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I I I I I I I I I I I I I I I I I I Br.;uh Jourrtal o(Addu:mn (1990) 85, 441-445 REPORTS FROM RESEARCH CEN.-TRES-21 Human Behavioral Pharmacology Laboratory University of Vermont JOHN R. HUGHES, STEPHEN T. HIGGINS & WARREN K. BICKEL The Human Behavioral Pharmacology Laboratory (HBPL) is a utut of the Department of Psychiatry, t'niversity of Vermont College of Medicine. The unit began in 1987 and presently consists of a psychiatrist (JRH), two psychologists (WKB, STH), two postdoctoral fellows, three research nurses and four graduate and two undergraduate students in psychology. Our major sources of funding are ten grants from the Vational Institute on Drug Abuse, National Institute on Alcohol Abuse and Alcoholism and National Heart, Lung and Blood Institute plus two gnats from pharma- ceuucal companies. These granu include First Investigator Research Scientist Transition (STH), Research Scientist Development (JRH), Young Investigator (WKB), and National Research Service (pre-doctoral) Awards plus a pre-doctoral fellow- ship. Our research typically uses the experimental analysis of behavior to determine envtronmental, biological and pharmacological factors that control the self-administntion of and behavioral effects from drugs of abuse. Our research spans several classca of drugs. Presently we are studying alcohol, amphetamines, benzodiazeptnes, cannabindmds, caffeine, cocaine, nicotme and opioids. Most of our research is human laboratory reseuch, with an emphasis on behavioral rather than physiological or biochemical outcomes. We often apply paradigms from animal research to humans (e.g. concurrent Requesu foc tapnats sDould be sddressed to: Joba R Hupes, Deparsmeat of Psychuury, Uaverury of Vamoat, BurhWon, ~T 05405, USA. access to drug and placebo to examine reinforcing effects, repeated acquisition of behavioral chains to examine learning and performance). Not tnfre- quently our human laboratory work leads us to clinical trials or epidemiological surveys to deter- mine the stgnif cance and generaluabiliry of our findings. Our three major areas of research interest are the direct effects of drugs, the reinforcing effects of drugs, and treatment of drug abuse. Direct effects of drup on behavior and physiology Ltarnmg and performance Q'e have been assessing the effects of a variety of abused drugs on human learamg and performance using the Repeated Acquisition and Performance of Response Chains procedure. This procedure perauts a simultaneous comparison of drug effects on the xquisition of behavior (i.e. learning) with effects on the performance of previously learned behavior (i.e. performance) using wtthin-sub}ect designs. Although originally developed with nonhumans the Repeated Acquuiuon and Performance procedure has been usefully extended to the study of humans as well. We have obtained dose-response relation- ships on the acquisition of response chains under both acute and chronic dosing reg:mens. Alcohoi, barbiturates and the bentodiazepusrs consistently disrupt buasan learning and performance when relatively high doses are studied. Stimulants (e.g. d-amphetanune) buspirone, and delta-9 THC generally do not disrupt leartung or perfotmance, 441 I

