BACKGOUND Alcohol use disorder (AUD) is devastating and poorly treated, and innovative targets are actively sought for prevention and treatment. The orphan G protein-coupled receptor GPR88 is enriched in mesocorticolimbic pathways, and Gpr88 knockout mice show hyperactivity and risk-taking behavior, but a potential role for this receptor in drug abuse has not been examined. METHODS We tested Gpr88 knockout mice for alcohol-drinking and -seeking behaviors. To gain system-level understanding of their alcohol endophenotype, we also analyzed whole-brain functional connectivity in naïve mice using resting-state functional magnetic resonance imaging. RESULTS Gpr88 knockout mice showed increased voluntary alcohol drinking at both moderate and excessive levels, with intact alcohol sedation and metabolism. Mutant mice also showed increased operant responding and motivation for alcohol, while food and chocolate operant self-administration were unchanged. Alcohol place conditioning and alcohol-induced dopamine release in the nucleus accumbens were decreased, suggesting reduced alcohol reward in mutant mice that may partly explain enhanced alcohol drinking. Seed-based voxelwise functional connectivity analysis revealed significant remodeling of mesocorticolimbic centers, whose hallmark was predominant weakening of prefrontal cortex, ventral tegmental area, and amygdala connectional patterns. Also, effective connectivity from the ventral tegmental area to the nucleus accumbens and amygdala was reduced. CONCLUSIONS Gpr88 deletion disrupts executive, reward, and emotional networks in a configuration that reduces alcohol reward and promotes alcohol seeking and drinking. The functional connectivity signature is reminiscent of alterations observed in individuals at risk for AUD. The Gpr88 gene, therefore, may represent a vulnerability/resilience factor for AUD, and a potential drug target for AUD treatment.

中文翻译：

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缺乏 Gpr88 的小鼠寻求酒精的增加涉及功能失调的中皮质边缘网络

背景 酒精使用障碍 (AUD) 具有破坏性且治疗效果不佳，因此积极寻求预防和治疗的创新目标。孤儿 G 蛋白偶联受体 GPR88 富含中皮质边缘通路，Gpr88 敲除小鼠表现出多动和冒险行为，但尚未研究该受体在药物滥用中的潜在作用。方法我们测试了 Gpr88 基因敲除小鼠的饮酒和寻求行为。为了获得对其酒精内表型的系统级理解，我们还使用静息状态功能磁共振成像分析了幼稚小鼠的全脑功能连接。结果 Gpr88 基因敲除小鼠在中度和过量水平下自愿饮酒增加，酒精镇静和代谢功能完好。突变小鼠还表现出对酒精的操作性反应和动机增加，而食物和巧克力操作性自我管理没有变化。伏隔核中的酒精位置调节和酒精诱导的多巴胺释放减少，这表明突变小鼠的酒精奖励减少，这可能部分解释了饮酒量增加的原因。基于种子的体素功能连接分析揭示了中皮质边缘中心的显着重塑，其标志是前额叶皮层、腹侧被盖区和杏仁核连接模式的显着减弱。此外，从腹侧被盖区到伏隔核和杏仁核的有效连接减少了。结论 Gpr88 删除破坏了执行、奖励、和情感网络的配置减少酒精奖励并促进酒精寻求和饮酒。功能连接特征让人想起在有 AUD 风险的个体中观察到的改变。因此，Gpr88 基因可能代表 AUD 的脆弱性/恢复力因素，以及 AUD 治疗的潜在药物靶点。