCI) by Haertzen and his colleagues (Haertzen, Hill, Belleville 1963; Haertsen 1966, 1974; Haertsen and Hooks 1969; Haertzen and Hiokey 1987). The ARCI contained scales that were empirically derived to be sensitive to the effects of specific drugs and drug classes (e.g., sedatives, stimulants, hallueinogens). One of the most useful scales was developed to measure the effects of morphine and benzedrine (a prototypical opioid and stimulant, respectively); this scale was subsequently referred to as the "Morphine Benzedrine Group" or "MBG" or "Euphoriant" scale, because morphine-like and benzedrine-like drugs increased the scale scores while simultaneous- ly producing feelings often reported as pleasurable (ttaertzen, Hill, Belleville 1963; Haertzen 1974). Scores on the MBG scale are also elevated by most other addicting drugs (Jasinskt 1977; Jasinski, Johnson, Henningfield 1984; Henningfield 1984). More recently, the highly specific drug discrimination testing procedures (described below) have been added to the human drug dependence potential testing armamentarium (Chait, Uhlenhuth, Johanson 1984, 1966). To the extent to which certain common features are identified using tests such as the above, they may be categorized together, e.g., as dependence-producing or addicting drugs. This is referred to as determining "pharmacologic" equivalence. Conversely, to the extent to which these same drugs differ in certain respects, they may also be subcategorized as, for instance, analgesics, sedatives, or stimu- lants. Such categorization must be viewed with caution, however, because overemphasis on any particular feature of a drug can be misleading. For instance, morphine, alcohol, and amphetamine can all produce behavioral and physiologic effects that are stimulant.like as well as effects that are sedative-like (Gilman etal. 1986; Dews and Wenger 1977). Nicotine has been viewed as both a stimulant ("excitant") (Lewln 1931) and a sedative (Armstrong-Jones 1927). Most commonly nicotine is now categorized as more stimulant.like than sedative-like, but with an appreciation of its diverse range of potential effects, which depend upon the does given and the measure used (Gilman et al. 1986). 271

Methods and Results Assessment of the psychoactivity of drugs in humans essentially entails giving either drug or placebo to volunteers and then asking them to report the nature of effects produced. Replicability and objectivity are increased by using standardized questionnaires such as those described above (e.g., "liking" scales, ARCI). In practice, several procedural variations are used to further enhance the reliability and validity of the results. The dose of the drug is varied to assess the nature of the dose-effect relationships; for all depen- denee-predueing drugs, ratings of dose strength or the percentage of accurate drug identifications is directly related to the dose given. Subjects with histories of use of a variety of drugs can be asked to report which, if any, of those drugs the test drug feels like; such testing isuseful.to determine the extent to which the test drug produces any effects on mood and feeling that resemble those of previously studied drugs. Subjects with histories of use of a variety of drugs and who report "liking" the effects of a range of drugs can be used to help assess the dependence potential of the test drug by rating how desirable they find it to be. Incorporation of several of these methods can add considerably to the strength of conclusions which can be drawn. For example, morphine-like opioids, pentobarbital-like barbiturates, amphet- amine.like stimulants (including cocaine), alcohol, and nicotine all produce rapidly oasetting and offsetting discriminative effects; the magnitude and duration of these effects are directly related to dose; all elevate scores on the liking and MBG scales; the effects of all are directly (though complexly) related to pharmacokinetic factors such as rate of systemic absorption; all produce discriminative effects that correspond to certain physiological changes; all produce effects that can be accurately identified by an observer; all are identified as known addicting drugs by subjects with a history of use of such drugs; pretreatment with antagonists may block these effects (only opioids and nicotine have been systematically studied on this dimension). Such orderly and consistent kinds of effects across drugs confirm that they are appropriately categorized together as addict- ing drugs. The selectivity and sensitivity of such procedures are illustrated in Figure 1. As shown in the Figure, when persons with multiple drug dependence histories were given drugs under double-blind condi- tions, they rated placebo (unconnected data point on each graph) and the nonaddicting zomepirac at a minimal level of "liking" (Jasiaski, Johnson, Henningfield 1984). As a direct function of dose, however, the known addicting drugs were rated with greater liking scores. As also illustrated in Figure 1, nicotine produced comparable dose related increases in drug liking scores as did amphetamine, mor- phine, and pentobarbital. Studies with human volunteers have also @ @ @ @ @ 272 •

MORPHINE (SC) d-AMPHETAMINE NICOTINE (SO) (IV) BUPRENORPHINE PENTAZOCINE (SL) (IM) ZY9.THC (PC) c PENTOBARBITOL CHLORDIAZEPOXIDE ZOMEPIRAO (PO) (PO) (POi Drug dose (rag) FIGURE L--Liking scale scores of the single-dose questionnaire NOTE: Sample sire ranges from 6 (pentobarbltsl aM chLordip~epoxidel to 13 (4-amphetsminel The high dose each drug fexeept zomepJra¢) prodti¢~l signiflcetnt Ip<0.05) lnore~ in accr~ abcve placebo. Data =re peak r~pcnse, which ~eur~-,d from approximately I minute {nicotineJ to ~5 ho~r# (bupre~orphineL Morphine and ~mepira¢ dJta ar® from the same group of ,ubject8 u pentob~rbital ~nd ehlordil~epoxide data The P + T point on the po n ta,'~ine graph is the ~ors given m 40 mg pentt~lne vombined with 60 mg trlpolennamine The N point on the ~-9.THC graph is the score, from the ~mv lubje~ts, ob~i n~J af~t smoking I mar ~j~ana ¢igmrette contsinlrlg 10 mg (1 percent by we[ghtl A-9-THC. SOURCE: Jasi~ekL Johnson, Henningfleld {1984~, shown that most of the known addicting drugs (including nicotine) produced certain changes in mood and feeling that resemble those produced by morphine or benzedrine enough to significantly elevate the MBG scale scores (Griffiths, Bigelow, Henningfield 1980; Hen- ningfield, Johnson, Jasinski 1987). 273

The validity of self-reported drug effects as objective indices of dependence potential has been tested using similar rating scales by observers who are blind to the condition. On the basis of their observations of subject behavior, observers report similar dose- related increases in scores on the strength of the drug effect and/or the level of drug liking for alcohol (Henningfield, Chait, Griffiths 1983), pentebarbital (Martin, Thompson, Fraser 1974; Henningfield, Chair, Griffiths 1983), morphine and heroin (Martin and Fraser 1961), amphetamine (Jasinski and Nutt 1972; Jasinski, Nutt, Griffith 1974), and a variety of other dependence-producing drugs (Jasinski 1977). A similar correspondence between subject and observer ratings was obtained when subjects were given either i.e. nicotine injections or research cigarettes which varied in nicotine dose (Henningfield, Miyasato, Jasinski 1985). Effects on mood and feeling also correspond to a variety of physiological effects. Some of these physiological changes vary by drug class. For example, pupil diameter increases appear to eorre. spend to early nicotine-induced subjective effects and to amphet- amine and cocaine administration (Henningfield et al. 1983; Jaffa 1985), whereas pupil diameter decreases when morphine is given (Jasiaski 1977). Other physiological effects show a greater degree of similarity across drug classes. For example, studies of ethanol administration in human subjects revealed that paroxysmal bursts of electroencephalogram (EEG) alpha activity paralleled subjective reports of euphoria during the ascending limb of the plasma ethanol curve (Lukas et al. 1986b,o), which also paralleled increases in plasma adrenocorticotropic hormone (ACTH) levels (Lukas and Mendelson, in press). Similar effects were observed following mari- juana smoking (Lukas et al. 1985, 1986a) and acute i.e. nicotine administration (Lukas and Jasinski 1983). In turn, similar changes In EEG alpha activity have been shown to correspond with subject- reported pleasurable states which can occur in the absence of drug administration (Lindsley 1952; Brown 1970; Wallace 1970; Matejcak 1982). Drug Discrimination Testing Drug discrimination testing in animals is assumed to provide information analogous to the above-described procedures for assess- ing the effects of drugs on mood and feeling in humans (Ooldberg, Spoalman, Shannon 1981). Drug discrimination testing can provide two general kinds of information. First, the ability of dependence- producing drugs to contrel behavior by serving as positive reinforc- ers or punishess is associated with whether they produce interecap- tive effects which are discriminated (or "felt"). Second, drugs can be compared with each other to determine the degree to which they are identified as similar or different. The methods used for drug 274 •

discrimination testing in animals were not systematized and widely utilized until the late 1960s and early 1970s (Overton 1971; Overton and Batta 1977; Schuster and Balster 1977; J~irbe and Swedberg 1982). Extension of animal discrimination study results to humans is limited by species differences and by-other unique human factors that may contribute to the dependence potential of a drug. Nonethe- less, animal studies are an important advance because they permit relatively inexpensive and rapid testing of a broad range of compounds and allow evaluations to be made without the possible confounding social and cultural factors. Animal studies also provide a means of gauging the biological generality of the drug discrimina- tion data (e.g., to determine if unusual genetic characteristics are necessary for certain drug effects). Methods and Results These procedures and variations have been described in greater detail elsewhere (Overton and Baita 1977; Colpaert 1986; Roseorans and Meltzer 1981. In brief, the basic method is to train animals to emit one response when given one drug and to emit another response when given either no drug (i.e., placebo) or a different drug. The animals are usually trained with either food reinforcement or the withholding of electrical shock for "correct" responses. When the animals have been trained to a level of 80 or 90 percent correct responses, they are. said to be discriminating drug from placebo. Then they are ready for the testing of different doses of the training drug or different drugs. This testing is often accomplished without the use of food or shock contingencies, so that it can be determined which response the animal will make when given the test drug. A check on the validity is to give lower doses of the training drug; the lower the dose, the less the animal should respond on the drug lever and the more on the placebo lever, A similar effect is obtained when an antagonist is given before testing with the training drug; as the dose of the antagonist is increased, the ability of the animal to discriminate the training drug decreases and the animal emits more no-drug responses. These effects have been demonstrated with both the opioids and nicotine (Overton 1971; Colpaert 1986; Rosecrans and Meltzer 1981; Chapter Ill); i.e., decreasing the dose of the opioid or nicotine or pretreating with an opioid or nicotine antagonist can produce decreased drug lever responding. The specificity of the stimulus produced by a drug can also be evaluated by testing drugs. The degree to which the animals make the "drug" responses or "mistake" the test drug for the training drug is termed "generalization" and indicates the level of similarity of effects between the drugs (Colpaert and Rosecrans 1978). Morphine analogs, amphetamine analogs, pentebarbital analogs, and nicotine 275

