Role of glycogen synthase kinase-3 in dependence and abuse liability of alcohol

Background Alcohol is a major abused drug worldwide that contributes substantially to health and social problems. These problems result from acute alcohol overuse as well as chronic use, leading to alcohol use disorder (AUD). A major goal of this field is to establish a treatment for alcohol abuse and dependence in patients with AUD. The central molecular mechanisms of acute alcohol actions have been extensively investigated in rodent models.Aims One of the central mechanisms that may be involved is glycogen synthase kinase-3 beta (GSK-3 beta) activity, a key enzyme involved in glycogen metabolism but which has crucial roles in numerous cellular processes. Although the exact mechanisms leading from acute alcohol actions to these chronic changes in GSK-3 beta function are not yet clear, GSK-3 beta nonetheless constitutes a potential therapeutic target for AUD by reducing its function using GSK-3 beta inhibitors. This review is focused on the correlation between GSK-3 beta activity and the degree of alcohol consumption.Methods Research articles regarding investigation of effect of GSK-3 beta on alcohol consumption in rodents were searched on PubMed, Embase, and Scopus databases using keywords "glycogen synthase kinase," "alcohol (or ethanol)," "intake (or consumption)," and evaluated by changes in ratios of pGSK-3 beta Ser9/pGSK-3 beta.Results In animal experiments, GSK-3 beta activity decreases in the brain under forced and voluntary alcohol consumption while GSK-3 beta activity increases under alcohol-seeking behavior.Conclusions Several pieces of evidence suggest that alterations in GSK-3 beta function are important mediators of chronic ethanol actions, including those related to alcohol dependence and the adverse effects of chronic ethanol exposure. Short Summary: In animal experiments, GSK-3 beta activity decreases in the brain under forced and voluntary alcohol consumption while GSK-3 beta activity increases under alcohol-seeking behavior. Thus, GSK-3 beta constitutes a potential therapeutic target for AUD by using selective and potential inhibitors for GSK-3 beta.