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.