Dopamine D 2/D 3 receptors modulate cocaine’s reinforcing and discriminative stimulus effects in rhesus monkeys

Abstract

Numerous studies have suggested that dopamine (DA) D 2 and D 3 receptors are involved in the behavioral effects of cocaine. The present experiments evaluated the reinforcing and cocaine-like discriminative stimulus effects of several D 2/D 3 agonists in rhesus monkeys. In the first experiment, animals ( n=4) were trained to self-administer 0.03 mg/kg/inj cocaine under a fixed-interval (FI) 5-min schedule. When substituted for cocaine, the D 2/D 3 agonist quinpirole (0.003–0.03 mg/kg/inj) functioned as a reinforcer in all monkeys. In two cocaine-naive monkeys trained to respond under an FI 3-min schedule of food presentation, quinpirole maintained low rates of responding in one subject, while at the highest dose (0.03 mg/kg/inj) it functioned as a reinforcer in the second monkey. In this animal, increased activity was observed at this dose, which may have contributed to the overall rate of responding. In the second experiment, monkeys ( n=4) were trained to discriminate cocaine from saline using a two-lever, food-reinforced, drug discrimination procedure. The D 2/D 3 agonists quinpirole, (±)-7-OH-DPAT, and R-(+)-7-OH-DPAT fully substituted for cocaine. However, the time-course of substitution differed between quinpirole, which substituted for cocaine 10 min after administration, and (±)- and R-(+)-7-OH-DPAT, which required 60-min pretreatments. The behavioral potencies, as determined from ED 50 values, correlated with previously reported in vitro binding affinity and functional activity at the D 3 receptor [R-(+)-7-OH-DPAT>(±)-7-OH-DPAT>quinpirole]. These results further indicate that direct-acting D 2/D 3 agonists can function as reinforcers and produce cocaine-like discriminative stimulus effects, and support the idea that D 3 receptors should continue to be a valuable target for future behavioral studies evaluating cocaine’s mechanisms of action.