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The GPR88 agonist RTI-122 reduces alcohol-related motivation and consumption
Lovelock, D. F., Liu, W., Ben Hamida, S., Victoria, C. L., Voorhies, K. V., Martin, M., Guimaras Olmo, I., Darcq, E., Rahman, M. T., Naassila, M., Kieffer, B. L., Jin, C., & Besheer, J. (2025). The GPR88 agonist RTI-122 reduces alcohol-related motivation and consumption. Addiction Biology, 30(6), Article e70058. https://doi.org/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.
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