Tobacco Documents Online

AC~RDIOVASCULAR, PHARMCOLOGY and CHE~+ffSTRY TN ro. C ~ COi41MIT`hEE : Dr. Cattell, Chm. Dr. Wilson Dr. Jacobson Dr. Little COUNCIL FOR TO1tACCO IZI:fi]:ARCR X. S. A. SUCCE.tsOR f0 T11A TOBi4CC0 INDUSTRY RI:SR/!RClf COAlh11T7EC 150 EAST FORTY•SLCOND STREET NEW YORX. N.Y. 20017 Renewal Application For Research Grant Dota APRX'L 28, 1964 1. Name of Investigrtor.. EDWARD F. DOMINO, M.D. 2. Title: Professor of Pharmacology 3. Institution & Address: 4. Project or Subject: The University of Michigan 64+0 Medical Science Building Department of P:aarmacology Ann Arbor, Michigan EFFECTS OF NICOTINE ON THE CENTRAL NERVOUS SYSTEM It is proposed to pursue our studies on the action of nicotine and its derivatives, either metabolites or natural alkaloids, in tobacco, on the central nervous system of animals and humans. The principal investigator feels that this is an extremely important area of research for we have only scratched the surface in unfolding the amazing effects of this alkaloid as described in the accompanying Progress Report #6. Two major areas of research will be pursued. (Application for a 3 - year period of support - January 1, 1965 to December 31, 1967) C 5. Detailed Plan of Procedure (Use reverse side if additional space is required). A. Behavioral and EEG Correlations in Animals and Man 06R6 Activated: 1/1/59 Renewed annually on the anniversary 01127845 In the past six months two different behavioral and EEG actions of 5-10 micro~:gm/kg doses of nicotine have been demonstrated in cats. The first acticn is a very mild and transient wake-up effect in the sleeping cat. The second action is a sleep promoting effect that is manifested by a"paradoxical" phase of EEG activity which lasts about 15-30 minutes. In man this type of activity has been associated with dreaming. In animals, it is also postulated to be a similar phenomenon as evidenced by a) eyeball movement, b) altered blood pressure, c) respiration, d) pulse rate, and e) activity. In animals, it,is proposed to study these effects of nicotine and relaced alkaloids on EEG activity of the linbic system,.reticular and hypo- thalamic activating systems and cerebral cortex before and after various bl ki ocng ` drsbs in order to ascertain central and peripheral components of nicotine action. These effects will be correlated with behavior through a oni-way window compartment. Both gross behavior as well as instrumental conditioning will be studied. It is proposed to obtain and study all of the known alkaloids of nicotine which are present in tobacco smoke as well as critical metabolites such as 5+~cotinine, etc. i~;: ..

2 5. (continued) Similar studies using the scalp EEG and evoked potentials as an index of arousal, sleep or dreaming will be carried out in a) normal human volunteers and b) selected psychiatric patients with and without tranquilizers or medication. It is a curious fact that many psychiatric patients smoke excessively. It is our belief that they do so for the beneficial actions of nicotine in promoting the "paradoxical" phase of sleep as well as its calming effect during wakefulness. The role of nicotine will be.determined as a "wake-up" agent in sleeping patients and as a promotor of the "paradoxical" phase of the EEG as associated with dreaming. B. Effects of Nicotine and Related Alkaloids on Learning in Aninals. Our studies on the effects of these agents on the acquisition of avoidance learning in the rat will be pursued. Are these actions directly on the central nervous system or a peripheral action due to a-fferent stimulation, catecholamine serotonin release? These studies have not been pursued suff_ciently and require the attention of a full time technician. C C

.. .. .,~.- . C C 6. Budget Plan: L a. Salaries (including ~ringe for each year benefits, 12/.) b. Expendable Supplies c. Permanent Equipment d. Overhead (15% of a, b, e) .. Other 7. Anticipated Duration of Work: 3 years $ 14,560 5.000 700 _2.A979 _300 Total ~ 2.3.,,532 8. Facilities and Staff Available: A neuropharmacolooical laboratory is in operation under the direction of the Principal Investigator. The funds for staff include salaries for Dr. Yamamoto ($6,000) and one full time ($4500) and one part time ($2500) technician. Some of the funds f or supplies and equipment include remodeling costs for a room with a one-way window, etc., for the human studies. 9. Additional Requirements: The assistance of the Council for Tobacco 'Research is requ.ested for supplies of (-)nicotine for human use as well as obtaining the minor alkaloids of tobacco from various sources. 10. Additional Information (Including relation of work to other projects and other sources of supply): A 3-year request for funds is made to provide stability for the research project. Funds are requested as follows:• $23,539 January 1, 1965 - December 31, 19%':;5 WSJ~ ~~:Q'+51 January 1, 1966 - December 31, 19466 24,000* January 1, 1967 - December 31, 1967 25,000* * 1966 and 1967 figures adjusted for estimated cost of living increases on salaries. Signature Director of Project Edward F. Domino, M.D. Business Officer of & Institution Harlah J. Wulder, Assistant Controller