analogs produce substantial amounts of generalization to morphine, amphetamine, pentobarbital, and nicotine, respectively. The fact that there is less generalization across drug classes is an index of the specificity of the drug stimulus. The cross-drug classifications which have resulted from animal discrimination studies are generally consistent with human data (Goldberg, Spealman, Shannon 1981). For instance, if an animal has been trained to press one lever when given amphetamine and another lever when given pentebarbital, it tends to press the amphetamine lever more often than the pentobar- bital lever following a nicotine injection (Scheeter 1961). This finding is consistent with that obtained in a study in which human volunteers frequently identified nicotine injections as amphetamine or cocaine at higher nicotine dose levels but not at the lower levels and only rarely identified the nicotine injections as sedatives (Henningfield, Miyesato, Jasinski 1985). A more recent development is the extention of the systematic drug discrimination procedures to use with human subjects. Similar methods are used, and initial findings with drugs such as nicotine and amphetamine are comparable to the results from animal studies (Kallman et el. 1982; Chait, Uhlanhuth, Johansen 1984). Specifically human volunteers can readily learn to differentially respond to the presence or absence of these drugs, and the effects are dose related. Drug SelfAdrninistration When given the mechanical means to do so, animals self-adminis- ter addicting drugs (including nicotine) much like humans; that is, drugs that function as rewards or reinforcers for humans also tend to function as reinforcers for animals. The conceptualization of depen- dence-producing drugs as reinforcers provided the framework for a highly predictive test strategy, the self-administration study, where- by animals or humans are given the opportunity to take drugs under laboratory conditions (Thompson and Schuster 1968). This research strategy permitted scientific analysis of the single common link across all forms of drug dependence, namely that the addictive behavior (for whatever reason) is motivated or controlled by the drug's reinforcing (rewarding) properties (Goldberg and Hoffmeister 1973; Thompson and Unna 1977; Selden and Balster 1985). Stimuli that can maintain and strengthen behavior leading to their presen- tation are termed "positive reinforcers" regardless of their hypothe- sized mechanism of action (e.g., alleviation of discomfort or produc- tion of pleasure) (Skinner 1953; Thompson and Schuster 1968). The reinforcing power or efficacy of a drug can be enhanced by a variety of conditions (e.g., deprivation of the drug which the organism had been repeatedly given, pain, food deprivation, social approval contingent on drug taking, and perceived useful effects) (Thompson and Schuster 1968; Thompson and Johanson 1981). Following g76 •

@ repeated exposure to a drug, a biologically mediated "drive" state can be established that did not preexist as do the drives for food, water, or sex. The potential of a drug to serve as a reinforcer can be directly assessed and quantified in laboratory studies of drug self-administra- tion. Essentially, a human or animal subject is given access to the drug; then his or her propensity to take the drug (i.e., to "self- administer" the drug) can be measured. The self-administration test provides the opportunity to rigorously study the main distinguishing feature of drug dependence, that is, drug-seeking behavior. As is the case in drug discrimination testing, animal date help to determine the generality of the biological basis of the addictive process for a given drug; for example, such data help to reveal if the process is unique to humans because of social, genetic, or other factors. If the drug is taken under a variety of prescribed conditions (summarized later in this Section), then it is said to be functioning as a "reinforcer" or "reward." The validity and generality of self-administration test results were demonstrated by the observations that (1) there was a remarkable degree of consistency between patterns of drug self-administration among laboratory animals and observations concerning human drug dependence (Jasinski 1977; Griffiths, Bigelow, Henningfleld 1980), (2) drugs that serve as reinforcers in self-administration studies also tend to be "liked" when given to humans, and (3) there was a high correlation among drugs which produced morphine-like euphoriant effects and those which were self-administered by animals (Griffiths and Balster 1979; Griffiths, Bigelow, Henningfield 1980; see related data in Schuster, Fisehman, Johansen 1981). Initiation of Drug Self-Administration As discussed earlier in this Chapter, drugs cannot produce dependence without initial exposure to them. Initiation of drug .use in humans is often mediated by social and other environmental sources of pressure. To determine if a drug will reinforce behavior in animals similarly requires some means of providing exposure to the drug. Strategies for establishing drug taking in animals are analo- gous in key respects to how humans may become dependent upon drugs. Four general categories of methods are most commonly used. The methods are not mutually exclusive and are sometimes used in combination. The first method of establishing drug self-administration in animals is to provide initial doses ("priming" or "free sampling") and then to gradually increase the dose ("graduation"). For instance, l.v. drug infusions may be given to animals on a chronic basis while the animals are also given the opportunities to take the drug. This provides art opportunity to determine if simple exposure to the drug 277

is sufficient to result in drug seeking. A minor variation is to gradually increase the dose of each injection over time. This general procedure has been used to establish i.e. self.administration of d" amphetamine, morphine, alcohol, pentobarbitai, cocaine, nicotine, and many other drugs (Deneau and Inoki 1967; Deneau, Yanagita, Seevexs 1969; Yanagita 1977; Woods, Ikomi, Winger 1971; Brady and Lukas 1984; Griffiths, Bigelow, Henningfield 1980; Melsch 1987; Henningfield and Goldberg 1983a). A second method of establishing drug self-administration is to substitute a new drug for one which was already serving as a reinforcer. Humans do this as a function of drug availability; they sometimes learn to like drugs which had not been taken previously and may even come to prefer the new drug. Using this method with animals provides a means of exposure to a new drug and may be useful in comparing one drug with another. In animal studies, cocaine is the most commonly used starter drug, because in animals (as in humans) cocaine seems to be a source of reinforcement and/or pleasure under an extremely broad range of conditions compared with most other drugs. Variations on this procedure have been used to evaluate the likelihood of self-administration of a wide range of drugs incldding amphetamine, barbiturates, alcohol, opioids, and nicotine (Griffiths et al. 1976, 1981; Woods 1980; Dencau 1977; Yanagita 1977; Griffiths, Bigelow, Henningfleld 1980; Brady and Lukas 1994; Me isch 1987; Chapter III). A third method is to induce the initial use of the test drug by prearranged environmental sources of "pressure" or "motivation." Induction of drug taking can be accomplished with very explicit contingencies. For example, presentation of food or withholding of electric shock can be made contingent on drug consumption (Mello and Mendelson 1971a,b). However, such direct contingencies often result in minimal response output (i.e., drug consumption) to obtain the positive reinforcer or to avoid the electric shock, and drug self- administration may not persist after the contingencies are removed (Mello 1973). For example, even when physical dependence on alcohol had developed in rhesus monkeys, the animals often rejected the drug when self-administration was not required to meet the contingency (Mello and Mendelson 1971a). Thus, these procedures have not been extensively used to generate animal models of human drug taking (Griffiths, Bigslow, Henningfield 1980). The fourth procedure for establishing drug self-administration seems somewhat more analogous to how drug dependence may sometimes develop in humans outside the laboratory, and has been widely used to study drug self-administration in the laboratory; this method is termed the "adjunctive behavior" or "schedule-induced behavior" strategy (Falk 1983). The method involves a less direct means of inducing drug intake; in fact, the drug does not need to be 278 •

taken to obtain the reinforcer or to avoid the punisher. Rather, the animal is simply given the opportunity to take the drug; at the same time, the experimenter arranges conditions that are highly likely to engage the animal in cycles of work and breaking from work. For example, the animal may have to press a lever to obtain food. The result is that when the animal is unable to work on the food schedule (e.g,, during the brief "timeouts" or "waiting" periods), the animal tends to take the drug. Eventually, the drug itself might come to function as a reinforcer in its own right, even in the absence of the environmental pressures that first led to its use. The dose level of the drug is then increased gradually over time. Variations on this procedure have been used to establish self-administration of alcohol (Falk, Samson, Winger 1972; Freed, Carpenter, Hyrnowitz 1970; Mcisch 1975), pentobarbital (Meisch, Kliner, HenniI£gfield 1981), nicotine (Singer, Wallace, Hall 1982), and a variety of other drugs (Brady and Lukas 1984; Meisch and Carroll 1981; Meisch 1987). Although many environmental conditions are present outside the laboratory that appear to function as do adjunctive schedules in the establishment of human drug dependence (e.g., boredom in occupa- tional settings), there have been few experimental studies of adjunctive drug taking by humans (Falk 1983). One such study by Cherek (1982) showed that volunteers took more puffs per cigarette when they were given monetary reinforcers at regular intervals: the volunteers had to press a button to obtain the reinforcer, but their behavior did not decrease the time theyhad to wait for each • reinforcer to become available. Evaluation of Reinforcing Effects Conclusive demonstration that the effects of the drug itself were the cause of the drug-seeking behavior is equivalent to showing that the drug itself is functioning as a positive reinforcer. The basic procedures were developed in animal studies (Pickens and Thompson 1968; Deneau 1977) and have been reviewed in detail elsewhere (Johanson and Schuster 1981; Balster and Harris 1982; Fischman and Schuster 1978; Yanagite 1980; Brady and Lukas 1984). The most fundamental procedure is to verify that drug self- administration occurs under conditions in which it is "optional" or "voluntary"; that is, explicit contingencies for drug taking (e.g., to obtain food, to avoid shock, or to obtain preferred liquid) are not required. It is also necessary to ensure that the drug taking is not simply maintained by the characteristics of the vehicle (e.g., water or a flavored solution into which alcohol is placed, or the tobacco smoke in which nicotine is delivered to smokers). If the drug is serving as a reinforcing stimulus, it should be capable of maintaining controlled behavior. For example, a complex chain of drug seeking (i~e., "procurement") might be required to 279

obtain the drug. An extension of this principle is to gradually increase the amount of work (i.e., the "cost") that must be expended to achieve drug delivery to determine how much the subject works ("pays") for a given drug or drug dose. For example, the ratio of lever press responses per drug injection is gradually increased in the "Progressive Ratio" procedure to determine the maximum ratio ("breaking point") that will be sustained (Yanagita 1977; Griffiths, Brady, Snell 1978a). If the drug is serving as a reinforcer, then stimuli associated with drug administration should also come to serve as reinforcers ("conditioned reinforcers"). Of all dependenco-preducing drugs, the importance of this factor may be most pronounced with regard to nicotine because the various effects of nicotine may be associated with tobacco smoke and other stimuli hundreds of times each day over the course of many years of smoking. A fundamental observa- tion is that even neutral-appearing stimuli can function as reinforc- ers in their own right when they are associated ("paired") with previously established reinforcers such as food, water, sex, or drugs (Skinner 1953; Thompson and Schuster 1968). For example, the taste and smell of alcohol are initially highly aversive to animals (Mello 1973), but in one study, the smell of alcohol was established as a conditioned positive reinforcer for animals: the smell of alcohol was enough to reinstate drug-seeking behavior even when the alcohol was not physically available (Meisch 1977). Seemingly arbitrary stimuli such as lights and tones can come to serve as reinforcers- after association with i.e. self-administered drugs including cocaine- like stimulants, opioids, barbiturates, and nicotine (Goldbel~g 1970; Goldberg, Kelleher, Morse 1975; Griffiths, Bigelow, Henningfield 1980; Goldberg et el. 1983). The basic methods described above are also used in human drug self-administration studies, although with various procedural adap- tations which have been described in detail elsewhere (Nathan, O'Brien, Lowenstein 1971; Cohen, Liebson, Faillace 1971; Mello, MeNamee, Mendelsen 1968; Meno 1972; Meyer and Mirin 1979; Bigelow, Griffiths, Liebson 1975; Henningfield, Lukas, Bigelow 1986). As in the animal drug self-administration studies, the human volunteers must emit a measurable response that may lead to drug ingestion: for example, riding an exercise bicycle (Griffiths, Bigolow, Lisbsen 1979; Jones and Prada 1975) or pressing a button on a portable work station (Mello and Mendeison 1978). Such work requirements then become established as part of the chain of drug- seeking behavior. They have an advantage over non-laboratory drug- seeking behavior in that the amount of work can be carefully measured. Such data provide quantitative estimates of the time and/or work expended for drugs (see examples in the following studies and reviews: Johansen and Uhlenhuth 1978; Bigelow, 28O •

