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.).
J Pharmacol Exp Ther. 2024 Nov 19;391(3):415-429. doi: 10.1124/jpet.124.002362.
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.
先前的研究表明，多巴胺 D 样和 D 样受体（DR 和 DR，分别）激动剂对可卡因自我给药有不同的影响。DR 激动剂在可卡因自我给药剂量-效应函数中的左移与 DR 激动剂在最大可卡因自我给药中的减少形成对比，而没有右移或左移。DR 激动剂的作用是否归因于 DR 的作用尚不确定，这可能是由于难以分离 DR 拮抗剂对 DR 激动剂和可卡因的作用。在本研究中，DR 激动剂（+）-SKF-81297（0.1-1.0mg/kg）和（±）-SKF-82958（0.032-0.32mg/kg）预处理剂量依赖性地降低了低于影响食物强化反应的剂量的最大可卡因自我给药。相比之下，DR 激动剂（-）-NPA（0.001-0.01mg/kg）和（-）-喹吡罗（0.01-0.1mg/kg）预处理剂量依赖性地向左移动可卡因自我给药剂量-效应函数。DR 拮抗剂 SCH-39166 以剂量依赖性方式拮抗 DR 激动剂对最大可卡因自我给药的减少，而单独使用时对可卡因自我给药没有影响。阻断 DR 激动剂对可卡因自我给药作用的 SCH-39166 剂量与将 DR 激动剂的自我给药向右移位的剂量相似，但对 DR 激动剂的自我给药没有影响。DR 激动剂的自我给药剂量依赖性地被选择性 DR 拮抗剂 L-741,626 向右移位，但不受 SCH-39166 的影响。这些结果表明，DR 激动剂在可卡因自我给药中的减少是选择性 DR 介导的，并支持多巴胺 D 样和 D 样受体在可卡因强化中具有根本不同作用的发现。
多巴胺 D 样（DR）激动剂减少最大可卡因自我给药，而 D 样（DR）激动剂向左移动可卡因自我给药剂量-效应函数，这些不同作用的机制尚不清楚。本研究表明，选择性 DR 拮抗剂 SCH-39166 阻断 DR1 介导的最大可卡因自我给药减少，剂量阻断其他 DR 介导的作用，但不阻断可卡因的作用，这表明多巴胺 D 样和 D 样受体在可卡因强化和 DR 激动剂的开发中具有根本不同的作用，作为可卡因使用障碍的潜在治疗方法。
