Dopamine D-Like Receptor-Mediated Insurmountable Blockade of the Reinforcing Effects of Cocaine in Rats.

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