Effects of different food-reinforcement histories on cocaine self-administration by rhesus monkeys

The purpose of the present study was to examine whether a history of responding under food reinforcement schedules that generated either high or low response rates would influence the acquisition and maintenance of cocaine self-administration. Eight experimentally naive rhesus monkeys were initially trained to respond on the right lever under either a fixed-ratio (FR) 50 or interresponse times (IRT) > 30-s schedule of food reinforcement. After 65 sessions of food-maintained responding, monkeys were surgically prepared with indwelling intravenous catheters and cocaine 0.03 mg/kg per injection (IV) was available on the left lever under a fixed-interval (FI) 5-min schedule. After at least 60 consecutive sessions at this dose, a cocaine dose-response curve (saline, 0.01–0.3 mg/kg per injection) was determined. The FR 50 schedule generated high rates of food-maintained responding (90.1±6.2 responses/min), while response rates under the IRT >30-s schedule were low (1.9±0.1 responses/min). Across the 60 consecutive sessions under the FI 5-min schedule, linear changes in response rates and cocaine intake were significantly different between FR- and IRT-history monkeys. FR-history monkeys responded at higher rates than IRT-history subjects, while cocaine intake during the first 15 sessions was lower in FR- compared to IRT-history monkeys. Rates of cocaine-maintained responding after food-reinforcement histories were compared to response rates of monkeys initially trained to self-administer cocaine under an FI 5-min schedule (Nader and Reboussin 1994). Response rates were higher in this latter group compared to rates generated by either group of monkeys after food-reinforcement histories. Furthermore, a significant interaction between behavioral history and cocaine dose on response rates was observed. Results from the present study indicate that a history of responding maintained by a nondrug reinforcer can have significant and long-lasting effects on response rates and total cocaine intake under an FI schedule. Furthermore, these results indicate that prior experiences may produce different effects on acquisition and maintenance of cocaine self-administration.     

A behavioral economic analysis of cocaine and remifentanil self-administration in rhesus monkeys

Rationale Behavioral economics can be used to evaluate the relative reinforcing effectiveness of drugs and the economic interaction between drugs, information which may help to explain patterns of polydrug abuse in humans. Objectives In phase 1, the reinforcing effectiveness of the opiate remifentanil and the stimulant cocaine was compared using a demand-curve analysis. In phase 2, the economic relation between these drugs was determined. Materials and methods Rhesus monkeys pressed levers according to fixed-ratio schedules for intravenous drug infusions. A demand-curve analysis was conducted (phase 1) in which drug consumption was measured as the response requirement, or price, was increased, and the rate at which consumption decreased with increases in price (demand elasticity) provided an index of the reinforcing effectiveness of each drug. Cocaine and remifentanil were then available concurrently (phase 2), and the price of one drug was increased (the manipulated-price alternative) while the price of the other drug was held constant (the fixed-price alternative). Consumption of the fixed-price alternative was measured as a function of increases in the price of the manipulated-price alternative, and demand for the manipulated-price alternative was assessed. Results The reinforcing effectiveness of cocaine and remifentanil did not significantly differ, and these drugs functioned as economic substitutes. As the price of the manipulated-price alternative increased, consumption of the fixed-price alternative increased. In addition, demand for the manipulated-price alternative became more elastic with the concurrent availability of the fixed-price alternative. Conclusion Polydrug use involving stimulants and opiates may occur because these drugs are highly substitutable. This work was supported by United States Public Health Service Grant DA 015449 and Training Grant DA 007268.     

