Tobacco Documents Online

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.~•- ., --' :~ ..; .. ..:_•:..<..... .. ._... _ n,. ,- ~,tiy ,:. ~y. Department of Pharmacology " a. To determine effects of inhaling tobacco smoke of high, and low nicotine con- ~ :,taining cigarettes on skeletal orsscle tone in animals and man. . To compare these effects with i.v. nicotine injections. . To further delineate the CNS actions of nicotine. C0Mi1TTEE• Dr. Cattell, Chm. Dr. Jacobson, Dr•. Little 1. Name of Investigator(s): rindud.jitte and Degrees) $dward- F. Domino, M.S., M~D., Professor of Pharmacology 4. dutitvtion b. z*'c'r 5-r+. ~, •. .'i:'.'. _ . . .: Addtess: University of Michigan - • 6440 Medical Science Bldg. ":- Ann Arbor, Michigan 48104 3. Short Title of Projocf: Effects of Tobacco Smoking and Nicotine on the Central Nervous System• 5.Antiupated;DorattonofthisSpecificStudy: Three years. Phase "a" should be completed within 1 year_ I. Proposed Starting Date: January 1, 1968 : 6. Brief Descripton of Objeqives or Specific Aims: 7. Givea6:iefStatementofyourWorkingHypotHesis: People smoke tobacco for the psychopharmacological, effects of nicotine. These effects are identifiable and. measurable us ing ob jective endpoints of central nervous system action. 0 `_

_.'J_ ....-.._.-~... . r _i.,. 6 D.tailsofExperimentalDesignondProcedureso(AttachSeparatePages) f•ur research approach has been oriented to the question of why people smoke tobacco. Tb date this research has dealt with the behavioral arousal effects of r.nicotine and tobaceo smoking. These effects are very mild and are accompanied by ;;4;41s..-...r previously by others as described in Tobaecot Experimental' and CLinical Studies" a unique relaxing efFect. -This unique muscle relaxant effect has been. observed by Larsony flaag and Silvette. Many. or the previous studies have used large toxic doses•of nicotine so that the relationship of data so obtained to tobacco smoking is unclear. Furthermore, it is our hypothesis that the pharmacologically active substance in tobacco, i.e., nicot•ine, acts mostly on the central nervous system in causing a reduction in skeletal muscle tone. Most of the known peripheril effects of small doses of nicotine are to increase skeletal muscle tone. The proposed research will be conducted in two phases. 1. Effects of tobacco smoking of high and, low nicotine content on skeletal -'•muscle tone. Effects of nicotine given intravenously on skeletal musale tone. 9. Physical Facitties Available (Where Other:than Administering Organization Indicate Geographical Location) (Cont 'd•. p. 2a) . :,':~`" nieotine and tobacco smoking. These have been published in detail by the principal Standard techniques will be used to evaluate the'skeletal muscle effects:of i:,>;::..:..'.n•::..:....;;r. ..... . .:a - Department of Pharmacology 6440 MedicaL Science Building Cigarettes of known tar and nicotine content are desireds These must look identical and hopefully taste somewhat similar. It is estimated about two cartons of each-type would be required. C 11. Biographical sketches of cll principal and professional personnel (append) : See appended vita of Drs. Domino, Miyasakarand Nakai 12. List of publications: (Five most recent as pertinent).(append) .,

2a invest.gator (see N. Y. Acad. Sci. 64: 705-729, 1956 and more recently, Centrally Acting Skeletal Muscle Relaxants, Chapt. 15, 313-324 in Evaluatioff of Drug Acti-:' vities: Pharmacometrics, Vol. 1~ D.R. Lawrence and A. L. Bacharach, Eds. Academic Press, Lond, 1964). In man the-EMG and patellar reflex will be measured in res=t' ponse to fixed muscle tensions. This will be done before, during, and after . y _ . .- ,tobaceo smoking of cigarettes of known nicotine content as phase I of this pro= Ject. A total of 10 smokers and 10 former or occasional smokers.will be studied: Each will be given 2 cigarettes to smoke at each recording session. Each M, cigarette will be smoked over a fixed-period of 3 minute$ during which muscle activity will be recorded. At weekly intervals the subjects will be given a cigarette of..t high, low, zero nicotine content and a sham-smoke in a Latin square design. During phase II the study will switch to the use of intravenous nicotine over-'1WA a 5 minute period to simulate the amount inhaled•from.the high nicotine content cigarette. A maximal dose of 10-20 microgm/kg will be given depending upon tolerance, etc. Similar studies will be conducted in the chioralose anesthetized cat using this as a model system to determine more precisely the site of action of nicotine. ';,=' r~r4 In addition our previous studies (seeProgress Report #9) on the effects of nicotine on the visual sensory input and its modulation will be continued as described previously. The correlation of nicotine content in the brain w~th its neurological ,., .: and behavioral effects will be studied as soon as a supply of 1'+C-labelled nicotine becomes available to us through Dr. Armitage of England. :

