Effects of memantine, haloperidol, and cocaine on primary and conditioned reinforcement associated with cocaine in rhesus monkeys

Rationale: The N-methyl-D-aspartate (NMDA) receptor has been implicated in mediating the reinforcing effects of abused drugs. Some reports indicate the uncompetitive NMDA antagonist, memantine, modulates the conditioned and unconditioned effects of stimulants in rats. Objective: The objective of this study was to evaluate the effects of memantine on the primary and conditioned reinforcing effects of cocaine in the rhesus monkey. Methods: Rhesus monkeys were trained to press levers reinforced with either cocaine-associated stimuli (brief stimuli, BS) or 30-mu g/kg cocaine infusion during daily, 75-min experimental sessions in which the reinforcers were independently available in separate components according to identical progressive ratio (PR) schedules. Memantine (0.3-10 mg/kg), and as comparators, haloperidol (0.001-0.1 mg/kg) and cocaine (0.01-1 mg/kg), were administered 5 min before experimental sessions. Results: Memantine (0.3-3 mg/kg) produced decreases in responding maintained by BS presentations at some doses which failed to affect cocaine self-administration when measured during equivalent periods early in the experimental session. Memantine (3 mg/kg) increased cocaine self-administration, however, later in the session. A low dose of haloperidol (0.001 mg/kg) increased the number of BS presentations, whereas higher doses decreased their number. Cocaine self-administration was not significantly affected by haloperidol until a behaviorally suppressant dose (0.1 mg/kg) was administered. Pretreatment with high doses of cocaine (0.3 and 1 mg/kg) decreased responding maintained by both reinforcers. Conclusion: These results suggest that while memantine may attenuate the conditioned reinforcing effects of cocaine-associated stimuli, it may also occasion increase levels of cocaine self-administration. These findings support the hypothesis that the NMDA receptor can play a role in modulating the conditioned and primary reinforcing effects of cocaine.