Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California; Developmental Exposure Alcohol Research Center and Behavioral Neuroscience Program, Department of Psychology, Binghamton University, State University of New York, Binghamton, New York.
Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California; Systems Neurobiology Laboratory, Salk Institute for Biological Studies, La Jolla, California.
Biol Psychiatry. 2022 Jun 15;91(12):1008-1018. doi: 10.1016/j.biopsych.2022.02.006. Epub 2022 Apr 13.
Alcohol use disorder (AUD) is a leading preventable cause of death. The central amygdala (CeA) is a hub for stress and AUD, while dysfunction of the noradrenaline stress system is implicated in AUD relapse.
Here, we investigated whether alcohol (ethanol) dependence and protracted withdrawal alter noradrenergic regulation of the amygdala in rodents and humans. Male adult rats were housed under control conditions, subjected to chronic intermittent ethanol vapor exposure to induce dependence, or withdrawn from chronic intermittent ethanol vapor exposure for 2 weeks, and ex vivo electrophysiology, biochemistry (catecholamine quantification by high-performance liquid chromatography), in situ hybridization, and behavioral brain-site specific pharmacology studies were performed. We also used real-time quantitative polymerase chain reaction to assess gene expression of α, β, and β adrenergic receptors in human postmortem brain tissue from men diagnosed with AUD and matched control subjects.
We found that α receptors potentiate CeA GABAergic (gamma-aminobutyric acidergic) transmission and drive moderate alcohol intake in control rats. In dependent rats, β receptors disinhibit a subpopulation of CeA neurons, contributing to their excessive drinking. Withdrawal produces CeA functional recovery with no change in local noradrenaline tissue concentrations, although there are some long-lasting differences in the cellular patterns of adrenergic receptor messenger RNA expression. In addition, postmortem brain analyses reveal increased α receptor messenger RNA in the amygdala of humans with AUD.
CeA adrenergic receptors are key neural substrates of AUD. Identification of these novel mechanisms that drive alcohol drinking, particularly during the alcohol-dependent state, supports ongoing new medication development for AUD.
酒精使用障碍（AUD）是可预防的主要死亡原因之一。中央杏仁核（CeA）是应激和 AUD 的中心，而去甲肾上腺素应激系统的功能障碍与 AUD 复发有关。
在这里，我们研究了酒精（乙醇）依赖和长期戒断是否会改变啮齿动物和人类杏仁核的去甲肾上腺素调节。雄性成年大鼠在对照条件下饲养，或接受慢性间歇性乙醇蒸气暴露以诱导依赖，或从慢性间歇性乙醇蒸气暴露中戒断 2 周，然后进行离体电生理学、生物化学（高效液相色谱法测定儿茶酚胺）、原位杂交和行为脑特异性药理学研究。我们还使用实时定量聚合酶链反应来评估男性 AUD 诊断和匹配对照受试者的人脑组织中α、β和β肾上腺素能受体的基因表达。
我们发现α受体增强 CeA GABA 能（γ-氨基丁酸能）传递，并驱动对照大鼠适度饮酒。在依赖大鼠中，β受体抑制 CeA 神经元的一个亚群，导致它们过度饮酒。戒断导致 CeA 功能恢复，局部去甲肾上腺素组织浓度无变化，尽管肾上腺素能受体信使 RNA 表达的细胞模式存在一些持久的差异。此外，死后大脑分析显示 AUD 患者杏仁核中的α受体信使 RNA 增加。
CeA 肾上腺素能受体是 AUD 的关键神经底物。这些驱动饮酒的新机制的确定，特别是在酒精依赖状态下，支持了 AUD 新药物的持续开发。
