Anjos-Santos Alexia, Erikson Chloe Michelle, Flores-Ramirez Francisco J, Rodriguez Larry, Barchiesi Riccardo, Vozella Valentina, Borgonetti Vittoria, Cruz Bryan, Zalfa Cristina, Hughes Kiley, Gandhi Pauravi, Bajo Michal, Vlkolinsky Roman, Mayfield R Dayne, Martin-Fardon Rémi, Roberto Marisa
Department of Translational Medicine, Scripps Research, La Jolla, California; Department of Pharmacology, Universidade Federal de São Paulo, São Paulo, Brazil.
Department of Translational Medicine, Scripps Research, La Jolla, California.
Biol Psychiatry. 2025 Apr 5. doi: 10.1016/j.biopsych.2025.03.024.
Alcohol use disorder (AUD) is a chronic relapsing disorder and a leading preventable cause of death worldwide. The central nucleus of the amygdala (CeA) is a hub for stress and AUD. Norepinephrine (NE), also known as noradrenaline, regulates the brain's response to stress and alcohol. We previously reported that α-adrenergic receptors drive moderate alcohol intake, while β receptors contribute to excessive drinking associated with dependence in male rats.
Here, we determined that alcohol dependence and withdrawal alter the CeA noradrenergic system in female rats using ex vivo electrophysiology, in situ hybridization, and site-specific behavioral pharmacology. We also analyzed RNA-sequencing data from postmortem CeA samples obtained from female donors with and without AUD.
NE bidirectionally (increase and decrease) modulated CeA GABAergic (gamma-aminobutyric acidergic) transmission via both α and β receptors. Prazosin, an α receptor antagonist, reduced moderate alcohol intake in nondependent female rats and excessive drinking in dependent females, while propranolol, a β receptor antagonist, reduced excessive drinking only in dependent females. While withdrawal produced a partial functional recovery of NE modulation of the CeA, some of the cellular patterns of adrenergic receptor messenger RNA expression persisted. Although we did not observe any differences in adrenergic receptor gene expression in the CeA from our human AUD donors, we found a downregulation of ADRA1A in the basolateral amygdala and the dorsolateral prefrontal cortex compared with control donors.
Amygdalar α- and β-adrenergic receptors are key neural substrates of AUD. Our results support ongoing development of receptor-specific medication for AUD and highlight promising efficacy in females.
酒精使用障碍（AUD）是一种慢性复发性疾病，是全球主要的可预防死亡原因。杏仁核中央核（CeA）是应激和AUD的枢纽。去甲肾上腺素（NE），也称为去甲肾上腺素，调节大脑对应激和酒精的反应。我们之前报道过，α-肾上腺素能受体驱动适度饮酒，而β受体则导致雄性大鼠与依赖相关的过度饮酒。
在这里，我们使用离体电生理学、原位杂交和位点特异性行为药理学方法，确定了酒精依赖和戒断会改变雌性大鼠的CeA去甲肾上腺素能系统。我们还分析了从有和没有AUD的女性供体获得的死后CeA样本的RNA测序数据。
NE通过α和β受体双向（增加和减少）调节CeAγ-氨基丁酸能（GABAergic）传递。α受体拮抗剂哌唑嗪减少了非依赖雌性大鼠的适度饮酒和依赖雌性大鼠的过度饮酒，而β受体拮抗剂普萘洛尔仅减少了依赖雌性大鼠的过度饮酒。虽然戒断使NE对CeA的调节部分功能恢复，但肾上腺素能受体信使RNA表达的一些细胞模式仍然存在。虽然我们在人类AUD供体的CeA中未观察到肾上腺素能受体基因表达的任何差异，但我们发现与对照供体相比，基底外侧杏仁核和背外侧前额叶皮质中的ADRA1A下调。
杏仁核α和β肾上腺素能受体是AUD的关键神经底物。我们的结果支持正在进行的针对AUD的受体特异性药物开发，并突出了在女性中的有前景的疗效。
