Drinking, Brain Acetate, and Stress - Abstract Alcohol abuse and dependence are global health concerns associated with numerouus comorbidities. Under normal conditions glucose is the primary fuel for brain energy metabolism, but when people drink, the liver converts most of the alcohol to acetate, and the brain utilizes that 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, and in single occipital volumes of the brain, we see alterations in brain acetate oxidation that are associated with drinking. Those alterations parallel certain changes that are also seen with cortisol and possibly regional brain volume loss. We now have the capacity to map brain acetate oxidation throughout the brain using a novel method called Deuterium Metabolic Imaging (DMI) together with administration of deuterated acetate, and we plan to test for relationships of regional brain acetate oxidation with cortisol, stress, alcohol-related behavior, and regional brain volumes. We hypothesize that frequent, intermittent exposure to elevated acetate can increase brain acetate oxidation globally and regionally, and that the near constant elevations of acetate in alcohol dependence has the opposite effect. We further propose that acetate oxidation is associated with brain volume deficits and cortisol levels and turnover. Our preliminary data support these hypotheses, 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. 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 binging in heavy, non-dependent drinkers and may promote prolongation of binges for caloric benefits. In dependent individuals, a reduction in the ability to oxidize acetate may exacerbate symptoms of withdrawal, which raises the possiblity of adjunct therapies of monocarboxylic acids like ketone bodies for detoxification. Because acetate is a significant contributor to cortisol synthesis, we will check for relationships between brain acetate oxidation and cortisol turnover using blood samples obtained during the DMI sessions.
