Repeated cycles of intoxication and withdrawal enhance the negative reinforcing properties of alcohol and lead to neuroadaptations that underlie withdrawal symptoms driving alcohol dependence. Pharmacotherapies that target these neuroadaptations may help break the cycle of dependence. The sigma-1 receptor (σ1R) subtype has attracted interest as a possible modulator of the rewarding and reinforcing effects of alcohol. However, whether the sigma-2 receptor, recently cloned and identified as transmembrane protein 97 (σ2R/TMEM97), plays a role in alcohol-related behaviors is currently unknown. Using a Caenorhabditis elegans model, we identified two novel, selective σ2R/Tmem97 modulators that reduce alcohol withdrawal behavior via an ortholog of σ2R/TMEM97. We then show that one of these compounds blunted withdrawal-induced excessive alcohol drinking in a well-established rodent model of alcohol dependence. These discoveries provide the first evidence that σ2R/TMEM97 is involved in alcohol withdrawal behaviors and that this receptor is a potential new target for treating alcohol use disorder.

中文翻译：

---

σ2R/ Tmem97的小分子调节剂可减少酒精戒断引起的行为。

重复的中毒和戒断循环会增强酒精的负面增强特性，并导致神经适应，这些神经适应是导致戒酒症状导致酒精依赖的基础。针对这些神经适应的药物治疗可能有助于打破依赖性循环。Sigma-1受体（σ1R）亚型作为酒精的奖励和增强作用的可能调节剂引起了人们的兴趣。然而，目前尚不清楚最近被克隆并鉴定为跨膜蛋白97（σ2R/ TMEM97）的sigma-2受体是否在酒精相关行为中起作用。使用秀丽隐杆线虫模型，我们鉴定了两个新颖的，选择性的σ2R/ Tmem97调节剂，它们通过σ2R/ TMEM97的直系同源物减少酒精戒断行为。然后，我们显示这些化合物之一在公认的酒精依赖啮齿动物模型中减弱了戒断引起的过量饮酒。这些发现提供了第一个证据，证明σ2R/ TMEM97参与戒酒行为，并且该受体是治疗酒精使用障碍的潜在新靶标。