Self-administration of cocaine: scopolamine combinations by rhesus monkeys

RATIONALE: Several halogenated analogs of benztropine (BZT) have previously been characterized as potent dopamine (DA) uptake inhibitors with diminished reinforcing effects relative to cocaine. In addition to their effects on DA uptake, these compounds are potent muscarinic cholinergic antagonists.OBJECTIVES: The present experiments were designed to examine the hypothesis that the anticholinergic action of the BZT analogs contributes to their relatively low levels of self-administration.METHODS: Rhesus monkeys self-administered cocaine (0.03 mg/kg per injection, i.v.) under either a fixed-ratio 25 (FR 25; n=5) or progressive-ratio (PR; n=5) schedule until stable responding was established. Saline, cocaine (0.0003-0.1 mg/kg per injection), scopolamine (0.001-0.1 mg/kg per injection), or various combinations of cocaine and scopolamine were then made available for self-administration.RESULTS: Cocaine maintained dose-related self-administration under both schedules whereas scopolamine did not. In the majority of cases, combinations of cocaine and scopolamine maintained less self-administration than cocaine alone.CONCLUSIONS: This study supports the hypothesis that anticholinergic actions contribute to the diminished self-administration of BZT analogs relative to cocaine. The mechanism may involve antagonism of the reinforcing effect of cocaine and/or punishment of the self-administration response by the addition of an anticholinergic component of action.     

Effects of dose and infusion delay on cocaine self-administration choice in rhesus monkeys

Rationale. Drug abuse is often considered a problem related to impulse-control disorders, but little is known about the factors that determine the choice to self-administer a drug in a self-control/impulsivity paradigm. Objective. The objective of the present study was to evaluate choice between a low dose of cocaine administered after a relatively short delay (impulsive option) and a high dose of cocaine following a relatively longer delay (self-control option). Methods. Rhesus monkeys self-administered intravenous cocaine in a discrete-trials choice procedure. First, choice was between different 3:1 doses (0.3/0.1 and 0.1/0.03 mg/kg per injection) following equal 30-s delays to infusion. Second, choice was between equal doses (0.1 mg/kg per injection) following 3:1 delays (30 s/10 s, 90 s/30 s, 270 s/90 s, 810 s/270 s). Third, choice was between 0.1 or 0.03 mg/kg per injection after the same 3:1 delays with the larger dose following the longer delay and the smaller dose following the shorter delay. Fourth, the same 3:1 delays were used to study choice between 0.3 and 0.1 mg/kg per injection. Results. With equal delays, the larger dose of cocaine was chosen almost exclusively, and with equal doses, the shorter delay was chosen almost exclusively. When both dose and delay were manipulated, mean large-dose (0.1 mg/kg per injection) choices for three of four subjects was 98% when the delays were the shortest (30 s/10 s), but this preference reversed as the delays increased, so that 74% of choices were for the smaller dose (0.03 mg/kg per injection) at the longest delays (810 s/270 s). This systematic decrease in large-dose choices as the absolute, but not relative, values of the delays were increased, was also observed with the higher dose combination. Conclusion. Delay discounting was supported by the present findings in that the value of a large reinforcer (higher cocaine dose) was decreased as its delay to presentation was increased. The importance of not only relative, but absolute, values of delays to drug reinforcement in determining drug choice was also demonstrated. Thus, a self-control/impulsivity paradigm can be extended to conditions with non-human subjects and drug reinforcers. Electronic Publication     

Effects of buspirone and gepirone on IV cocaine self-administration in rhesus monkeys

Buspirone and gepirone were evaluated as potential pharmacotherapies for cocaine abuse by studying the effects of acute and repeated treatment on IV cocaine self-administration in rhesus monkeys. Chlorpromazine was also evaluated as a positive control. Effects of IV drug pretreatments were tested during daily 60-min sessions with lever-pressing reinforced under a fixed-ratio 10 schedule of 0.02 or 0.05 mg/kg cocaine infusions. Acute pretreatment with buspirone (0.1 and 0.3 mg/kg, IV) increased rates of cocaine self-administration without disrupting food pellet consumption. Some doses of buspirone also produced changes in rates of cocaine self-administration without altering the within-session pattern of responding. In contrast, acute doses of gepirone had little effect on rates of cocaine self-administration, while disruptions in food consumption and changes in the within-session pattern of cocaine self-administration were obtained at the highest dose of gepirone tested (1.0 mg/kg). When either buspirone (0.1 and 0.3 mg/kg, IV) or gepirone (0.1 mg/kg, IV) were administered daily for 10 days, consistent effects on cocaine self-administration were not observed. Thus, the effects of acute buspirone administration on cocaine-maintained behavior were similar to the effects produced by chlorpromazine and other dopaminergic antagonists, whereas, gepirone was ineffective. These results provide some support for further evaluation of buspirone as a potential pharmacotherapy for cocaine abuse, although its lack of efficacy with repeated treatment is not encouraging. The negative results with gepirone provide less rationale for continued investigations with this drug, possibly because of its lesser involvement than buspirone with dopaminergic neurotransmission.     

