Ethanol as Fuel for the Brain in Rats

描述(由申请人提供)：酗酒和依赖是全球健康问题，与许多共病有关。低血糖是一种共病，尤其与酗酒有关。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、酮体和醋酸盐，所有这些都通过相同的单羧酸转运体穿过血脑屏障。饮酒时，身体会将酒精转化为醋酸盐，提高血液中的醋酸盐水平，并可能提供一种替代葡萄糖消耗的大脑燃料。对糖尿病和饥饿时的低血糖的研究表明，由于血液中单羧酸的升高，单羧酸的运输和利用得到了增强。我们假设，反复暴露于高浓度的醋酸盐、酮类和乳酸会增加长期接触乙醇的大鼠的醋酸盐消耗量。我们还假设一些乙醇在大脑中被氧化。我们提出了两个目标，以测量系统生成的醋酸盐和脑内乙醇对12个脑区大脑代谢的相对贡献，并估计脑内酒精消费的潜在神经胶质和神经元贡献的程度。如果这个项目的假设得到支持，酒精的燃料生成方面可能会提供一个新的奖项，促进持续大量饮酒，并延长狂欢的时间。大脑中酒精的消耗可能会提供一种营养奖励，一种乙醛奖励，这可能会导致氧化损伤。需要回答的中心问题是：系统生成的醋酸盐和脑内乙醇在多大程度上为大脑能量代谢提供了底物，酒精消费能否增加这些贡献？二次评估是脑内乙醇氧化的相对神经胶质和神经元部分。在[2-13C]乙酸盐和[2-13C]乙醇的输注过程中，将测量大鼠脑内乙酸乙酯和乙醇的浓度和利用率。这些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。 与公共健康相关：人们的大脑通常几乎所有的能量需求都来自糖类葡萄糖，但有时当人们大量饮酒时，他们的血糖会下降，特别是如果他们饮食不正常的话。为了生存，大脑可能会转向其他替代品，比如肝脏从酒精中产生的醋酸盐，或者酒精本身，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的酒，同时损害脑细胞。在这项研究中，我们将确定酗酒者是否更能将醋酸盐和酒精作为大脑的燃料，如果是的话，那么酗酒者继续饮酒的可能性存在，不仅是因为酒精及其产品的已知药物效应，而且是为了在饮食不正常时为大脑提供营养，支持营养是减少酗酒或停止饮酒的能力的关键因素的观点。

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.