Ethanol as Fuel for the Brain in Rats

描述（由申请人提供）：酒精滥用和依赖是与多种合并症相关的全球健康问题。低血糖症是一种与暴饮暴食特别相关的合并症。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于血乳酸、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。当饮酒时，身体将酒精转化为乙酸盐，提高血液中的乙酸盐水平，并可能提供替代大脑的燃料，部分取代葡萄糖的消耗。对糖尿病和饥饿中低血糖的研究表明，血液中一元羧酸的升高可增强一元羧酸的转运和利用。我们假设，反复暴露于升高的醋酸盐、酮和乳酸盐会增加长期暴露于乙醇的大鼠的醋酸盐消耗。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，以测量系统产生的乙酸和脑内乙醇的脑代谢的相对贡献在12个脑区，并估计潜在的神经胶质细胞和神经元的贡献脑内乙醇消耗的程度。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，促进持续大量饮酒和酗酒。脑内乙醇的消耗可能提供一种营养奖励，一种乙醛奖励，这可能导致氧化损伤。要回答的核心问题是：在多大程度上系统产生的乙酸和脑内乙醇提供大脑能量代谢的底物，乙醇消费可以增加这些贡献？次要评估是脑内乙醇氧化的相对胶质细胞和神经元分数。在输注[2- 13 C]乙酸盐和[2- 13 C]乙醇期间，将测量大鼠中乙酸盐和脑内乙醇的浓度和利用率。测量将利用脑提取物的13 C MRS来检测脑中13 C-谷氨酸和谷氨酰胺的时间过程。 公共卫生相关性：人们的大脑通常几乎所有的能量需求都来自葡萄糖，但有时当人们喝大量的酒时，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，大脑可能会转向替代品，例如肝脏从酒精中产生的乙酸盐，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，我们将确定重度饮酒者是否更能够使用醋酸盐和酒精作为大脑的燃料，如果是的话，重度饮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，而且是为了在饮食不当时为大脑提供营养，支持这样一种观点，即营养是减少大量饮酒或停止饮酒的关键因素。

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.