Abstract: Close to 90% of individuals 18 years and older in the United States will consume alcohol at some point in their lives. Although 7% of men have alcohol use disorder (AUD) compared to 4% of women, women are more at risk for the negative health and safety effects of alcohol. Therefore, understanding sex differences is important to understanding mechanisms behind individual differences in vulnerability to developing AUD and its pathology. Allopregnanolone, a metabolite of the steroid hormone, progesterone, is a positive allosteric modulator of GABA, the main inhibitory neurotransmitter in the brain. This specific endogenous neuroactive steroid produces similar anxiolytic effects to that of ethanol by potentiating the inhibitory function of GABAA receptors and modulating the acute effect of the drug. Repeat exposure to alcohol reduces the anxiolytic effects of the drug and may involve changes in the synthesis of these endogenous neurosteroids. Here, we assessed rapid tolerance to the anxiolytic effect of ethanol by measuring avoidance behaviors of mice in the elevated plus-maze (EPM) after exposure to ethanol. Future studies will perform IHC to compare the activity of neurosteroid-sensitive GABAergic interneurons in the basolateral amygdala across treatment and sex, and ELISA assays to compare changes in circulating progesterone and allopregnanolone levels across males and females. We propose a relationship between the development of tolerance to the anxiolytic effects of ethanol and adaptations in neurosteroidogenesis, and further posit that this relationship may underlie sex differences in the development of rapid tolerance. This ongoing study will strengthen our understanding of potential biological mechanisms mediating susceptibility to alcohol abuse, and has important implications for approaches to hormone-dependent and gender-specific mood disorders.
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