A reciprocal relationship between alcohol and the p450 enzyme aromatase

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Project Summary Excessive alcohol consumption is a significant problem in our society that causes far-reaching health, economic, and personal issues. The steroid hormone estrogen (17β-estradiol; E2) is synthesized in organs throughout the body, including the brain, via the conversion of testosterone into E2 by the cytochrome p450 enzyme aromatase (AROM). E2 made in the ovaries has been shown to increase reward sensitivity, learning, and alcohol consumption. In addition, there is clinical evidence that chronic alcohol consumption may upregulate AROM activity and E2 synthesis, suggesting that additional sources of AROM may contribute to alcohol-related behavior. I find that acute pharmacological AROM inhibition reduces alcohol drinking in males following 3 weekly cycles of binge drinking and in females following 10 cycles. The bed nucleus of the stria terminalis (BNST), a brain region highly associated with reward, anxiety, and addiction, is a known source of E2 receptor expression and E2 transmission. Our laboratory has found that E2 administration to the BNST increases binge alcohol consumption and increases glutamate release onto BNST corticotropin releasing factor (CRF) neurons. The overarching hypothesis of this proposal is that there is a reciprocal relationship between alcohol and AROM, such that alcohol drinking recruits increased AROM expression, resulting in increased E2 tone in the BNST that promotes further binge alcohol consumption. I have developed a comprehensive research plan to address the scientific questions derived from this hypothesis. In Aim 1, I will execute electrophysiological and behavioral techniques to examine whether alcohol-induced E2 acts in the BNST to promote drinking. In Aim 2, I will determine sites of increased AROM in the brain and body and evaluate their roles in binge drinking behavior using electrophysiological, molecular, genetic, and behavioral techniques. The proposed work seeks to provide information on the mechanisms driving binge alcohol consumption and has significant implications for the widespread public health issue of excessive alcohol drinking.