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Effects of antipsychotic compounds in rhesus monkeys given a choice between cocaine and food
Drug and Alcohol Dependence, 8 (1981) 69 0 Elsevier Sequoia S.A., Lausanne - Printed
- 78
69
in The Netherlands
EFFECTS OF ANTIPSYCHOTIC COMPOUNDS IN RHESUS MONKEYS GIVEN A CHOICE BETWEEN COCAINE AND FOOD
WILLIAM Department University, (Received
L. WOOLVERTON*
and ROBERT
of Pharmacology, Medical College Richmond, VA 23298 (U.S.A.)
L. BALSTER of
Virginia,
Virginia
Commonwealth
May 20, 1981)
Summary Chlorpromazine (CPZ) and haloperidol (H) have been suggested as possible antagonists of the reinforcing effects of psychomotor stimulant drugs. To test this hypothesis in animals, four rhesus monkeys were trained in a preference procedure to choose between intravenous injections of cocaine or food presentation. Frequency of cocaine choice increased as unit dose of cocaine was increased. Continuous infusions of low or intermediate doses of CPZ or H either did not affect or increased the frequency of cocaine choice. Higher doses of CPZ or H completely suppressed responding for both reinforcers. Although there appears to be a mutual antagonism of some of the effects of cocaine and these antipsychotic compounds, the results of the present experiment fail to support the hypothesis that the reinforcing effects of cocaine can be antagonized with CPZ or H.
Introduction The ability of many psychomotor stimulants to function as positive reinforcers clearly plays a major role in the initiation and maintenance of selfadministration and consequent toxicity when intake is excessive. Thus, the ability to reduce or block the reinforcing effects of a stimulant would seem useful in the treatment of abuse. To this end, a number of investigators have determined the effects of several antipsychotic compounds in animals allowed to respond for intravenous injections of a psychomotor stimulant, since these compounds block the biogenic amine receptors that are believed by many to mediate stimulant reinforcement. Pharmacologically, the effect of an antagonist on stimulant-maintained responding should be analogous to a reduction in the unit dose of the drug and should, therefore, result in an increased rate
*Present Physiological
address: Sciences,
University of Chicago, Department of Pharmacological 947 E. 58th Street, Chicago, IL 60637, U.S.A.
and
of responding for the drug under schedule conditions in which this is possible. Indeed, this has been found to be the case with catecholaminergic receptor blockers in rats [I] and monkeys [Z - 41 allowed to self-administer central nervous system stimulants under a variety of conditions. That this effect is specific to psychomotor stimulants as reinforcers is supported by the observations that response rates only decreased following injections of antipsychotic compounds when responding was maintained by food [ 4, 51 or pentobarbital [ 2 1. Moreover, antipsychotic compounds have been found to interfere with the ability of dopaminergic agonists to establish other environmental stimuli as conditioned positive reinforcers [6]. Thus, there is considerable evidence to suggest that antipsychotic compounds can alter the reinforcing properties of psychomotor stimulants. The use of response rate as a quantitative measure of reinforcing efficacy, as was the case with the studies cited above, presents problems of interpretation. These problems arise from the fact that under simple schedules of drug presentation, the rate of responding for a psychomotor stimulant is only partially determined by its reinforcing efficacy. Intravenously delivered drugs have at least two effects on ongoing behavior that may be opposite in direction. As a reinforcing event, drug delivery tends to increase the probability of the response that preceded it. However, drug delivery may also decrease ongoing responding by virtue of non-specific rate-decreasing effects. Thus, the response rate increases obtained in animals responding on simple schedules for intravenous psychomotor stimulants may be the result of antagonism of the effects of the drug that tend to decrease behavior and may be independent of any changes in the reinforcing efficacy of the drug. Indeed. in a recent series of experiments, Woods et al. [ 41, and Herling and Woods [ 51 have interpreted rate increases for cocaine reinforcement following pretreatments with chlorpromazine (CPZ) or haloperidol (H) as representing a mutual antagonism of the rate-decreasing effects of either drug by the other. These experiments provided little support for the notion of antagonism of the reinforcing properties of psychomotor stimulants by antipsychotic compounds. Furthermore, the possibility that an increase in rate of responding for psychomotor stimulants represents a general tendency of antipsychotic compounds to increase low rate responding regardless of the reinforcing event (i.e., the effects are rate-dependent) should be considered [7 - 91. Because of the limitations of response rate as a measure of relative reinforcing efficacy, procedures have been developed to evaluate drug selfadministration under conditions which minimize or eliminate the nonspecific, rate-decreasing effects of a drug [ 10 - 121. The important procedural variables in evaluating relative reinforcing efficacy of drugs seem to be: (1) to allow sufficient time between injections for the rate-modifying effects of the drug to dissipate, and/or (2) to allow drug self-administration to occur in an environment in which alternative reinforcers are available to the animal. Data collected to date using these procedures suggest that it is possible to directly evaluate changes in reinforcing efficacy (e.g., dose changes) without the confounding influences of multiple drug effects on response rate. With
these considerations in mind, we have tested CPZ and H as possible antagonists of the reinforcing properties of cocaine in monkeys given a choice between cocaine and food. Neither antipsychotic compound was effective in decreasing the reinforcing efficacy of cocaine, and each increased the frequency of cocaine choice in some instances.
