Abstract
Previous studies indicated differing effects of dopamine D(1)-like and D(2)-like receptor (D(1)R and D(2)R, respectively) agonists on cocaine self-administration. Leftward shifts by D(2)R agonists in the cocaine self-administration dose-effect function contrast with decreases by D(1)R agonists in maximal cocaine self-administration without rightward or leftward displacement. Whether the effects of the D(1)R agonists are due to actions at D(1)Rs has not been determined, possibly due to the difficulty in separating the blockade by a D(1)R antagonist of the effects of the D(1)R agonists and those of cocaine. In the present study, pretreatment with the D(1)R 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 D(2)R 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 D(1)R agonists in maximal cocaine self-administration were dose-dependently antagonized by the D(1)R antagonist SCH-39166 at doses that alone had no effects on cocaine self-administration. Doses of SCH-39166 that blocked the effects of the D(1)R agonists on cocaine self-administration were like those that shifted self-administration of D(1)R agonists to the right but had no effects on self-administration of D(2)R agonists. Self-administration of the D(2)R agonists was dose-dependently shifted to the right by the preferential D(2)R antagonist L-741,626 but not by SCH-39166. These results demonstrate that the decreases by the D(1)R agonists in cocaine self-administration are selectively D(1)R-mediated and support findings suggesting fundamentally distinct roles of the D(1)Rs and D(2)Rs in cocaine reinforcement. SIGNIFICANCE STATEMENT: Dopamine D(1)-like (D(1)R) agonists decrease maximal cocaine self-administration, whereas D(2)-like (D(2)R) agonists shift the cocaine self-administration dose-effect function leftward, with mechanisms for those different effects unclear. The present study demonstrates blockade by the selective D(1)R antagonist SCH-39166 of D1R-mediated decreases in maximal cocaine self-administration at doses that blocked other D(1)R-mediated effects but not effects of cocaine, suggesting fundamentally distinct roles of the dopamine D(1)-like and D(2)-like receptors in cocaine reinforcement and development of D(1)R agonists as potential treatments for cocaine use disorder.