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• Objectives and, Specific Aims (Continued) It was conjectured that these delayed changes in behavior following nicotine injections could .; -conceivably be related to epinephrine output. Si.l'vette et al., in their extensive review (1), found ;~ ''':'::it".difficult to ascribe the above reported effects to any pharmacolocrical action of a sina(e iniection of nicotine three days previously. A more likely conclusion would seem to be that the animals werey ~ ::effected by some other part of the experimental procedure rather than the nicotine per se." :=1t is of interest to note that a later study (10) reported'an increase in excretion of urinary epinephrine produced by chronic injections of nicotine. The excretion reached a peak after three ;.,.days of treatment. . The intent of the proposed research is to measure rate of acquisition of discrimination behavior '_.i'n laboratory animals who are administered nicotine chronically during acquisition training. 0 ~ OO W CJ1 ~ CA 0

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food rewards, the expertmental condt trons wi 11 be as fol ows: ran om presentahons O tg t s tmu F', =tion of nicotine on the learning of an auditory discrimination 8ased;on punishmenti("conflict"). ~ ,.,. s'iVi- .% ~ PrnCrdurP A_ Hunarv animals wilN feam,to aress a lever in order to obtoin a Iiauid or solid the general tQcEltt/eS at tne ~outnwest tounaarlon ror tcesearcn ano cuucanon ure ovunuuie I arthis project. These include adequate office, laboratoryy and onimaf room space. C] 1. Biographical sketches of all principal and professional peraonnel (append). L ~,food reward'. Once the animals learn that depressing the lever is associated with the delivery at I d fl'h t' Ii ype}c61~4^: . '.v.,c:.:~:~.::: ~ ~{, _ p.xpenmenta(Des:gncndProcedures:(Attach5eparatePages) The subjectswill be white rats, squirrel ij.ADetailsof "-monkeys and cynomologous monkeys. They wil1i be gradually reduced to 80a/o of tl.eir body weight x and maintained at this weight by limited feedings throughout the course of the experiment. The r, apparatus will consist of two operant conditioning chambers fon rats, conditioning chambers for • A.;squirrel.monkeys and two Foringer monkey chairs. '. ' . . Sg*`; y~s:-Two experimental procedures wilt be employed. Procedure A will involve the effects ot ~."t.zchro nic administration of nicotine on the learning of a visuahor auditory discrimination based:on ~}.•positive reinforcement (food reward). Procedure B will involVe the effects of chronic administra- the .. erimental chambers will serve as a signol that a lever response will be incorrect and will the ex p a tone stimulus occom- If howevea cond eriod of darkness for the animals nished b a 30 s `u'p~'~b . , p y e pu e •-3~;r panies the presentation of the tight stimulus, a lever response wi!l be correct' and the hungry animal will be reinforced with- food, For some animals light alone wi(b indicate an incorrect response, F••while light and'tone will indicate a correct response. For another group ot animals tone alone will ...:.: tndtcate an tncorrect response, wHtte tone pius•Itght will tndtcate a correct response. ( ee ttac ment) 9 Physical Focilties Available (Where.Other fNan Adminut0ring Organizotion Jndicate Geographical Location) 12. Listofpubllcations:(Fivemostrocentaspertinent){append) Attached Attached

