A reciprocal relationship between alcohol and the p450 enzyme aromatase

项目摘要 过度饮酒是我们社会中的一个重大问题，它对健康、经济、 和个人问题类固醇激素雌激素（17β-雌二醇; E2）在整个器官中合成 身体，包括大脑，通过细胞色素p450芳香酶将睾酮转化为E2 （AROM）。卵巢中产生的E2已被证明可以增加奖励敏感性，学习和酒精 消费此外，有临床证据表明，长期饮酒可能会上调AROM 活性和E2合成，这表明AROM的额外来源可能有助于酒精相关的 行为我发现，急性药理AROM抑制减少饮酒的男性3周后， 酗酒周期和女性10个周期后。终纹床核（BNST）， 与奖赏、焦虑和成瘾高度相关的大脑区域是E2受体表达的已知来源 E2传输我们的实验室发现，给予BNST E2会增加酗酒 消耗和增加谷氨酸释放到BNST促肾上腺皮质激素释放因子（CRF）神经元。的 该建议的首要假设是酒精和AROM之间存在相互关系， 这样，饮酒新兵增加AROM表达，导致BNST中E2张力增加， 进一步促进酗酒。我已经制定了一个全面的研究计划， 从这个假设衍生出来的科学问题。在目标1中，我将执行电生理和行为 技术来检查酒精诱导的E2是否在BNST中起作用以促进饮酒。在目标2中，我将 确定大脑和身体中AROM增加的部位，并评估它们在酗酒行为中的作用 使用电生理学、分子、遗传和行为技术。拟议的工作旨在提供 关于驱动酗酒的机制的信息，并对 过度饮酒是一个普遍的公共卫生问题。

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.