Methods Animals
and apparatus
The animals were four adult male rhesus monkeys (#3015, 3142, 7233, 7234) that weighed between 6.4 and 10.3 kg at the beginning of the experiment. Each was fitted with a stainless steel restraint harness and spring arm which was attached to the rear of the experimental cubicles [13]. The animals lived in the experimental cubicles (96 cm deep X 86 cm high X 81 cm wide) 24 hours per day for the duration of the experiment. Water was continuously available and each monkey received 100 g of Purina Monkey Chow and a chewable multiple vitamin tablet each day beginning on the first day of training. On the front of the cubicle two response levers were mounted on the transparent Plexiglas door 20 cm above the floor with a food dish mounted between them, and three jewelled stimulus lights above each lever. Peristaltic infusion pumps (Cole-Palmer Co ., Chicago, IL) delivered cocaine injections and an automatic syringe pump (Sage Instruments, Cambridge, MA) delivered infusions of CPZ or H via a double lumen intravenous catheter made of polyvinyl chloride (U.S. Catheter, Itasca, IL). An automatic pellet feeder (BRS/LVE, Beltsville, MD) delivered 1 g food pellets (P. J. Noyes Co., Lancaster, NH). Stimulus events and data collection were controlled by solid state programming and recording equipment located in an adjacent room. Procedure
The choice procedure was similar to the one described previously Initially, the animals were food deprived and conditioned to press the right lever for food delivery in the presence of the right lever stimulus lights. One lever press resulted in the delivery of one food pellet. After responding was established on the right lever, the animals were conditioned to press the left lever in the presence of the left lever lights to illuminate the right lever lights. The response requirement on the right lever was gradually increased to 32 responses for the delivery of one food pellet (Fixed Ratio 32: FR 32). Following establishment of this response chain, each animal was removed from the cubicle and surgically prepared with an intravenous double lumen catheter. The catheter was placed in one of the major veins (internal or external jugular or femoral) with the proximal tip at or near the level of the right atrium, anchored in muscle tissue adjacent to the vein, and the distal end threaded subcutaneously to an exit wound between the scapulae. The animal was returned to the cubicle. The catheter was threaded out from the spring arm, and connected to the drug pumps. [ 10,141.
72
The next day, training on the terminal contingencies was begun. Every 15 minutes, 32 times a day, the lights came on above the left lever and, simultaneously, a red or green light was illuminated above the right lever. Four consecutive responses (FR 4) on the left lever switched the color on the right lever (from red to green or green to red). After at least three color changes (to insure that the animal was exposed to each option on every trial), the first response on the right lever turned off the lights above the left lever and ‘locked’ in the choice of reinforcement conditions. Responses on the right lever before completion of the required number of switches reset the switching contingency so that a minimum of three additional switches were required. Responses on the left lever after a choice had been locked in had no consequence. Thirty-one additional responses on the right lever (FR 32) resulted in the delivery of either a drug infusion or two 1 g food pellets, depending on the color of the stimulus light locked in above the right lever. If these 31 responses were not completed in 5 minutes (limited hold) a new trial was initiated. One color light was associated with drug delivery, the other with food delivery. These stimulus conditions could be reversed when an animal showed a preference for one reinforcer or the other, to ensure that the animal had a reinforcer preference and not a color preference. Initial choice behavior was determined with saline and unit doses of cocaine that ranged between 50 and 300 gg/kg per injection, tested in an irregular order. Physiological saline was infused continuously via the syringe pump through the second lumen of the catheter during this period. Following establishment of stable behavior with 100 pg/kg per injection cocaine as the drug alternative, infusions of CPZ or H were begun through the second lumen of the double lumen catheter. Infusions continued 24 hours per day for 6 10 days until one of three conditions was obtained: (1) the test compound (CPZ or H) had no effect or no trends were seen; (2) the test compound altered drug preference; or (3) severe Parkinsonian symptoms developed and/ or responding was suppressed for both reinforcers. If the test compound had no effect, the dose was doubled until drug preference was altered or Parkinsonian symptoms resulted. If choice behavior was altered, stimulus lights were reversed to assure that a reinforcer preference rather than a color preference had developed. If Parkinsonian symptoms resulted or behavior was suppressed, the dose of the test compound was reduced and light stimuli were reversed. Thus, the effects of doses up to and including the highest dose of antipsychotic compound that did not produce Parkinsonian symptoms or totally suppress responding were determined in each animal. In summary, animals were allowed to self-administer cocaine through one lumen of a double lumen intravenous catheter while an antipsychotic compound was continuously infused through the second lumen. In this way it was hoped to test for partial or complete antagonism of the reinforcing properties of cocaine by CPZ or H. Partial antagonism of cocaine might result in choice behavior similar to that observed when a lower dose of cocaine was the drug alternative. Complete antagonism should result in choice behavior like that observed when saline was the drug alternative.
13
Data analysis
The results were graphed for the total number of injections chosen out of the 32 choices per day. In addition, since occasionally animals did not complete all 32 trials, the total number of trials completed per session was plotted. Results are presented individually for each of the four subjects. If an animal chose cocaine on at least 24 trials per day (2 75%), it was considered a drug preference. On the other hand, if the animal chose the cocaine alternative 8 or less times a day (< 25X), it was considered a food preference. Data were collected for several other measures of performance (e.g. number of switches and inappropriate responding). Since neither cocaine nor CPZ nor H had any effect on these measures, their analysis was omitted.
