Summary: Dr. Nora Volkow, of NIDA observed that alcohol consumption decreased brain glucose utilization in alcoholic subjects in a pattern which resemble GABAergic stimulation (24). Dr. T.K. Ki pointed out that the decrease in glucose utilization could be explained by the brain metabolism of acetate, which reaches blood levels of 2 mM during ethanol metabolism. In collaboration with Dr. George Kunos and members of the Lab of Physiological Studies, we determined that brain uptake of F dexoyglucose was significantly decreased by elevation of blood acetate to 5 or 2 mM acetate, the Km for acetate transport into brain being about 5 mM. Simple measurement of a decreased rate of glucose utilization provides little information on the effects of switching from glucose to acetate metabolism on brain energetics, neurotransmitter, transcription or neuropeptide metabolism. Accordingly we have proposed a metabolomic program, utilizing cappilary electrophoresis and mass spectrometry to more rapidly determine the changes in brain substrate levels changes while at the same time determining the rate of the changes in pathway fluxes which occur as the brain switches from glucose to acetate metabolism. It is anticipated that the development of these new methods will have wide applicability beyond this immediate project and will address in a practical way the NIH thrust toward metabolomics by determining changes in defined metabolic pathways. This study is expected to take about 2 years to complete. While the effects of ethanol on brain and liver function have been extensively studied by the NIAAA and others for many years, there has been relatively little attention paid to the effects on energy and neurotransmitter metabolism resulting from the utilization of the acetate produce by hepatic ethanol metabolism upon extra hepatic tissue. It can be expected that the switch from glucose to acetate metabolism will have significant and hither to unexpected effects. SIGNIFICANCE TO THE PROGRAMS OF THIS INSTITUTE Acetate is the metabolic product produced by the liver during ethanol consumption. The effects of the metabolism of acetate by brain have not been systematically investigated and are expected to yield significant results on our understanding of the effects of alcohol consumption, particularly upon alcohol withdrawal syndrome and alcohol effects upon mood. The methods of metabolic control analysis and the more rapid methods of metabolite analysis are expected to contribute significantly to the NIH road map plan of investigating the metabolome in a way which combines enzyme kinetics and thermodynamics of defined portions of the great metabolic chart.