Griffiths, Liebson 1975; Mclio and Mendelson 1978; Fischman and Schuster 1982; Henningfield and Goldberg 1983b; Jasinski, Johnson, Henningfield 1984). Results from Drug Self-Administration Studies Most categories of drugs which have been found to cause wide- spread drug dependence in the nonlaboratory setting have been tested with animals and humans in laboratory settings. Results of these studies have been reviewed in detail elsewhere (Griffiths, Bigelow, Henningfield 1980; Brady and Lukas 1984; Henningfield, Lukas, Bigelow 1986). Several categories of drugs have been found to be self-administered by humans and animals in the laboratory settings, to meet criteria as positive reinforcers, and to exhibit orderly relations as a function of drug dose, drug pretreatment, and other factors known to affect the intake of dependence-producing drugs. These include alcohol, morphine, pentobarbital, amphet- amine, cocaine, and nicotine in the forms of cigarettes and i.v. injection. Self-administration studies with animals are much more extensive and have also been reviewed in detail elsewhere (Johanson and Schuster 1981; Balster and Harris 1982; Fischman and Schuster 1978; Yanagite 1980; Brady and Lukas 1984; Young and Herliug 1986}. In brief, drug self-administration studies in animals in the 1960s showed that a range of drugs including opioids, amphetamines, barbiturates, certain, organic solvents, alcohol, cocaine, and nicotine were self-administered (Weeks 1962; Thompson and Schuster 1964; Deneau, Yanagita, Ssevers 1969; Deneau and Inokl 1967). All of these drugs were found to maintain powerful chains of drug-seeking behavior, even when insufficient drug was taken to produce a clinically significant degree of physical dependence (Goldberg, Morse, Goldberg 1976). Drugs that did not serve as reinforcers in these studies included caffeine, lysergie acid diethylamide (LSD), and the major tranquilizer chlorpromazine. The speed of drug delivery can affect its reinforcing efficacy (Kate, Wakasa, Yanagita 1987). Thus, the inhaled form of cocaine ("crack") is considered more reinforcing and dependence producing than other forms of cocaine delivery, with oral cocaine apparently among the least reinforcing of the commonly used rout~ of delivery (see also US DHHS 1987). Analogously, nicotine taken by the slow release oral preparation (nicotine polacrilex gum) appears to be much less reinforcing than nicotine taken by quicker release oral preparations (e.g., chewing tobacco) or cigarette smoke (Chapters IV and VII). Research findings have continued to extend the early observations (Deneau, Yanagita, Seevers 1969) that the results with animals were remarkably consistent with observations regarding human drug dependence. For example, initial exposure of humans to drugs such 281

as opioids and stimulants led to addictive patterns of use, whereas chlorpremazine rarely did, and LSD infrequently did (Jasinski 1977; Griffiths et el. 1980). Earlier studies had suggested that alcohol, caffeine, and nicotine were not reinforcers in animals (Mello '1973; Russell 1979; Griffiths et el. 1988). However, by the early 1970s for alcohol (Meisch and Thompson 1971; Meisch 1977, 1982} and 1981 for nicotine (Goldberg, Spealman, Goldberg 1981), it had been confirmed that these drugs could also serve as effective reinforcers for nonhumaas. The relatively little research done to assess the dependence potential of caffeine has not as conclusively demon- strated that it serves as a reinforcer in animals (Griffiths and Woodsen 1988b). Drug Dose as a Determinant of Drug Intake Drug dose per administration is a major factor that affects self- administration of dependence-producing drugs. The resultant dose-response relationships are orderly, and the data have been reviewed extensively (Griffiths, Bigelow, Henningfield 1980; Jchan- sen and Schuster 1981; Young and Herling 1986). In brief, the relationship between the dose size available and the number of doses taken is often referred to as an inverted U-shaped function because of the shape of a graph that results when the number of injections (y- axis) is plotted as a function of dose (maxis) across a wide range of doses to which a subject is given access. Over the range of doses which appear to be functioning as effective reinforcers, changes in dose are accompanied by compensatory changes in number taken such that total drug intake is somewhat stabilized. It appears that a determinant of such compensatory changes in drug self-adminlstration is the apparent upper and lower "boundaries" or "thresholds" for aversive effects that might occur when either too much drug is obtained or when insufficient drug is obtained to prevent withdrawal responses (Kozlowski and Herman 1984). It should be noted, however, that in most studies, compensato- ry changes in drug intake as dose level is changed are almost never perfect and are frequently quite crude (Griffiths, Bigalow, Hennlng- field 1980). (See Yokel and Pickens 1974 for an example of a study in which drug intake was unusually stable across a range of amphet- amine doses.) Thus, the usual observation related to drug dose is that as dose is increased, the rate of drug taking decreases somewhat but more total drug is obtained. This relationship is observed in studies of i.v. nicotine in animals (Ooldberg et al. 1983) and humans (Henningfield, Miyasate, Jasinskl 1988) and when tobacco smoke dose is manipulated in humans (Chapter IV). A misinterpretation of dose-rosponse relationships by tobacco researchers, largely in the 1970s, led to the controversy that marked the so-called "titration studies" of tobacco intake. Specifically, it was Q O 282 •

assumed that if a drug was serving as a reinforcer, then compensa- tion for changes in dose level should have been more effective than they appeared to be. Hence, some questioned whether nicotine was serving as a reinforcer because dose-response relationships in nicotine studies appeared very crude (Russell 1979). The question that arose was not whether cigarette smokers showed compensatory changes in responses to changes in dose level; they did. In fact, the nicotine dose-response relationship has probably been better studied and established, over a wider range of conditions and techniques of study, than have dose-response relationships with any other class of drugs which are salf-administerod by humans (Gritz 1980; Griffiths, Bigelow, Henningfield 1980; Henningfield 1984). The question was, rather, why.compensatory changes in cigarette smoke intake often appear to be inadequate to maintain stable levels of nicotine intake. There are two main problems in interpreting these data, however. The first is that in the vast majority of human cigarette smoking studies, attempts to manipulate the dose delivered were not well controlled and the measures used to assess the possible effects of intended dose manipulations were not necessarily sensitive to compensatory changes (see Chapter IV and Henningfield 1984b). The second problem is that there is simply no basis for determining what degree of compensation should occur, because the degree of compen- sation observed in animal studies varies widely by drug and test condition, and because there are relatively few human data involv- ing drugs other than nicotine to which such a comparison might be made (Griffiths, Bigalow, Hennin~ield 1980; Henningfield, Lukas, Bigelow 1986). Cost of the Drug as a Determinant of Intake Cost of the drug is a determinant of intake in both laboratory and non-laboratory settings. Evaluation of this phenomenon is objective- ly carried out in the laboratory in which the amount of work required to obtain the drug can be varied. From an economic perspective, this is similar to varying the price of the commodity which is available for purchase. Such manipulations with both humans and animals have shown that cost (e.g., amount of work required) affects drug intake: usually, the lower the cost, the greater the intake. In some studies manipulations of both cost and drug dose have been carried out (e.g., Moroton et al. 1977; Lemaire and Meisch 1986). These studies show that when the dose of the drug is reduced, drug-seeking behavior may increase at first and thereby maintain fairly stable intake, but if dose continues to decrease (or cost continues to increase), the behavior will not be maintained (Lemaire and Meish 1985). Early studies with cocaine, for example, showed that if access to cocaine was limited, either by time or work ("cost") requirements, cocaine self-administration could be maintained indef- 283

initely without serious apparent adverse effects (Pickens and Thompson 1968). However, if access to cocaine was nearly unlimited and the cost requirement low, monkeys might self-administer toxic dose levels (Deneau, Yanagita, Seevers 1989). Use of tobacco in humans and intravenous nicotine self-adminis- tration by animals appear to be similarly affected by manipulations of cost as is use of other dependence-producing drugs. Specifically, as the amount of work required to obtain nicotine injections in animals is increased, the number of injections is decreased (Goldberg and Henningfield, in press). Analogously, human cigarette smokers and other drug users can also be motivated with both positive and negative cost incentives (Bigelow et el. 1981; McCaul et al. 1984; Stltzer et el. 1982, 1986; Stitzer and Bigelow 1985). These laboratory findings with animals and humans correspond to the effects of changes in the price of cigarettes on ciga÷ette sales (Lewit, Coats, Grossman 1981; Lewit and Coate 1982; Warner ]986a), Such relationships are also observed with other dependence-producing drugs including opioids, sedatives, alcohol, and amphetamines (Griffiths, Bigelow, Henningfield 1980; Yanagita 1977). Place Conditioning Studies Ingestion of dependence-producing drugs can lead to both positive and negative associations with the setting in which the drag effects were experienced. Whether the effects of a particular drug are positive or negative depends on the dose that was given and other factors that are discussed in this Section. A scientific methodology for studying such phenomena is the "place.conditioning" or "place-preference.aversion" procedure (Bo- zarth 1987a). This procedure provides an indirect means of assessing the potential of a drug to establish drug seeking in the absence of any explicit contingencies on the behavior. These procedures deter- mine if exposure to a drug in a given environmental setting enhances the preference of the animal for that setting. Conversely, the procedure can be used to determine if exposure to a drug in a specific environmental setting establishes an aversion of the animal to that setting. Because of their convenient size and the general validity of their use as models for behavioral dependence potential testing, rats most commonly are used as subjects in place-conditioning studies. The general experimental procedure is to place the animal in one environment (e.g., one chamber of a multiple-chamber test appara- tus) when a drug is given and in another environment (e.g., distinct in color, shape, or odor) when a placebo is given. Then, the animal is given access to both environments (i.e., placed in a connecting passage or placed in one chamber or the other) to determine which environment (chamber) it prefers (van der Kooy 1987; Bozarth @ @ O @ @ 284 •

