MIFEPRISTONE DECREASES GABA TRANSMISSION IN THE CENTRAL NUCLEUS OF THE AMYGDALA - ROLE OF SEX AND ALCOHOL HISTORY

Previous studies indicate an association between alcohol dependence and levels of phosphorylated glucocorticoid receptors (GR) in the central nucleus of the amygdala (CeA), a brain area highly involved in the development and maintenance of alcohol dependence. Furthermore, systemic and intra-CeA injection of the GR-antagonist mifepristone reduced compulsive-like alcohol consumption. However, the cellular effects of GR-antagonism in the CeA are unknown. Here, using slice electrophysiology we investigated the effects of selective GR-antagonism using mifepristone (10 μM) on CeA spontaneous and evoked GABAergic transmission in naïve and ethanol dependent male and female rats. Our study revealed that mifepristone significantly decreased spontaneous action-potential dependent GABA transmission in the CeA of both naïve and dependent rats via reduced GABA release irrespective of sex. Notably, in males the mifepristone-induced decrease of GABA release was significantly larger in dependent compared to naïve controls. In contrast, mifepristone appeared to be more efficacious in decreasing GABA release in naïve females compared to dependent females. Similar results were observed for mifepristone effects on evoked local CeA GABAergic responses across groups. Importantly, our preliminary data also indicate similar efficacy of mifepristone on GABA transmission in male rats after 2 weeks withdrawal suggesting that alcohol dependence induces long-lasting disruptions of GR-signaling. Collectively, our cellular data highlight potential sex differences in the CeA GR system and further support a role for disrupted CeA GR-signaling in alcohol dependence.