Parametric analysis of cocaine self-administration under a progressive-ratio schedule in rhesus monkeys

The present study was designed to investigate parameters and quantitative analysis of cocaine self-administration under a progressive-ratio (PR) schedule of reinforcement, with the goal of enhancing the resolution of PR schedules for measuring reinforcing efficacy. Six rhesus monkeys were prepared with chronic intravenous catheters and trained to self-administer cocaine under a PR schedule. The schedule consisted of five components, each made up of four trials (i.e., 20 trials total). Each trial within a component had the same response requirement. Three initial response requirements were tested: fixed-ratio (FR) 60, FR 120 and FR 240. The response requirements doubled in successive components to a maximum of FR 960, FR 1920 or FR 3840, respectively, in the fifth component. A trial ended with an injection or the expiration of a 12- or 24-min limited hold (LH). The inter-trial interval (ITI) was 15 or 30 min. Four dependent measures were assessed: break point (last FR completed), injections/session, responses/session and response rate (responses/s). For the three initial FRs, the break point, number of injections/session, responses/session and rate increased with dose of cocaine (0.013–0.1 mg/kg per injection) at both ITI/LH values. At the ITI15/LH12, responding decreased at higher doses, i.e., the dose-response functions were biphasic. In contrast, at the ITI30/LH24, responding reached an asymptote at higher doses. In general, cocaine maintained significantly higher break points, injections/session, responses/session and rate at ITI30/LH24 than at ITI15/LH12. However, at both ITI/LHs, as initial FR was increased, injections/session at the higher doses decreased while break point, total responses/session and rate did not change. A ceiling on performance, as assessed by break point, total responses/session and response rate, may have limited the number of cocaine injections an animal could take in a session. The results of this study indicate that optimal conditions for measuring the reinforcing efficacy of cocaine were obtained at the longer ITI/LH and at initial FRs above 60.     

Effects of delivery rate and non-contingent infusion of cocaine on cocaine self-administration in rhesus monkeys

 The goal of this study was to determine whether slowly infused, response-independent cocaine would reduce cocaine self-administration in an animal model of drug abuse. Seven male rhesus monkeys self-administered IV cocaine on a fixed-ratio 30 schedule (5-min time-out). With unit dose (0.056 mg/kg per infusion for one monkey and 0.032 mg/kg per infusion for the rest) and infusion volume (0.5 ml) held constant, the rate of delivery was manipulated (0.125, 0.1875, 0.375, 0.75 and 3 ml/min, with infusions lasting 240, 160, 80, 40, and 10 s, respectively). Response rates increased monotonically as a function of delivery rate. Responding for cocaine at the slowest delivery rate did not differ from saline. The effects of infusing additional cocaine (starting 30 min prior to the session) at this non-reinforcing rate (0.125 ml/min) were then determined. Delivery rate of the self-administered infusion was manipulated as before. Non-contingent cocaine significantly increased responding for cocaine (at the fastest delivery rate) and for saline. While non-contingent cocaine reduced responding for cocaine in two of the seven monkeys, it also significantly reduced responding in three monkeys that responded for food on the same schedule. Plasma levels of cocaine delivered at rates of 0.125 and 3 ml/min were compared in five other monkeys. While a higher peak was reached with the faster infusion, levels did not differ after 5 min. Thus, when an infusion became available (after the 5-min time-out) in the self-administration experiments, plasma levels should not have differed regardless of the delivery rate. These results suggest that a low-dose, slow-delivery treatment with cocaine might prime or reinstate drug seeking rather than decrease it. Received: 1 July 1997 / Final version: 4 January 1998     

The effects of benzamide analogues on cocaine self-administration in rhesus monkeys