Results Dose-response relationships for cocaine and choice behavior are shown in Fig. 1. Given a c.hoice between an injection of saline or food presentation, all animals clearly preferred the food alternative. As the unit dose of cocaine was increased, the frequency of cocaine choice increased in all four animals. Thus, the relative frequency of drug self-administration was a direct function of unit dose under these conditions. The animals differed slightly in their sensitivities to the reinforcing properties of cocaine. For two animals (7233 and 7234) 100 pg/kg per injection cocaine was preferred to food on more than 90% of the trials. However, in the other two animals it was necessary to increase the unit dose of cocaine to 300 - 500 pg/kg per injection to see this level of cocaine preference. The effects of continuous infusions of CPZ on choice between cocaine (100 /*g/kg per injection) and food are shown in Fig. 2. Chlorpromazine affected behavior differently in the two animals that showed no preference between cocaine and food. In monkey 3015, CPZ had no effect on responding until responding for either reinforcer was completely suppressed at a dose of 4.0 mg/kg per day. On the other hand, monkey 3142 developed a preference for cocaine at this dose of CPZ. When the stimulus lights were reversed, this monkey died during the first session. In the two animals that preferred 100 pg/kg per injection cocaine to food, CPZ (1.0 - 4.0 mg/kg per day) had no effect on choice behavior. At a high enough dose (8.0 mg/kg per day) responding for both reinforcers was suppressed after a stimulus reversal in monkey 7233. Monkey 7234 completed the first session at this dose of CPZ but was found prostrate the following morning. These effects of CPZ could be immediately and dramatically reversed by intravenous (i.v.) infusion of 0.4 mg/kg cocaine. However, infusion of this dose of CPZ was stopped because of concern for the health of the animal. The effects of continuous infusion of various doses of H on choice between cocaine and food are shown in Fig. 3. In monkey 7233, doses of H between 25 and 400 pg/kg per day had no effect on choice behavior. The infusion of 400 E.cg/kgper day was stopped after seven sessions because the
MONK
MONK
3015
MONK 0
3142 c-----a
7233
28 24 -
6
g
32_
32-
MONK 0
2824 2016 12 ES-
k
IOE3b0 COCAINE
k
/ 50
I 100
1
300
( rG/KG/INJ)
Fig. 1. Frequency of saline (S) or cocaine choice when food was the alternative for four rhesus monkeys. Ordinate : number of trials on which cocaine was chosen (0) and the total number of trials completed (0). Abscissa: unit dose of cocaine. For each dose at which a clear preference was seen (< 8 or > 24 injections) light stimuli were reversed and the data for the last three sessions in each condition were averaged (six sessions total). Where no preference was found, each point represents the last three sessions in that condition with no stimulus reversal. Vertical lines represent the range.
animal had stopped eating. In monkey 7234,25 and 50 pg/kg per day H did not alter choice behavior. During the first session of infusion with 100 pg/kg per day H, the animal chose cocaine on 16 of 18 completed trials. As with the highest dose of CPZ, this animal was found prostrate following the first session of 100 pg/kg per day H, and this effect could be reversed with 0.4 mg/kg cocaine (i.v.). The infusion of this dose of H was also discontinued out of concern for the animal. In contrast, monkey 3015 initially had no preference between 100 pg/kg per injection cocaine and food, and infusion of 25 pg/kg per day H failed to alter choice (Figs. 3 and 4). Increasing the dose of H to 50 pg/kg per day increased the frequency of cocaine choice but, when the light stimuli were reversed, virtually all responding was suppressed. Following a period of saline infusion to allow the effects of H to dissipate, the infusion of 50 pg/kg per day H was reinstated and the original effect gradually disappeared. However, when the dose of H was increased to 100 pg/kg per day, the preference for cocaine returned and persisted after a stimulus reversal. The 6 - 7 sessions required to reverse color choice was typical for this animal under conditions of a cocaine preference without H. When the dose of H was increased to 200 gg/kg per day, muscle rigidity developed and the animal was unable to respond. Following a two week period with no drug owing to a catheter failure, the catheter was replaced and choice behavior
75 MONK
3015
MONK
7233
12 a4-
4-
o-
O5
m-1 IO
20
I. I s IO
40
CHLORPROMAZINE
20
(MG/KGIDAYl
40
80
I
2Fz& HALOPERIDOt
( rG/KG/DAY)
Fig. 2. Frequency of cocaine choice when saline (S) or various doses of chlorpromazine were infused continuously, 24 h/day. The unit dose of cocaine was 100 ,ug/kg per injection in all cases. *CPZ infusion was stopped owing to either gross intoxication or the appearance of Parkinsonian symptoms. Other details are the same as in Fig. 1. Fig. 3. Frequency of cocaine choice when saline (S) or various doses of haloperidol were infused continuously 24 h/day. Other details are as in Figs.. 1 and 2. MONK
3015
Fig. 4. Frequency of cocaine (100 pg/kg per injection) choice by monkey 3015 on daily sessions with continuous infusions of saline or haloperidol (H). Doses of H are expressed in pg/kg per day. Rev indicates stimulus reversals. Other details are as in Fig. 1.
76
for 100 pg/kg per injection cocaine was reestablished at the original level with a continuous saline infusion. The effect of 100 pg/kg per day H was then redetermined with results that were identical to those found in the first determination. When H was subsequently removed, frequency of cocaine choice declined to the original level (Fig. 4).
