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Regulator of G protein signaling 6 (RGS6) is a critical modulator of reward behavior and dopamine signaling in the mesolimbic circuit
Author(s) -
Spicer Mackenzie,
Weber Matthew,
Yang Jianqi,
Stewart Adele,
Luo Zili,
Narayanan Nandakumar,
Fisher Rory
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2021.35.s1.02562
Subject(s) - nucleus accumbens , autoreceptor , dopamine , neuroscience , ventral pallidum , ventral tegmental area , brain stimulation reward , gene knockdown , psychology , pharmacology , medicine , biology , receptor , dopaminergic , central nervous system , basal ganglia , genetics , serotonin , gene , globus pallidus
Spicer MM 1,2 , Weber MA 3 , Yang J 1 , Stewart AM 6 , Luo Z 5 , Yang J 1 , Narayanan NS 3,4 , and Fisher RA 1,2,4 . 1 Department of Neuroscience & Pharmacology, 2 Interdisciplinary Graduate Program in Molecular Medicine, 3 Department of Neurology, 4 Iowa Neuroscience Institute, 5 Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, IA 52242 6 Department of Biomedical Sciences, Florida Atlantic University Brain Institute, Florida Atlantic University, Boca Raton, FL 33431 Alcohol (EtOH) is the most commonly abused drug worldwide and chronic EtOH consumption often leads to development of dependence and abuse. EtOH dependence is characterized by progressive, neuroadaptive changes to the brain's reward system resulting from chronic EtOH exposure. The neurobiological mechanisms underlying EtOH‐seeking behavior and dependence are not fully understood, resulting in limited therapeutics. Currently, abstinence remains the only effective way to prevent alcohol use disorders (AUDs). We previously discovered that loss of RGS6 in mice leads to reduced EtOH seeking and reward behaviors. GABA B and D 2 autoreceptor (D 2 R) antagonism partially reduced EtOH seeking in RGS6 ‐/‐ mice, whereas singular inhibition of the dopamine (DA) transporter (DAT) completely reversed this effect. Moreover, RGS6 ‐/‐ mice exhibited reduced striatal DA content. These findings led us to hypothesize that RGS6 promotes mesolimbic DA neurotransmission by suppressing GPCR‐Gα i/o ‐mediated upregulation of DAT. To investigate this possibility, we examined the effects of RGS6 loss on DAT expression in VTA cell bodies and synaptic terminals in the nucleus accumbens (NAcc). In addition, we examined the effects of RGS6 loss on mesolimbic neuronal activity and DA transmission using c‐Fos staining and EtOH‐induced release of DA from VTA neurons, respectively. We found robust RGS6 expression in VTA cell bodies and terminals, where its loss led to upregulated expression of DAT. Additionally, RGS6 loss reduced VTA neuronal activity as measured by c‐Fos immunostaining. These findings suggest that RGS6 functions to promote EtOH seeking and reward behavior by promoting DA transmission in the mesolimbic circuit by suppressing GPCR‐Gα i/o signaling, thereby promoting VTA neuronal activity and suppressing DAT upregulation.