Rationale: Based on the differential distribution of dopamine (DA) D₃ receptors in mesolimbic regions relative to nigrostriatal regions, the hypothesis was that D₃-selective antagonists (i.e., higher affinity at D₃- than D₂-receptors) would be more potent than D₂-selective antagonists at decreasing total cocaine intake relative to disrupting rates of responding. Objective: To evaluate the effects of acute administration of seven DA antagonists with varying affinities for D₂ and D₃ receptors in monkeys self-administering cocaine. Methods: Rhesus monkeys were trained to self-administer intravenous cocaine (0.01–0.3 mg/kg per injection) under a fixed-interval (FI) 5-min schedule during daily 4-h sessions. The use of a FI schedule allowed for independent assessment of rate effects and changes in reinforcement frequency as a consequence of drug pretreatments. The compounds examined, in order of D₃ binding affinity, were: 2,3-dimethoxy-N-(9-p-fluorobenzyl)-azabicyclo[3.3.1]nonan-3β-yl benzamide (MABN) = eticlopride = 5-bromo- 2,3-dimethoxy-N-[1-(4-fluorobenzyl)piperidin-4-yl]benz-amide (BBP) > spiperone > fluoroclebopride (FCP) > 2,3-dimethoxy-N-(p-fluorobenzyl)piperdin-4-yl benzamide (MBP) > haloperidol. Results: In the absence of any pretreatments, cocaine-maintained responding varied as a function of dose and was characterized as an inverted U-shaped function, while cocaine intake increased in a dose-related fashion. When the dose of cocaine that maintained peak rates was available, all DA antagonists decreased response rates and cocaine intake in a dose- dependent manner. Increases in cocaine dose attenuated the effects of the DA antagonists, resulting in rightward shifts of the cocaine dose–response curves. Based on the ratio of behavioral potency at decreasing response rates relative to intake (ED₅₀ rate/ED₅₀ intake) when the highest cocaine dose was available, the order of potency and ED₅₀ ratio values were: MABN (2.5) > eticlopride (1.63) > BBP = spiperone (1.5) > FCP (1.35) > MBP = haloperidol (0.89). This order parallels each compound’s affinity at D₃ receptors (r ²=0.84) to a greater degree than D₂ receptor affinity (r ²=0.34). Conclusions: These results, using a FI schedule of cocaine self-administration, suggest that D₃ receptor antagonists are more likely to selectively decrease intake relative to response rates than D₂ receptor antagonists. Received: 8 January 1999 / Final version: 15 June 1999     

Comparative behavioral profile of cocaine and norcocaine in rats and monkeys

The effects of cocaine and norcocaine were compared using locomotor activity, fixed-ratio 100 (FR 100) and fixed-interval 4 min (FI 4 min) food reinforcement and free feeding paradigms in rat and intravenous self-administration tests in rhesus monkeys. Cocaine was shown to significantly increase locomotor activity at doses of 20 and 40 mg/kg, while norcocaine had no effect at these doses and produced convulsions and death at 60 and 80 mg/kg. Both compounds significantly reduced food consumption at one or more of the doses tested. Cocaine and norcocaine at doses of 20 and 40 mg/kg, produced decreases in FR responding. Cocaine at doses of 10, 20, and 40 mg/kg, produced increases in FI responding; norcocaine had no effect following 10 mg/kg and decreased responding at 20 and 40 mg/kg. Cocaine (0.2 mg/kg/inj) and norcocaine (0.5, 0.2, 0.8 mg/kg/inj) maintained intravenous self-administration in all three monkeys tested. The data indicate that norcocaine is a pharmacologically active metabolite of cocaine which could account for some of the activity heretofore attributed to cocaine. However, the lack of any stimulatory effect of norcocaine or locomotor activity and the lack of increased responding produced by norcocaine on fixed-interval behavior suggest that norcocaine differs qualitatively from cocaine.     

