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.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Exploratory/Developmental Grants (R21)
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Health Services Research Review Subcommittee (AA)
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Grandison, Lindsey
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Yale University
Schools of Medicine
New Haven
United States
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