We are investigating the actions of ethanol in cell membranes. We know that ethanol has the effect of making cell membranes abnormally fluid and flexible, and we plan to continue our investigations along these lines, using electron spin resonance and fluorescence polarization techniques. We will study the factors that make different cells differentially vulnerable to this effect, including the lipid composition of the membranes and type of tissue or animal from which they are taken. We plan to study red cells from people at risk for alcoholism and from people who are unusually resistant or unusually sensitive to the behavioral effects of the drug. Since it is not yet known how disorder in cell membranes leads to (or is correlated with) intoxication, we will begin studies of cell function associated with disordering, using well defined enzyme systems in plasma membranes and a functional measure, chloride transport in synaptosomes. Chronic effects of ethanol will be analyzed in terms of possible adaptation to the disordering effect of acute ethanol administration. We will investigate changes in membrane lipid composition, trying to understand the increased rigidity of membranes from alcohol-treated mice in terms of their cholesterol or fatty acyl chain composition. We will see whether ethanol affects incorporation of lipids into nonliving cell extracts, and compare the apparently nonspecific actions of ethanol with the effects of a small increase in temperature. In humans, alcohol intake has important effects, both adverse and beneficial, on plasma lipid metabolism. These might be explained by hydrophobic interactions of the kind we are studying. We will examine passive transfer of cholesterol among different plasma lipoproteins and cell membranes, and find out whether lecithin:cholesterol acyltransferase activity is affected. Finally we will use strains of mice that show different intensity of withdrawal convulsions to see whether there are corresponding differences in their synaptosomal membranes. This may provide further evidence for or against our hypothesis that intoxication is associated with disordered membranes and hyperexcitability or convulsions with abnormally rigid membranes.
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