Discussion The data from the present experiment confirm and extend the findings of others that drug self-administration can be analysed in the context of a multi-operant environment, i.e., one in which alternative reinforcers are available to the organism [ 12,14,15]. As compared to simpler schedules of drug availability, this complex procedure has several virtues. Behaviorally, the multi-operant environment is probably a better reflection of the human situation, since for humans, drug self-administration can often alter availability of other reinforcers. By allowing animals to choose between cocaine and food, it was possible to make a direct comparison between the reinforcing efficacy of various doses of cocaine and a well-known and efficacious reinforcer, food. Pharmacologically, the procedure provides a measure of relative reinforcing efficacy (drug choice) that is a monotonic function of drug dose and which is relatively free of other drug effects that might alter intake. Specifically, the influence of rate-modifying effects of cocaine on intake was eliminated by allowing these effects to dissipate between trials. This procedural modification is particularly useful in an antagonism study as a way to eliminate antagonism of rate-modifying effects as an explanation of changes in cocaine self-administration. Manipulations that decrease the relative reinforcing efficacy of cocaine (or, conversely, increase the relative reinforcing efficacy of food) should be analogous to a reduction in the unit dose of cocaine and should result in relatively fewer cocaine choices. If, as has been postulated, the reinforcing properties of cocaine are mediated by changes in catecholamine metabolism, there should be many ways to alter this effect. Our approach was one of using drugs that block the receptors that are reputed to mediate cocaine reinforcement. Surprisingly, the results failed to support the hypothesis that the catecholaminergic receptor blockers CPZ and H can reduce the reinforcing efficacy of cocaine. In animals that chose cocaine on over 90% of the available trials, CPZ and H did not affect responding until doses high enough to suppress all responding were achieved. Moreover, the compounds increased the frequency of cocaine choice in two of the three cases where this effect was possible. Thus, the implication of this experiment is that in rhesus monkeys CPZ and H either do not affect or actually increase the relative reinforcing efficacy of cocaine. These results are similar to those of Griffiths et al. [ 111 who found increases in heroin choices in baboons infused with a narcotic antagonist. The two experiments are not entirely analogous since the baboons in Griffiths’ study
were physically dependent on heroin and the antagonist undoubtedly increased the reinforcing efficacy of heroin in relieving withdrawal symptoms. However, since CPZ and H have been shown to be negative reinforcers in the rhesus monkey [ 16, 171, it is possible that the reinforcing efficacy of cocaine was increased to the extent that it could relieve the aversive effects of these two antipsychotic compounds. Be that as it may, in no case did CPZ or H decrease the relative reinforcing efficacy of cocaine. Considered together with the findings of others [ 2 - 41, the present experiment does not eliminate the possibility that CPZ and H do not antagonize the ratedecreasing effects of cocaine since there is no measure of this effect in the present experiment. It should be noted that on several occasions, severe sedative effects of high doses of CPZ or H could be immediately and dramatically reversed by infusion of 0.4 mg/kg cocaine. At high doses of either antipsychotic compound responding was frequently completely suppressed following a stimulus reversal when, or perhaps because, cocaine intake was low. Indeed, one animal (3124) died in just such a situation at a dose of CPZ that was well tolerated when cocaine intake was high. Thus, it seems that cocaine can reverse some of the effects of antipsychotic compounds. These results are generally consistent with the hypothesis of Woods et al. [4] and Herling and Woods [ 51 of a mutual antagonism of the rate-decreasing effects of cocaine and antipsychotic compounds with little evidence for antagonism of the reinforcing properties of cocaine in the rhesus monkey. This is in contrast to the data available in rats where several experimenters have presented evidence in support of antagonism of the reinforcing properties of psychomotor stimulants by catecholaminergic blockers [ 1, 61. It remains for future research to establish the generality of these phenomena in other species, including humans. Over the past 20 years, considerable research has established the remarkable correlation between drugs that will be self-administered by rhesus monkeys and those which are likely to be abused by humans [ 18 - 201. The dose range of cocaine that is reliably preferred to food in the rhesus monkey (100 - 300 pg/kg per injection) is comparable to the dose range that produced verbal reports of pleasant effects when delivered intravenously to humans [ 211. In addition, the range of doses of CPZ and H that were tested in monkeys covers the dose range that is recommended for use in humans 1221. To the extent that the rhesus monkey is a reliable model for the effects of these drugs in humans, the finding, that the frequency of choice of cocaine relative to another reinforcer never decreased and occasionally increased, suggests that the use of antipsychotic compounds in the treatment of psychomotor stimulant abuse should be considered with caution. Acknowledgements This research was supported and DA 01442 (R.L.B.).
by N.I.D.A.
Grants DA 05164 (W.L.W.)
