Ethanol exerts its primary mode of action by interacting with CNS membranes. Our recent studies have indicated a positive involvement of acidic phospholipids (PS, PA, PI and poly-PI) in brain membranes with respect to chronic ethanol administration. An increase in metabolism of these phospholipids is regarded as part of an intricate system associated with neuronal stimulation. The increase in PS may also explain the adaptive increase in membrane transport enzymes such as (Na+K)-ATPase. The main objective of the proposal is to investigate the effects of acute and chronic ethanol on the acidic phospholipids and their metabolism.
Specific aims are: (1) to correlate the changes in acidic phospholipids and the subcellular site of occurrence with respect to chronic ethanol administration and tolerance development, (2) to examine the incorporation of [14C]-arachidonic acid into membrane phospholipids and to test the sensitivity of synaptosomal acyltransferase towards in vitro challenge of ethanol, (3) to study the acetylcholine-mediated hydrolysis of poly-PI by the phosphodiesterase in synaptosomes and to elucidate the effects of ethanol in vivo and in vitro on this process, and (4) to examine the effects of acute and chronic ethanol on acidic phospholipid metabolism in brain and to compare the in vivo response of ischemia-mediated poly-PI breakdown in controls and ethanol-treated rats. Adult male Sprague Dawley rats will be given ethanol in the form of a liquid diet. Controls will be given the same diet, except that ethanol will be substituted with an isocaloric amount of glucose. Delineation of the effects of ethanol on these important metabolic processes will undoubtedly provide new information to explain the molecular basis of ethanol-membrane interaction and the mechanism of tolerance development.
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