title: Regulator of G protein signaling 6 is a critical mediator of both reward-related behavioral and pathological responses to alcohol.
abstract: 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 GABA(B) 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.
authors: Department of Pharmacology and.
authors: Adele
authors: A
authors: Stewart
authors: Department of Pharmacology and.
authors: Biswanath
authors: B
authors: Maity
authors: Department of Pharmacology and.
authors: Simon P
authors: SP
authors: Anderegg
authors: Central Microscopy Facility, University of Iowa Carver College of Medicine, Iowa City, IA 52242.
authors: Chantal
authors: C
authors: Allamargot
authors: Department of Pharmacology and.
authors: Jianqi
authors: J
authors: Yang
authors: Department of Pharmacology and rory-fisher@uiowa.edu.
authors: Rory A
authors: RA
authors: Fisher
mesh_terms: D000428:Alcohol Drinking; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001522:Behavior, Animal; D009202:Cardiomyopathies / Q000209:etiology; D003216:Conditioning, Operant; D051379:Mice; D018345:Mice, Knockout; D020710:RGS Proteins / Q000235:genetics / Q000502:physiology*; D012201:Reward
chemical_list: D020710:RGS Proteins; C485692:Rgs6 protein, mouse
keywords: GPCRs; RGS proteins; RGS6; alcoholism; dopamine transporter
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