78
References 1 H. Dewit and R. A. Wise, Can. J. Psychol., 31 (1977) 195. 2 C. E. Johanson, D. A. Kandel and K. Bonese, Pharmacol. Biochem. Behau., 4 (1976) 427. 3 M. C. Wilson and C. R. Schuster, Psychopharmocologia, 26 (1972) 115. 4 J. H. Woods, S. Herling and G. Winger, in P. Deniker, C. Radouco-Thomas and A. Villenauve (eds.), Neuro-Psychopharmacology, Pergamon Press, New York, 1978, p. 1485. 5 S. Herling and J. H. Woods, J. Pharmacol. Exp. Ther., 214 (1980) 354. 6 W.M. Davis and S. G. Smith, Life Sci., 20 (1977) 483. 7 R. T. Kelleher and W. H. Morse, Ergeb. PhysioZ., 60 (1968) 1. 8 J. D. Leander and D. E. McMillan, J. Pharmacol. Exp. Ther., 188 (1974) 726. 9 M. J. Marr, J. Exp. Anal. Behau., 13 (1970) 291. 10 T. Aigner and R. L. Balster, Science, 201 (1978) 534. 11 R. R. Griffiths, R. M. Wurster and J. V. Brady,Pharm. Rev., 27 (1976) 357. 12 C. E. Johanson and C. R. Schuster, J. Pharmacol. Exp. Ther., 193 (1975) 676. 13 G. A. Deneau, T. Yanagita and M. H. Seevers, Psychopharmacologia, 16 (1969) 30. 14 W. L. Woolverton and R. L. Balster, Comm. Psychopharm., 3 (1979) 309. 15 J. D. Findley, W. W. Robinson and L. Peregrino, Psychopharmacologia, 26 (1972) 93. 16 F. Hoffmeister, J. Pharmacol. Exp. Ther., 200 (1977) 516. 17 F. Hoffmeister and W. Wuttke, Pharm. Rev., 27 (1976) 419. 18 R. R. Griffiths and R. L. Balster, Clin. Pharmacol. Ther., 25 (1979) 611. 19 C. E. Johanson and R. L. Balster, Bull. Narc., 30 (1978) 43. 20 C. R. Schuster, Pharm. Reu., 27 (1976) 511. 21 M. W. Fischman, C. R. Schuster, L. Resnekov, J. F. E. Schick, N. A. Krasnegor, W. Fennel1 and D. X. Freedman, Arch. Gen. Psychiat., 33 (1976) 983. 22 R. J. Baldessarini, in A. G. Gilman, L. S. Goodman and A. Gilman (eds.), The Pharmacological Basis of Therapeutics, MacMillan, New York, 1980, p. 391.
- 78
69
in The Netherlands
EFFECTS OF ANTIPSYCHOTIC COMPOUNDS IN RHESUS MONKEYS GIVEN A CHOICE BETWEEN COCAINE AND FOOD
WILLIAM Department University, (Received
L. WOOLVERTON*
and ROBERT
of Pharmacology, Medical College Richmond, VA 23298 (U.S.A.)
L. BALSTER of
Virginia,
Virginia
Commonwealth
May 20, 1981)
Summary Chlorpromazine (CPZ) and haloperidol (H) have been suggested as possible antagonists of the reinforcing effects of psychomotor stimulant drugs. To test this hypothesis in animals, four rhesus monkeys were trained in a preference procedure to choose between intravenous injections of cocaine or food presentation. Frequency of cocaine choice increased as unit dose of cocaine was increased. Continuous infusions of low or intermediate doses of CPZ or H either did not affect or increased the frequency of cocaine choice. Higher doses of CPZ or H completely suppressed responding for both reinforcers. Although there appears to be a mutual antagonism of some of the effects of cocaine and these antipsychotic compounds, the results of the present experiment fail to support the hypothesis that the reinforcing effects of cocaine can be antagonized with CPZ or H.
Introduction The ability of many psychomotor stimulants to function as positive reinforcers clearly plays a major role in the initiation and maintenance of selfadministration and consequent toxicity when intake is excessive. Thus, the ability to reduce or block the reinforcing effects of a stimulant would seem useful in the treatment of abuse. To this end, a number of investigators have determined the effects of several antipsychotic compounds in animals allowed to respond for intravenous injections of a psychomotor stimulant, since these compounds block the biogenic amine receptors that are believed by many to mediate stimulant reinforcement. Pharmacologically, the effect of an antagonist on stimulant-maintained responding should be analogous to a reduction in the unit dose of the drug and should, therefore, result in an increased rate
*Present Physiological
address: Sciences,
University of Chicago, Department of Pharmacological 947 E. 58th Street, Chicago, IL 60637, U.S.A.
and
of responding for the drug under schedule conditions in which this is possible. Indeed, this has been found to be the case with catecholaminergic receptor blockers in rats [I] and monkeys [Z - 41 allowed to self-administer central nervous system stimulants under a variety of conditions. That this effect is specific to psychomotor stimulants as reinforcers is supported by the observations that response rates only decreased following injections of antipsychotic compounds when responding was maintained by food [ 4, 51 or pentobarbital [ 2 1. Moreover, antipsychotic compounds have been found to interfere with the ability of dopaminergic agonists to establish other environmental stimuli as conditioned positive reinforcers [6]. Thus, there is considerable evidence to suggest that antipsychotic compounds can alter the reinforcing properties of psychomotor stimulants. The use of response rate as a quantitative measure of reinforcing efficacy, as was the case with the studies cited above, presents problems of interpretation. These problems arise from the fact that under simple schedules of drug presentation, the rate of responding for a psychomotor stimulant is only partially determined by its reinforcing efficacy. Intravenously delivered drugs have at least two effects on ongoing behavior that may be opposite in direction. As a reinforcing event, drug delivery tends to increase the probability of the response that preceded it. However, drug delivery may also decrease ongoing responding by virtue of non-specific rate-decreasing effects. Thus, the response rate increases obtained in animals responding on simple schedules for intravenous psychomotor stimulants may be the result of antagonism of the effects of the drug that tend to decrease behavior and may be independent of any changes in the reinforcing efficacy of the drug. Indeed. in a recent series of experiments, Woods et al. [ 41, and Herling and Woods [ 51 have interpreted rate increases for cocaine reinforcement following pretreatments with chlorpromazine (CPZ) or haloperidol (H) as representing a mutual antagonism of the rate-decreasing effects of either drug by the other. These experiments provided little support for the notion of antagonism of the reinforcing properties of psychomotor stimulants by antipsychotic compounds. Furthermore, the possibility that an increase in rate of responding for psychomotor stimulants represents a general tendency of antipsychotic compounds to increase low rate responding regardless of the reinforcing event (i.e., the effects are rate-dependent) should be considered [7 - 91. Because of the limitations of response rate as a measure of relative reinforcing efficacy, procedures have been developed to evaluate drug selfadministration under conditions which minimize or eliminate the nonspecific, rate-decreasing effects of a drug [ 10 - 121. The important procedural variables in evaluating relative reinforcing efficacy of drugs seem to be: (1) to allow sufficient time between injections for the rate-modifying effects of the drug to dissipate, and/or (2) to allow drug self-administration to occur in an environment in which alternative reinforcers are available to the animal. Data collected to date using these procedures suggest that it is possible to directly evaluate changes in reinforcing efficacy (e.g., dose changes) without the confounding influences of multiple drug effects on response rate. With
these considerations in mind, we have tested CPZ and H as possible antagonists of the reinforcing properties of cocaine in monkeys given a choice between cocaine and food. Neither antipsychotic compound was effective in decreasing the reinforcing efficacy of cocaine, and each increased the frequency of cocaine choice in some instances.
