Reports from the Research Laboratories. of the Department of Psychiatry. Self-Administration of Amphetamine and Cocaine by Rats by ROY PICKENS.

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1 Reports from the Research Laboratories of the Department of Psychiatry SelfAdministration of Amphetamine and Cocaine by Rats by ROY PCKENS and TRAVS THOMPSON MSDf\1\ P5 R311r Report Number PR664 September 3, 1966

2 ! 1 THE LBRARY (!f l j! i MSDM P9.5 qr3llr tlntversity Archives 1 l l ' f t! ' t ' l f

3 H:D1 p <] _; r...,, \ r q :',.5 SelfAdministration of Amphetamine and Cocaine by Rats 1 by Roy Pickens and Travis Thompson September E PR This research was supported in part by research grants ivh18565 and MH11135 from U.S.P.H.S. to t!le University of Minnesota.

4 Abstract Rats were conditioned to intravenouslv selfadminister ' damphetamine or cocaine or fixed ratio reinforcement schedules. hesponse frequency was studied as a function of dosage per infusion (reinforcement magnitude) and the number of responses required per infusion (fixed ratio size). Frequency of selfadministration was found to vary inversely as a function of drug dosage. The frequency of responding varied directly as a function of the value of the fixedratio schedule of amphetamine reinforcement, while the number of infusions per hour remained essentially unchanged.

5 The prolonged selfadministration of drugs by animals has been regarded as an instance of operant conditioning, in whic the drug serves as a reinforcer for the behavior that leads to drug injection. Thus, while such drugs as morphine codeine, cocaine., amphetamine pentobarbital, and ethanol are knon to be selfadministered by animals (Deneau, Yanagita, and Seevers, 1964), only morphine has been used in attempts to systematically determine the factors which influence drug reinforcement (Davis and Nichols, 1962; Thompson and Schuster, 1964; Weeks) 19E2). The present experiment investigates certain reinforcement factors which may influence the selfadministration of amphetamine and cocaine. The effects of magnitude of reinforcement (drug dosage per infusion) on the selfadministration of amphetamine and cocaine, and the effects of the contingencies for drug reinforcement on the selfadministration of amphetamine were determined. These factors were selected for study because they have been shown to affect the selfadministration of morphine (Weeks, 1962), and are known to affect the ntai nterrance o conditioned responses. other operant ly 1

6 Method Subjects The subjects were s1x male albino rats of the Holtzman strain. They were 1218 days old and weighed 351 gm. at the start of the experiment. Five of the subjects were used for amphetamine selfadministration and one subject was used for cocaine selfadministration. Aaratus The apparatus was similar to several that have been developed to permit the intravenous selfadministration of drugs by unrestrained animals (Davis, 1966; Vleeks, 1962). Briefly, it consisted of equipping each subject with a chronic jugular catheter which connected at a shoulder harness to a length of needle tubing that passed out the top of the animal's cage (see Figure 1). The needle tubing was joined to an infusion pump by a swivel and tube arrangement that allowed the animal to move and turn about in the cage. By pressing a lever located on the cage wall, the animal activated the infusion pump and received a 5sec. intravenous injection of.5 cc of drug solution. The animal cage was a standard operant conditioning chamber that had been modified to incorporate the infusion apparatus. 2

7 The cage contained a continuous supply of food and water, and was located 1n a ventilated, soundshielding box. The programming and recording of all experimental events were controlled automatically by electromechanical equipment located in an adjacent room. Frqct=Jdure Following catheterization the subjects were placed in the selfadministration cages where the) lived for the duratic of the experiment, a;,d allowed to develop a stabilized patterr. of responding reinforced by drug infusion. )_\.:ring this time) each lever press delivered a.5 mg/kg infusion of dextroamphetamine sulfate or cocaine hydrochloride in isotonic saline solution. After drug selfadministrations had stabilized, the magnitude of reinforcement {infusion dosage of drug) or the number of responses required to receive reinforcement was varied for each animal. The value of drug dosage ranged from.25 to 1. mg/kg/infusion for damphetamine, and from.25 to 1.5 mg/kg/infusion for cocaine. The schedule of drug reinforcemen which was varied for damphetamine only, 3

8 ranged from a fixedratio one to a fixedratio 3 schedule of reinforcement. That is from one response per infusion, to 3 responses per infusion. Results and Discussion A stable pattern of drug selfadministration developed for both amphetamine and cocaine within 13 days after the subjects were placed in the infusion cages. Throughout the experiment, periods of responding for drug infusion alternate with periods of no responding. The length of the responding and noresponding periods was 2472 hrs. and 124 hrs. for amphetamine, and 1248 hrs. and 118 hrs. for cocaire, respectively. The length of a given period did not seem to be related to the length of the preceding period or to the drug dosage. t was noted that during a noresponding period a period of responding could be initiated by "priming" the animals with a single drug injection. The effects of magnitude of reinforcement (drug dosage per infusion) on the frequency and patterning of drug selfadministrations are shown for amphetamine in Figures 27, 4