1987a), and, conversely, which environment it avoids. Studies have shown that conditioned preferences can be established for morphine (Bardo and Neisewander 1986), cocaine (Spyraki, Fibiger, Phillips 1982), alcohol (Stewart and Grupp 1985), and nicotine (Fudala, Teoh, Iwamoto 1985; Fudala and Iwamoto 1987; Chapter IV). The relevance of place conditioning as a factor that incrcases the control of nicotine over behavior in human cigarette smokers may exceed that of other dependence-producing drugs. This possibility follows from the fact that the cigarette smoker has the ability to readily produce a critical environmental cue associated with smok- ing (cigarette smoke itself). Therefore, it should be possible for the smoker to "enhance" the reinforcing efficacy of a range of environ- ments (lwamoto et al. 1987); the highly discriminating sight, smell, and taste stimuli produced by tobacco smoke may effectively 'permit the smoker to establish a "prcferrcd environment." This could contribute to the dependence potential of nicotine. The observation is also consistent with the finding that removal of the tobacco smoke- associated stimuli is accompanied by decreased pleasure and/or smoking (Grltz 1977; Goldfarb st al. 1976; Rose et al. 1987). As early as 1899 it was observed, for example, "that the pleasure derived from a pipe or cigar is abolished for many persons if the smoke is not seen, as when it is smoked in the dark" (Cushny 1899). Constraints on Dependence Potential Testing The main constraint on procedures used to evaluate the depen- dence potential of drugs is that they may fail to identify drugs which only lead to dependence under unusual or uniquely human circum- stances. For example, LSD does not serve as an effective reinforcer for animals, and although its effects may be liked by humans under certain conditions, it also produce feelings of fear, paranoia, and other adverse effects (Griffiths, Bigelow, Henningfield 1980; Haert- zen 1966, 1974). Caffeine provides an example of another kind of drug which is sometimes used in the face of adverse effects, even though the overwhelming majority of users do not use it in ways that are considered to be of significant adverse health effect (Gilbert 1976; Greden 1981). The antieholinergic drug, atropine, is another that is representative of a class of drugs that occasionally are used in nontherapeutic settings but do not appear to possess a marked dependence potential when objectively tested (Penetar and Hennlng- field 1986). The wide range of factors that may result in occasional harmful use of some substances (e.g., caffeine) or which may contribute to the use of dependence-producing substances such as nicotine (Chapters IV and VI) is not routinely explored in current laboratory depen- dence potential tests. Thus, these drug dependence potential testing procedures appear more likely to underestimate than to overesti- 285

mate the pharmacological potential of a drug to cause dependence outside of the laboratory. Furthermore, as discussed by Katz and Ooldberg (1988), because a variety of drug and nondrug factors determine the actual prevalence of drug dependence outside of the laboratory, dependence potential data are most reliable when drawing qualitative conclusions. For example, such data are used to determine whether a drug is dependence producing, or whether it is more sedative- or stimulant-like. Dependence Potential Testing: Tolerance and Withdrawal In addition to taking control over behavior by virtue of reinforcing and other behavior modifying effects, many addicting drugs can also produce a physiological change termed physical dependence. Once physically dependent, the person may experience an even greater loss of control over use of a particular drug because abstinence from the drug may be accompanied by discomfort and heightened urges to take the drug (withdrawal syndrome). Technically, physical dependence refers to physiological and behavioral alterations that become increasingly manifest after repeated exposure to a pharmacologic agent. As noted earlier, the primary indication of physical dependence is the observation of drug- abstinence-associated withdrawal signs and symptoms, although tolerance is a frequent concomitant (Kalant 1978; Cochin 1970; Kalant, LeBlanc, Gibbins 1971; Eddy 1973; Clouot and Iwatsubo 1975; Yanagita 1977). This phenomenon is also referred to as. "neuroadaptation" or "physiological" dependence (WHO 1981; Wool- verton and Schuster 1983). It should be noted that use of the term "physical" imports no greater degree of objectivity to phenomena associated with physical dependence than to the phenomenon of compulsive drug seeking: both physical dependance and drug seeking involve physiologically mediated drug receptor interactions that vary with the dose, kinetics, and type of drug. Furthermore, both of these kinds of drug-associated phenomena involve behavioral and physiological effects. For example, conventional measures of physi- cal dependence include responses that are often considered behavior- al (e.g., urge to use a drug, sleep time, food intake). Research on opioid dependence in the 1940s focused largely on the physical dependence that developed when opioids were given to humans or certain animals (Martin and Isben 1978). In particular, characterizing the level of tolerance that was acquired when morphine was repeatedly given, as well as the behavioral and physiological sequelae of abrupt termination of such administration, was a msjor contribution to the development of objective methods for testing dependence-producing drugs in general. Observations emerg- ~ng from such research in the 1940s led to strategies that are still accepted as the definitive means to measure what may be termed the Q 286 •

TABLE 5.--Observations pertaining to the evaluation of physical dependence potential, derived from studies of morphine-like drugs 1, Repeated drug administration leads to diminished responsiVeneSs <ie., tolerancel that is more or less complete, depending upon the response measured, Responsiveness might he at least partially overcome by increasing the dose. The degree of tolerance that develol~ is generally directly related to the overall dosing level, but varies widely acrc~s various possible me~sures 2. The establishment of tolerance ta one opioid is shared among many opium-derived and related chemicals: the principle of "cre~s-toleranee" emerged as one means to further classify a dependenee-preducing chemical. 3. Abrupt termination of uee leads to behavioral and physiol0fieal responses that often tend to be opposite of responses produced by acute drug edmin[stratlon. When these opposite responses actuMly exceed normal baseline levels (e.g., opioid.induced constipation may be replaced by diarrhea for a few dalai, they are termed "rebound" Pesponses; hence the frequent labeling of withdrawal ~ *'rebound syndrome." Together, these responsel are termed "the withdrawal syndrome" 4. Severity of the withdrawal syndrome is related to the duration and dose levels of preabstinence exposure to the drug. 5. During withdrawal, raadministration of the chronically given opioid can reverse the signs and symptoms ef the syndrome 6 A range of opioids can subetitu~ for the one to which an organism was chronically exposed, thereby maintaining the level of physi~l dependence and preventing the onset of a withdrawal reaction. These same drugs can he used to revere the syndrome of withdrawal precipitated by removal of the chronically given ¢pinid, This observation provided the rational basis for the systematic development of *'substitution" or "replacement" therapy for drug dependence. NOTI~: Details of the origlnaL experiment~, and subsequent r~arch upon which these obsereation~ follow, h~ve been reviewed IMartin and Isbell 1978; Martin 197?;.Sharp 1084; ~ al~o Denenu 197'71 "physical dependence potential" of e chemical (Jasinski 1977). Specifically, these tests could be used to evaluate the likelihood that (1) repeated use of a drug would lead to tolerance (physiological adaptation) such that effects of repeated use would diminish and (2) abrupt abstinence would be accompanied by a syndrome of behavior- al and physiological disruption (withdrawal syndrome). Table 5 summarizes the prominent observations that emerged from these early studies (Martin and Isbell 1978; Martin 1977). These observa- tions provide the conceptual framework within which physical dependence is assessed (Thompson and Unna 1977). Tolerance As noted earlier, repeated ingestion of most dependence-producing drugs leads to diminished effects unless larger doses of the drug are taken: this phenomenon is termed tolerance. One reason that toleranse is an important factor in drug dependence is that it may contribute to the escalation of drug self-admlnistration that occurs over time. This relationship is often misinterpreted, however. Specifically, it is sometimes stated that tolerance results in a 287

continuous escalation of drug dose; however, lethal or aversivc dose levels prevent indefinite escalation. Procedures for assessing tolerance development rely heavily on procedures developed for assessing the direct effects of drugs (Kalant, LeBlane, Gibbins 1971; Abood 1984). Because psychoactive drugs exert effects on numerous physiological systems and behavior- al responses, almost any of a wide range of response measures can serve in studies. Perhaps the most fundamental strategy of tolerance assessment is to repeatedly present a given drug dose while measuring the subsequent responses to drug administration. When the response diminishes across drug presentations, tolerance to that response is said to have occurred. Among the most frequent measures of tolerance which have been used to assess psychoactive drugs are .discrimination of drug administration, analgesia, heart rate, nausea, sedation, EEG activity, and performance on a behavior- al task. Some measures (e.g., sedation from barbiturates) are more specific to certain drug classes, whereas others (e.g., pleasurable and dysphoric effects) are useful across a wider range of psychoactive drugs. A variation on the foregoing procedure is to increase the drug dose after responses have diminished to determine if the original response level can be partially or completely restored. Cross-ToTerance Cress-tolerance is demonstrated when pretreatment with one drug or formulation type produces tolerance to another drug or formula- tion type (Wenger 1983; Yanura and Suzuki 1977; Martin and Fraser 1961). For example, a person who is maintained on an adequate dose level of methadone will experience relatively little effect if he or she injects his or her usual dose of herein (Kreek 1979). Similarly, persons given nicotine polacrilex gum may experience attenuated effects from cigarettes, including reduced satisfaction from smoking (Nemeth-Coslett et al. 1987). Mechanisms of Tolerance Several mechanisms of tolerance can be differentiated (Kalant, LeBlane, Gibblns 1971; Abood 1984; Haefely 1986; Sharp 1984; WHO 1981). For instance, if a drug impairs the ability to perform a task that produces some form of reinforcement (e.g., humans working for money or animals pressing a lever for food), the performance may return to predrug exposure levels after repeated drug exposure over time. In this example, at least four distinct mechanisms of tolerance may have been operational; they are not mutually exclusive and may co-occur (Kalant, LeBlanc, Gibbins 1971; Abood 1984; Haefely 1986; Sharp 1984; WHO 1981; Eikelboom and Stewart 1979; Siegel 1975, 1976). 288 •

(1) The rate at which the drug was eliminated from the blood by metabolism (detexificetion) or excretion (in urine, feces, sweat, or expired air) may have increased, This is frequently termed "disposi- tional" or "metabolic" tolerance. A general method used to assess dispositional tolerance is to measure the rate of decline in plasma drug levels after varying amounts of drug exposure. (2) The response at the cellular level might have decreased as the drug receptor physiologically adapted to the drug or as the number of receptors was altered (thereby functioning as though the systemic dose had been reduced). This is frequently termed "functional" or "pharmacedynamie" tolerance. One method used to assess function- al tolerance is to hold the plasma drug levels constant while measuring the response after varying amounts of drug exposure. (3) The learning and motivational aspects of a behavioral situation may have resulted in. compensatory behaviors that reduced thb magnitude of the performance effects. This is frequently termed "behavioral" tolerance, "drug sophistication," or "behavioral adap- tation." Behavioral tolerance can be assessed by presenting the drug at such long intervals so as to minimize the possible development of functional or metabolic tolerance (e.g., Stitzer, Morrizen, Domino 1970), or by using a variety of other controlled procedures (Krasne- gor 1978b). (4) Another behavioral mechanism that can lead to the develop- ment of tolerance results from the classical or Pavlovlan condition- ing process that may occur where a drug i~ given. Pavlov (1927) found that drug administration could .produce an unconditioned response that could subsequently occur as a conditioned response to an associated environmental stimulus. However, sometimes the conditioned response is opposite that of the drug response (Siegel 1975); when a drug-opposite response has been established, this conditioning mechanism may reduce the strength of the response to the drug itself (Goudie and Demellwcok 1986). The kinds of tolerance described above are sometimes categorized together as '*acquired" tolerance, which emphasizes the fact that they have developed in an organism as a function of drug exposure (WHO 1981). Tolerance development can be affected by the unit drug dose, total daily dose, route of administration, prevailing environ- mental stimuli, and exposure dynamics (exposure dynamics refers to whether exposure to a drug is relatively continuous (Way, Loh, Shen 1969) or via multiple, discrete doses (Lukas, Moreton, Khasan 1982)) (see also, Dewey 1984; Adler and Geller 1984; O'Brien 1975; Blgsig et al. 1978; Okamote, Rao, Walewskl 1988). Acquired tolerance has been demonstrated to occur with opioids and with most nonopioid dependence-producing drugs, including nicotine (Martin 1977; Ka- lant, LeBlanc, Gibbins 1971; Abood 1984; Haefely 1986; Domino 1978; Chapter Ill). In fact, classic techniques of measuring tolerance 289

