The goal of this proposal is to characterize the molecular basis for gender differences underlying ethanol dependence. The objective is to test the hypothesis that gender influences neuroadaptations of GABA and glutamatergic systems elicited by chronic ethanol exposure. GABAA and NMDA receptors are key sites in the brain mediating the effects of ethanol. Ethanol dependence results in subunit selective alterations in gene expression and function for both GABAA and NMDA receptors. We have recently found profound gender differences in the effects of chronic ethanol consumption on GABAA receptor alpha and NMDA NR1 subunit expression. This shows that gender impacts the effects of ethanol dependence on gene expression for these two key neurotransmitter systems. This suggests that neuroadaptations associated with ethanol dependence and withdrawal may be dependent on the hormonal context of the ethanol exposure. However, there is little evidence showing a direct association between ethanol dependence and withdrawal behaviors and the molecular changes observed for GABAA and NMDA receptors. The proposed studies will investigate the molecular basis for gender differences in the effects of ethanol dependence and withdrawal by correlating the development of and recovery from ethanol dependence with changes in gene expression and receptor regulation. This proposal will test the hypothesis that ethanol dependence induces gender-selective alterations in 1) GABAA receptor regulation, function and gene expression, 2) NMDA receptor regulation, function and gene expression, and 3) levels of several key neuroactive steroids. We will determine whether these alterations show a temporal correlation with behavioral manifestations of ethanol dependence and withdrawal. These studies are particularly important as the expression of neuroadaptations to chronic ethanol consumption varies according to gender, even though both genders display similar behavioral signs of dependence and withdrawal. It is critical to ascertain whether the timing of functional or molecular changes in GABAA or NMDA receptors are associated with physiological manifestations of dependence and withdrawal, including the influence of differing endogenous regulation. These investigations are important for understanding the neurobiological basis of ethanol dependence and withdrawal in both males and females.