The Scripps Research Institute, Department of Molecular Medicine, 10550 N Torrey Pines Rd, La Jolla, CA 92037, USA.
Alcohol Alcohol. 2021 Aug 30;56(5):581-588. doi: 10.1093/alcalc/agab034.
Alcohol use disorder (AUD) is linked to hyperactivity of brain stress systems, leading to withdrawal states which drive relapse. AUD differs among the sexes, as men are more likely to have AUD than women, but women progress from casual use to binge and heavy alcohol use more quickly and are more likely to relapse into repetitive episodes of heavy drinking. In alcohol dependence animal models of AUD, the central amygdala (CeA) functions as a hub of stress and anxiety processing and gamma-Aminobutyric acid (GABA)ergic signaling within the CeA is involved in dependence-induced increases in alcohol consumption. We have shown dysregulation of CeA GABAergic synaptic signaling in alcohol dependence animal models, but previous studies have exclusively used males.
Here, we used whole-cell patch clamp electrophysiology to examine basal CeA GABAergic spontaneous inhibitory postsynaptic currents (sIPSC) and the effects of acute alcohol in both naïve and alcohol dependent rats of both sexes.
We found that sIPSC kinetics differ between females and males, as well as between naïve and alcohol-dependent animals, with naïve females having the fastest current kinetics. Additionally, we find differences in baseline current kinetics across estrous cycle stages. In contrast to the increase in sIPSC frequency routinely found in males, acute alcohol (11-88 mM) had no effect on sIPSCs in naïve females, however the highest concentration of alcohol increased sIPSC frequency in dependent females.
These results provide important insight into sex differences in CeA neuronal function and dysregulation with alcohol dependence and highlight the need for sex-specific considerations in the development of effective AUD treatment.
酒精使用障碍（AUD）与大脑应激系统的过度活跃有关，导致戒断状态，从而促使复发。AUD 在性别之间存在差异，男性比女性更容易出现 AUD，但女性从偶尔使用发展为狂欢和重度饮酒的速度更快，并且更有可能反复出现重度饮酒。在 AUD 的酒精依赖动物模型中，中央杏仁核（CeA）作为应激和焦虑处理的枢纽，CeA 内的γ-氨基丁酸（GABA）能信号参与了依赖诱导的酒精摄入量增加。我们已经表明，在酒精依赖动物模型中，CeA GABA 能突触信号传导失调，但以前的研究仅使用雄性动物。
在这里，我们使用全细胞膜片钳电生理学技术，研究了两性未受酒精影响和酒精依赖的大鼠的 CeA GABA 能自发性抑制性突触后电流（sIPSC）的基础活动以及急性酒精的影响。
我们发现，sIPSC 动力学在雌性和雄性之间以及在未受酒精影响和酒精依赖的动物之间存在差异，未受酒精影响的雌性动物具有最快的电流动力学。此外，我们还发现基线电流动力学在发情周期各阶段存在差异。与通常在雄性中发现的 sIPSC 频率增加相反，急性酒精（11-88mM）对未受酒精影响的雌性动物的 sIPSCs 没有影响，但最高浓度的酒精增加了依赖雌性动物的 sIPSC 频率。
这些结果为 CeA 神经元功能和酒精依赖时的失调中的性别差异提供了重要的见解，并强调了在开发有效的 AUD 治疗方法时需要考虑性别特异性。
