Role of the Serotonergic System in Alcohol Dependence

Sari, Youssef; Johnson, Verity; Weedman, Jason M.

doi:10.1016/b978-0-12-385506-0.00010-7

Cited by 78 publications

(99 citation statements)

References 294 publications

(352 reference statements)

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“…The use of baclofen is controversial, however, because of potent sedative and muscle relaxant actions that are additive with alcohol and additional interactions with other drugs of abuse. Drugs targeting the opioid, DA, and 5-HT neurotransmitter systems have also been proposed as novel alcoholism therapies (15)(16)(17), but only one drug (naltrexone) is Food and Drug Administration approved. Clearly,…”

Section: Rgs6mentioning

confidence: 99%

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

Stewart¹,

Maity²,

Anderegg³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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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.

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Section: Rgs6mentioning

confidence: 99%

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

Stewart¹,

Maity²,

Anderegg³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…The serotonergic system has been shown to be important in mediating alcohol reward, preference, dependence, and craving 25 . Studies concerning the association of alcohol dependence with serotonin polymorphisms generally have focused on the serotonin transporter gene.…”

Section: Discussionmentioning

confidence: 99%

Association of the DRD2 TaqIA, 5-HT1B A-161T, and CNR1 1359 G/A Polymorphisms with Alcohol Dependence

Şengül

et al. 2014

Klinik Psikofarmakoloji Bülteni-Bulletin of Clinical Psychophar

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“…As the majority of neurotransmitters in the mesolimbic pathway (e.g., dopamine (DA), GABA, opioids, and serotonin (5-HT)) interact with GPCRs, G protein-dependent signaling may offer a therapeutic target in the treatment of alcohol abuse. With this in mind, multiple drugs targeting these neurotransmitter receptors have been recommended for the treatment of alcoholism (40)(41)(42). One such drug, baclofen, a GABA B R agonist, has been approved in Europe as a treatment for alcohol withdrawal symptoms and cravings (43)(44)(45).…”

Section: Alcohol Use Disordersmentioning

confidence: 99%

“…In addition, there was also evidence to suggest that RGS6 was capable of regulating the signaling of other GPCRs, such as 5-HT 1A Rs and μ-opioid receptors (22,46), which had already been identified as potential therapeutic targets in the treatment of alcoholism (40,42). Both immunohistochemical and western blot studies in wild type (RGS6+/+) mice subsequently demonstrated that RGS6 protein expression was upregulated in the ventral tegmental area (VTA) of the mesolimbic system following prolonged alcohol exposure.…”

Section: Alcohol Use Disordersmentioning

confidence: 99%

RGS6 as a Novel Therapeutic Target in CNS Diseases and Cancer

Ahlers

Chakravarti

Fisher

2016

AAPS J

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Abstract. Regulator of G protein signaling (RGS) proteins are gatekeepers regulating the cellular responses induced by G protein-coupled receptor (GPCR)-mediated activation of heterotrimeric G proteins. Specifically, RGS proteins determine the magnitude and duration of GPCR signaling by acting as a GTPase-activating protein for Gα subunits, an activity facilitated by their semiconserved RGS domain. The R7 subfamily of RGS proteins is distinguished by two unique domains, DEP/DHEX and GGL, which mediate membrane targeting and stability of these proteins. RGS6, a member of the R7 subfamily, has been shown to specifically modulate Gα i/o protein activity which is critically important in the central nervous system (CNS) for neuronal responses to a wide array of neurotransmitters. As such, RGS6 has been implicated in several CNS pathologies associated with altered neurotransmission, including the following: alcoholism, anxiety/depression, and Parkinson's disease. In addition, unlike other members of the R7 subfamily, RGS6 has been shown to regulate G protein-independent signaling mechanisms which appear to promote both apoptotic and growth-suppressive pathways that are important in its tumor suppressor function in breast and possibly other tissues. Further highlighting the importance of RGS6 as a target in cancer, RGS6 mediates the chemotherapeutic actions of doxorubicin and blocks reticular activating system (Ras)-induced cellular transformation by promoting degradation of DNA (cytosine-5)-methyltransferase 1 (DNMT1) to prevent its silencing of pro-apoptotic and tumor suppressor genes. Together, these findings demonstrate the critical role of RGS6 in regulating both G protein-dependent CNS pathology and G protein-independent cancer pathology implicating RGS6 as a novel therapeutic target.

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Role of the Serotonergic System in Alcohol Dependence

Cited by 78 publications

References 294 publications

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

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

Association of the DRD2 TaqIA, 5-HT1B A-161T, and CNR1 1359 G/A Polymorphisms with Alcohol Dependence

RGS6 as a Novel Therapeutic Target in CNS Diseases and Cancer

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