Brain Acetate and Ethanol Metabolism in Alcohol Dependence and Abuse

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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.