Methods Animals
and apparatus
The animals were four adult male rhesus monkeys (#3015, 3142, 7233, 7234) that weighed between 6.4 and 10.3 kg at the beginning of the experiment. Each was fitted with a stainless steel restraint harness and spring arm which was attached to the rear of the experimental cubicles [13]. The animals lived in the experimental cubicles (96 cm deep X 86 cm high X 81 cm wide) 24 hours per day for the duration of the experiment. Water was continuously available and each monkey received 100 g of Purina Monkey Chow and a chewable multiple vitamin tablet each day beginning on the first day of training. On the front of the cubicle two response levers were mounted on the transparent Plexiglas door 20 cm above the floor with a food dish mounted between them, and three jewelled stimulus lights above each lever. Peristaltic infusion pumps (Cole-Palmer Co ., Chicago, IL) delivered cocaine injections and an automatic syringe pump (Sage Instruments, Cambridge, MA) delivered infusions of CPZ or H via a double lumen intravenous catheter made of polyvinyl chloride (U.S. Catheter, Itasca, IL). An automatic pellet feeder (BRS/LVE, Beltsville, MD) delivered 1 g food pellets (P. J. Noyes Co., Lancaster, NH). Stimulus events and data collection were controlled by solid state programming and recording equipment located in an adjacent room. Procedure
The choice procedure was similar to the one described previously Initially, the animals were food deprived and conditioned to press the right lever for food delivery in the presence of the right lever stimulus lights. One lever press resulted in the delivery of one food pellet. After responding was established on the right lever, the animals were conditioned to press the left lever in the presence of the left lever lights to illuminate the right lever lights. The response requirement on the right lever was gradually increased to 32 responses for the delivery of one food pellet (Fixed Ratio 32: FR 32). Following establishment of this response chain, each animal was removed from the cubicle and surgically prepared with an intravenous double lumen catheter. The catheter was placed in one of the major veins (internal or external jugular or femoral) with the proximal tip at or near the level of the right atrium, anchored in muscle tissue adjacent to the vein, and the distal end threaded subcutaneously to an exit wound between the scapulae. The animal was returned to the cubicle. The catheter was threaded out from the spring arm, and connected to the drug pumps. [ 10,141.
72
The next day, training on the terminal contingencies was begun. Every 15 minutes, 32 times a day, the lights came on above the left lever and, simultaneously, a red or green light was illuminated above the right lever. Four consecutive responses (FR 4) on the left lever switched the color on the right lever (from red to green or green to red). After at least three color changes (to insure that the animal was exposed to each option on every trial), the first response on the right lever turned off the lights above the left lever and ‘locked’ in the choice of reinforcement conditions. Responses on the right lever before completion of the required number of switches reset the switching contingency so that a minimum of three additional switches were required. Responses on the left lever after a choice had been locked in had no consequence. Thirty-one additional responses on the right lever (FR 32) resulted in the delivery of either a drug infusion or two 1 g food pellets, depending on the color of the stimulus light locked in above the right lever. If these 31 responses were not completed in 5 minutes (limited hold) a new trial was initiated. One color light was associated with drug delivery, the other with food delivery. These stimulus conditions could be reversed when an animal showed a preference for one reinforcer or the other, to ensure that the animal had a reinforcer preference and not a color preference. Initial choice behavior was determined with saline and unit doses of cocaine that ranged between 50 and 300 gg/kg per injection, tested in an irregular order. Physiological saline was infused continuously via the syringe pump through the second lumen of the catheter during this period. Following establishment of stable behavior with 100 pg/kg per injection cocaine as the drug alternative, infusions of CPZ or H were begun through the second lumen of the double lumen catheter. Infusions continued 24 hours per day for 6 10 days until one of three conditions was obtained: (1) the test compound (CPZ or H) had no effect or no trends were seen; (2) the test compound altered drug preference; or (3) severe Parkinsonian symptoms developed and/ or responding was suppressed for both reinforcers. If the test compound had no effect, the dose was doubled until drug preference was altered or Parkinsonian symptoms resulted. If choice behavior was altered, stimulus lights were reversed to assure that a reinforcer preference rather than a color preference had developed. If Parkinsonian symptoms resulted or behavior was suppressed, the dose of the test compound was reduced and light stimuli were reversed. Thus, the effects of doses up to and including the highest dose of antipsychotic compound that did not produce Parkinsonian symptoms or totally suppress responding were determined in each animal. In summary, animals were allowed to self-administer cocaine through one lumen of a double lumen intravenous catheter while an antipsychotic compound was continuously infused through the second lumen. In this way it was hoped to test for partial or complete antagonism of the reinforcing properties of cocaine by CPZ or H. Partial antagonism of cocaine might result in choice behavior similar to that observed when a lower dose of cocaine was the drug alternative. Complete antagonism should result in choice behavior like that observed when saline was the drug alternative.
