Blockade of the discriminative stimulus effects of cocaine in rhesus monkeys with the D(1) dopamine antagonists SCH-39166 and A-66359.

Rhesus monkeys were trained in a 2-lever, food-reinforced drug discrimination paradigm to discriminate cocaine (0.2 or 0.4mg/kg, i.m., 10min pre-session) from saline. Before test sessions, in which responding on either lever was reinforced, the monkeys were injected with various doses of cocaine alone or in combination with the D(1) dopamine antagonists SCH-39166 or A-66359. Administration of cocaine alone (0.025-0.4mg/kg, i.m.) resulted in a dose-related increase in the percent of responses that occurred on the drug-appropriate lever. Both SCH-39166 (0.05-0.1mg/kg, i.m., 60min pre-session) and A-66359 (0.2-0.4mg/kg, i.m., 30min pre-session) reduced cocaine-appropriate responding from more than 80% to less than 20% at least at one dose combination in all monkeys. Also for both drugs and in all monkeys, the blockade was overcome by increasing the dose of cocaine. SCH-39166 was more potent and longer acting than A-66359. The results provide further evidence that D(1) dopamine receptors are involved in the discriminative stimulus effects of cocaine and that D(1) antagonists may block the subjective effects of cocaine.