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 当人们饮酒时，乙醇可以为大脑提供能量，随着慢性、重度饮酒的增加，这种供应会增加 在老鼠和人身上暴露。能量部分来自肝脏产生的醋酸盐，以及 释放到血液中，然后被输送到大脑。然而，乙醇也可以在 大脑。这一过程有助于酒精的行为影响，包括运动减少。 酒精对大鼠的影响，以及酒精滥用的易感性与 大脑和全身的乙醇代谢会发生，尽管这两个过程都是有毒的。我们建议量化 大脑乙醇氧化，包括一种评估过氧化氢酶相对于大脑总乙醇流动速率的方法 氧化。我们将研究大脑酒精代谢如何与性别和长期酒精暴露相互作用 影响急性和慢性酒精暴露后的行为。 过氧化氢酶被认为是大脑乙醇氧化的主导者。我们建议获取运动活动的测量方法 在有和没有过氧化氢酶抑制的情况下进行代谢，以量化大脑中流动的乙醇氧化部分 通过过氧化氢酶。有很强的理由相信雄性和雌性大鼠在酶方面会有所不同。 对酒精的活动、新陈代谢和行为反应，包括慢性酒精暴露后，所以我们 将研究雄性和雌性大鼠，并使用蒸汽室来实现日常暴露。其他酶， 细胞色素P450，特别是CYP2E1亚型，可能在一定程度上是脑酒精 脱氢酶，也可能有助于大脑的乙醇氧化。然而，我们正在将资源集中在 这个R21项目是关于(1)在代谢率测量的背景下建立酶程序 与行为有关，(2)确定暴露导致大脑乙醇氧化增加的程度 是由于过氧化氢酶而不是其他酶，以及(3)评估新陈代谢和暴露如何相互影响 不同性别的行为差异。 该项目与人类健康有关，因为众所周知，酒精对男性和女性的影响不同。 由于多种原因，这个项目可能会阐明有助于这些性行为的代谢机制 不同之处。这些结果最终将提供有关酶靶标的信息，这些酶靶标对 防止酒精的神经毒性效应，这可能与酒精滥用和依赖的脆弱性有关。