R: REDACTED MATERIAL Estimated Future Requirements: Total `L Consvmable 5upplies Qist by catepories) Animal Surgical Chemical Glassware _:,'PHotographia Polygraph recording paper Sub-Total . C Other Expenses (itemize) . 12%-Staff benefits for personnel Student Volunteers Travel to yearly Pharmacology Meetings D. Nrmanent Equipment ('rkmize) Sub-Total. ' -' ' Infusion pump '• ' Strain gauge, •amplifier' and coupler Respirator _' SMG amplifier and integrator Year 2• Year 3, In applying for a grant have read and found acceptable TelepHone It is understood that the applicant and institutional officers DW~r.f~t qe~t Salaries 9'. Consumable.Suppt. Olher Expenses Permanent Equip. 1800 1000 300 3100 400 400 500 700 2000' 5250 3200 2000 -3307 • 29,507 5512 3300 2000 3472 30.821 Signature /• .•+~".- • f _-7 -.0,i i r• :~t. Qverhead the Council's "Stotement.of Policy Containing Conditions Signaturc and Terms Under Which Project Grants Are Model" IuJ..u olru r.t 1h. bueti.e.. Telephone 40M 611~

list flnonttal support for research from all:ouress, including own InstituNon, for this andlor related stsarch'projacts." : The above grant will terminate 8-31-67. A.competing renewal grant is being submitted with a May 1, 1968 start- ing date.. However, even if approved this grant only is in- directly related to the tobacco and nicotine project as it involves central cholinergic mechanisms since nicotine is not a neurotransmitter substance. 9SS9PSEOOZ JPII

R: REDACTED MATERIAL Name• Title- ~ - Matue Miyasaka • 40 Placee o,f Birth: "Postdoctoral Fellow Present Nationality: Sex: -Sucaa City, Nagano Prefecture Japanese ~ Japan EDUCATION Birthdate•.. . P_ Male Institution: De ree: Year: Tokyo Medical and Dental University M.D. 1955 Tokyo Medical and Dental University D.Med.Sc. 1960 Maior Research Interest: Relationship to Pro•'tect: Postdoctoral Fellow Research and Professional Experience: Rotating internship, First National Hospital of Tokyo 1955-1956 Postgraduate Course, Department of Neuro-psychiatry 1956-1960 Official staff, Neuropsychiatric Department, Tokyo University 1960-1965 Postdoctoral Fellow, Department of Pharmacology, , University of Michigan 1966-present Publications: Twenty-seven major publications.have been published in various medical and scientific journals.

R: REDACTED MATERIAL Edward,F. Domino Place of Birth: Professor of Pharmacology "Present Nationality: ,Chicago, Illinois :. U S Citizen EDUCATION • • Instiiu tion• University of Illinois, Urbana, Illinois University of I1linois, Chicago, Illinois University of Illinois, Chicago, Illinois De ree- B.S. 1948 ri.s. (Pharmacology)1951 M.-D. _(With, honors) 1951 Ma:ior Research Interest: Experimental and Clinical Neuropsychopharmacology Relationship to Pro;ect: - Principal Investigator Research and Professional Experience: Professor of Pharmacology, The University of Michigan Associate Professor of Pharmacology, The University of Mich. Assistant Professor of Pharmacology, The University of Mich. Instructor, Pharmacology, The University of Michigari Instructor, Pharmacology, University of Illinois Rotating Internship, Presbyterian Hospital, Chicago Publications: 1962 to present 1958-1962 1954-1958. 1953-1954 1952-1953 1951-1952 Over 160 full-length manuscripts and abstracts on neuro- and psychopharmacology have been published in various:scientific journals. t ~..~._._.. .

R: REDACTED MATERIAL Name: ~ Yoshihisa Nakai Place of Birth: BIOGRAPHICAL SKETCHES.-= -- - Title • . .. Postdoctoral Fellow Present Nationality: Sex: Institution: Japanese EDUCATION De -ree: Male Year: Kyoto University, Kyoto, Japan B.S. 1955 Kyoto University, Kyoto, Japan M.D. 1959 Kyoto University, Kyoto, Japan D.Med.Sc. 1965 Major Research Interest: Sensory evoked responses Relationship to Project: Postdoctoral Fellow Research and Professional Experience: Internship at Kyoto University Hospital 1959-1960 Residency at Kyoto University Hospital 1960-1962 Postgraduate course at the Department of Pharmacolagy, Faculty of Medicine at Kyoto University 1961-1965 Postdoctoral Fellow, Department of Pharmacology, University of Michigan Publications: 1966-present Seven major publications have been pu~lished'covering various aspects of the neuropharmacology of psychoactive drugs. ~