Pharmacological characterization of the discriminative stimulus effects of cocaine in rhesus monkeys.

Rhesus monkeys (n = 6), trained in a two-lever, food-reinforced paradigm to discriminate cocaine (0.2 or 0.4 mg/kg, i.m.) from saline, received injections of cocaine (0.025-0.40 mg/kg, i.v. or i.m.) or various direct and indirect acting agonists (i.v.). Administration of cocaine resulted in a dose-related increase in the percentage of responses that occurred on the drug-appropriate lever. The indirect dopamine agonists GBR 12909 (0.2-1.6 mg/kg), mazindol (0.025-0.4 mg/kg), nomifensine (0.025-0.2 mg/kg) and bupropion (0.1-1.6 mg/kg) each produced dose-related increases in cocaine-appropriate responding, with complete substitution for cocaine achieved at the highest doses of each drug. In contrast, the norepinephrine re-uptake blockers tomoxetine (0.8-6.4 mg/kg) and nisoxetine (0.4-1.6 mg/kg), the serotonin re-uptake blocker fluoxetine (1.6-12.8 mg/kg), the D1 agonist SKF 38393 (3.2-12.8 mg/kg) and the D2 agonist quinpirole (0.05-0.2 mg/kg) failed to engender cocaine-appropriate responding. Administration of the D1 antagonist SCH 23390 (0.05-0.2 mg/kg, i.m.) 20 min before cocaine resulted in a 4- to 8-fold parallel shift to the right in the cocaine dose-response function. Similarly, the D2 antagonist haloperidol (0.003-0.012 mg/kg, i.m.) produced at least a 2-fold shift to the right in the cocaine dose-response function. The results indicate that blockade of dopamine re-uptake is sufficient to mimic the cocaine discriminative stimulus and suggest that stimulation of either D1 or D2 receptors is necessary but not sufficient for the expression of the discriminative stimulus effects of cocaine.