I I I I I I I I I I I I I I I I I I 442 John R. Hughes, Stephcn T. Higgtns & R'arren K. Bickel although they do disrupt learnmg in some indivtdu- als. Importantly, abused drugs disrupt learning at low doses that do not disrupt performance. Compu- isons with results from nonhumans indicates an impressive degree of concordance. Social interaction Most drugs of abuse increase human social interac- tion. R'e have been investigating whether such effects occur because these drugs increase the control exerted by social reinforcers. To test this we use a two-choice concurrent schedule where normal volunteen choose between socially interacting with another same-se: volunteer versus earning money. In this setting, d-amphetamtne increases choice for social over monetary reinforcement. Preliminary results indicate that secobarbital produces a similar effect. These results are consistent with the notion that some of the reinforcing effects of abused drugs is associated with their ability to increase social interaction. Cardiac furtcnon Recent studies have focused on the cardiac effects of using stimulants (e.g. cocaine, d-amphetamtne) alone and in combination with alcohol. Interestin- gly, the cardiac effects of d-amphetamine are enhanced when combined with alcohol. Thus, the common practice of abusing drugs in combination may increase risks of toxicity beyond the risks of using these drugs alone. Summary Our work on direct effects of drugs makes a contribution to behavioral pharmacology in that it demonstrates (1) the generality of behavioral prtn- csples across human and nonhuman behavior, (2) the tntegration of findings using operant procedures with those more traditional 'learning and memory' tasks, (3) the influence of envuronmental factors (i.e. acquisition versus performance) on the effects of drugs on bunsan learning, and (4) the utility of the Repeated Acquuttion and Performance proce- dure in the detection of behavioral effects of commonly used and abused drugs. Reinforcing effects of drup RetnJorctng effeur of nieowu In placebo-controUed cliaical trials and on-site laboratory studies, nicotine via nicotine gum often induces long-term use. Self-admtntstrauon of aico- ttne gum is controlled by cost to obtain nicotine, dose, instructions, past drug history and setung. Dose-response effects of nicotine gum appear to vary by outcome (i.e. withdrawal relief versus cessatton). The role of physical dependence (i.e. withdrawal) in the reinforcing effects of nicotine is not well examined. Our studies in smoking cessation programs, medical practice and self-quttter popula- uons have shown that cessation of tobacco produces a reliable, observabie group of stgns and symptoms, many of which are due to nicotine deprivation. Dose, instructions, setting and subtect character- istics, have been shown to influence the degree of withdnwal. Surprisingly, in our studies, withdrawal has not been shown to robustly influence smoking cessation. . Reinforcing efjecu of caffeinr In a series of double-blind tests, some coffee drinkers given concurrent access to decaffeinated coffees with and without caffeine quite reliably show stgas of physical dependence and self-admin- ister caffeinated coffee in preference to decaffein- ated coffee. Doses as low as 25 mg (half of that found in soda or tea) are reliably self-administered. Survey studies indicate that a signi5cant minority of coffee drinkers fulfill DSM-111-R criteria for de- pendence when applied to coffee use. Future studies plan to examine factors tbat might determine whether coffee is used for the effects of caffeine (e.g. sleep deprivation) and to examine the ability of subjects to discriminate low doses of caffeine. Our labontory and survey studies indicate that removal of caffeine from coffee produces reliable wtthdrawal symptoms (e.g. headaches, drowsiness and fatigue) that can, at times, be severe. Importantly, the occurrence of such effects appears to be associated with the reinforcing effects of caffeine. Treatment studies Treatmntr of xiconne drpendencs In a large study in general practice, nicotine gum was not found to iacrease quit rates over placebo when used with brief physician advice and in unselected smokers. We are presently conducting a study of 2 versus 4 mg nicotine gum and of a nicotine patch. I

