Douglas Mental Health University Institute, Montreal, Quebec, Canada.
INSERM UMR 1247, University of Picardie Jules Verne, Amiens, France.
Addict Biol. 2022 Nov;27(6):e13227. doi: 10.1111/adb.13227.
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.
GPR88 是一种孤儿 G 蛋白偶联受体，被认为是治疗神经精神疾病（包括成瘾）的潜在靶点。大多数关于 GPR88 功能的知识都源于基因敲除小鼠研究，而体内药理学研究仍然很少。在这里，我们研究了新型脑穿透激动剂 RTI-13951-33 在几种与酒精相关的小鼠行为中的作用。在间歇性双瓶选择范式中，该化合物减少了过度的自愿饮酒，而饮水量保持不变。这在 C57BL/6 小鼠中观察到，在对照而非 Gpr88 基因敲除小鼠中观察到，证明了该药物在体内的疗效和特异性。在暗室饮酒范式中，RTI-13951-33 也减少了对照而非 Gpr88 基因敲除小鼠的 binge 样饮酒行为，证实了药物的酒精消耗减少作用和体内特异性。当 C57BL/6 小鼠接受酒精自我给药训练时，RTI-13951-33 减少了 4 小时内的鼻触次数，并减少了舔舐次数和舔舐爆发次数，表明获得酒精的动机降低。最后，RTI-13951-33 没有诱导任何位置偏好或厌恶，但减少了对酒精的条件性位置偏好表达，表明减少了对酒精的寻求。总的来说，数据表明，RTI-13951-33 在需要摄取行为、操作性反应或与环境线索相关联的不同条件下限制了酒精摄入。因此，RTI-13951-33 是评估 GPR88 作为治疗酒精使用障碍的潜在靶点的有前途的先导化合物。更广泛地说，RTI-13951-33 代表了一种独特的工具，可以更好地理解 GPR88 的功能，将受体在发育中的作用与成年后的作用区分开来，并可能解决其他神经精神疾病。
