The GPR88 agonist RTI-13951-33 reduces alcohol drinking and seeking in mice

Sami Ben Hamida (1) , Michelle Carter , Emmanuel Darcq (2) , Marion Sourty (3, 4, 5) , Md Toufiqur Rahman (6) , Ann M. Decker , Chunyang Jin (7) , Brigitte L. Kieffer (8, 9, 10, 7)

1 GRAP - Groupe de Recherche sur l'alcool et les pharmacodépendances - UMR INSERM_S 1247
2 NCPS - Neuropsychologie Cognitive et Physiopathologie de la Schizophrénie
3 ICube - Laboratoire des sciences de l'ingénieur, de l'informatique et de l'imagerie
4 IMIS - Imagerie Multimodale Intégrative en Santé [Strasbourg]
5 The University of Sydney
6 Center for Drug Discovery
7 Douglas Hospital Research Center, Department of Psychiatry, Faculty of Medicine
8 IGBMC - Institut de génétique et biologie moléculaire et cellulaire
9 CNRS - Centre National de la Recherche Scientifique
10 UNISTRA - Université de Strasbourg

GPR88 is an orphan G-protein-coupled receptor that is considered a potential target to treat neuropsychiatric disorders, including addiction. Most knowledge about GPR88 function stems from knockout mouse studies, and in vivo pharmacology is still scarce. Here we examine the effects of the novel brain-penetrant agonist RTI-13951-33 on several alcohol-related behaviours in the mouse. In the intermittent-access-two-bottle-choice paradigm, the compound reduced excessive voluntary alcohol drinking, while water drinking was intact. This was observed for C57BL/6 mice, as well as for control but not Gpr88 knockout mice, demonstrating efficacy and specificity of the drug in vivo. In the drinking-in-the-dark paradigm, RTI-13951-33 also reduced binge-like drinking behaviour for control but not Gpr88 knockout mice, confirming the alcohol consumption-reducing effect and in vivo specificity of the drug. When C57BL/6 mice were trained for alcohol self-administration, RTI-13951-33 decreased the number of nose-pokes over a 4-h session and reduced the number of licks and bursts of licks, suggesting reduced motivation to obtain alcohol. Finally, RTI-13951-33 did not induce any place preference or aversion but reduced the expression of conditioned place preference to alcohol, indicative of a reduction of alcohol-reward seeking. Altogether, data show that RTI-13951-33 limits alcohol intake under distinct conditions that require consummatory behaviour, operant response or association with contextual cues. RTI-13951-33 therefore is a promising lead compound to evaluate GPR88 as a therapeutic target for alcohol use disorders. More broadly, RTI-13951-33 represents a unique tool to better understand GPR88 function, disentangle receptor roles in development from those in the adult and perhaps address other neuropsychiatric disorders.

Mots clés: alcohol use disorder; GPR88; in vivo pharmacology; mouse behaviour; agonist

Domaines: Médecine humaine et pathologie

Sami Ben Hamida, Michelle Carter, Emmanuel Darcq, Marion Sourty, Md Toufiqur Rahman, et al.. The GPR88 agonist RTI-13951-33 reduces alcohol drinking and seeking in mice. Addiction Biology, 2022, 27 (6), ⟨10.1111/adb.13227⟩. ⟨hal-03767753⟩