I I I I I I 1 I I I I I I I I I I Human Behatnora! Pharmcology Labaratorv Untoerrtty of Vmnont 443 Tfearmn+t of coca:nc abusr aCe are presently embarking on a series of studies to assess the efficacy of behavioral interventions for treating cocaine dependence. The studies will assess whether a behavioral intervention involving com- munity reinforcement of abstinence and basic con- tingency •management procedures is more effective than standard alcohol and drug counselling. Subse- quently, we will experimentally assess the ef5cacy of the different components of our behavioral interventton, Finally, we will assess whether com- bined behavioral and pharmacological therapy (e.g. destpramtne treatment) significantly enhances out- come above what is achieved with either alone. Other areaa of interest .bfethodologieal studies We have conducted empirical different procedures to assess studies to examine reinforcing effects, methods to increase recruitment and follow-up in clinical studies, and measures of nicottae with- drawal. 77seorerual work We are interested in conceptual issues such as the role of stimulus control in both drug self-admuus- trauon and in the direct effects of drugs, the factors that influence the verbal behavior of scientists, definitions of drug withdrawal and dependence, and combining behavioral and pharmacological treat- ments for substance abuse. Future studies At this point, we have no plans to change our focus or types of activities. We do plan to expand our training of postdoctoral sad graduate students. There are two research areas that will be of special interest to us in the future. The first is the development and testing of a human drug discrtmt• nation procedure for sedative-hypnoucs. The sec- ond is the application of behavioral economics to quantify reinforcing effects of drugs, to study drug interactions, and to study bow non-drttg reinforcers nttght decrease drug intake. Our first study on cigarette and coffee use demonstrated the utility of such an economic conceptualization. Further informarioa We publish a semt-annual report in April and October that list recent publications. To obtain the report and reprints wrtte Human Behavioral Phar- macoiogy Laboratory, Depattment of Psychiatry, University of Vermont College of Medicine, Burlington, VT 05405. Bibliography The following is a list of our published articles in the last year. BtcxEt., W. K., Biost.ow, G. E., PRzrrox, K. L. & LtEUON, I. A. (1989) Opsoid drug discnminauoa Ln humans: stability, spect5ctry and relauoa to self- reported drug effect, Jorrnal of Pharnsacology G EzpenrRmtd lheraprsutcs, 251, pp. 1053-1063. BtcT.Et., W. K. & HiGGINs, S. T. (1989) Acqutsttton and performance of response chains: modulauon by envtroa- mental and pharmacolopcal factors, Pharwsacolaly, Buxhhnutry ard Bekaflsor, 29 p. 657. Btcxat., W. K., HtcGirs, S. T. & Gwrmu, R. R. (1989) Repeated duzepam administration: Effects on the acquisition and performance of response chams in humans, Yournai of the Ezpertswsrsta! Arsdyru of &ka- tno+, 52, pp. 42-45. Btcitat, W. K., Hluaixs, S. T., Kautr, K. & JoHrtsoN, L. M. (1989) Effects of schedule history and >ued-rauo requirement on fited-usterval schedule performance, Joumal of t1u Espersru" .4nalyru of Behavso+, 50, pp. 211-218. Btcrut., W. K., Hiuctxs, S. T., GttLtss, M. & Huans, J. R. Effects of trtuolam and buspuone on the icquisiuon and performance of response chuas in humans, in: L. S. HNtlus (Ed.) P*oblestu of Drug Depessdesce, 1988, N1DA Reuarch Monod.aph (Wuh- cngton, DC, US Goverameat Pnnuag Office) p. 318. BtcstEL, W. K., HIGGIxs, S. T. & Huaias, J. R. (1990) Human behsvioral phumacotop of beazodazeptnes as assessed by the repeated acquisition of behavioral chauns, Drug Developrnenr Research (in press). BtesCiL, W. K. 8 KitzY, T. H. (1988) The relauonship of stimulus control to the tttatment of substance abuse, in: B. RAr (Ed.) Lsams,Y Factort ur Subuai+ce Abuse (Washiniton D.C., National Institute on Drug Abuse) pp. 122-140. BtcuW. K., Srrrau, M. K., Bton.a., G. E., Lmsox, 1.A., Jtisnrstu, D. R. A Jornvson, R. E. (1989) Buproaorphaae: dose-related blocksde of opioid chal- leap effects in opod dependent humaas, Josnwal of Pha++Raco/o& & F-sper-s,tal Therapeuata, 247, Pp- 47-53. Btcui, W. K., KxsoKr, W. F., PatdAGtosot+us, P., Ktatxrr, R., K!