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

Abstract

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. 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. 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. 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. 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.