Lovelock Dennis F, Liu Wen, Hamida Sami Ben, Cordero Victoria L, Van Voorhies Kalynn J, Martin Marion, Olmo Isabella Guimaraes, Darcq Emmanuel, Rahman Md Toufiqur, Naassila Mickael, Kieffer Brigitte L, Jin Chunyang, Besheer Joyce
Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
INSERM UMR 1247, University of Picardie Jules Verne, Amiens, France.
Addict Biol. 2025;30(6):e70058. doi: 10.1111/adb.70058.
GPR88, an orphan G protein-coupled receptor primarily expressed in the striatum, has emerged as a potential target for treating alcohol use disorder (AUD) due to its role in modulating reward and motivational pathways. In this study, we investigated the effects of the GPR88 agonist RTI-122 on alcohol intake and motivation to self-administer alcohol under different conditions. In mice, RTI-122 reduced alcohol consumption in a two-bottle choice paradigm, which was prevented by Gpr88 knockout, confirming a GPR88-specific effect on the attenuation of alcohol drinking. In rats, RTI-122 dose-dependently reduced operant alcohol self-administration and decreased motivation to self-administer alcohol in progressive ratio tasks, regardless of whether the alcohol was adulterated with quinine or not. Additionally, a high dose of RTI-122 reduced yohimbine-induced reinstatement. Importantly, RTI-122 did not affect water intake in mice or sucrose self-administration in rats, indicating receptor- and reward-specific modulation of alcohol intake. These findings suggest that RTI-122, through GPR88 agonism, effectively reduces alcohol consumption and motivation across various contexts, positioning it as a promising lead for the development of new AUD treatments.
GPR88是一种主要在纹状体中表达的孤儿G蛋白偶联受体，由于其在调节奖赏和动机途径中的作用，已成为治疗酒精使用障碍（AUD）的潜在靶点。在本研究中，我们研究了GPR88激动剂RTI-122在不同条件下对酒精摄入量和自我给药酒精动机的影响。在小鼠中，RTI-122在双瓶选择范式中减少了酒精消耗，而Gpr88基因敲除可阻止这种减少，证实了GPR88对减少酒精饮用具有特异性作用。在大鼠中，无论酒精是否用奎宁掺假，RTI-122在渐进比率任务中剂量依赖性地减少了操作性酒精自我给药，并降低了自我给药酒精的动机。此外，高剂量的RTI-122减少了育亨宾诱导的复吸。重要的是，RTI-122不影响小鼠的水摄入量或大鼠的蔗糖自我给药，表明对酒精摄入具有受体和奖赏特异性调节。这些发现表明，RTI-122通过激动GPR88，在各种情况下有效地减少了酒精消耗和动机，使其成为开发新的AUD治疗方法的有希望的先导药物。