evolved in a series of studies involving nicotine by Langley, Dixon, and others near the end of the 19th century (Langley 1905; Dixon and Lee 1912); these researchers found that tolerance to nicotine was rapid and could be partially overcome by increasing the dose. Constitutional Tolerance Historically, although less commonly in recent years, tolerance has been used to differentiate individuals or populations with regard to their "preexisting" or "constitutional" level of drug responsive- ness (Shuster 1984). This phenomenon has been designated "initial" tolerance by a subcommittee of the WHO (WHO 1981) and is also often referred to as "drug sensitivity" or "innate drug responsive. ness." The mechanisms may be similar to those described above; for example, individuals may be born with differing numbers of receptors for a particular drug or with different abilities to detoxify a drug on the basis of enzymatic capacity of their liver. Analogously, for reasons that ere not related to drug exposure, certain populations or individuals may be more effective in general at behaviorally compensating for impediments to learning or performance. Genetic, dietary, and early (including prenatal) development are possible sources of such variation that are under study (Abood 1984). Whereas a fairly wide range of variation among such preexisting levels of drug sensitivity has not been shown to affect the course of development of drug dependence, extreme or qualitative differences may have some impact. Such differences are sometimes held to alter the vulnerability of various individuals or populations to the development of drug addiction. One apparent example of such an effect is the markedly higher percentage of Oriental persons who, compared with most other populations in the United States, show an aversive reaction to alcohol ("flushing" response). This reaction results from slower metabolism of the alcohol metabolito, acetylai. dehyde, in Orientals compared with many other ethnic groupings (Nagoshi et al. 1987). However, cultural factors also appear to strongly influence rates of alcohol use in Orientals so that even persons who show the flushing response may develop alcoholism (Sue 1987; Johnson et al. 1987). Differences in constitutional levels of tolerance among individuals have been observed for all dependence-producing drugs, including nicotine (Chapter II). However, the importance of such individual and/or population differences remains unclear. In fact, a remarkable feature of opioids, sedatives (including alcohol), and stimulants (including nicotine) is the degree to which use has become en- trenched in nearly any culture into which they have been introduced (Austin 1979). Similarly, initial exposure to opioids, sedatives, alcohol, cocaine-like stimulants, and nicotine has been shown for each to lead to drug-seeking behavior in a wide range of animal 29O •

species including primates, dogs, and rodents (Deneau 1977; Yanagi- ta 1977; Woods, Ikomi, Winger 1971; Brady and Lukas 1984; Griffiths, Bigelow, Henningfield 1980; Meisch 1987; Meisch and Carroll 1981). Withdrawal Syndromes As discussed earlier, documentation of a drug withdrawal syn- drome is the primary line of evidence used to decide whether particular drug can cause physical dependence. The methods used to properly conduct such tests and provide definitive results are complex. This Section provides a summary of how such tests are conducted and some of the main findings from tests of drugs such morphine, pentebarbital, and nicotine. Measurement of drug withdrawal phenomena entails recording physiological, subjective, and behavioral responses that occur when drug administration is terminated, as well as those that occur following drug administration. If the organism has developed a sufficient degree of tolerance, such that levels of drug which formerly disrupted physiological and behavioral functioning have become necessary for relatively normal functioning, then the organism is said to be physically dependent. Such drug abetinence- induced disruption of functioning is termed a drug "withdrawal" or "abstinence" 1reaction or syndrome. The behavioral and physiological responses include some that are opposite those produced by drug administration. For instance, opioid-inducod pupillary constriction, alcohol-induced muscle relaxation, and nicotine-indueed tachycardia may be replaced by pupillary dilation, convulsive muscle activity, and bradycardia, respectively. Each drug withdrawal syndrome is unique to a particular drug class and animal species and also varies somewhat within individuals of a given species which are tested with the same drug. Both frequency and magnitude of withdrawal responses are typically measured. In human studies, the range of measures available to assess withdrawal reactions is considerable. They may be designated by three categories', autonomic (e.g., blood pressure, pulse, core temper- ature, respiratory rate, pupillary diameter, diarrhea), somatomotor (e.g., nociception, neuromuscular reflexes, auditory and visual evoked potentials), and behavioral (e.g., irritability, sleep/awake cycle, hunger, urge to take the drug, i.e., "craving"). Himmelsbach and Andrews (1943) incorporated these distinctions into a weighted- point system used for rating the severity of these signs and symptoms of withdrawal (Fraser and Isbell 1960; Jasinski 1977). Refinements in the scaling of opioid withdrawal responses have continued (e.g., ARCI, weak opiate withdrawal scale) (Haertzen 1966; Bradley at al. 1987; Handelsman et al. 1987). 291

Opioid withdrawal phenoaena remain the most rigorously studied and well characterized among the dependence-producing drugs. In part, this is because of the ready observability of many of the signs (e.g., dilated pupils, sweating, diarrhea). Other drugs for which withdrawal reactions are now known or suspected to occur in humans (e.g, amphetamine, cocaine, marijuana, phencyclidJne) have been much less thoroughly studied than the epioids and sedatives (Mendelsen and Mello 1984; Jones and Benowltz 1976). Studies with these drugs are also hindered by the fact that there are fewer readily observable signs of withdrawal, placing a greater burden off sephisti- cated technology (e.g., EEG and neurohormonal assessment) and procedures (e.g., performance assessment). Two basic methods are used to measure withdrawal reactions. After a period of chronic drug administration, behavioral and "physiological responses are measured following either abrupt drug abstinence ("spontaneous withdrawal") or the administration of a drug antagonist ("precipitated withdrawal") (Thompson and Unna 1977; Martin 1977). Spontaneous Withdrawal Syndromes Experimental studies of spontaneous withdrawal reactions include two procedures for obtaining subjects which have been chronically exposed to the drug. One procedure, termed the "direct addiction" procedure, is to administer the drug to the subject at gradually increasing dose levels, then to stabilize the dose for a predetermined time interval. Drug administration is then abruptly discontinued, and withdrawal measures are taken. This method has been used to study withdrawal from opioids, barbiturates, benzodiazepines, stimu- lants, ethanol, PCP, and gaseous anesthetics in a number of animal species and humans (Brady and Luka$ 1984). A variation on this procedure is to abruptly withdraw subjects from a drug which they had been chronically receiving in the nonlaboratery environment. In human subjects, withdrawal reactions following cessation of use of opioids, alcohol, nicotine, sedatives, and other drugs have been studied using this procedure (Brady and Lukes 1984; Chapter IV). A second procedure, termed the "substitution procedure," involves maintaining subjects at a given dose level of a standard or baseline drug; periodically, doses of the standard drug are replaced with either a placebo or a test drug to determine if there are signs of withdrawal that occur before the next dose of the baseline drug (Fraser 1957). This procedure provides information analogous to that obtained from studies of cress-tolerance; namely, it permits determi- nation of whether cross-dependence exists. If the test drug prevents the expected onset of a withdrawal syndrome that should have accompanied abstinence from the maintenance drug, then it is possible that the two drugs produce similar kinds of physical 292

dependence. Because it is possible to suppress certain withdrawal responses by using unrelated drugs (e.g., clonidine can suppress certain aspects of morphine and nicotine (Jasinski, Johnson, Hen- ningfield 1984)), a variety of control procedures are necessary to identify the mechanism by which the replacement drug suppressed the withdrawal responses (Martin 1977; Deneau and Weiss 1968; Yanagita and Takahashi 1973; Okamoto, Rosenberg, Boisse 1975; Jones, Prada, Martin 1976; Yanaura and Suzuki 1977). In human subjects, both the direct addiction and substitution strategies were used to evaluate withdrawal reactions from opioids, barbiturates, and alcohol at the Addiction Research Center in the 1940s and 1950s (Himmelsbach 1941; Himmelsbach and Andrews 1943; Isbell et aL 1950, 1955). However, since those classic studies, most dependence potential studies in humans have been conducted with subjects who had been using the drug in a nonexperimental setting prior to the study. The effects of abstinence from chronic administration of opioids, barbiturates, benzodiazepines, caffeine, and nicotine have been studied using these variations of spontaneous withdrawal assessment (Benzer and Cushman 1980; Charney et al. 1981; Jaffe et al. 1983; Griffiths and Woodson 1988a; Greden 1981; Hatsukami, Hughes, Pickens 1985; Chapter IV). A disadvantage of such approaches is that it is not always possible to stabilize the subjects at a known dose level, which results in considerable cross- subject variation. The consequence of such dose-related variability is that it can raise the threshold for the detection of significant effectS. This source of variability probably contributed to some of the earlier inconsistent findings regarding the nature and severity of withdraw- al reactions from tobacco (see further discussions in Murray and Lawrence 1984). Early in the 20th century, analogous seemingly inconsistent data led to debates about the existence of an alcohol withdrawal syndrome (Isbell et al. 1955). Precipitated Withdrawal Syndromes Precipitated withdrawal responses may occur when a drug antago- nist abruptly displaces the dependence-producing drug from its binding sites on receptors. The viability of this approach depends on the availability of a specific receptor antagonist which does not have other actions that would preclude assessment of a withdrawal syndrome. The antagonist is often given parenterally (e.g., intrave- nously or intramuscularly) to maximize its rate of onset and hence the likelihood of precipitating a withdrawal reaction. Because of the availability of specific opioid antagonists, prsolpita. tion of withdrawal phenomena associated with abstinence from the morphine-like drugs has been most thoroughly studied using this strategy (Martin et at. 1987). The studies have shown that the process that leads to physical dependence begins with the first dose 293