-osea, J., 2au.ortT, R. D., Mrwot+, 1. & Lowrxsort, J. H. (1989) Combined behasoral aad pharmacological treatment of alcoholic methadone pa- uents, Josnwa/ oJ Sybsrsnu Abssse, 1, pp. 161-171. HetsvL+au, D. K., DNa-awr, L, Ztwuauur, K. !~ HuotQs, J. R. (1988) Symptoms of tob.eeo wtthdrawal frm total csgarette cessation vs parual ciprette redtx- uoa. PryckopAarwuzcoloV, 94, pp. 242-247. Harstrsuxt, D. K., Ptcgmts, R. p., Svtus, D. S. k I

I I I I I I I I I I I I I I I 1 444 John R, Hughes, Stephen T. Htggtns G IT'arren K. Bsckrl HL'GHES, J R. (1988) Smoking topogzapbv and blood nicotine ieveis, Addictive Behar:o+s, 13, pp 91-96. HEN NINGFiELD, J E. & HIGGINS, S. T (1989) On the in9uence of behaviora! research: a response to the Surgeon General's report, The Health Consequences of SmoKing: Nicotine Addiction', The Behavior Asalys4 ;:, pp 99-101. HIGGIsS, S. T., CAfELESS, M., HCGHES, J. R. & BEL7NSON, M Behavioral and cardiovascular effects of alcohol and d•amphe:amme conbinations in normal volunteers, in: L. S. HA1uus ( Ed. ) 1'roblems of Dru6 Dependence, 1988, .`'IDR Research .Nonog+aph, 90, pp.35-36, (Washsng- toa, DC US Government Printing OfSce). HIGG1Ns, S. T., HEvNiNGFIELD,J. E. & LAnU,R. J. (1989) Behavioral and physiological effects of atropine in norttul volunteers, PhanRacoloV, Biochemusry & Be- hatno., 34, pp. 303-311. HIGGIHS, S. T., B1cxFS., W. K., HUGHES, J. R., RusH, C. R., PEPPEIt, S. & LrNtr, M. (1989) Comparable rates of responding and reinforcement do not elsmsnate the differential effects of ethanol on response chain acquisi- tion and performance, T),e Prycholohcal Record, 39, pp. 583-595. HtoGt.s, S. T., HUGHES, J. R. & GAUaGHEIt, R, yi. (1988) Introducing the unfamsl3ar to behavioral phar- macologti~ a review of pnmen by A. Poling and P. L. Carlton, The Beharto* Malyst, 10, pp. 277-281. H1oG1Ns, S. T., Koaus, E. K. & JoHNSON, L. K. (1989) Social traasussssioa of superstitious behavior in pre- school children, Prycholohca/ Record, 39, pp. 307-323. HtGGtxs, S. T., PteESroN, K., CANE, E., HEwxr.+GrgLD, J. E. & JAFFEE, J. (1988) Behavioral, phystolopcal and hormonal effects of a nalosone challenge following acute morphine pre-treatment in humaas, in: L. S. HAStltss (Ed.) Problems of Dnug Dependence, 1987, :JIDA Research Monoaraph 81, pp. 202-208 (Washaag- ton, DC, US Goverament Prmung Offlce). H1GGtNS, S. T. & SrrtZElt, M. L. (1989) :Konolo`ue speech: effects of d-amphetamsne, secobarbttal and dsuepam, PharmacoloV, Bioclsemurry & Behatnor, 34, pp. 609-618. HtGGtNs, S. T. & StTTZF.It, M. L. (1990) Companson of tbe effects of secobarbital and diazepam on the acqutsi- uoa of response sequences in humaas, D*v8 Develop- mens Research, 10, pp. 317-398. HtGGtxs, S. T. & StnZl?&,K. L. (1988s) Time allocation in a concurrent schedule of soual tnteracuoa and moaeur7 reinforcement: Effects of d-amphetaaune, Phar+nacotoV, B»chensttry, as.d Bskcmor, 31, pp. 227-231. HtGGets, S. T. & STrrzEit, M. L. (1988b) Effects of alcobol on speaktng sn ssolated subpects, PryclsopAm>aea- colopr, 95, pp. 189-194. Htacros, S. T., Wooa.AitD, B. M. & HENxt:'+GFrzLD, J. E. (1989) Time-coune of the effects of atsoptne on repeated scqtuutsoa and performance of response se- quences in hamaas, Journal of elu Erpenme+ssal .lnaty- su of BeMavsor, 51, pp. 5=15. Htcctlvs, S. T., HuGms, J. R. & Btcul., W. K. (1989) Effects of d-ampbeumsne on cbou:e of soctal rerstu monetary