Effects of buprenorphine on candy and sweetened fluid self-administration by rhesus monkeys

Abstract Rationale. Previous studies have shown that buprenorphine differentially suppresses the reinforcing effects of different drugs (cocaine, alfentanil), drug versus nondrug reinforcers (food, drug), and the same reinforcer (food) maintained under different schedules of reinforcement. Objectives. The purpose of the present study was to determine whether buprenorphine (0.03, 0.1, 0.3 mg/kg) differentially affects candy versus sweetened fluid self-administration. The hypotheses were that (1) candy would maintain higher rates of responding and would be chosen on more occasions than sweetened fluid, and (2) buprenorphine would produce smaller disruptions in responding for the more-preferred reinforcer. Methods. During separate sessions, rhesus monkeys self-administered candy alone, sweetened fluid alone, or had the opportunity to choose between candy and sweetened fluid. Monkeys responded under a second order, two-chain schedule of reinforcement. Results. Candy was a more-preferred reinforcer than sweetened fluid. Buprenorphine significantly decreased rates of responding for fluid, but increased rates of responding for candy. Although buprenorphine significantly decreased both candy and fluid intake, it produced a more robust, and longer-lasting suppression of sweetened-fluid intake than candy. Choice to self-administer candy or fluid was not affected by buprenorphine. Conclusions. These results demonstrate that behavior maintained by a less-preferred reinforcer is more easily disrupted by buprenorphine than is behavior maintained by a more-preferred reinforcer. Electronic Publication     

Effects of bromocriptine and desipramine on behavior maintained by cocaine or food presentation in rhesus monkeys

This experiment tested whether bromocriptine or desmethylimipramine (DMI), both agents used clinically to treat cocaine abuse, could specifically alter behavior maintained by cocaine injections. Rhesus monkeys were trained to press a lever in daily experimental sessions under a three-component multiple schedule of reinforcement. In the first and third components, food was available under a fixed-ratio (FR) 30 schedule. In the second component cocaine (0.025 or 0.050 mg/kg/injection, IV) was available under a FR 30 schedule. Monkeys received continuous (24 h/day) IV infusions of several doses of bromocriptine or DMI. Bromocriptine (0.8–6.4 mg/kg/day) was infused for at least the same number of sessions as was required for responding to decline to low levels when the monkeys were allowed to self-administer saline. DMI (0.8–12.8 mg/kg/day) was infused for a minimum of 3 weeks. In some instances, low doses of bromocriptine decreased responding maintained by cocaine without reducing food-maintained responding, while higher doses of bromocriptine decreased responding maintained by either food or cocaine. However, bromocriptine doses that reduced cocaine intake also caused overt stimulation of locomotor activity. In contrast, DMI, at doses as much as 10 times higher than those used clinically to treat cocaine abuse did not affect responding maintained by cocaine or food. These results indicate that bromocriptine can selectively reduce behavior maintained by cocaine, although apparently by a mechanism other than blockade of reinforcing effects. On the other hand, DMI did not alter the reinforcing effects of either cocaine or food under these conditions.     

Phencyclidine self-administration in the rhesus monkey

Two experiments were performed in which rhesus monkeys self-administered phencyclidine through indwelling venous catheters. In the first experiment, monkeys trained to lever press for cocaine injections, maintained higher response rates as compared to saline control rates when phencyclidine at unit doses from1.5?25.0 μg/kg were substituted for the cocaine baseline. In the second experiment, experimentally naive monkeys spontaneously initiated lever-pressing for injections of 50 μg/kg/inj phencyclidine. In both studies the animals self-administered enough drug to produce behavioral effects resembling general anesthesia.     

Effects of chronic administration of the D1 receptor partial agonist SKF 77434 on cocaine self-administration in rhesus monkeys