.shown efficiency or how well the animal . is* performing. TheRse points are determined by taking"' -AIl experimental animals will receive chronic administrations of nicotine during acquisition :,'training, while control animals wil(: receive saline. ~.. . I the ratio of right responses divided by right and wrong or -RTy- = efficiency. bf the animal is making an equal number of right and wrong responses, he is not discriminating and the point would 2C •~~ - :. fall at 0.50. If the animal's wrong responses exceed the right, responses, the point would fall below_ :;T 0.50. Points lying above .50 indicate that right responses exceed wrong responses and: thal" the ~_~a, .:: animal is acquiring the discrimination. The solid red line in the figure representing data for the li i l d d i f h h l h h : ne an ma an t e sa iscr mination aster t - . is anima acquire t e nicotine rat shows that t ; When the performance of the discrimination began to drop, on the 20 to 23 day, the nicotine dose .~'n` . Experimental, Design and Procedures (Continued) • : Treatment of Data: In Figure 1 are preliminary data for two of four experimental rats which illustrate nicotine effects on the acquisition of such a. discrimination. On the ordinate'is ' m orm e n e g n was mcrease rom . o. mg . g an e per e i p ~_'S a ' airn b came su erior to ~" al a a c of th d f 0 T t 25 /k d th f ; that of the sal ine rat. d d' i i i l i h di i i i h h i on more ne an ma o acqu m nat e propose exper ment, t e n cot s re t e scr If, in t it may be of interest to determine whafi effect the discontinuance rapidly than the saline controls , of nicotine injections will have on the performance of the discrimination. Possible Results: T. Nicotine treated animals will acquire the discrimination more rapidly than saline controls. 2. Saline controls will acquire the behavior more rapidly than nicotine animals. . There will be no significant differences bet~ • en nicotine and saline animals in the rate of acquisition of the discrimination. • Procedure B: This procedure, developed by this- investigator and colleagues in 1957, is ..currently used extensively in the pharmaceutical industry for the pre-clinical evaluation of the minor tranquilizers (anti-anxiety agents). The behavior involves the learning of an auditory dis- crimi'nation (or visual) based on punishment. The auditory discrimination is condilioned in hungry laboratory animals by simultaneously rewarding! with food and punishing wi.th- mild electric shock all lever responses made in the presence of a discriminative stimulus (tone or light). Appropriate setting of the shock intensity results in suppression of ongoing lever pressing, in the presence of the discriminative stimulus. The intent of this experiment is to investigate the rate of acquisi- tion of such a discrimination in animals administered nicotine chronically. The hungry laboratory animals first learrn to press a lever irrorder to obtain food rewards which are obtainable on the average of once every two, minutes (2 minute VI). When lever pressing rates have stabilized a tone or light stimulus of 3 minute duration is introduced at regular intervals during the lever-pressing session. This stimulus serves as a signal for the animal that all lever responses will be reinforced with food. The discriminative stimulus signals a change from a reLatively undesirable schedule ofi reinforcement (2 minute VI) to a schedule with a higher '"pay-off" of reinforcements (continuous reinforcement). When the behavior has stabilized, a. " 1003546953

~8. Experimental Design and Procedures (Continued) punishment contingency is added so• that, during• the discriminative stimulus,lever pressing is 's:"~; t~.= .d rewarded with food but also produces mild shock to the feet of the animal . The hungry animal must balance the positive aspects.of obtaining food against the negative aspects of accepting ;~r;~electric shocks in order to obtain the food. After a period of time these experimental contin- • s ' ~;;gencies result in a suppression of lever-pressing behavior during stimulus periods. Anti-anxiety raining and•will later be compared with saline controls. . tion in laboratory animals. Animals will be administered nicotine chronically during acquisition .~ • This investigation wil.lt test the effects of nicotine on the acquisition of such a discrimina- agents will reinstate lever pressing behavior that has been suppressed by punishment (11,12,13). ` Possible Results: . Nicotine animals will acquire the punishment discrimination•more rapidly than saline controls. • Saline animabs will acquire the punishment discrimination more rapidly than nicotine animals. • There will be no significant difference between saline and;nicotine animals in acquisition of the punishment discrimination. :....The data from these experiments will show. whether nicotine treated animals will acquire - a discrimination more rapidly than saline controls. They will also show if the findings are similar (d inf-mation nishment riminati ns ba d n ositi d a ll as will fo dis Th i ' p pu . y e r c o se o ve rewar s we ey . - with regard to reproducibiliity of the phenomenon between species. Findings may or may not be :_i_qualitatively similar for rats, squirrel monkeys, and old world monkeys.

