Mood disorders are often comorbid with alcohol use disorder (AUD) and play a considerable role in the development and maintenance of alcohol dependence and relapse. Because of this high comorbidity, it is necessary to determine shared and unique genetic factors driving heavy drinking and negative affective behaviors. In order to identify novel pharmacogenetic targets, a bioinformatics analysis was used to quantify the expression of amygdala K⁺ channel genes that covary with anxiety-related phenotypes in the well-phenotyped and fully sequenced family of BXD strains. We used a model of stress-induced escalation of drinking in alcohol-dependent mice to measure negative affective behaviors during abstinence. A pharmacological approach was used to validate the key bioinformatics findings in alcohol-dependent, stressed mice. Amygdalar expression of Kcnn3 correlated significantly with 40 anxiety-associated phenotypes. Further examination of Kcnn3 expression revealed a strong eigentrait for anxiety-like behaviors and negative correlations with binge-like and voluntary alcohol drinking. Mice treated with chronic intermittent alcohol exposure and repeated swim stress consumed more alcohol in their home cages and showed hypophagia on the novelty-suppressed feeding test during abstinence. Pharmacologically targeting Kcnn gene products with the K_Ca2 (SK) channel-positive modulator 1-EBIO decreased drinking and reduced feeding latency in alcohol-dependent, stressed mice. Collectively, these validation studies provide central nervous system links into the covariance of stress, negative affective behaviors, and AUD in the BXD strains. Further, the bioinformatics discovery tool is effective in identifying promising targets (i.e., K_Ca2 channels) for treating alcohol dependence exacerbated by comorbid mood disorders.

情绪障碍通常与酒精使用障碍 (AUD) 共存，并且在酒精依赖的发展和维持以及复发中发挥着相当大的作用。由于这种高合并症，有必要确定导致酗酒和负面情感行为的共同和独特的遗传因素。为了确定新的药物遗传学靶标，使用生物信息学分析来量化杏仁核 K ⁺通道基因的表达，这些基因在表型良好且测序完全的 BXD 菌株家族中与焦虑相关表型共变。我们使用压力诱导酒精依赖小鼠饮酒增加的模型来测量戒酒期间的负面情感行为。使用药理学方法来验证酒精依赖、应激小鼠的关键生物信息学发现。Kcnn3的杏仁核表达与 40 种焦虑相关表型显着相关。对Kcnn3表达的进一步检查揭示了焦虑样行为的强烈特征，以及与暴饮暴食和自愿饮酒的负相关。接受慢性间歇性酒精暴露和反复游泳压力治疗的小鼠在笼子里消耗了更多的酒精，并在禁欲期间的新奇抑制喂养测试中表现出吞咽不足。_{在药理学上，用 K Ca} 2 (SK) 通道正调节剂 1-EBIO 靶向Kcnn基因产物可减少酒精依赖、应激小鼠的饮酒并缩短进食潜伏期。总的来说，这些验证研究提供了中枢神经系统与 BXD 菌株中压力、负面情感行为和 AUD 的协方差的联系。此外，生物信息学发现工具可有效识别治疗因共病情绪障碍而加剧的酒精依赖的有希望的靶点（即K _Ca 2 通道）。