Univ. Bordeaux, CNRS, EPHE, INCIA, UMR 5287, Bordeaux, France.
Institut Pasteur, Université Paris Cité, CNRS UMR 3571, Integrative Neurobiology of Cholinergic Systems, Paris, France.
Transl Psychiatry. 2024 Nov 6;14(1):461. doi: 10.1038/s41398-024-03164-8.
Genome wide association and animal studies have implicated genetic variations in CHRNΑ5, encoding the α5 subunit-containing nicotinic acetylcholine receptors (α5nAChRs), as a risk factor for developing alcohol use disorders (AUDs). To understand how α5nAChR mutations may influence alcohol (EtOH) drinking behavior, we used a two-bottle choice procedure with intermittent access to alcohol in male and female transgenic mice expressing either the highly frequent human single nucleotide polymorphism (α5SNP/rs16969968) or a deletion of the Chrna5 gene (α5KO). AUDs-related preconsommatory traits (anxiety, sensation-seeking and impulsivity) were assessed with a battery of relevant tasks (elevated-plus maze, novel place preference and step-down inhibitory avoidance). The implication of the α5-expressing IPN GABAergic neurons in AUDs and related behavioral traits was verified using neurospecific lentiviral (LV)-induced reexpression of the α5 subunit in α5KOxGAD-Cre mice. Both α5SNP and α5KO mice showed over-consumption of EtOH, but displayed opposite vulnerability profiles consistent with Cloninger's subtypes of human AUDs. α5SNP mice showed Type I-like characteristics, i.e., high anxiety, novelty avoidance, whereas α5KOs exhibited Type II-like features such as low anxiety and high impulsivity. LV re-expression of the α5 subunit in IPN GABAergic neurons restored the control of EtOH intake and improved the impulsive phenotype. We demonstrate that the SNP (rs16969968) or null mutation of Chrna5 result in increased volitional EtOH consumption but opposite effects on anxiety, novelty-seeking and impulsive-like behaviors that match Cloninger type I and II of AUDs, including sex-related variations. IPN GABAergic neurons expressing α5*nAChRs play a key role in limiting both EtOH drinking and motor impulsivity.
全基因组关联和动物研究表明，编码含有α5 亚基的烟碱型乙酰胆碱受体（α5nAChRs）的 CHRNA5 中的遗传变异是导致酒精使用障碍（AUDs）的风险因素。为了了解α5nAChR 突变如何影响酒精（EtOH）的饮酒行为，我们使用了一种双瓶选择程序，雄性和雌性转基因小鼠间歇性地接触酒精，这些转基因小鼠表达的是高度频繁的人类单核苷酸多态性（α5SNP/rs16969968）或 Chrna5 基因缺失（α5KO）。使用相关任务（高架十字迷宫、新颖性位置偏好和下台阶抑制性回避）评估了 AUD 相关的预消费特征（焦虑、寻求刺激和冲动）。通过神经特异性慢病毒（LV）诱导的α5KOxGAD-Cre 小鼠中α5 亚基的重新表达，验证了表达α5 的 IPN GABAergic 神经元在 AUD 和相关行为特征中的作用。α5SNP 和 α5KO 小鼠均表现出 EtOH 的过度消耗，但表现出相反的脆弱性特征，与 Cloninger 人类 AUD 亚型一致。α5SNP 小鼠表现出类似于 I 型的特征，即高焦虑、回避新奇，而α5KOs 则表现出类似于 II 型的特征，如低焦虑和高冲动性。LV 重新表达 IPN GABAergic 神经元中的α5 亚基恢复了 EtOH 摄入的控制，并改善了冲动表型。我们证明，SNP（rs16969968）或 Chrna5 的缺失突变导致自愿性 EtOH 消耗增加，但对焦虑、寻求新奇和冲动样行为的影响相反，与 AUD 的 Cloninger 类型 I 和 II 相匹配，包括性别相关的变化。表达α5*nAChRs 的 IPN GABAergic 神经元在限制 EtOH 饮酒和运动冲动性方面发挥着关键作用。
