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.

SIGNIFICANCE STATEMENT Dopamine D1-like (D1R) agonists decrease maximal cocaine self-administration, whereas D2-like (D2R) 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 D1R antagonist SCH-39166 of D1R-mediated decreases in maximal cocaine self-administration at doses that blocked other D1R-mediated effects but not effects of cocaine, suggesting fundamentally distinct roles of the dopamine D1-like and D2-like receptors in cocaine reinforcement and development of D1R agonists as potential treatments for cocaine use disorder.

This work was supported by the Intramural Research Program of the National Institute on Drug Abuse (Z1A DA000103-26 to J.L.K.). T.H. was also supported by National Institutes of Health National Institute on Drug Abuse US Public Health Service [Grant R01DA058018].

No author has an actual or perceived conflict of interest with the contents of this article.

Portions of this manuscript were presented as follows: Hiranita T and Katz JL (2011) Contributions of dopamine D1-like and dopamine D2-like receptor to the self-administration of cocaine in rats. Annual Meeting of the Behavioral Pharmacology Society; 2011 Apr 7–8; Washington, DC.

dx.doi.org/10.1124/jpet.124.002362.