The GPR88 Agonist RTI-122 Reduces Alcohol-Related Motivation and Consumption

IF 2.6 3区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY
Dennis F. Lovelock, Wen Liu, Sami Ben Hamida, Victoria L. Cordero, Kalynn J. Van Voorhies, Marion Martin, Isabella Guimaraes Olmo, Emmanuel Darcq, Md Toufiqur Rahman, Mickael Naassila, Brigitte L. Kieffer, Chunyang Jin, Joyce Besheer
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Abstract

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.

Abstract Image

GPR88激动剂RTI-122降低酒精相关动机和消费
GPR88是一种主要在纹状体中表达的孤儿G蛋白偶联受体,由于其在调节奖励和动机通路中的作用,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和自我饮酒动机的影响。在小鼠中,RTI-122在两瓶选择范式中减少了酒精消耗,这被Gpr88敲除所阻止,证实了Gpr88对饮酒衰减的特异性作用。在大鼠中,RTI-122剂量依赖性地减少了操作性酒精自我给药,并降低了进行性比例任务中自我给药的动机,无论酒精是否掺入奎宁。此外,高剂量RTI-122可减少育亨宾诱导的恢复。重要的是,RTI-122不影响小鼠的饮水量或大鼠的蔗糖自我给药,表明受体和奖励特异性调节酒精摄入。这些发现表明,RTI-122通过GPR88的激动作用,有效地减少了各种情况下的酒精消耗和动机,将其定位为开发新的AUD治疗方法的有希望的先导。
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来源期刊
Addiction Biology
Addiction Biology 生物-生化与分子生物学
CiteScore
8.10
自引率
2.90%
发文量
118
审稿时长
6-12 weeks
期刊介绍: Addiction Biology is focused on neuroscience contributions and it aims to advance our understanding of the action of drugs of abuse and addictive processes. Papers are accepted in both animal experimentation or clinical research. The content is geared towards behavioral, molecular, genetic, biochemical, neuro-biological and pharmacology aspects of these fields. Addiction Biology includes peer-reviewed original research reports and reviews. Addiction Biology is published on behalf of the Society for the Study of Addiction to Alcohol and other Drugs (SSA). Members of the Society for the Study of Addiction receive the Journal as part of their annual membership subscription.
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