Abstract

Previous studies indicated differing effects of dopamine D₁-like and D₂-like receptor (D₁R and D₂R, respectively) agonists on cocaine self-administration. Leftward shifts by D₂R agonists in the cocaine self-administration dose-effect function contrast with decreases by D₁R agonists in maximal cocaine self-administration without rightward or leftward displacement. Whether the effects of the D₁R agonists are due to actions at D₁Rs has not been determined, possibly due to the difficulty in separating the blockade by a D₁R antagonist of the effects of the D₁R agonists and those of cocaine. In the present study, pretreatment with the D₁R agonists R(+)-SKF-81297 (0.1–1.0 mg/kg) and (±)-SKF-82958 (0.032–0.32 mg/kg) dose-dependently decreased maximal cocaine self-administration at doses below those affecting food-reinforced responding. In contrast, pretreatment with the D₂R agonists R(−)-NPA (0.001–0.01 mg/kg) and (−)-quinpirole (0.01–0.1 mg/kg) dose-dependently left-shifted the cocaine self-administration dose-effect function. The decreases by D₁R agonists in maximal cocaine self-administration were dose-dependently antagonized by the D₁R antagonist SCH-39166 at doses that alone had no effects on cocaine self-administration. Doses of SCH-39166 that blocked the effects of the D₁R agonists on cocaine self-administration were like those that shifted self-administration of D₁R agonists to the right but had no effects on self-administration of D₂R agonists. Self-administration of the D₂R agonists was dose-dependently shifted to the right by the preferential D₂R antagonist L-741,626 but not by SCH-39166. These results demonstrate that the decreases by the D₁R agonists in cocaine self-administration are selectively D₁R-mediated and support findings suggesting fundamentally distinct roles of the D₁Rs and D₂Rs in cocaine reinforcement.