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

Abstract

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.

Fig. 1

Schematic of final parameters for multiple chained schedule of cocaine discrimination and self-administration. Link 1 consisted of an FR 50 schedule of self-administration that terminated in a single 10-s injection followed by a TO. The injection from Link 1 served as the discriminative stimulus for Link 2 which was a two-lever, food-reinforced drug discrimination task that lasted until 50 reinforcers were delivered or for 15 min and was followed by a 30-min TO. The second component of the multiple schedule consisted of self-administration under a PR schedule of reinforcement. Each injection was followed by a 15-min TO

Fig. 2

Acquisition of cocaine self-administration under a progressive-ratio schedule of reinforcement. a Group (n=4) mean (±SEM) number of injections self-administered during the first 20 sessions under a PR schedule of reinforcement. b Individual mean (±SD) number of injections and breakpoints for the last 5 days of a 30-day access period to PR self-administration. Asterisks indicate significant (p<0.05) difference from saline. During acquisition, the cocaine dose was 0.1 mg/kg per injection

Fig. 3

Discrimination of self-administered cocaine. The effect of varying doses of cocaine on cocaine discrimination (closed squares) and response rates (open squares). Each point is the mean (±SD) of at least two determinations in each monkey. Arrows below the abscissa indicate the training dose of cocaine

Fig. 4

The discriminative stimulus and reinforcing effects of self-administered cocaine assessed under a multiple chained DD, PR SA schedule of reinforcement. The effect of various cocaine doses (abscissa; S, saline) on the percent cocaine-appropriate responding (closed squares, left ordinate) during cocaine discrimination and number of injections (open squares, right ordinate) self-administered under a PR schedule of reinforcement. Each point is the mean (±SD) of at lease two determinations in each monkey. Asterisks indicate significant (p<0.05) difference from saline. Pound sign indicates single determination. Arrows below the abscissa indicate the training dose of cocaine used in DD link of the chained schedule of reinforcement. For R-1524, the 0.15 mg/kg cocaine dose was studied under the PR schedule during training, but not after DD performance had been established. All other points reflect data from the combined schedule

Fig. 5

Cocaine self-administration as a function of discriminative stimulus generalization. Individual mean (±SD) number of injections (ordinate) of cocaine (0.015–0.56 mg/kg) self-administered under a PR schedule graphed as a function of the percent cocaine-appropriate responding (abscissa) engendered by those same doses of cocaine