Regulator of G protein signaling 6 is a critical mediator of both reward-related behavioral and pathological responses to alcohol

Significance Almost 20% of women and 40% of men in the United States abuse alcohol or have experienced alcohol dependence in their lifetime. Though accidents, traffic fatalities, and violent crimes account for the majority of alcohol-involved mortalities, excessive, chronic drinking also causes often irreversible heart and liver damage. We identify regulator of G protein signaling 6 (RGS6) as a novel drug target with substantive potential clinical utility in the treatment of alcoholism and amelioration of the resultant hepatic and cardiac toxicity. Mice lacking RGS6 exhibit a reduction in voluntary alcohol consumption, conditioned reward and withdrawal. In addition, RGS6−/− mice are largely protected from alcohol-induced cardiomyopathy, hepatic steatosis, gastrointestinal barrier dysfunction, and endotoxemia. Thus, targeting RGS6 could reduce alcohol cravings while simultaneously protecting the heart and liver from damage. Alcohol is the most commonly abused drug worldwide, and chronic alcohol consumption is a major etiological factor in the development of multiple pathological sequelae, including alcoholic cardiomyopathy and hepatic cirrhosis. Here, we identify regulator of G protein signaling 6 (RGS6) as a critical regulator of both alcohol-seeking behaviors and the associated cardiac and hepatic morbidities through two mechanistically divergent signaling actions. RGS6−/− mice consume less alcohol when given free access and are less susceptible to alcohol-induced reward and withdrawal. Antagonism of GABAB receptors or dopamine D2 receptors partially reversed the reduction in alcohol consumption in RGS6−/− animals. Strikingly, dopamine transporter inhibition completely restored alcohol seeking in mice lacking RGS6. RGS6 deficiency was associated with alterations in the expression of genes controlling dopamine (DA) homeostasis and a reduction in DA levels in the striatum. Taken together, these data implicate RGS6 as an essential regulator of DA bioavailability. RGS6 deficiency also provided dramatic protection against cardiac hypertrophy and fibrosis, hepatic steatosis, and gastrointestinal barrier dysfunction and endotoxemia when mice were forced to consume alcohol. Although RGS proteins canonically function as G-protein regulators, RGS6-dependent, alcohol-mediated toxicity in the heart, liver, and gastrointestinal tract involves the ability of RGS6 to promote reactive oxygen species-dependent apoptosis, an action independent of its G-protein regulatory capacity. We propose that inhibition of RGS6 might represent a viable means to reduce alcohol cravings and withdrawal in human patients, while simultaneously protecting the heart and liver from further damage upon relapse.