Alcohol use disorder (AUD) is a chronic condition with devastating health and socioeconomic effects. Still, pharmacotherapies to treat AUD are scarce. In a prior study aimed at identifying novel AUD therapeutic targets, we investigated the DNA methylome of the nucleus accumbens core (NAcc) of rhesus macaques after chronic alcohol use. The G-protein coupled receptor 39 (GPR39) gene was hypermethylated and its expression downregulated in heavy alcohol drinking macaques. GPR39 encodes a Zn2+-binding metabotropic receptor known to modulate excitatory and inhibitory neurotransmission, the balance of which is altered in AUD. These prior findings suggest that a GPR39 agonist would reduce alcohol intake. Using a drinking-in-the-dark two bottle choice (DID-2BC) model, we showed that an acute 7.5 mg/kg dose of the GPR39 agonist, TC-G 1008, reduced ethanol intake in mice without affecting total fluid intake, locomotor activity or saccharin preference. Furthermore, repeated doses of the agonist prevented ethanol escalation in an intermittent access 2BC paradigm (IA-2BC). This effect was reversible, as ethanol escalation followed agonist "wash out". As observed during the DID-2BC study, a subsequent acute agonist challenge during the IA-2BC procedure reduced ethanol intake by ~47%. Finally, Gpr39 activation was associated with changes in Gpr39 and Bdnf expression, and in glutamate release in the NAcc. Together, our findings suggest that GPR39 is a promising target for the development of prevention and treatment therapies for AUD.

中文翻译：

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Gpr39（一种与非人类灵长类动物饮酒相关的 G 蛋白偶联受体）的调节可抑制小鼠的乙醇摄入。


酒精使用障碍 (AUD) 是一种慢性疾病，会对健康和社会经济造成破坏性影响。尽管如此，治疗 AUD 的药物疗法仍然很少。在之前的一项旨在确定新的 AUD 治疗靶点的研究中，我们研究了长期饮酒后恒河猴伏隔核核心 (NAcc) 的 DNA 甲基化组。在大量饮酒的猕猴中，G 蛋白偶联受体 39 (GPR39) 基因高度甲基化，其表达下调。 GPR39 编码一种 Zn2+ 结合代谢型受体，已知可调节兴奋性和抑制性神经传递，其平衡在 AUD 中发生改变。这些先前的研究结果表明 GPR39 激动剂可以减少酒精摄入量。使用黑暗中饮酒两瓶选择 (DID-2BC) 模型，我们发现急性 7.5 mg/kg 剂量的 GPR39 激动剂 TC-G 1008 可减少小鼠的乙醇摄入量，而不影响总液体摄入量，运动活动或糖精偏好。此外，重复剂量的激动剂可防止间歇性 2BC 范式 (IA-2BC) 中乙醇的升高。这种效应是可逆的，因为乙醇的浓度随着激动剂的“清洗”而增加。正如 DID-2BC 研究期间观察到的那样，IA-2BC 过程中随后的急性激动剂激发使乙醇摄入量减少了约 47%。最后，Gpr39 激活与 Gpr39 和 Bdnf 表达以及 NAcc 中谷氨酸释放的变化相关。总之，我们的研究结果表明 GPR39 是开发 AUD 预防和治疗疗法的一个有前途的靶点。