REFERENCES. Med. Monthly, 85, 472-484, 1958. Silvette, H., Larson, P. S. and Haag, H. B.: Medical uses of tobacco past and presen Smith, C. S., Rosenfeld, S. and'Sacks, L. J.: Study of the effect of nicotinism in the ` ~ albino rat J Pharmacol . 55 274-287 1935. Kuschinsky, G. and Hotovy, R.: Uber die zentral erregendeWirkung des nicotins. Klin Wschr. 22, 649-650, 1943. . Heimstra, H. W., Grodsky, M. A. and Davis, R. T.: Sanddigging behavior of rats. Proc. S. Dak. Acad. Sci. 34, 96-102, 1955. Cervalo, B. A. and Cheskey, C.: Effects of nicotine sulfate injections on sand digging behavior of rats. Proc. S. Dak. Acad~. Sci. 36, 222-225, 1957. . Bonta, I.L.; Delver, A., Simons, L. and De Vos, C. J.: A newly developed motility apparatus and its applicability in two pharmacological designs. Arch. tnt. Pharmacodyn.. ,:129, 381-394, 1960. central nervous system functions, Pharm. Rev. 14, 137-173, 1962. . Silvette, H., Hoff, E. C., Larson, P. S. and Haag, H. B.: The actions of nicotine on Research Conference and Workshop on Nicotine. Sponsored by AMA and held in Colorado Springs, November 1-3, 1966. . Geller, I., De Marco, A. 0.. and Seifter, J.: Delayed effects of nicotine on timing -behavior in the rat. Science. 131: 1960 ., 10. Westfall, T. C. and Watts, D. T.: The effect.of nicotine on amines of brain and urine in 'the rat. J. of Neurochem. 11, 397-402, 1964. 11. Geller, I. and Seifter, J.: Effects of ineprobamate, barbiturates, d-amphetamine an.d promazine on experimentally induced conflict in the rat. Psychopharmacologia. I, 1960. 12. Geller, I. and Seifter, J.: The effects of monourethanes, diurethanes and barbiturates on a punishment; discrimination. J. Pharmacol . Exptl. Therapeutics. 136, No. 3, 1962. 13. Gell.er, I.: Use of approach avoidance ESehavior (conflict) for evaluating depressant drugs. Chapter 33, in Nodine (ed.), Psychosomatic Medicine, The First Hahnemann Symposium, Lea and Febiger: Philadelphia; 1962. Is 1UU3546955

R: REDACTED MATERIAL . Date. of Birth: •~` Educa"tion: Institution CURRICULUM V'ITAE Irving Geller, Ph. D. : George Washington Univ. B. A. 1949 Pre-med. ... George Washington Univ. M. A. _ 1951 Psychology American University Ph. D. 1957 Psychology ;.Present Position (s): '.Chairrnan- of the Department of Pharmacology, Division of Biological Growth and ~Developrnent, Southwest Foundation for Research and Education. August 1966 -. revious Positions: iation Psychologist - Naval Res. Lab. , Washington, D. C. ; Forbes Air Force Base, : Topeka, Kansas, March 1951-November 1951. 'Research Psychol'ogist - VIWalter Reed Army Inst. of Research, Washington, D. C. .<.::1952-1957. =Ser.ior Research Scientist - Wyeth Labs. Inc. , Radnor, Penna. 1 957'-1964. aAssociate Research Professor of Pharmacology - New York Med;ical College, 1964 - - 1 966. ~:. `_.•=Professiona.l Societies: :: American Psychologi-ca=1 Association "'' h~ew York A'cademy of Science . .r_: ... ~ -:.:Psychonomic Society -'Sigma Xi " American Society for Pharmacology and EXperi•mental Therapeutics.