13
Data analysis
The results were graphed for the total number of injections chosen out of the 32 choices per day. In addition, since occasionally animals did not complete all 32 trials, the total number of trials completed per session was plotted. Results are presented individually for each of the four subjects. If an animal chose cocaine on at least 24 trials per day (2 75%), it was considered a drug preference. On the other hand, if the animal chose the cocaine alternative 8 or less times a day (< 25X), it was considered a food preference. Data were collected for several other measures of performance (e.g. number of switches and inappropriate responding). Since neither cocaine nor CPZ nor H had any effect on these measures, their analysis was omitted.
Results Dose-response relationships for cocaine and choice behavior are shown in Fig. 1. Given a c.hoice between an injection of saline or food presentation, all animals clearly preferred the food alternative. As the unit dose of cocaine was increased, the frequency of cocaine choice increased in all four animals. Thus, the relative frequency of drug self-administration was a direct function of unit dose under these conditions. The animals differed slightly in their sensitivities to the reinforcing properties of cocaine. For two animals (7233 and 7234) 100 pg/kg per injection cocaine was preferred to food on more than 90% of the trials. However, in the other two animals it was necessary to increase the unit dose of cocaine to 300 - 500 pg/kg per injection to see this level of cocaine preference. The effects of continuous infusions of CPZ on choice between cocaine (100 /*g/kg per injection) and food are shown in Fig. 2. Chlorpromazine affected behavior differently in the two animals that showed no preference between cocaine and food. In monkey 3015, CPZ had no effect on responding until responding for either reinforcer was completely suppressed at a dose of 4.0 mg/kg per day. On the other hand, monkey 3142 developed a preference for cocaine at this dose of CPZ. When the stimulus lights were reversed, this monkey died during the first session. In the two animals that preferred 100 pg/kg per injection cocaine to food, CPZ (1.0 - 4.0 mg/kg per day) had no effect on choice behavior. At a high enough dose (8.0 mg/kg per day) responding for both reinforcers was suppressed after a stimulus reversal in monkey 7233. Monkey 7234 completed the first session at this dose of CPZ but was found prostrate the following morning. These effects of CPZ could be immediately and dramatically reversed by intravenous (i.v.) infusion of 0.4 mg/kg cocaine. However, infusion of this dose of CPZ was stopped because of concern for the health of the animal. The effects of continuous infusion of various doses of H on choice between cocaine and food are shown in Fig. 3. In monkey 7233, doses of H between 25 and 400 pg/kg per day had no effect on choice behavior. The infusion of 400 E.cg/kgper day was stopped after seven sessions because the
MONK
MONK
3015
MONK 0
3142 c-----a
7233
28 24 -
6
g
32_
32-
MONK 0
2824 2016 12 ES-
k
IOE3b0 COCAINE
k
/ 50
I 100
1
300
( rG/KG/INJ)
Fig. 1. Frequency of saline (S) or cocaine choice when food was the alternative for four rhesus monkeys. Ordinate : number of trials on which cocaine was chosen (0) and the total number of trials completed (0). Abscissa: unit dose of cocaine. For each dose at which a clear preference was seen (< 8 or > 24 injections) light stimuli were reversed and the data for the last three sessions in each condition were averaged (six sessions total). Where no preference was found, each point represents the last three sessions in that condition with no stimulus reversal. Vertical lines represent the range.
animal had stopped eating. In monkey 7234,25 and 50 pg/kg per day H did not alter choice behavior. During the first session of infusion with 100 pg/kg per day H, the animal chose cocaine on 16 of 18 completed trials. As with the highest dose of CPZ, this animal was found prostrate following the first session of 100 pg/kg per day H, and this effect could be reversed with 0.4 mg/kg cocaine (i.v.). The infusion of this dose of H was also discontinued out of concern for the animal. In contrast, monkey 3015 initially had no preference between 100 pg/kg per injection cocaine and food, and infusion of 25 pg/kg per day H failed to alter choice (Figs. 3 and 4). Increasing the dose of H to 50 pg/kg per day increased the frequency of cocaine choice but, when the light stimuli were reversed, virtually all responding was suppressed. Following a period of saline infusion to allow the effects of H to dissipate, the infusion of 50 pg/kg per day H was reinstated and the original effect gradually disappeared. However, when the dose of H was increased to 100 pg/kg per day, the preference for cocaine returned and persisted after a stimulus reversal. The 6 - 7 sessions required to reverse color choice was typical for this animal under conditions of a cocaine preference without H. When the dose of H was increased to 200 gg/kg per day, muscle rigidity developed and the animal was unable to respond. Following a two week period with no drug owing to a catheter failure, the catheter was replaced and choice behavior
75 MONK
3015
MONK
7233
12 a4-
4-
o-
O5
m-1 IO
20
I. I s IO
40
CHLORPROMAZINE
20
(MG/KGIDAYl
40
80
I
2Fz& HALOPERIDOt
( rG/KG/DAY)
Fig. 2. Frequency of cocaine choice when saline (S) or various doses of chlorpromazine were infused continuously, 24 h/day. The unit dose of cocaine was 100 ,ug/kg per injection in all cases. *CPZ infusion was stopped owing to either gross intoxication or the appearance of Parkinsonian symptoms. Other details are the same as in Fig. 1. Fig. 3. Frequency of cocaine choice when saline (S) or various doses of haloperidol were infused continuously 24 h/day. Other details are as in Figs.. 1 and 2. MONK
3015
Fig. 4. Frequency of cocaine (100 pg/kg per injection) choice by monkey 3015 on daily sessions with continuous infusions of saline or haloperidol (H). Doses of H are expressed in pg/kg per day. Rev indicates stimulus reversals. Other details are as in Fig. 1.
