Brain Acetate and Ethanol Metabolism in Alcohol Dependence and Abuse

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，因此在低血糖时，大脑越来越依赖血乳酸、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。当饮酒时，身体将酒精转化为醋酸盐，大脑能够利用醋酸盐，部分取代葡萄糖的消耗。对糖尿病和饥饿时的低血糖的研究表明，低血糖和单羧酸的升高可以促进单羧酸的运输和利用。因此，我们假设，在不进食时，通过反复暴露于高浓度的醋酸盐和急性酒精诱导的低血糖，酗酒者比饮酒者和不饮酒者有更大的能力消费从乙醇中提取的醋酸盐。我们的初步数据支持这一假设，在这项建议中，我们计划通过评估戒酒超过六个月的酒精依赖者的醋酸盐摄入量是否正常化，来测试这种情况是一种状态还是一种特征。我们假设大量饮酒的人会比少量饮酒的人和长期戒酒的人摄入更多的醋酸盐。如果这个项目的假设得到支持，酒精产生燃料的方面可能会提供一种新的奖励机制，促进酗酒的持续，并有助于延长酗酒的时间。另一种来自酒精氧化的化学物质是乙醛，它在大脑中有益，但在身体的其他部位却令人厌恶。如果大脑不仅可以从醋酸盐中获得能量，而且还可以从大脑中乙醇的氧化中获得能量，那么大脑就可以产生乙醛，从而产生另一个饮酒的触发因素。我们假设大脑确实会氧化乙醇，而且酗酒者比饮酒者氧化更多。如果人类大脑氧化乙醇，它会为人类提供一种新的奖励机制，这种机制可以通过遗传学和家族史等多种方法进行研究。这些问题将在13C标记的醋酸盐或乙醇输注过程中用13C MRS得到回答。

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, so in hypoglycemia the brain relies 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, and the brain is able to utilize the acetate, partially replacing glucose consumption. Studies of hypoglycemia in diabetes and in starvation show that the transport and utilization of monocarboxylic acids are enhanced by hypoglycemia and by elevations in monocarboxlyic acids. Therefore, we hypothesize that through repeated exposure to elevated acetate and acute alcohol-induced hypoglycemia when not eating, heavy drinkers have a greater capacity to consume the acetate derived from ethanol than are light drinkers and non-drinkers. Our preliminary data support this hypothesis, and in this proposal we plan to test whether the condition is a state or a trait, by assessing if acetate consumption normalizes in alcohol-dependent people who have been sober for more than six months. We hypothesize that the heavy drinkers will consume more acetate than the light drinkers and long-term sober individuals. If the hypotheses of this project are supported, the fuel-generation aspect of alcohol may provide a novel reward mechanism that promotes the continuation of heavy drinking and helps to prolong episodes of binge-drinking. Another chemical derived from oxidation of alcohol is acetaldehyde, which is rewarding in the brain but aversive in the rest of the body. If the brain can derive energy not only from acetate, but also from the oxidation of ethanol within the brain, then the brain can generate acetaldehyde, creating another trigger to drink alcohol. We hypothesize that the brain does oxidize ethanol and that heavy drinkers oxidize more than light drinkers. If the human brain oxidizes ethanol, it provides a novel reward mechanism in humans, a mechanism that can be investigated with many approaches such as genetics and family history. These questions will be answered with 13C MRS during infusions of 13C-labeled acetate or ethanol.