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.

摘要 当人们喝酒时，乙醇可以为大脑提供能量，这种供应随着慢性、重度 在大鼠和人类中的暴露。能量部分来自肝脏产生的乙酸盐， 释放到血液中，然后被带到大脑。然而，乙醇也可以在反应器内被氧化。 个脑袋这一过程有助于乙醇的行为效应，包括与酒精相关的运动减少。 乙醇管理大鼠，并可能有关系的脆弱性酒精滥用和如何 发生脑和全身乙醇代谢，尽管这两个过程都是有毒的。我们建议量化 脑乙醇氧化，包括评估过氧化氢酶相对于总脑乙醇的流速的方法 氧化我们将研究大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。 过氧化氢酶被认为主导脑乙醇氧化。我们建议获得运动活动的测量值 以及有和没有过氧化氢酶抑制的代谢，以量化脑乙醇氧化的部分， 通过catalase。有充分的理由相信，雄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，包括慢性乙醇暴露后，所以我们 将研究雄性和雌性大鼠，并使用蒸汽室来实现每日暴露。其他酶， 细胞色素P450，特别是Cyp2e1亚型，以及可能在有限程度上的脑酒精 脱氢酶，也可能有助于脑乙醇氧化。然而，我们正在集中资源， 这个R21项目（1）在代谢率测量的背景下建立酶程序 与行为有关，（2）确定有多少酒精诱导的脑乙醇氧化增加， 是由于过氧化氢酶与其他酶，（3）评估代谢和暴露如何相互作用， 性别行为差异。 该项目与人类健康有关，因为人们知道乙醇对男性和女性的影响不同 有多种原因，这个项目可能会阐明有助于这些性别的代谢机制， 差异这些结果最终将提供有关酶靶点的信息，这些靶点对 防止乙醇的神经毒性作用，这可能与酒精滥用和依赖的脆弱性有关。