PUBLICATIONS lrving Geller, Ph. D. ;I . Geller, Irving, M. Sidman and J.:.V. Brady, "The Effects of Electroconvulsive Shock on a Conditioned. EmotionaG Response: A Control for Acquisition, R'ecency, ° J. Comparative and:Physiol. Psychol., Vol,. 48, Nb. 2, 130-131 (1955). . Geller', Irving, and J. Seifter, "The Effects of Promazine and Phenergan on Mulltipfe ' Sched'ule Reinforcement Performance in the Albino Rat," Fed. Proc., Vol. 18, (1959). ,• 3. Geller, lrvin.g, A. O. DeMarco and.J. Seifter, "Delayed Effects of Nicotine on TWing Behavior in the Raty" Science, Vol. 131, No. 3402, 735-737(1960)'. 4. Geller, Irving, and Joseph Seifter, "The Effects of Meprobamate, Barbiturates, d-Amphetamine and Promazine on Experimentally Induced Conflict in the Rat," Psycho- . pharmacologia, 1, 482=492, (1960). --5. Geller, Irving, "The Acquisition tand Extinction of Conditioned Suppression as a Function ; : of the Base-Line Reinforcer," J. Expmntl. Anal. Behavior, Vol. 3, N'o. 3, 235-240 (1960)'. 6. -Geller, Irving, "Behavioral Procedures Used' in Evaluation of the Psychopharmacollogical! Effects of Carphenazine," Diseases of the Nervous System, Supplement, Vol. XXII, No. 2 7. Geiler, Irving, and•J . V. Brady, "Effect of Electroconvulsive Shock on an Extinguished ."Fear" Response," Science, Vol.. 133, No. 3458, 1080-1081 (1961):. 8. Ge ller, Irving, "Use of Approach Avoidance Behavior (Conflict) for Evaluating Depressant Drugs," 1st Hahnemann,Symp. on, Psychosomatic Medicine, Chap. 33, 267-274 (1962). 9. Geller, Irving, J. T. Kulak, Jr. and J. Seifter, "The Effects of Chlordiazepoxide and 7:Chlorpromazine on a Punishment Discrimination," Psychopharmacologia, 3, 374-385, (1962). '10. Geller, Irving, "Experimentally (nduced Conflict for Evaluation of Psychopharmacologic Agents" (A Scientific Exhibit~) (1962)•. 1•1 . Geller, Irving, E. Bachman and J. Seifter, "Effects of Reser.pine and'Morphine on Behavior Suppressed by Punishment," Life Sciences, No. 4, 226-2311 (1963). 12. Geller, Irving and'J. Seifter, "The Effects of Mono-Urethans, Di-Urethans and B'arbiturates on a Punishment Discrimination," J. Pharm!. and Exptl . Therapeutics, Vol. 136, No. 3, 284-288 (1962) (one copy only). 13. 'GeII'er, Irving, "Conriitioned "Anxiety" and: Punishment EfEects on Operant Behavior of Goldf ish (Carassius auratus)." Science, 141, 3578, 351-353 (1.963),. 0 1003 546957.

.0 )Ji •? . ~ . ... .. .. _ „ '...'_. . .cl~r.:'~_. a:r. " ^4h yi 14. DelYlarco, A. O. and (. Geller, "Effects of Acceleration Forces on Timin( Bzhavior in the White Ratt," Aerospace Medicine, Vol. 35, No. 1, 30-32 (1964). .. ~ ~,: , . . . . ' 15. Geiler, Irving, "Relotive Potencies of Benzodiazepines as Measured by Their Effects on ConflIctBehavior, Arch. cnt. Phanmacodyn, 149 , No. 1-2, 243-247(1964). . . . . .,..:. ::~ ;;:16. Geller, Irving, "Conditioned Suppressiora im Goldfish as a Function of Shoclc-Reinforcemen z~ Schedul+eJ. Experimental Analysis of Behavior, Vol . 7, No. 5, 345-349 (1964). y: . Geller, Irving, "Psychopharmacology of tybamate," Journal of Psychopharmocology, ~~ ~ VoL. 1, No. 2; 47-55.(1966). ;. ...:..:*i..a~.-...~:...d..~.~ ...w....~......... -.~...,...........~.s... .._ _.,...~a._..-..... ~ .w n ... _..,. .._ _.n... _a... ....L•,~.+.~c:.-,..~na~J'.r.+c'-`- :.' -- - '~ ,~y,~-SL°-- .....