of morphine (Higgins et el. 1987; Bickel et el. 1988) although such low levels of physical dependence are not generally considered sufficient for the clinical diagnosis of physical dependence. Analo- gous studies have been conducted using the antagonists of the benzodiazepines (e.g., diazepam (Lukas and Griffitbs 1982, 1984)) and are one element in the conclusive demonstration that these drugs do produce physical dependence (WHO 1981, 1987), With regard to tobacco or other forms of nicotine delivery, no such comparable studies have been conducted, although, as discussed in Chapter IV, preliminary and related data suggest the theoretical possibility that nicotinic antagonists may be used to precipitate nicotine withdrawal responses (Pickworth, Herning, Henningfield, in press). Q O Variability in Withdrawal Syndromes There are multiple determinants of the course and magnitude of the withdrawal reaction from a drug. Factors which have been studied in the laboratory are similar to those which affect the development of tolerance described earlier. These include the total daily dose of the drug that was given, specific drug type, the duration of exposure, the schedule of termination, genetic constitution, gender, and the prevailing environmental stimuli (Suzuki et el. 1987; Suzuki et el. 1983; O'Brien et el. 1978; Suzuki et al. 1985; Yanagita and Takahashi 1973; Yanagita 1973). In general, the magnitude of the withdrawal reaction is directly correlated with the dose level given, the duration of exposure, and the rapidity with which drug• levels at the receptor sites decrease. Conversely, lower dose levels, shorter times of exposure, and gradual dose reduetion (as opposed to abrupt abstinence) can attenuate the withdrawal syndrome (Ks]ant, LaBlanc, Gibbins 1971; Abood 1984; Jaffa 1985; Okamote 1984). Because withdrawal signs and symptoms vary among individuals using the same drug, the syndrome may net be apparent when a small number of individuals are studied. Lack of general understand- ing of such factors probably contributed to the fact that the nature of morphine withdrawal phenomena in humans was not rigorously documented until the studies by Himmelsbach and his esworkers in the 1940s (Himmelsbach 1941; Himmelsbach and Andrews 1943). Similarly, withdrawal responses from chronic alcohol administra- tion were not conclusively characterized and demonstrated until the pioneering studies by ]sbell and his eoworkers in the 1950s (Ishell et al. 1955). Research involving comparable strategies of assessment of physical dependence on cocaine, amphetamine, marijuana, PCP, and nicotine, only began in the late 1970s. In the absence of such data, these drugs were sometimes held to be nonaddicting (e.g., President's Advisory Commission 1963), Nonetheless, for several of such drugs it had long been recognized that some drug withdrawal phenomena did occur (Jaffa 1970, 1976, 1980, 1985) and that such phenomena were 294 •

of clinical significance in the treatment of persons who were attempting to abstain from them (Jaffe 1970, 1976, 1980, 1985; Zweben 1986). For example, even prior to the rigorous studies of tobacco withdrawal phenomena in the early 1980s (Chapter IV), the Tobacco Withdrawal Syndrome had been recognized by the Ameri- can Psychiatric Association (APA) as aa Organic Mental Disorder in its Diagnostic and Statistical Manual (DSM) of Mental Disorders (APA 1980) on the basis of the extensive clinical observations and other sources of information prior to the 1980s (Chapter IV). The specificity of tobacco withdrawal to nicotine itself was acknowledged in the revised DSM (APA 1987). Cmv!ngs or Urges Among the most frequently discussed aspects of drug dependence is the recurrent and often persistent urge to use drugs in drug- dependent persons. The urge or desire to use a drug is widely termed "craving." However, how craving is defined and how craving-related data are interpreted comprise one of the most problematic areas in drug dependence research. For example, the term craving has been used in such a variety of ways that its use may actually impede accurate communication (Kozlowski and Wilkinson 1987; Henning- field 1987): In the present Report, where possible, the term "craving" has been replaced by more descriptive terms and phrases such as "strength of an urge to use a drug" wherever the original meaning of the referent material is not changed. Whereas the urge to use a drug is a correlate of drug abstinence, it is not an invariant one. For example, although urges to take drugs reliably increase during early abstinence from morphine- and pentabarbital-like (short-acting sedatives-hypnotics) drugs, they are not a necessary concomitant of withdrawal reactions from other opioids (e.g., eyclasocine) (Martin et al. 1965; Jasiaski 1978), and alcoholics often "voluntarily" abstain and undergo withdrawal even when alcohol is available (Meno 1968; Mandelson and Mello 1966). Moreover, such urges are also evoked-by stimuli associated with drugs and even by administration of the drug itself (O'Brien, Ehrman, Ternes 1986; Childrees et al., in press). Thus, urges to use drugs also occur (often at high levels) when there is little other evidence that physical dependence is present (e.g., many years after drug abstinence) or when drug intake is sufficient so that no other withdrawal signs or symptoms are present. Because drug abstinence is only one of many factors that can evoke the urge to use a drug and because such urges are not necessarily alleviated by suppressing physiological withdrawal signs, conclusions based upon such data must be carefully considered and appropriately qualified. For instance, although methadone can block withdrawal responses (at adequate dose levels), it does not reliably 295

diminish urges to use other opioids or opioid self-administration (Jones and Prada 1975; Grabowski, Stitser, Henningfield 1984; Henningfield and Brown 1987). It would not be appropriate to conclude that methadone did not effectively block withdrawal reactions from morphine-like drugs simply because it did not eliminate such urges, because by other measures, methadone is effective at blocking opioid withdrawal (Kreek 1979; Jaffe 1985; Jasinski and Henningfield 1988). Analogously, as reviewed in Chapters IV and VII, most tobacco withdrawal re- sponses are effectively suppressed by nicotine replacement even though urges to use cigarettes are not reliably diminished (see also Henaingfield and Jasinski 1986). Constraints on Physical Dependence Potential Testing There are both practical and conceptual constraints on physical dependence potential testing. The practical constraints have been discussed above and are related to the multiple sources of variability in the intensity of withdrawal responses, which can result in failure to detect withdrawal or in unreliable date. The main conceptual eonstreint is that physical dependence is neither a necessary nor sufficient condition to establish or maintain drug-seeking behavior. For instance, drug-seeking and drng-taking behaviors can persist at small doses of cocaine or morphine which produce no significant degree of physical dependence in animals (Schuster and Woods 1967; Dcneau, Yanaglta, Seevers'1969; Johan- son, Baister, Bonese 1976; Jones and Prada 1977; Bozarth and Wise 19B1) or in human subjects (Zinberg 1979). Conversely, animals in the laboratory and humans in hospitals can be made physically dependent on drugs such as opioids and barbiturates and yet never display controlled or addictive drug-seeking behavior (WHO 1961; Bell 1971). Similarly, compounds such as propranolol, cyclazocine, and nitrites have clear physical dependence potentials in that tolerance develops after repeated dosing and an abstinence syn- drome appears upon cessation, yet drug-seeking or drug.taklng behavior does not reliably occur (Myers and Austin 1929; Crandall et al. 1981; Rector, Selden, Copenhaver 1955; Jasinski 1976; Jaffe 1986). Another constraint is the difficulty in determining whether abstinence-associated symptomology is specific to an individual or to an underlying medical disorder that became evident upon removal of the drug (Woody, MeLellan, O'Brien 1984; Zweben 1986; Kesten, Rounsaville, Kleber 1986; Stitzer and Gross 1988). For instance, an opioid might alleviata depression in a person with primary affeetive disorder. In general, as will be described below (see also Chapter IV), withdrawal responses may be distinguished from other abstinence- associated symptomology by their relative consistency among indi- •

viduals, by their transient nature, and by the direct relationship between their magnitude and the level of preabstinence drug intake. Finally, although the magnitude of the withdrawal syndrome is a widely used index for assessing the degree of physical dependence, it should be noted that this single measure is not always sufficient. For instance, several studies have demonstrated that spontaneous with- drawal from chronic levo-alpha-acetylmethadol (LAAM) or bupre. norphine administration failed to result in pronounced signs of withdrawal (Jasinski, Pevnick, Griffith 1978; Young, Steinfels, Khasan 1979). Such observations could lead to the false conclusion ~' that LAAM and buprenorphine do not produce significant degrees of physical dependence, when in fact a variety of other lines of evidence confirm that -they do. For example, administration of an opioid antagonist such as naloxone precipitates a marked and intense withdrawal syndrome in LAAM-maintained animals (Young, Stein- -fals, Khasan 1979). Analogously, Dum, Bl~sig, and Herz (1981) performed a substitution type of experiment demonstrating that chronic administration of bupi'enorphine also results in physical dependence. The explanation for the misleadingly weak spontaneous withdrawal phenomena for LAAM and buprenorphine seems to be the slow elimination of these drugs from the plasma, which permits the body to adjust more gradually to drug abstinence. The long elimination half-life of LAAM's active metabolites (Kaiko and Inturrisi 1975) and buprenorphine's unique affinity for the opiate receptor and long elimination half-life (Cowan, Lewis, MacFarlane 1977) contribute 'to the lack of observed withdrawal signs after chronic exposure is terminated. A similar example exists for the long-acting benzodiazepine, diazepam. A delayed and relatively mild withdrawal syndrome appears after spontaneous withdrawal, but administration of the benzodiazepine receptor antagonist, Ro15-1789 (flumasenil), precipitates an immediate, intense abstinence syn- drome (Lukas and Griffiths 1982, 1984). Analogous results are produced when the daily dose level of shorter acting drugs is gradually decreased. A practical application of the finding that the magnitude of withdrawal reactions tends to be inversely related to rate of drug elimination is the gradual elimination of drugs from individuals who are suspected of being highly physically dependent. Such gradual elimination reduces the magnitude of the withdrawal syndrome. This is the basis of the gradual withdrawal of morphine, alcohol, or nicotine after a period of chronic intake at high dose levels (Jaffe 1985). Although gradual dose reduction of opioids and nicotine reduces the magnitude of most aspects of the withdrawal syndrome, it is not clear that such an approach improves overall treatment outcome compared with much more rapid drug cessation (i.e., "cold turkey") (Jasinski and Henningfield 1988; Chapter VII). 297

Therapeutic or Useful Effects of Dependence-Producing Drugs With many dependence-producing drugs, the same biologica! properties that ere important in their dependence-producing proper- ties may also ]end them to therapeutic application. In fact, mast classes of drugs which cause dependence, including opioids, seda- tives, alcohol, cocaine-like drugs, and nicotine, have been used as medieinals to treat specific medical disorders and human discom- forts. Descriptions of the approved and general uses are available in the American Hospital Formulary Service (1987), the Physician's Desk Reference (Medical Economies Company 1988), the Unitecl States Pharmacopeia (United States Pharmacopeial Convention • 1985), and Goodman and Gilman's Pharmacological Basis of There- peutics (Gilman et al. 1985) (see also Table 6). Although each of the drugs listed in Table 6 has a range of potential or actual therapeutic applications, past and current uses are often related to their effects on mood, feeling, and behavior. For instance, the stimulants may be used to modulate arousal level the opialds to alleviate pain, the sedatives to alleviate anxiety; the drugs are sometimes systematically used to treat the dependence which may have previously developed on them or on another drug in the same class. Nicotine is no exception tothese observations. Historical- ly, tobacc6 was used to treat a range of disease states, although usually without evidence of efficacy (Corti 1931; Austin 1979). Nicotine in the polaerilex gum form is a drug approved by the FDA for treatment of nicotine dependence (see Chapter VII). The therapeutic effects of dependence-producing drugs not only illustrate an important point of commonality among these drugs, but these effects also may be important in the drug dependence process itself. Such potential drug actions can be important in the initiation, maintenance, and relapse to drug dependence. The dependence process may have been precipitated by the therapeutic use (medical. ly approved or self-initiated) of a drug. The dependence process may be exacerbated by the real or perceived benefit of the drug to the individual as such actions strengthen the reinforcing power of the drug. The therapeutic actions of a drug may be associated with relapse to drug use after many years of abstinence. These aspects of dependence potential as they pertain to nicotine are discussed in Chapter VI. Adverse and Toxic Drug Effects As discussed earlier, adverse drug effects are important clinical features of drug dependence. These effects may be used as fa0ters in objective determinations of the overall liability associated with a drug (Yanugite 1987; Griffiths et el. 1985). For instance, chronic administration of sedatives or alcohol can produce intoxication and Q @ 298 •

