Relationship of Brain Ethanol Oxidation with Behavior

脑乙醇氧化与行为的关系

• 批准号: 10244983
• 负责人: GRAEME F. MASON
• 金额: $ 19.89万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10244983
• 关键词: Acetaldehyde; Acetates; Acute; Adverse effects; Affect; Alcohol abuse; Alcohol consumption; Alcohol dehydrogenase; Alcohol dependence; Alcoholic beverage heavy drinker; Alcohols; Behavior; Behavioral; Blood; Brain; Chronic; Consumption; Cytochrome P450; Data; Dependence; Enzymes; Ethanol; Ethanol Metabolism; Female; Future; Gender; Generations; Glutamates; Glutamine; Health; Hepatic; Human; Infusion procedures; Label; Literature; Liver; Locomotion; Maintenance; Measurement; Measures; Mediating; Metabolic; Metabolism; Methods; Motor Activity; Neuroglia; Neurons; Outcome Measure; Oxides; Pathway interactions; Play; Poison; Procedures; Process; Protein Isoforms; Rat-1; Rattus; Reporting; Resources; Role; Sample Size; Sex Differences; System; Testing; Therapeutic Intervention; Woman; Work; alcohol behavior; alcohol effect; alcohol exposure; alcohol response; awake; base; behavior influence; behavioral response; catalase; enzyme activity; gender difference; inhibitor/antagonist; male; men; metabolic rate; neurotoxic; novel; oxidation; prevent; sex; sobriety; targeted treatment; vapor

Abstract When people drink, the ethanol can provide energy for the brain, and that supply increases with chronic, heavy exposure in rats and humans. The energy derives partly from acetate that is generated hepatically and released into the blood, which is then carried to the brain. However, ethanol can also be oxidized inside the brain. This process contributes to behavioral effects of ethanol, including the locomotor reduction seen with ethanol administration in rats, and there may be relationships between vulnerability to alcohol abuse and how brain and systemic ethanol metabolism occurs, even though both processes are toxic. We propose to quantify brain ethanol oxidation, including a way to assess rates of flow through catalase relative to total brain ethanol oxidation. We will examine how brain ethanol metabolism interacts with gender and chronic ethanol exposure to affect behavior following acute and chronic ethanol exposure. Catalase is believed to dominate brain ethanol oxidation. We propose to obtain measures of locomotor activity and metabolism with and without catalase inhibition to quantify the portion of brain ethanol oxidation that flows through catalase. There is strong reason to believe that male and female rats will differ with respect to enzyme activity, metabolism, and behavioral responses to ethanol, including following chronic ethanol exposure, so we will study male and female rats and use vapor chambers to achieve daily exposure. Other enzymes, cytochrome P450, specifically the Cyp2e1 isoform, and possibly to a limited extent brain alcohol dehydrogenase, may also contribute to brain ethanol oxidation. However, we are focusing the resources of this R21 project on (1) establishing the enzyme procedure in the context of the metabolic rate measurements as related to behavior, (2) determining how much of the exposure-induced increase in brain ethanol oxidation is due to catalase versus other enzymes, and (3) assessing how metabolism and exposure interact to affect behavior differences by sex. The project relates to human health because men and women are known to be affected differently by ethanol for multiple reasons, and this project may illuminate metabolic mechanisms that can contribute to these sex differences. The results will ultimately provide information about enzyme targets of potential importance to prevent the neurotoxic effects of ethanol that may be related to vulnerability to alcohol abuse and dependence.

抽象的 当人们喝酒时，乙醇可以为大脑提供能量，而供应随着慢性，沉重的 老鼠和人类的暴露。能量部分源自乙酸盐，该乙酸盐是肝发出的， 释放到血液中，然后将其传播到大脑。但是，乙醇也可以被氧化 脑。这个过程有助于乙醇的行为影响，包括与 老鼠的乙醇给药，并且脆弱性滥用酒精与如何之间存在关系 即使两个过程都有毒性，大脑和系统性乙醇代谢也会发生。我们建议量化 脑乙醇氧化，包括一种评估过氧化氢酶相对于总脑乙醇的流动速率的方法 氧化。我们将研究脑乙醇代谢如何与性别和慢性乙醇暴露相互作用 影响急性和慢性乙醇暴露后的行为。 据信，过氧化氢酶占主导地位的脑乙醇氧化。我们建议获得运动活性的度量 并具有有或没有过氧化氢酶抑制的代谢，以量化流动的脑乙醇氧化的一部分 通过过氧化氢酶。有充分的理由相信，男性和雌性大鼠在酶方面会有所不同 活动，代谢和对乙醇的行为反应，包括遵循慢性乙醇暴露，所以我们 将研究雄性和雌性大鼠，并使用蒸气室进行日常暴露。其他酶， 细胞色素P450，特别是CYP2E1同工型，可能在有限的程度上 脱氢酶也可能有助于脑乙醇氧化。但是，我们集中于 （1）在代谢率测量的背景下建立酶程序的R21项目 与行为相关，（2）确定暴露诱导的脑乙醇氧化增加了多少 是由于过氧化氢酶与其他酶引起的，（3）评估新陈代谢和暴露与影响的相互作用 性别的行为差异。 该项目与人类健康有关，因为众所周知，男人和女人受到乙醇的影响不同 出于多种原因，该项目可能会阐明可以促成这些性别的代谢机制 差异。结果最终将提供有关潜在重要性的酶的信息 防止乙醇的神经毒性作用可能与酗酒和依赖性有关。