This study will focus on the acute effects of ethanol in combination with other commonly used drugs on biomembrane structure and both enzyme and receptor function. Among the drugs to be studied are pentobarbital, chlorpromazine, and diazepam. Such drugs, in the presence of ethanol, are associated with enhanced psychomotor impairment and respiratory depression. Separately these drugs and ethanol alter membrane fluidity. Furthermore, pentobarbital and ethanol exhibit cross-tolerance in both inhibition of the righting reflex of the rat and perturbation of fluidity in mice synaptosomal membranes. Indeed, there is much evidence that the physiological effects of ethanol alone and of many other drugs are connected with the fluidization, penetration, and/or alteration of transition temperatures of cell membranes. Such parameters will be quantitated in synaptosomal and liver plasma membranes by ESR spectroscopy under varying perturbant conditions. Once significant structural alterations are verified, changes in activities of membrane-bound enzymes such as the Na+/K+ dependent ATPase and acetylcholinesterase, as well as changes in receptor binding of 3-quinuclidinyl benzilate and 5-hydroxytryptamine will be monitored. Emphasis will be placed on whether the ethanol-drug combination is synergistic, additive, or antagonistic in altering structure, function or both. Significant correlations between changes in biomembrane structure and enzymatic activity or receptor binding will suggest a more general involvement of membrane structure in such changes versus enzyme or receptor specific alterations. The determination of the effects of perturbants on the structural parameters of protein-free phospholipid vesicles formed from extracts of plasma membranes and from commercial sources will further distinguish between membrane-perturbant in contrast with protein-perturbant interactions. This study should enhance our understanding of the heretofore sparsely investigated response of biomembranes to simultaneous exposure to ethanol and other drugs. It will explore the hypothesis that part of the potentiating effects of simultaneously administered drugs on the higher functions of complex organisms orginates with synergistic changes in membrane structure. Furthermore, it may find an enzyme or receptor which might be particularly susceptible to the combination of ethanol and a drug in low (possibly clinically relevant) concentrations.