RATIONALE: Dopamine D1 receptor partial agonists have been proposed as candidate medications for the treatment of cocaine dependence. However, there currently is scant information regarding how chronic exposure to D1 agonists may modify behavioral effects of cocaine and, especially, whether tolerance develops to their effects on cocaine self-administration. OBJECTIVE: The present studies were conducted to evaluate the effects of chronic treatment with the D1 receptor partial agonist SKF 77434 on IV cocaine self-administration in rhesus monkeys. METHODS: A protocol was developed to rapidly evaluate the effects of chronic drug exposure on extinction behavior, threshold dose of self-administered cocaine, and the dose-effect function for cocaine self-administration behavior. Monkeys performed in daily sessions of IV cocaine self-administration under a fixed-ratio schedule of reinforcement and food presentation under either a fixed-ratio or fixed-interval schedule of reinforcement. When both types of performance were stable, chronic exposure to SKF 77434 followed with month-long regimens of IV treatment with each of two or three dosages. RESULTS: The effects of SKF 77434 were dose-related. Exposure to 1.0 mg/kg per day of SKF 77434 yielded a moderate and persistent rightward shift in the descending portion of the dose-effect function for cocaine self-administration but did not alter the threshold dose and did not disrupt either extinction behavior or food-maintained performance. An increase in dosage to 3.2-5.6 mg/kg per day displaced the dose-effect function for cocaine self-administration downward from its prechronic position, altered threshold dose values, and disrupted food-maintained performance. CONCLUSIONS: Chronic treatment with D1 receptor partial agonists produced dose-dependent effects on cocaine self-administration that may be relevant to their further evaluation as candidate medications for the treatment of cocaine dependence.     

Effects of delay to reinforcement on the choice between cocaine and food in rhesus monkeys

Rationale Although a delay between behavior and reinforcer has been shown to weaken behavior, little is known about the effects of delay on drug choice.Objectives The present study examined effects of delay between lever press and reinforcer presentation on the choice between a drug and non-drug reinforcer and between different drug doses.Materials and methods Monkeys (n=4) were allowed to choose 32 times/day between cocaine and four food pellets. The delay between lever press and a preferred dose of cocaine (0.05 mg/kg/injection) was increased systematically from 0 to 240 s, while the delay to food remained at 0 s. A second group of monkeys (n=4) was allowed to choose between 0.05 mg/kg/injection and a lower dose of cocaine (0.025 mg/kg/injection). Next, a delay that resulted in less than 20% choice of 0.05 mg/kg/injection cocaine was selected and delay to the alternative was varied.Results Results were similar across groups. The choice of 0.05 mg/kg/injection approximated 100% at 0 delay and decreased to near 0 as delay increased. As the delay to alternative was subsequently increased from 0 to 240 s, choice of 0.05 mg/kg/injection increased, though full cocaine choice was not generally restored. The delay estimated to maintain 50% choice (indifference point) was lower for the cocaine-food choice (mean=64 s) than for the cocaine–cocaine choice (mean=207 s).Conclusions This experiment demonstrates that the choice between cocaine and a non-drug or drug alternative can be modified by increasing the interval between behavior and drug injection. Overall, the results are consistent with a temporal discounting model of drug choice.     

Self-administration of the dopamine D3 agonist 7-OH-DPAT in rhesus monkeys is modified by prior cocaine exposure

Cocaine self-administration was compared with responding maintained by the dopamine D₃ agonist 7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT) in rhesus monkeys. In the first experiment, monkeys (n=3) with an extensive cocaine history responded under a fixed-interval (FI) 5-min schedule of IV cocaine (0.03 mg/kg per injection) presentation, during daily 4-h sessions. When responding was stable, dose-response curves were determined for cocaine (0.01-0.3 mg/kg per injection) and 7-OH-DPAT (0,001–0.1 mg/kg per injection); each dose was available for at least five consecutive sessions. When substituted for the baseline dose of cocaine, other doses of cocaine and 7-OH-DPAT maintained rates higher than responding maintained by saline injections, in all monkeys. 7-OH-DPAT maintained response rates equal to or higher than rates of cocainemaintained responding in all monkeys. In a second experiment, acquisition of 7-OH-DPAT self-administration was evaluated in a group of cocaine-navie monkeys (n=3). Various doses of 7-OH-DPAT (0.003–0.03 mg/kg during daily 4-h sessions. After 10–13 sessions, 7-OH-DPAT self-administration could not be trained in any cocaine-naive monkey. When cocaine was made available to these monkeys, responding was reliably maintained within one to four sessions and the schedule was gradually increased to FI 5-min. After stable responding under an FI 5-min schedule of 0.03 mg/kg per injection cocaine presentation, 7-OH-DPAT (0.01 mg/kg per injection) was again made available to two of the monkeys, and maintained responding at rates higher than saline. To determine better whether a history of responding maintained by another reinforcer would result in high rates of 7-OH-DPAT self-administration, two cocaine-naive monkeys were trained to respond under an FI 5-min schedule of food presentation. Substituting 7-OH-DOAT (0.003–0.03 mg/kg per injection) for food resulted in very low rates of responding. Taken together, these results suggest that despite comparable reinforcing effects in cocaine-substitution studies, 7-OH-DPAT and cocaine differ in their rate of acquisition, perhaps indicating a lower abuse liability for 7-OH-DPAT.     