• • • • • • • • • • • B TABLE 6.--Effects that may be produced by addicting drugs Attribute NtcQtine • Cocaine Morphine like Alcohol Discriminable interoceptive (su'~j~tlve} effects Produce dose-related increases in self-reported "liking" scores Henningfleid and Goldl~rg tl~,% M~ and Stephenson t 1969) + Henningfleld, Miyasato, Jasinski { 19~51 Produce elevated r~p0nse on MBG + (euphorla~ scale of ARC inventory Henningfield, Miyagato, J~inski (1985) Positive reinforcer in animal drug seif-ndmlnistratwm studies + Goklberg. Spealman. Go!dberg II~IL Deneau and Inoki (IE~/). Ando and Yanagita (l@lk Henningf~ekl and GoMberg { 198Xa~ Fischman et al. t1970 + Henningf~.ld et aL tl~7) F~'hrnan et al q976) ÷ IX, ckens and Thompson (1968L Deneaa et aL (1S~9) POSitive reinforcer in human + * drdg self-adminlstratlc~ studies Hennlngfield. Miyasato, Fisehman and Schuster J~sinski ~1~3) <1982) Terry and PelLen* i1970) + Martin and Fraser 119Gl) t Hvert~en et a] 41963) + Headl~e et aL <196.5)+ Thompson and Schuster I1964) Jones and Prada I19751 Carpenter t 19621 *? Mello (19¢~) ÷ Henningfield et al q9~4,. Stltzer et al qlg@ll Deneau et a[ q1969+ Winger and Woods ~197;I, l~i~elv'~, et al. (1975). de Wit et al d.q871 tO tD ~D

TABLE ~---Conbnued 8 Attribute Nic~i~,~ ' Cocaine Morphia-like Alcohol PlaCe conditioning + Fudala. Teob. hearl~o (L9~5} Physlc~} dependence develops such that + withdrawal a~c~rap~nle~ Hatsukaml et al ~|~c~S4t. abrupt ab~inence Ht~ghes and Hatsukami c|986~ ToLerance develops Therapeutic ~LSe in treatmem or medical d~rder + Langley tlS~5~. Domino qlO78L i~mrk~ Bureh. Collins fl983~. Je4ne~ FarrelL Herning 119781 J.i AMA [19~3). Gilman e~ al Company (19871, and others fipyraki, Fiblger. PhilliPS t 19@2) ~? Carl*oil and Lac ql~71. Jones 119841 J. !Tatum and Seeve~ ¢1929]. :Downs and Eddy ~1932~. :W~Nenon and Schtw;ter ,11977}. Weed and Emmett- Oglesby (I~7~ AMA II~k Gilman et aL (IS~5~ M~ Eccr.,~k~ 'Company (19~71, and others Barde and Ne~ewander + Light and Torrance 419"25#-aL Kolb and Himmeb2~ach 41~1. Himmelsb~lch ~19411 Light and Torrance (1929b, AMA ~1S83~ Gilman et al. ~19~5~. Medical Economics Company (1~71. and others Stewart and Grupp ,19~, ~l} et al ~1955~ + Goldberg (1943~ AMA d983~. Gilman et a]. ~1985*. Medlca} F, eonomie~ Company (l~Tt, arid othe~ $, • • • • • • • • • •

TABLE 6c---Continued Att r]~ute Caffeine Marina Lysergic. acid diethylam~de Odorpromazlne l)im'tlmlrmble intor~e~a~ Cm~tiye) effee~ Produce des~related incre~es in sdf-repor~d "llking~ scor~ Produce elevated respcase on MBG (euphoria) ~le cl" ARC in'ventm3' ~e reinforcer in animal drug self~lministration stud~ Positive relnf~ in human ~1 f~dminist m~on stad~ Place cQnditloning + + Gilbert (19"/6), Grimths and Siler et al. (1933) Woodsoa (1~) +- + Gfiffiti~ Bigdow, GebsonHigglm and Stit~r {1~). et aL tl~), ChaA and Cone et al. (I~) Grimths (l~3)t, Grifl'~s and Woo&on (1988b) +- Chait arKi Griffiths (19~]) Demmu et el. (19~9), Gtlfr, ths and Wood~m (19~8b) +? Gei~,tbs. Bigeimv. Liebson et al. (19~. Grlf~tbs. Bigelow. Liebson (19~6t, Gri~tbs and Woocbcn 11988b) Higgins and Stltzer (1~). Cone et al. (1~6) Har~ et ed. (1974) + Mtmdels~n and Mello (1S~4) t.t + Ho fmann (1975} + Grimth~. Bigelow, 119791 ? lLgel~zen et al. (1963~ Hoffmeister a~d Wuttke (197~ Stltzer et al. (I~i] Hoff~i~er and Go]dberg (19T3~, Hoffrnei~ter [1975). Denesu et a~. (1969) Gri~ths, Bigelow, 1|9791

TABLE 6.~ntinued to Attritmte Caffeine Marijuana Lysergic scld diethylamide C-nlorprome2ine Physical de.nee d~ such that will e~t'0mpe~ies abr,pt ,,l~inee~ Tolerance develops Therapeutic use in t~ffivA~lent of medal disorder + Griflith~ Bigelow. Liebs0n (19~6k ~ av~ Pfeiffer {)943). Ho~t et eL (1934). Grimths and Wcodson (1988a) + Carney (19~2), Eddy emd IDow~ (192gl, Grlffiths and Wcodsoa (1988a) J~s AMA (1983), Gilman et eL (19S5), Medical Economies Company (19~7k and othe~ *? Jo~s and Benowitz (1976k Mevdels~ et eL (1984), Ford and McMinan (1972k Beardsley eL at. (19~6~ + McMillan et at. (1970), Weft et aL (1968), Babor et al. (1975), Cane et al (1986~ +s AMA (1983k Gilman et al. (19~5}, I~edi~l E¢onomlcs Company (1967), and others l.~5~ll et al. (19~6) + Isbell et al. (1956) ?7 AMA (1983),+Gilman e~ al (I~5), Medical E~oaomlc~ Company t19~?), and o*J',ers ? Bat~ess~L~i (~9~0) +m AMA (19~3), Gil~a~ et at 11985), Medical F.covom]cs Company (19~71, and others N(fJ~ + in (~ ;¢.~t~'~ that drug sdminlst ratlon pv0d~ t}te effect. - indi~de~ that drug ~dminlst rat ion ~oes not pr~t,~e the effect: ? ir~i<~t es t ~',at available scient i~c d~ta art* inad~uate to draw conclm • FurLher dLsc~ss,on can t~ found in ot her chapters ca" thi~ Repot t ' A~ ald to stop ¢igarat te smc~ing and ~o treat nK~tlr~ de~ AS topic~ ae~tt~etic (~arely ~1 fo~ ear. ~mSel eye, and thr~L = ( ] ) ~s st rcog ~halge~ics ~or ~reatt~ent of bpth ~ and ¢hr0n~c paia • 12} t r~tment for myocaTdial infa~ (~m. anx~[y~m, and r~d~k-t~ I¢f¢ vent~l~r w0rk.h~d ~d ~ardml vxygea requi~'~t$), 13) fc~r obstetn¢ a~a~, (4) ~ ~U: reed k~tion to msoc4Ji ihductm~. {5) t r~t merit for p~Jmonar7 edema. (6~ ~ cowgh ~p~sanL [7} t~t~t for ~ diarrhea "(1) .~ a~tlsep~ ~geht On skin, (21 intrave~,.sly Io great ~. L~ ( uterine ~elax~nt ), (3) t ~t~t rnent of .pe<ti~it y by local or intr~t henri inject ic*~ cf dilute ~b~mlute alco]lc~ ~ uti~n, t4i vehicle in de~matol~g;¢ p~m~tica~ (ant ~septi~ acL.onI astringent e<t ~;~, Cooling eff~t ), (S) t reatr.tent o~- alco;io] withdrawal i l I Iheorp~e~ted with ~ t he.ounce- e~a]ges~ (e~., asplnn } ~ tr~t Ot~i~ry ~emt~ t m and relieve inflammatory p~i~ (scant s~teatiC~ data to substant i~tel, i21 in comblnat lO~ with e~ot ~lkalold IO tr~L mi~r~i~ hee~ee~he. (3) in combination "~th ~Tml~atho~im~i¢ eg~nt~ pte~s~ big ano]'e~'t ic prope~ies in v~.t -loss rn~ic~t io~% (4~ ~ sllmul~nL iS} t reaLW, e.nt (cllr~;~l tz~h,I tot ]~ inf~mt ap~ea of tmdete~ne~ origin. (6p ~vely for treatment Of ~n~*~l ,~er~otm sy~em depressant ~nin~ • ( 1J AS ~ntlemetlc for ~ cheroot herapy pat ~e~L (2) gla~om~ t re~t ment

TABLE 6.--Continued , No(w at ~'~ent, but ~ ~ in ~ I11 as ~,~b.en~?y aid, t2) lts ~ in m ai~ and op~ a~mn trestcc~nt, 13J ~ ~d)u~t m terminal ~c~r p~uent therapy tQ red~e ~o~ a~tges~ nee~ ~,d indoce ~r~quility ~I) lv~trm~n~nt of ~y~hotk: disorder f0~t~ (21 t reatre~nt for rt~ms~ ~md vomlt ;e~. (31 reltef of p;%*surgetW restl~ and apprehension. ~4) ~l~*~meht for ~te. intt~mlt tent p~hyrl~. ~5) as a~junct in tetanus t reatra~nt* (6) to control mania n mnif~t~ons in mani~iep~esmve illn~* 17) t reetmem f~ int r~c~ib]e hi~up~ (~) treetmerit of child ren'~ sex, re bel~vior~t d~order~ cha~ by c~mb~i~ or hyperexettabl~ bt~mvior, (9) ~ st'egnd~tine U~t t ~ent for rm~ychotie a~xle~y ~.-]L~n~' w~ ~ m~oved, bm the ~creme~ s~res ~ a te~ic~ s~d a~ety ~le susa~sted ~ "~1~"