76
for 100 pg/kg per injection cocaine was reestablished at the original level with a continuous saline infusion. The effect of 100 pg/kg per day H was then redetermined with results that were identical to those found in the first determination. When H was subsequently removed, frequency of cocaine choice declined to the original level (Fig. 4).
Discussion The data from the present experiment confirm and extend the findings of others that drug self-administration can be analysed in the context of a multi-operant environment, i.e., one in which alternative reinforcers are available to the organism [ 12,14,15]. As compared to simpler schedules of drug availability, this complex procedure has several virtues. Behaviorally, the multi-operant environment is probably a better reflection of the human situation, since for humans, drug self-administration can often alter availability of other reinforcers. By allowing animals to choose between cocaine and food, it was possible to make a direct comparison between the reinforcing efficacy of various doses of cocaine and a well-known and efficacious reinforcer, food. Pharmacologically, the procedure provides a measure of relative reinforcing efficacy (drug choice) that is a monotonic function of drug dose and which is relatively free of other drug effects that might alter intake. Specifically, the influence of rate-modifying effects of cocaine on intake was eliminated by allowing these effects to dissipate between trials. This procedural modification is particularly useful in an antagonism study as a way to eliminate antagonism of rate-modifying effects as an explanation of changes in cocaine self-administration. Manipulations that decrease the relative reinforcing efficacy of cocaine (or, conversely, increase the relative reinforcing efficacy of food) should be analogous to a reduction in the unit dose of cocaine and should result in relatively fewer cocaine choices. If, as has been postulated, the reinforcing properties of cocaine are mediated by changes in catecholamine metabolism, there should be many ways to alter this effect. Our approach was one of using drugs that block the receptors that are reputed to mediate cocaine reinforcement. Surprisingly, the results failed to support the hypothesis that the catecholaminergic receptor blockers CPZ and H can reduce the reinforcing efficacy of cocaine. In animals that chose cocaine on over 90% of the available trials, CPZ and H did not affect responding until doses high enough to suppress all responding were achieved. Moreover, the compounds increased the frequency of cocaine choice in two of the three cases where this effect was possible. Thus, the implication of this experiment is that in rhesus monkeys CPZ and H either do not affect or actually increase the relative reinforcing efficacy of cocaine. These results are similar to those of Griffiths et al. [ 111 who found increases in heroin choices in baboons infused with a narcotic antagonist. The two experiments are not entirely analogous since the baboons in Griffiths’ study
were physically dependent on heroin and the antagonist undoubtedly increased the reinforcing efficacy of heroin in relieving withdrawal symptoms. However, since CPZ and H have been shown to be negative reinforcers in the rhesus monkey [ 16, 171, it is possible that the reinforcing efficacy of cocaine was increased to the extent that it could relieve the aversive effects of these two antipsychotic compounds. Be that as it may, in no case did CPZ or H decrease the relative reinforcing efficacy of cocaine. Considered together with the findings of others [ 2 - 41, the present experiment does not eliminate the possibility that CPZ and H do not antagonize the ratedecreasing effects of cocaine since there is no measure of this effect in the present experiment. It should be noted that on several occasions, severe sedative effects of high doses of CPZ or H could be immediately and dramatically reversed by infusion of 0.4 mg/kg cocaine. At high doses of either antipsychotic compound responding was frequently completely suppressed following a stimulus reversal when, or perhaps because, cocaine intake was low. Indeed, one animal (3124) died in just such a situation at a dose of CPZ that was well tolerated when cocaine intake was high. Thus, it seems that cocaine can reverse some of the effects of antipsychotic compounds. These results are generally consistent with the hypothesis of Woods et al. [4] and Herling and Woods [ 51 of a mutual antagonism of the rate-decreasing effects of cocaine and antipsychotic compounds with little evidence for antagonism of the reinforcing properties of cocaine in the rhesus monkey. This is in contrast to the data available in rats where several experimenters have presented evidence in support of antagonism of the reinforcing properties of psychomotor stimulants by catecholaminergic blockers [ 1, 61. It remains for future research to establish the generality of these phenomena in other species, including humans. Over the past 20 years, considerable research has established the remarkable correlation between drugs that will be self-administered by rhesus monkeys and those which are likely to be abused by humans [ 18 - 201. The dose range of cocaine that is reliably preferred to food in the rhesus monkey (100 - 300 pg/kg per injection) is comparable to the dose range that produced verbal reports of pleasant effects when delivered intravenously to humans [ 211. In addition, the range of doses of CPZ and H that were tested in monkeys covers the dose range that is recommended for use in humans 1221. To the extent that the rhesus monkey is a reliable model for the effects of these drugs in humans, the finding, that the frequency of choice of cocaine relative to another reinforcer never decreased and occasionally increased, suggests that the use of antipsychotic compounds in the treatment of psychomotor stimulant abuse should be considered with caution. Acknowledgements This research was supported and DA 01442 (R.L.B.).
by N.I.D.A.
Grants DA 05164 (W.L.W.)
78
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