The relatively modest and inconsistent effects of pharmacological concentrations of ethanol (=100mm) on brain Na, K-ATPase activity have impeded an understanding of these integral membrane protein in the context of ethanol sensitivity and abuse. We have demonstrated that concentrations of ethanol as low as 10ml modulate the activity of the alpha 2/3 isozyme(s) with no effect on the activity of the alpha1 isozyme. Further, the magnitude and direction of the response is dependent on the level of basal (no ethanol) alpha 2/3 activity. When basal alpha 2/3 activity is low, a 2-fold stimulation by ethanol can be observed. In contrast, when basal alpha 2/3 activity is high, up to 30 percent inhibition of alpha 2/3 activity is obtained. Current investigations are aimed at distinguishing between alpha 2 activity and alpha 3 activity as well as understanding the basis for the variance in basal activity. Parallel to these studies, experiments are ongoing investigating the nature of interaction between ethanol and regulatory proteins at the intracellular membrane surface.