The generalized matching law as a predictor of choice between cocaine and food in rhesus monkeys

Rationale: The generalized matching law predicts that the relative rate of behavior maintained by different reinforcers will match the relative rate of reinforcement. It has previously been shown that responding maintained by either food deliveries or cocaine injections under concurrent variable-interval (conc VI) schedules is well described by the generalized matching law. However, the generality of this conclusion to the choice between a drug and a non-drug reinforcer has not been well established. Objective: The objective of the present study was to determine the extent to which the generalized matching law could account for choice between cocaine and food. Methods: Four male rhesus monkeys (Macaca mulatta) lever pressed under various pairs of conc VI schedules with food and/or cocaine injection as the maintaining events. Two doses of cocaine (0.025 and 0.05 mg/kg per injection) were selected to provide information about reinforcer magnitude. Results: As has been found in a context of choice between identical reinforcers, the generalized matching law accounted for most behavior. As in earlier studies with identical reinforcers, there was less responding apportioned to the alternative with the greater reinforcement frequency than predicted by the generalized matching law, i.e., undermatching was observed frequently. There was a tendency for more responding to be emitted toward the food alternative when the lower dose of cocaine was available and toward the drug alternative when the higher dose of cocaine was available. Conclusion: These results suggest that, as proposed by the generalized matching law, relative reinforcement rate is an important determinant of choice between a drug and a non-drug reinforcer. Electronic Publication     

Influence of a conditioned light stimulus on cocaine self-administration in rats

RATIONALE: A number of studies have suggested that the continued presentation of stimuli associated with cocaine may contribute to drug-seeking and drug-taking. The influence of conditioned stimuli on the maintenance of self-administration has not, however, been systematically investigated. OBJECTIVES: This study was designed to determine whether omission of a stimulus that had been paired with self-administered cocaine would influence the maintenance of cocaine self-administration and whether the effect was dependent on cocaine dose or session length. METHODS: During self-administration training, self-administered cocaine infusions were always paired with the illumination of a light. On test days, self-administered cocaine was delivered either with or without the cocaine-associated cue. For one group of rats, responding maintained by cocaine (0.50 mg/kg per infusion) was measured during daily 18-h sessions. For other groups, responding maintained by additional doses of cocaine (0.125, 0.25, or 1.0 mg/kg per infusion) was measured during daily 8-h sessions. For a final group, daily test sessions (4-5 h) produced the dose-effect curve (0.015-1.0 mg/kg per infusion) by repeatedly reducing the cocaine dose from a starting dose of 1.0 mg/kg per infusion. RESULTS: Removal of the light cue decreased cocaine self-administration. The magnitude of this effect was dependent on the dose of self-administered cocaine and on the test session duration. Greater decrements in responding were produced as session length increased or when low doses of cocaine were self-administered. CONCLUSIONS: These findings demonstrate that in the absence of a cocaine-associated stimulus, cocaine self-administration is attenuated and that maintenance of cocaine self-administration is maximally affected by the presence or absence of the conditioned stimulus when the self-administered dose is low and/or when session duration is long.     

A within-subject assessment of the discriminative stimulus and reinforcing effects of self-administered cocaine in rhesus monkeys

Rationale

Drug discrimination (DD) and drug self-administration (SA) are frequently used preclinical assays. All preclinical studies with cocaine have examined the discriminative stimulus (S^D) and reinforcing (S^R) effects in separate groups of subjects.