9 and for cocaine 1n Figures 8 and 9. These data are summarized in Table 1. As can be seen, decreases in drug dosage are associated with increases in selfadministrations and increases in dosage are associated with decreases in selfadministrations. Thus, for each subject about the same total amount of drug was taken at all dosages. The mean drug intake was.54 mg/kg/hour for the amphetamine animals and 4.8 mg/kg/hour for the cocaine animals. lhe effects of varying the value of the schedule of amphetamine reinforcement on response frequency and number of reinforcements are shown 1n Figures 115 and summarized in Table 2. When the value of a fixedratio schedule of drug reinforcement was increased, response frequency increased accordingly and the number of drug reinforcements per hour remained about the same. The mean amphetamine intake over all fixedratio values was.52 mg/kg/hour. The finding of an inverse relationship between frequency of drug selfadministration and drug dosage, and a direct relationship between the frequency of responding for selfadministration and value of fixedratio schedule of reinforcement) is in accord other work involving morphine selfadministration (vveeks 1962). 5

10 References Davis, J. D. A method for chronic intravenous infusion in freely moving rats. J. exp. Anal, Behav , ' Davis, W , and Nichols.; J. R. Physical dependence and sustained opiatedirected behavior in the rat. A preliminary report. Psychopharmaco 1oe ia, 1962,,a, Deneau, G. A., Yanagita, T., and Seevers, M. H. Psychogenic dependence to a variety of drugs in the monkey. Pharmacologist, 1964, b, 182. Thompson, T.., and Schuster, C. R. Morphine selfadministration) foodreinforced and avoidance behaviors in hesus monkeys. Psychopharmacologia, 1964,!!, Weeks, J. R. Experimental morphine addiction: Method for automatic intravenous injections in unrestrained rats. Science, 1962, 138,

11 TABLE 1 Effects of Magnitude of Reinforcement (Drug Dosage per nfusion) on Amphetamine and Cocaine SelfAdministration. AMPHETAMNE COCANE Rat #5 Rat #7 Rat #12 Rat #2J mg/kg Drug Responses mg/kg Responses mg/kg Responses mg/kg Per Hour Drug Per Hour Drug Per Hour Drug Responses Per Hour

12 TABLE 2 Effects of ntermittency of Reinforcement on Response Rate and,nfusion F.ate of Amphetamine SelfAdministration Rat #4 Rat #7 Rat #8 FixedRatio Schedule Kesponses Per Hour.5 mg/kg FixedRatio Responses.5 mg/kg FixedRatio nfusions Schedule Per Hour nfusions Schedule Fer Hour Fer Hour Responses Per Hour.25 mg/kg nfusions Per Hour i l.o

14 ' ::J :r: ' en en c a. en a: Rat #5 FR Mg Kg nfusion Amphetamine

15 QJ E Qj E. E <( ::::s QJ ' QJ a.. L(). L() 1'. L() (\J ' ::::s

16 \.. ::l 2.5 ' :r: 2. ' ' (1) (J') c 1.5 a.. a:: 1. g Rat# 7 FR 1l Mg Kg nfusion Am ph eta mine

17 E....s:::.. E <(... ::s... OJ (f)... "... CL 1' a:: l() N. 1 f;; " ::s :r: C\J l().

18 3. Rat # 12 FR \,... ::3 :t: ' c a. a:: 2. *)< >9< c 1..5» ;< '><' X < )< ;< x 1>.375 v ><x ) )'. '),, :> ><'>&.25 X X!.5 Mg/ Kg nfusion Amphetamine

20 Rat # 2 12 '") 1 FR l :J ' en (./) :J " Mg Kg nfusion Cocaine.5

21 (\j L() :: c u r... C/) c C/) C/) ::3 ::3... c c... (f)... C/) c " a_ L() ld LO q L() (\j UO!SnJU 1 1 f>>t 1 DV\1

22 Rat #4 5 :'l ' './), Q. en,,a:::.,(1) 4 3 r 2 1 X X X (</ y.'/ X;<;, X > y< )( )< )< y< X ) Q< ) y y<.>< $g )<')(< ><Xc y )c )C!)(< XXc '><x ><.><X(')( 9<V FR FR 5 FR FR 2 FR 3 Schedule of Amphetamine Reinforcement

23 ' 2. Rat #4 :::J.. "...,C (J) ::).. c ' , '. FR FR 5 FR 1 FR 2 FR 3 Schedule of Reinforcement (.5 Mg/ Kg/ nfusion) Am ph eta mine

24 :::3.. ' (1) Q. tj) :: c OJ Rat # 7 ::E FR FR 2 FR 3 FR 5 ' Schedule of Reinforc ement Amphetamine

25 . 5 Rat # 7 ; CJ) ::l 1. "'t. 5 ' o ' FR FR 2 FR 3 FR 5 Schedule of Reinforcement (. 5 Mg /Kg nfusion) Amphetamine

26 : \... :s,j: ' en tf') c '.. rcn i lo:: j 1 5 Rat # 8.c FR FR 2 FR 3 FR 5 Schedule of Reinforcement Am ph eta mine

27 .""'; < 1 () :c ' ' i :J "+ QJ Rat # 8..,! FR FR 2 FR 3 FR 5 Schedule of Reinforcement (.25 Mg/ Ka/ nfusion) Amphetamine

ASSOCIATED WITH NALORPHINE IN

JOURNAL OF THE EXPERIMENTAL ANALYSIS OF BEHAVIOR CONDITIONED SUPPRESSION BY A STIMULUS ASSOCIATED WITH NALORPHINE IN MORPHINE-DEPENDENT MONKEYS1 STEVEN R. GOLDBERG AND CHARLES R. SCHUSTER UNIVERSITY OF