| Autor: |
Hiranita T; Department of Pharmacology, Joe R. and Teresa Lozano Long School of Medicine, UT Health San Antonio, San Antonio, Texas (T.H.); Department of Psychology, Louisiana State University, Baton Rouge, Louisiana (P.L.S.); and Psychobiology Section, Molecular Neuropsychiatry Research Branch, Intramural Research Program, Department of Health and Human Services, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland (J.L.K.)., Soto PL; Department of Pharmacology, Joe R. and Teresa Lozano Long School of Medicine, UT Health San Antonio, San Antonio, Texas (T.H.); Department of Psychology, Louisiana State University, Baton Rouge, Louisiana (P.L.S.); and Psychobiology Section, Molecular Neuropsychiatry Research Branch, Intramural Research Program, Department of Health and Human Services, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland (J.L.K.)., Katz JL; Department of Pharmacology, Joe R. and Teresa Lozano Long School of Medicine, UT Health San Antonio, San Antonio, Texas (T.H.); Department of Psychology, Louisiana State University, Baton Rouge, Louisiana (P.L.S.); and Psychobiology Section, Molecular Neuropsychiatry Research Branch, Intramural Research Program, Department of Health and Human Services, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland (J.L.K.). |
| Abstrakt: |
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.
(U.S. Government work not protected by U.S. copyright.) |
