Dopamine D2/D3 receptors modulate cocaine's reinforcing and discriminative stimulus effects in rhesus monkeys

Numerous studies have suggested that dopamine (DA) D2 and D3 receptors are involved in the behavioral effects of cocaine. The present experiments evaluated the reinforcing and cocaine-like discriminative stimulus effects of several D2/D3 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 D2/D3 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 D2/D3 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 ED50, values, correlated with previously reported in vitro binding affinity and functional activity at the D3 receptor [R-(+ )-7-OH-DPAT > (+/-)-7-OH-DPAT > quinpirole]. These results further indicate that direct-acting D2/D3 agonists can function as reinforcers and produce cocaine-like discriminative stimulus effects, and support the idea that D3 receptors should continue to be a valuable target for future behavioral studies evaluating cocaine's mechanisms of action.