These experiments are a continuation of our examination of the effects of ethanol on cation transport, the interaction between ethanol and norepinephrine in vivo, and the susceptibility to membrane effects in man. Na+,K+-ATPase has a central role in the regulation of cation gradients, membrane potential, cell excitability, and activity-linked energy metabolism in excitable cells. Ethanol alters regulation of Na+,K+-ATPase but there are no data about whether these effects are relevant to the changes in cell cation concentrations that accompany electrical activity. The studies will continue the previous work to examine the relationship between membrane effects of ethanol and the responses of cation transport to neural activity. The experiments will focus on four questions: 1) the locus of the ethanol effect on transport: the hypothesis is that ethanol affects internal cation binding sites that regulate Na+,K+-ATPase conformation. 2) Functional aspects of transport regulation as examined by effects on Na+/K+ selectivity of the internal cation sites and by stimulation of transport by increased cell Na+. 3) The interaction between norepinephrine and ethanol in terms of active cation transport and possible receptor-mediated changes in membrane properties. 4) Adaptation to effects of ethanol and norepinephrine in vivo. These experiments will examine functional aspects of cation transport and norepinephrine effects from selected experiments on questions 1)-3) in rats treated with chronic ethanol combined with direct noradrenergic stimulation or depletion. Effects on red blood cells will be compared to those on brain tissue, in order to determine the applicability of clinical material. These experiments will establish whether effects of ethanol on transport are likely to be relevant in vivo. If the effects are relevant, the results will provide the basis for studies of cation transport in alcoholism.