resafoesemeat: a dsscrete-rrsai test, Pkama- coloV, Bioclsen<ssrry & Beheetor, 34, pp. 297-301. HUGHES, J. R., Axotu, G. & HATSU><Axt, D. (1988) Free reprnnts to increase the return of follow-up quesuon- nures: a repitcatton test, Amertcan Journal of Public Health, 77, pp. 1474-1475. HL'GHES, J. R. (1988) Clowdine, depression and smoking cessation, Journal of the .lsrsericaR .Nedccal .4ssoaasson, 254,pp,2901-2902. HCGHES, J. R. (1989a) Preveauag relapse of the e:- smoker: the show must go on, Journa/ of the Amertcan Medical Assoctanon ( ia press ). HUGHES, J. R. (1989b) Ce1a n'etast pas une couverrure, Joumal of theAme+tcan Medual Assoctaton, 261, p. 2956. Ht:GHES, J. R., AMOSU, G., HATSL'xAAU, D. K. & LwtGNE, F. (1988) A survey of phvstcun advice about caffeine, Journal of Substance Abuse, 1, pp. 67-70. HuGHES, J. R. (1989) Eavironmental determinants of the reinforcing effects of nicotine, Journal of Substance Abuse, 1, pp. 319-329. HUGHES, J. R., ARANA, G., Sh.AttT, F. & WosuAUlr, R. (1988) Effect of tobacco wuhdnwal on the dezamethr soae suppression test, Btolortcal Prych:arry, 23, pp. 96-98. HUGHES, J. R., BICxEL, W. K. & HIGGtxs, S. T. (1989) Successful tnnsfer to buprenorphsne m a patient on morphine, tn: L. S. HAttlus (Ed.) P+oblems of Dne6 Dependence, 1988, NIDA Research Monor*aph, p. 357 (Washsngton, DC, US Government Printing OfSce). HuoHEs, J. R., Gcu.>ZM S. B., AA+au, G., Nsn>:.+vLT, G. & FE*tsx'.>t, J. (1990) Effect of instructions and nicotine on smoksng cessation, withdrawal symptoms and self-admsnsstrauon of nscoune gum, Prychopharma- colo&, 99, pp. 486-491. HuGHS, J. R., Gus-r, S. W., KEENAN, R. K., FErmC><, J. W. Et HLt1.t', 4t. L. (1989) Nicotine vs piacebo gum tn general practice, Journai of du Amertcan Medical dssocusnon, 261, pp. 1300-1305. Ht:GHFs, J. R. & HATSU>tAAU, D. K. (1984) Free repnats to increase retusa of follow-up quesuoanaues, Behavior Tknapy, 15, pp. 557-558. HUGHES, J. R., HlGCms, S. T. & B1cxaL, W. K. (1989) Behavioral 'properues' of drugs, PrychopharmacoloV, 96, pp. 557. HUGHES, J. R., HtGGtxs, S. T. & HATSVxAxt, D. K. (1990) Effect of abstinence from tobacco, in: L. T. KozLo.stu, H. Axxu, H. D. CArr=u- et al. (Eds) Research Advances tn Akohol and Drug Probienu, 10, pp. 31 7-398 (New York, Pleaum Press). HUGHES, J. R., KEENAS+, R. & YFJ-t.114, A. (1988) Effect of tobacco withdrawal on sustuned attention, Addscate Behavsors, 14, pp. 577-580. JOMN30H, L. M., Blc>tl!J-, W. K., Hsootxs, S. T. & MosUtts, E. K. (1990) The effects of scbedule hsstory and avaslabWty of an adluncta.e response on responduig dursag a Szed-uster.al scbeduk of tesnforsement, Joumal of the EEspersnsensal Analysts of Behavso+ (us press ). Kllur, K. C. & Btcx>ri, W. 1C (1989) Toward an explicit analysis geaerahzauon: a stsmulus control Laterpreta- tson, Tke Behaoso+al Anatys; 11, pp. 115-129 KorrLl:, T. E., Buxu, M. L., SocsatG, L. I. & HUGHES, J R. (1989) A raadomszed trtal to mcrease smoksa; intervention by pbysicuns: Doctors Helpusg Smokers, Round I, Jou.ral of the Aiwencros Medaca/ Auoc+aaon, 26, pp. 2101-2106. Loetsmno, T. W., Huatas, J. R. & Ftcou, J. D. (1988) Failure to suppvrt the .aLdst7 of the Faterstsom

I I I I I I I I I I I I I I I I I I Xumcn Behavtosai Pharmcology LaboratorS L'ntvenuy of Vermont Tolenace Quesuoanure as a me2sure of pbvsiotogual toierance to dependeace, Addicttve Behav:ors, 13, pp 8%-90 POME1tLfaL', 0., POMERLEAt.',C., FAGERSTROM, K•0 , HEN-,'tNGFtELD, J E, & HLGHES, J. R. (1988) J'icottne Replacement en the Treatment of Snsoktng (New Y'ork, Alan Goldstein). 445 PREStoti, K. L., B1GELow, G. E., BtacaL„ R' K. & L1EDSOV, I. A. (1988) Drug ducnmtaauon tn human post•addtcts. mued agonist•antagontsts, in: L. S. HAIt• RlS (Ed ) Probltmt of Drug Dependence, 1987, pp. 209-215 (Washington D.C., Vauonai Instttvte on Drug Abuse). I