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 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.

The evolution of regulators of G protein signalling proteins as drug targets – 20 years in the making: IUPHAR Review 21

“…À/À mice display a reduction in alcohol seeking behaviour compared to wild-type mice, as well as diminished symptoms of conditioned reward and withdrawal (Stewart et al, 2015). Inhibition of RGS6 has also been implicated as a promising therapeutic strategy in depression and anxiety (Stewart et al, 2014).…”

RGS6 as a Novel Therapeutic Target in CNS Diseases and Cancer

“…Furthermore, i.p. injection of RGS6−/− mice with the DAT inhibitor GBR-12909 promoted voluntary alcohol consumption in these mice to an even greater degree than either of the GABA B R and D 2 R inhibitors (21). These findings suggest that RGS6 inhibition of GPCR-mediated signaling may prevent upregulation of DAT and assure the normal synthesis and release of DA that is responsible for alcohol reward behaviors (Fig.…”

“…PFC prefrontal cortex, STR striatum, NAc nucleus accumbens, HP hippocampus, DOPAL 3,4-dihydroxyphenylacetaldehyde, DOPAC 3,4-dihydroxyphenylacetic acid. Image adapted from references (21)(22)(23) as a critical regulator of 5-HT 1A heteroreceptor signaling (22). Not only is RGS6 present in cortical and hippocampal neurons, as shown through immunohistochemistry and western blot, but RGS6−/− mice also display spontaneous antidepressant and anxiolytic behaviors which are reversed through i.p.…”

“…The Fisher lab has also demonstrated using western blot that certain tissues express multiple distinct RGS6 protein isoforms natively. For example, the brain expresses at least two distinct RGS6 isoforms that are larger (∼61 and 69 kDa) than ubiquitously expressed smaller forms of the protein (21,33). Interestingly, western blot analysis of brain tissue lysates using the antibody against the N-terminal protein domain, common to all RGS6L proteins, reveals a broad band of RGS6 immunoreactivity which could be explained by the presence of multiple RGS6L Fig.…”

Roles for Regulator of G Protein Signaling Proteins in Synaptic Signaling and Plasticity

“…Studies indicate that RGS6 antagonizes GABA B R-mediated GIRK currents, as shown by ataxia and increased cerebellar granule neuron GIRK currents exhibited by RGS6-KO mice that can be rescued by administration of a GABA B R antagonist (Maity et al, 2012). Additionally, RGS6 is required for adult maintenance of dopaminergic neurons in the ventral substantia nigra (Bifsha et al, 2014) and a recent study has proposed a role for RGS6 as a key mediator of both reward-related behavioral and pathologic responses to alcohol (Stewart et al, 2015), although it is unclear whether these effects are due to changes in synaptic signaling or plasticity. Furthermore, RGS6 is expressed in the soma and dendrites of hippocampal and cortical neurons.…”