Ethanol as Fuel for the Brain in Rats

乙醇作为大鼠大脑的燃料

• 批准号: 7982345
• 负责人: GRAEME F. MASON
• 金额: $ 23.25万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-10 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7982345
• 关键词: Acetaldehyde; Acetates; Acetyl Coenzyme A; Acids; Alcohol abuse; Alcohol consumption; Alcoholic beverage heavy drinker; Alcohols; Award; Blood; Blood - brain barrier anatomy; Blood Glucose; Body Water; Brain; Brain region; Calories; Chemicals; Chronic; Comorbidity; Consumption; Dependence; Diabetes Mellitus; Drops; Eating; Energy Metabolism; Energy-Generating Resources; Ensure; Ethanol; Ethanol Metabolism; Exposure to; Failure; Funding; Generations; Glucose; Glutamates; Glutamine; Heavy Drinking; Human; Hypoglycemia; Infusion procedures; Ketone Bodies; Ketones; Kinetics; Label; Lead; Liver; Measurement; Measures; Metabolic; Metabolism; Monocarboxylic Acid Transporters; Neuroglia; Neurons; Nutritional; Oxidative Stress; Pattern; Pharmaceutical Preparations; Production; Rattus; Relative (related person); Research Design; Rewards; Route; Source; Starvation; Testing; Time; alcohol effect; alcohol exposure; binge drinking; brain cell; brain metabolism; chronic alcohol ingestion; deprivation; drinking; feeding; global health; novel; nutrition; oxidation; oxidative damage; public health relevance; sugar; vapor

DESCRIPTION (provided by applicant): Alcohol abuse and dependence are global health concerns associated with numerous comorbidities. Hypoglycemia is a comorbidity particularly associated with binge-drinking. Under normal conditions glucose is the primary fuel for brain energy metabolism, but during hypoglycemia the brain may rely increasingly on blood lactate, ketone bodies, and acetate, all of which cross the blood-brain barrier by the same monocarboxylic acid transporter. When drinking, the body converts alcohol to acetate, raising blood acetate levels, and possibly providing an alternate brain fuel partially replacing glucose consumption. Studies of hypoglycemia in diabetes and in starvation show that the transport and utilization of monocarboxylic acids are enhanced by blood elevations in monocarboxlyic acids. We hypothesize that repeated exposure to elevated acetate, ketones, and lactate will increase consumption of acetate in rats chronically exposed to ethanol. We also hypothesize that some ethanol is oxidized within the brain. We propose two aims to measure the relative contributions of systemically generated acetate and intracerebral ethanol to brain metabolism in 12 brain regions and estimate the extent of potential glial and neuronal contributions to intracerebral ethanol consumption. If the hypotheses of this project are supported, the fuel-generation aspect of alcohol may provide a novel award that promotes continued heavy drinking and prolongs episodes of binging. The consumption of intracerebral ethanol may provide a nutritive reward, an acetaldehyde reward, which could lead to oxidative damage. The central questions to be answered are these: To what extent do systemically generated acetate and intracerebral ethanol provide substrates for brain energy metabolism, and can ethanol consumption increase those contributions? A secondary assessment is the relative glial and neuronal fractions of intracerebral ethanol oxidation. The concentrations and rates of utilization of acetate and intracerebral ethanol will be measured in rats during infusions of [2-13C]acetate and [2-13C]ethanol. The measurements will utilize 13C MRS of brain extracts to detect time courses of 13C-glutamate and glutamine in the brain. PUBLIC HEALTH RELEVANCE: People's brains usually derive nearly all their energy needs from the sugar glucose, but sometimes when people drink large quantities of alcohol, their blood sugar drops, particularly if they are not eating properly. To survive, the brain may turn to alternatives such as acetate that the liver makes from alcohol, or the alcohol itself, which leads to the formation of other chemicals that may lead people want to drink more, while damaging brain cells. In this study, we will determine if heavy drinkers are more able to use acetate and alcohol as fuels for the brain, and if they are, the possibility exists that heavy drinkers continue drinking not only for the known drug-effects of alcohol and its products, but to provide sustenance for the brain when not eating properly, supporting an idea that nutrition is a key player in the ability to reduce heavy drinking or stop drinking alcohol.

描述（由申请人提供）：酒精滥用和依赖是与许多合并症相关的全球健康问题。低血糖是一种合并症，特别与酗酒有关。在正常情况下，葡萄糖是大脑能量代谢的主要燃料，但在低血糖期间，大脑可能越来越依赖血乳酸、酮体和乙酸盐，所有这些都通过相同的单羧酸转运蛋白穿过血脑屏障。饮酒时，身体会将酒精转化为乙酸盐，从而提高血液中乙酸盐的水平，并可能提供替代的大脑燃料，部分替代葡萄糖的消耗。对糖尿病和饥饿引起的低血糖的研究表明，单羧酸的运输和利用通过血液中单羧酸的升高而增强。我们假设，反复暴露于升高的乙酸盐、酮和乳酸盐会增加长期暴露于乙醇的大鼠的乙酸盐消耗。我们还假设一些乙醇在大脑内被氧化。我们提出了两个目标，测量系统产生的乙酸盐和脑内乙醇对 12 个脑区的脑代谢的相对贡献，并估计神经胶质和神经元对脑内乙醇消耗的潜在贡献程度。如果该项目的假设得到支持，那么酒精的燃料生成方面可能会提供一个新的奖励，促进持续大量饮酒并延长暴饮暴食的时间。脑内乙醇的消耗可能提供营养奖励，即乙醛奖励，这可能导致氧化损伤。要回答的核心问题是：系统产生的乙酸盐和脑内乙醇在多大程度上为脑能量代谢提供底物，乙醇消耗能否增加这些贡献？次要评估是脑内乙醇氧化的相对神经胶质和神经元部分。在输注[2-13C]乙酸盐和[2-13C]乙醇期间，将在大鼠中测量乙酸盐和脑内乙醇的浓度和利用率。测量将利用大脑提取物的 13C MRS 来检测大脑中 13C-谷氨酸和谷氨酰胺的时间进程。 公众健康相关性：人们的大脑通常几乎所有的能量需求都来自葡萄糖，但有时当人们大量饮酒时，他们的血糖会下降，特别是在饮食不当的情况下。为了生存，大脑可能会转向替代品，例如肝脏从酒精中产生的醋酸盐，或酒精本身，这会导致其他化学物质的形成，这些化学物质可能会导致人们想要喝更多，同时损害脑细胞。在这项研究中，我们将确定酗酒者是否更有能力使用醋酸盐和酒精作为大脑的燃料，如果是的话，酗酒者继续饮酒的可能性不仅是因为酒精及其产品的已知药物作用，而是在饮食不当时为大脑提供营养，这支持了这样一种观点，即营养是减少大量饮酒或停止饮酒的能力的关键因素。