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 rats are 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, ketones, lactate, and hypoglycemia, heavy drinkers who experience repeated episodes of hypoglycemia are more able to consume the acetate derived from ethanol than are light drinkers and non-drinkers. If the hypotheses of this project are supported, the fuel-generation aspect of alcohol may provide a novel award mechanism that promotes the continuation of heavy drinking and helps to prolong episodes of binge-drinking. The central question to be answered is this: Can heavy drinkers readily transport and utilize acetate for brain energy metabolism? A secondary question will be answered: For brain metabolism, do heavy drinkers more readily transport and utilize acetate than light/non- drinkers? These questions will be examined in three components during infusions of [2-13C]acetate. Measurements will be (1) brain acetate concentrations, (2) oxidize acetate more rapidly, and (3) blood-brain transport capacity of heavy drinkers relative to light/non-drinkers. The concentrations and rates of utilization acetate will be measured in 10 heavy drinkers and 10 light/non-drinkers during infusions of [2-13C]acetate. The measurements will utilize 13C MRS at 4 Tesla to detect the time courses of 13C-labeled acetate, glutamate, and glutamine in the brain.

Public Health Relevance

Under most circumstances, people's brains derive nearly all their energy needs from the sugar glucose. Sometimes when people drink large quantities of alcohol, their blood sugar drops, particularly if they are not eating properly, and to survive, the brain must find alternatives to glucose. One alternative chemical that the brain can consume is acetate that the body forms from alcohol. In this study, we will determine if heavy drinkers are more able to use acetate as fuel for the brain. If they are, the possibility exists that heavy drinkers continue drinking not only for the known drug-effects of alcohol, but to provide sustenance for the brain when they do not eat 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)
Project #
Application #
Study Section
Health Services Research Review Subcommittee (AA)
Program Officer
Matochik, John A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Yale University
Schools of Medicine
New Haven
United States
Zip Code
Abdallah, Chadi G; Niciu, Mark J; Fenton, Lisa R et al. (2014) Decreased occipital cortical glutamate levels in response to successful cognitive-behavioral therapy and pharmacotherapy for major depressive disorder. Psychother Psychosom 83:298-307
Solecki, Wojciech; Wickham, Robert J; Behrens, Shay et al. (2013) Differential role of ventral tegmental area acetylcholine and N-methyl-D-aspartate receptors in cocaine-seeking. Neuropharmacology 75:9-18
Wang, Jie; Du, Hongying; Ma, Xiaoxian et al. (2013) Metabolic products of [2-(13) C]ethanol in the rat brain after chronic ethanol exposure. J Neurochem 127:353-64
Wang, Jie; Du, Hongying; Jiang, Lihong et al. (2013) Oxidation of ethanol in the rat brain and effects associated with chronic ethanol exposure. Proc Natl Acad Sci U S A 110:14444-9
Herzog, Raimund I; Jiang, Lihong; Herman, Peter et al. (2013) Lactate preserves neuronal metabolism and function following antecedent recurrent hypoglycemia. J Clin Invest 123:1988-98
Jiang, Lihong; Gulanski, Barbara Irene; De Feyter, Henk M et al. (2013) Increased brain uptake and oxidation of acetate in heavy drinkers. J Clin Invest 123:1605-14
De Feyter, Henk M; Mason, Graeme F; Shulman, Gerald I et al. (2013) Increased brain lactate concentrations without increased lactate oxidation during hypoglycemia in type 1 diabetic individuals. Diabetes 62:3075-80
Wang, Jie; Jiang, Lihong; Du, Hongying et al. (2012) An ethanol vapor chamber system for small animals. J Neurosci Methods 208:79-85
Gomez, Rosane; Behar, Kevin L; Watzl, June et al. (2012) Intravenous ethanol infusion decreases human cortical ?-aminobutyric acid and N-acetylaspartate as measured with proton magnetic resonance spectroscopy at 4 tesla. Biol Psychiatry 71:239-46
Rothman, Douglas L; De Feyter, Henk M; de Graaf, Robin A et al. (2011) 13C MRS studies of neuroenergetics and neurotransmitter cycling in humans. NMR Biomed 24:943-57

Showing the most recent 10 out of 12 publications