A reciprocal relationship between alcohol and the p450 enzyme aromatase

酒精和 p450 芳香酶之间的相互关系

• 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
• 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

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.

项目摘要 过度饮酒是我们社会的一个重大问题，它会导致深远的健康、经济、 还有个人问题。类固醇激素雌激素(17β-雌二醇；E_2)在人体各器官中合成。 身体，包括大脑，通过细胞色素P450酶芳香化酶将睾酮转化为E2 (AROM)。研究表明，卵巢中产生的雌激素可以提高对奖励的敏感度、学习能力和酒精含量 消费。此外，有临床证据表明，长期饮酒可能会使arom升高。 活性和E2的合成，这表明额外的芳香烃来源可能有助于酒精相关 行为。我发现急性药物性芳香烃抑制可以减少男性饮酒，每周3次。 狂饮的周期，女性在10个周期之后。终纹床核(BNST) 大脑区域与奖赏、焦虑和成瘾高度相关，是E2受体表达的已知来源 和E2传播。我们的实验室发现，给BNST注射E2会增加酗酒的程度 BNST促肾上腺皮质激素释放因子(CRF)神经元消耗谷氨酸并增加谷氨酸释放。这个 这一建议的首要假设是酒精和芳香烃之间存在相互作用的关系， 因此，饮酒会增加AROM的表达，导致BNST中E2水平的增加，从而 进一步促进饮酒狂欢。我已经制定了一个全面的研究计划来解决 从这一假说中引出的科学问题。在目标1中，我将执行电生理和行为 检查酒精诱导的E2是否在BNST中起促进饮酒作用的技术。在《目标2》中，我会 确定大脑和身体中芳香胺增加的部位，并评估它们在酗酒行为中的作用 使用电生理、分子、遗传和行为技术。拟议的工作旨在提供 关于导致酗酒的机制的信息，并对 过度饮酒是普遍存在的公共卫生问题。