severe mood swings (Mello and Mendelson 1970; Mello 1968; Isbell et al. 1950); erratic supplies of opioids may be associated with sociop- athic drug-seeking and withdrawal-related mood effects (Jasinski 1977); erratic supply of tobacco can also result in disruption of ongoing activities in an effort to obtain tobacco or as a consequence of withdrawal. Consideration of multiple factors such as the dependence potential of a drug, the extent of its actual use, and the degree to which it produces adverse effects can be used to access the overall liability associated with the use of a drag (i.e., "abuse liability"} (Brady and Lukas 1984; Griffiths et al. 1985; Yanagita 1987). For example, caffeine produces only minimal (if any) disruptive behavioral or physiological effects and is not generally regarded as posing a serious public health problem even though self-administration may be widespread (e.g., caffeine in teaor coffee) (Griffiths and Woodson 1988a,b). In contrast, drugs which produce disruptive physiological and behavioral changes even when self-administered infrequently may be considered to represent a more serious health hazard (e.g., LSD). Drugs may fall anywhere on the continuum defined by these parameters, and the relative impact on health is most effectively determined by a comprehensive assessment of these interactive behavioral and physiological dimensions (Griffiths, Brady, Snell 1978b; Griffiths et al. 1985; Brady and Lukas 1984; Yanagita 1987). Identification of Dependence-Producing Drugs Independent of whether use of a substance has been observed to lead to addiction, it is possible to directly and objectively test a chemical to determine if it is addicting. Such tests provide data used by Federal (e.g., FDA~ Drug Enforcement Administration) and International (e.g., WHO) agencies as to how to regulate chemicals. In fact, new drugs are usually evaluated and regulated ("scheduled") before they are ever made available for medical application. Such decisions rely heavily upon the known properties of addicting drugs and on the methods used to test for such properties (bath described in this Chapter). Although the physicechemical structure of the drug is one determinant of the stimulus effects produced by drug adminis- tration, simply knowing the drug structure is rarely sufficient to predict the nature and magnitude of possible drug effects (Barnett, Trsie, Willette 1978); behavioral and physiological testing in animals and humans is usually necessary. When there is convergent evidence from multiple measures of dependence potential; then the drug is appropriately regarded as addicting or dependence producing. Whether humans outside the laboratory actually become addicted will depend on additional factors such as availability, price, and social acceptability of the drug (US DHHS 1987; also see discussion by Katz and Galdberg 1988). O 394 •

Table 6 provides a comparison of several drugs in terms of the major measures that have been reviewed in this Chapter. As shown in the table, drugs known to produce widespread problems in a given population are characterized by positive responses with most of these measures (cocaine, morphine-like drugs, alcohol, and nicotine). Conversely, drugs not contributing to such problems have fewer positive responses on the various tests (cholorpremazine). Intermedi- ate drugs are associated with intermediate levels of difficulty in management of use. Comparison Among Drugs Within a given class of drugs, it is sometimes possible to rate their .celative efficacy as reinforcers by how much behavior was affected (e.g., how many lover prossos would occur or how much money would be paid) (Griffiths etal. 1981; Yanagita 1987). For instance, the slowor onsetting/offsotting formulations of opioids, barbiturates, stimulants, and nicotine appear to hays a lower dependence poten- tial than the quicker onsotting and offsetting formulations (Jaffe 1985). The practical gonecaiity of such comparisons, however, is limited beeauso many other factors determine the overall level of depon- dence that might dovolop, the extent 'of social and/or personal damage, and the resulting level of social concern (Yanagita 1987; Katz and Goldberg 1988). For example, the increasing availability and decreasing relative price of cocaine in recen.t years are major factors contributing to increased levels of use and resultant social damage (US DHHS 1987). Analogously, the widespread ready availability and the relatively low cost of tobacco products and alcohol have probably contributed to the much higher rates of addiction and mortality associated with alcohol and tobacco than with drugs such as cocaine, even though cocaine may appear to be a more offoctivo reinforcer in animals. Social or cultural factors may also contribute to the spread and levels of drug use. For example, sensational press reporting may have contributed to the populariza- tion of barbiturates in the 1960s (Breoher 1972), and the mass marketing and advertising of tobacco products is likely to have contributed to the use of these products, ospecially among women and ospecially in the case of smokeless tobacco products (Ernster 1985, 1986; Warner 1986b; Davis 1987; Tye, Warrior, Giants 1987). Four oxamplos of drugs associated with striking changes in the prevalence of use among various populations as well as associated morbidity are: alcohol, for which use and associated disoases decreased during the Prohibition years early in the 20th century; lysorgic acid diethylamide (LSD), for which use and associated hospitalizations were elevated during the 1960s; cocaine, for which use and associated hospitalizations increased during the 1970s 305

(Crowiey and Rhine 1985; Levine 1984; Nahas and Frick 1991; Dupont, Goldstein, Brown 1979; Holder 1987; US DHHS 1987); tobacco, in which consumption of smokeless tobacco products in- creased among youth in 1970s and cigarette consumption increased sharply among women in the 1950s and 1960s (US DHHS 1991, 1986; Appendix A). As discussed in the aforementioned references, the changes in use of these drugs were not due to changes in the pharmacologic actions of the drug or sudden changes in genetic constitution of the populations, but rather to changes in factors such as availability, cost, social acceptability, regulatory controls, market- ing efforts, and general perceptions about the risks associated with use. Finally, various other factors contribute to the level of social concern and may be only indirectly related or unrelated to the pharmacologic properties of the drug itself. For instance, the observations on transmission of AIDS by way of shared needles among i.e. drug users and on cancer caused by tobacco smoke carcinogens have greatly increased the liability of use attributed to these drugs in recent years. Environmental Determinants of Drug Dependence Including Behavioral Cond/tionlng A common feature of use of all dependence.producing drugs is that the positive (satisfaction symptoms) and negative (e.g., withdrawal symptoms) effects may become conditioned responses to associated environmental stimuli, The implications of this are important for understanding the chronic and self-sustaining nature of drug dependencies. Such conditioning is a powerful behavioral mechan- ism by which the drug comes to control an increasing amount of the behavior of the drug user (Thompson and Schuster 1968; Goldberg 1976a). Some of the important environmental determinants of drug dependence are discussed elsewhere in this Chapter in the context of drug self-administration studies. These factors include: (I) the behavioral or economic cost of the drug itself or of taking the drug, (2) direct pressure to take the drug by making other reinforcers contingent upon drug taking, and (3) the other ongoing activities of the person (e.g., demanding work schedule) that tend to enhance drug taking. The focus of the present Section is on environmental stimuli that may contribute to drug dependence by evoking urges to use drugs, and by eliciting bodily responses that mimic the usual effects of either drug taking or drug withdrawal reactions. 306 •

Drug Taking as a Learned Behavior The interface between a drug and its effects is the behavior of obtaining and ingesting the drug. Such behavior is learned behavior, and as discussed earlier in this Chapter, many of the factors that modulate this behavior are similar to those which modulate other learned behaviors including eating, exercise, and occupational skills (Thompson and Schuster, 1968). Technically, drug taking is "operant behavior" and includes "respondent" or "classically conditioned" components. The basic governing principle of operant behavior is that it occurs in the context of certain stimuli and is either strengthened or weakened by the nature of the consequence (a positive reinforcer strengthens the response and a punisher weakens the response} (Skinner 1938, 1953). Thus, for example, a friend might offer a drug (antecedent stimulus); the drug is ingested (operant behavior or response); and the effects of the drug strengthen the behavior (positive reinforcement). Respondent conditioning occurs simultaneously and further contributes to the strength of the behavior (Bouton and Swartzentruber 1986). A drug might serve as an unconditioned stimulus which elicits a relatively involuntary response (e.g., nicotine and morphine can elicit feelings of pleasure and/or nausea); when physical dependence has occurred, drug abstinence can also elicit certain responses (e.g., anxiety and urges to take the drug). Any environmental or even internal stimulus can become part of this conditioning process by repeated association with the elicited response. For example, the taste of alcohol, the smell of' smoke, "thinking" about use of the substance, and the sight of cocaine- or opioid-associated paraphernalia can elicit feelings associ- ated with either the administration or withdrawal of the drug (Childress, McLenan, O'Brien 1986a,b; Ludwig 1986; Ludwig and Stark 1974; Erben 1977; Gotestam and Melin 1983; Pickeus, Bigelow, Griffiths 1973; Rickard-Figueroa and Zeichner 1985; Levine 1974). The simultaneous operation of both operant and respondent conditioning can converge to generate and maintain powerful chains of behavior over which the individual may have little control. As shown earlier in this Chapter, highly addicting drugs are those which are very effective at reinforcing behavior and eliciting responses. Their power can be increased by factors such as drug deprivation, which may be associated with a discomforting with- drawal syndrome. In the presence of withdrawal, the person may behave in a way to relieve the discomfort of a withdrawal syndrome', in this case the withdrawal syndrome itself may be said to be functioning as a negative reinforcer. When drugs are readily available, as with tobacco for most people or opioids for physicians, these behavioral conditioning processes may be very subtle because the drug can be taken in a pattern that avoids excessive discomfort. For example, early interoceptive or subjective withdrawal cues that 307

are evident upon waking in the morning signal that "it is time to smoke a cigarette," and thus the smoker neither "forgets to smoke" nor experiences pronounced withdrawal symptoms. As implied by the foregoing discussion, the strength and persis- tence of drug-seeking behavior are not just functions of the drug itself or of withdrawal. Rather, they are determined by many factors, such as the number of times that certain reponses are associated with certain stimuli, the presence or absence of such stimuli, the subjective discomfort occurring as part of withdrawal, and the availability of the drug. The convergence of so many environmental and subjective forces can result in extremely persistent behavior that may appear disproportionate to the pleasure actually experi- enced when the drug is taken (e.g., the few minutes of pleasure from the postdinner cigarette or when heroin is taken after 8 to 12 hr of deprivation). In fact, the subjective pleasure itself may be very mild, and the person may describe the role of the drug as "simply maintaining feelings of normalcy or comfort" and not as "getting high" per se. The scientific basis for these observations has been actively and systematically studied since the pioneering work of Wikler and others (Wikler 1973) and has been reported and reviewed in detail elsewhere (Goudie and Demellweek 1986; O'Brien, Ehrman, Ternes 1986; Grabowski and Cherek 1983; Grabowski and O'Brien 1981; Childress, McLenan, O'Brien 1986a,b; McLellan et el. 1986; Wikler 1973; Meyer and Mirin 1979). Drug-Associated Stimuli Modulate Drug Seeking Stimuli associated with drug effects may come to elicit ("trigger") those same effects or sometimes opposite effects (withdrawal re. sponses). For example, increased heart rate induced by stimulant administration may become associated with multiple environmental stimuli - the color of the tablet, the individual who provided it, and the office environment in which the drug was taken. These stimuli may act alone or in concert. One stimulus may produce a slight heart rate change; two such stimuli may produce a larger change; and the presentation of many such stimuli may have a synergistic effect. Other stimuli may counteract or facilitate these effects (Schindler, Katz, Goldberg, in press). The response produced in relation to environmental correlates may differ qualitatively from the direct drug effect. For instance, the direct effect of a drug may be a heart rate increase, whereas the conditioned or learned response to drug.associated stimuli may be either a decrease or an increase in heart rate. Changes may be particularly evident for agents with biphasie effects such as nicotine. Whatever the direction of change in response value, the events may be of physiological and behavioral significance (for example, see Childreas, McLellan, O'Brien 1986a,b; O'Brien, Ehrman, Ternes Q 308 •