The effects of eticlopride and the selective D₃-antagonist PNU 99194-A on food- and cocaine-maintained responding in rhesus monkeys

The dopamine D₃ receptor is mainly expressed in regions of the brain associated with the limbic system. D₃ receptor blockade may antagonize cocaine reinforcement while producing less severe extrapyramidal side effects than blockade of D₂ receptors. The purpose of the present studies was to evaluate the effects of a selective D₃ receptor antagonist and a non-selective D₂/D₃ receptor antagonist on food- and cocaine-maintained responding under two schedules of cocaine self-administration. Adult male rhesus monkeys were trained to respond under multiple schedules of food (1.0 g pellets) and cocaine (0.01-0.3 mg/kg/injection) presentation. In one experiment (n = 4), the schedule was a fixed-interval (FI) 3-min and a second study (n = 6) was conducted using a second-order fixed-ratio 5 (FI 6-min : S) schedule. The D₃ antagonist PNU 99194-A (0.3-3.0 mg/kg), which is 14-fold selective for D₃ relative to D₂ receptors, or the D₂/D₃ antagonist eticlopride (0.001-0.03 mg/kg) was administered immediately prior to the experimental session for at least 5 consecutive sessions. Under the multiple FI 3-min schedule of food and cocaine presentation, PNU 99194-A and eticlopride decreased food- and cocaine-maintained responding in a dose-dependent manner and irrespective of cocaine dose. Under the multiple second-order schedule of food and cocaine presentation, at least one dose of PNU 99194-A and eticlopride decreased cocaine- and food-maintained responding. These findings indicate that PNU 99194-A can decrease operant responding in monkeys, but not in a manner that would suggest selectivity of cocaine- over food-maintained responding. Future studies with more selective D₃ antagonists are needed to better address the role of this receptor subtype in cocaine addiction.