Objective

The objective of the study is to train drug-naïve rhesus macaques to discriminate self-administered cocaine from saline and to assess S^D and S^R effects using a within-subjects design.

Materials and methods

Adult male rhesus monkeys (n?=?4) were trained to self-administer cocaine (0.1 mg/kg per injection) under a progressive-ratio (PR) reinforcement schedule. Next, they were trained to discriminate self-administered cocaine (0.45 or 0.56 mg/kg) or saline under a fixed-ratio (FR) 50 schedule of food presentation. The final schedule combined DD and SA into a multiple [chained FR 50 SA (cocaine or saline), food-reinforced DD] and PR SA schedule.

Results

Each subject acquired SA under a PR schedule with significant differences in breakpoint between saline and cocaine evident by session 5. Self-administered cocaine was established as an S^D, such that 80% of responding before delivery of the first reinforcer and 90% of all responding occurred on the injection-appropriate lever. In all monkeys, there was at least one cocaine dose that did not engender cocaine-appropriate responding during DD (i.e., <20% cocaine-appropriate responding) yet functioned as a reinforcer during PR SA, suggesting that cocaine-like S^D effects are not necessary for cocaine reinforcement.

Conclusions

This within-subject model may provide new information related to the behavioral mechanisms of action leading to the high abuse potential of cocaine; such information may lead to novel pharmacological treatment strategies for addiction.     

Effects of drug history on the acquisition of responding maintained by GBR 12909 in rhesus monkeys

The reinforcing effects of cocaine have been associated with its actions at the dopamine reuptake site. Previous studies have shown that selective dopamine reuptake inhibitors can attenuate cocaine self-administration in animals, suggesting that they may serve as pharmacotherapeutic agents. In order to assess the potential reinforcing effects of one of these agents, the acquisition and maintenance of GBR 12909 self-administration were studied in different groups of rhesus monkeys (Macaca mulatta) that were either experimentally naive or experienced with respect to the self-administration of cocaine or GBR 12909. Lever-pressing was maintained under a multiple FR30 schedule with alternating components of either food or drug presentation. Experimentally naive monkeys failed to self-administer low doses of GBR 12909 (3–30 µg/kg per injection). However, after a history of cocaine self-administration, GBR 12909 (56 µg/kg per injection and then 30 µg/kg per injection) maintained numbers of drug deliveries similar to those maintained by cocaine. When another group of experimentally-naive monkeys was initially exposed to GBR 12909 self-administration, 56 µg/kg per injection failed to maintain responding. However, subsequent exposure to 100 µg/kg per injection established GBR 12909 self-administration, and high levels of responding were sustained later when the unit dose was decreased to 30 µg/kg per injection. In monkeys with prior experience with cocaine self-administration (75 sessions) unit doses of either 30 µg/kg per injection or 56 µg/kg per injection GBR 12909 maintained responding. In another group of monkeys with a more extensive history of cocaine self-administration (320 sessions), unit doses of either 10 µg/kg per injection or 30 µg/kg per injection GBR 12909 maintained responding. These results show that drug-maintained responding can be established with higher unit doses of GBR 12909. After exposure to these higher, more effective doses of GBR 12909, or effective doses of cocaine, lower doses of GBR 12909 are more likely to support drug-maintained responding.     

Effects of local anesthetics on fixed-interval responding in rhesus monkeys

Several local anesthetics of both the ester and amide type were administered IM to rhesus monkeys trained to respond on a fixed-interval 5 min schedule of food delivery. With the exception of procainamide, all local anesthetics produced dose-related decreases in response rates. Effects on pattern of responding varied between local anesthetics. With some (cocaine, dimethocaine and lidocaine), rate-dependent effects were apparent. When control rates were low, these compounds increased rates; when control rates were high, they decreased rates. However, with others (procaine, chloroprocaine, tetracaine and propoxycaine) no rate-dependent effects were noted; i.e., these compounds had little or no effect on the pattern of responding, even at doses that substantially reduced response rates. Consistent with other experiments with these compounds, cocaine was the most potent of the group. In several instances, local anesthetics which had similar stimulus properties in other behavioral paradigms differed in terms of their effects on fixed-interval behavior.