A reciprocal relationship between alcohol and the p450 enzyme aromatase

酒精和 p450 芳香酶之间的相互关系

基本信息

批准号：
10386167
负责人：
Lia Juliet Zallar
金额：
$ 4.6万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-30 至 2024-09-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10386167
关键词：
Acute Address Adipose tissue Alcohol consumption Alcohols Anxiety Aromatase Aromatase Inhibition Aromatase Inhibitors Attenuated Automobile Driving Bathing Behavior Behavioral Brain Brain region Chronic Clinical Corticotropin-Releasing Hormone Cytochrome P450 Data Electrophysiology (science)Enzymes Estradiol Estrogens Female Feminization Frequencies Fulvestrant Glutamates Gonadal structure Heavy Drinking Laboratories Learning Letrozole Link Liver LoxP-flanked allele Maintenance Malignant Neoplasms Measurement Measures Mediating Molecular Genetics Mus Neurons Organ Ovary Pathologic Peripheral Pharmacology Physiology Plasma Play Process Public Health Recording of previous events Research Rewards Risk Factors Role Signal Transduction Site Societies Source Stress Structure of terminal stria nuclei of preoptic region Sucrose Synaptic Transmission Techniques Testosterone Time Tissues Up-Regulation Viral Water Work addiction alcohol abuse therapy alcohol behavior alcohol exposure alcohol measurement alcohol use disorder anastrozole binge drinking brain tissue chronic alcohol ingestion drinking drinking behavior drinking water health economics inhibitor/antagonist knock-down male men postsynaptic protein expression receptor receptor expression recruit relating to nervous system response sex social steroid hormone transmission process

项目摘要

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.

项目概要过量饮酒是我们社会的一个重大问题，会造成深远的健康、经济、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) 在卵巢中产生的 E2 已被证明可以提高奖赏敏感性、学习能力和酒精含量。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，表明 AROM 的其他来源可能有助于酒精相关我发现，每周 3 周后，急性药理学 AROM 抑制可减少男性的饮酒量。酗酒周期和女性 10 个周期后的终纹床核 (BNST)。与奖励、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我们的实验室发现，给予 BNST 的 E2 会增加酗酒的风险。消耗并增加 BNST 促肾上腺皮质激素释放因子 (CRF) 神经元上谷氨酸的释放。该提案的总体假设是酒精和 AROM 之间存在相互关系，饮酒会增加 AROM 表达，导致 BNST 中 E2 音调增加，促进进一步酗酒我制定了一项全面的研究计划来解决这个问题。在目标 1 中，我将执行电生理学和行为学问题。技术来检查酒精诱导的 E2 是否在 BNST 中发挥作用，以促进饮酒。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拟议的工作旨在利用电生理学、分子、遗传和行为技术提供。有关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。