Sex Differences in Acute Alcohol Sensitivity of Naive and Alcohol Dependent Central Amygdala GABA Synapses

Aims: 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. Methods: 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 naive and alcohol dependent rats of both sexes. Results: We found that sIPSC kinetics differ between females and males, as well as between naive and alcohol-dependent animals, with naive 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 naive females, however the highest concentration of alcohol increased sIPSC frequency in dependent females. Conclusion: 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.

Automated summary

The study reveals gender and baseline differences in the dynamics of CeA GABAergic spontaneous inhibitory postsynaptic currents in female and male rats. While acute alcohol has no effect on sIPSCs in naive female rats, it increases sIPSC frequency in dependent female rats. These findings emphasize the importance of considering sex-specific factors in the development of effective treatment for AUD.