Regulator of G protein signaling 6 (RGS6) in ventral tegmental area (VTA) dopamine neurons promotes EtOH seeking, behavioral reward and susceptibility to relapse

Mackenzie M Spicer; Matthew A Weber; Zili Luo; Jianqi Yang; Nandakumar S Narayanan; Rory A Fisher

doi:10.1101/2023.10.24.563844

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Regulator of G protein signaling 6 (RGS6) in ventral tegmental area (VTA) dopamine neurons promotes EtOH seeking, behavioral reward and susceptibility to relapse

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Regulator of G protein signaling 6 (RGS6) in ventral tegmental area (VTA) dopamine neurons promotes EtOH seeking, behavioral reward and susceptibility to relapse

Mackenzie M Spicer, Matthew A Weber, Zili Luo, Jianqi Yang, Nandakumar S Narayanan and Rory A Fisher

bioRxiv : the preprint server for biology

Cold Spring Harbor Laboratory

10/25/2023

DOI: 10.1101/2023.10.24.563844

PMCID: PMC10634791

PMID: 37961154

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https://doi.org/10.1101/2023.10.24.563844View

Preprint (Author's original)This preprint has not been evaluated by subject experts through peer review. Preprints may undergo extensive changes and/or become peer-reviewed journal articles. Open Access

Abstract

Mesolimbic dopamine (DA) transmission is believed to play a critical role in mediating reward responses to drugs of abuse, including alcohol (EtOH). EtOH is the most abused substance worldwide with chronic consumption often leading to the development of dependence and abuse. Unfortunately, the neurobiological mechanisms underlying EtOH-seeking behavior and dependence are not fully understood, and abstinence remains the only effective way to prevent alcohol use disorders (AUDs). Here, we developed novel RGS6 fl/fl ; DAT-iCreER mice to determine the role of RGS6 in VTA DA neurons on EtOH consumption and reward behaviors. We found that RGS6 is expressed in DA neurons in both human and mouse VTA, and that RGS6 loss in mice upregulates DA transporter (DAT) expression in VTA DA neuron synaptic terminals. Remarkably, loss of RGS6 in VTA DA neurons significantly reduced EtOH consumption, preference, and reward in a manner indistinguishable from that seen in RGS6 -/- mice. Strikingly, RGS6 loss from VTA DA neurons before or after EtOH behavioral reward is established significantly reduced (∼50%) re-instatement of reward following extinguishment, demonstrating distinct roles of RGS6 in promoting reward and relapse susceptibility to EtOH. These studies illuminate a critical role of RGS6 in the mesolimbic circuit in promoting EtOH seeking, reward, and reinstatement. We propose that RGS6 functions to promote DA transmission through its function as a negative modulator of GPCR-Gα i/o -DAT signaling in VTA DA neurons. These studies identify RGS6 as a potential therapeutic target for behavioral reward and relapse to EtOH.

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Title: Subtitle: Regulator of G protein signaling 6 (RGS6) in ventral tegmental area (VTA) dopamine neurons promotes EtOH seeking, behavioral reward and susceptibility to relapse
Creators: Mackenzie M Spicer - University of Iowa
Matthew A Weber - University of Iowa
Zili Luo - University of Iowa
Jianqi Yang - University of Iowa
Nandakumar S Narayanan - University of Iowa
Rory A Fisher - University of Iowa
Resource Type: Preprint
Publication Details: bioRxiv : the preprint server for biology
DOI: 10.1101/2023.10.24.563844
PMID: 37961154
PMCID: PMC10634791
Publisher: Cold Spring Harbor Laboratory
Language: English
Date posted: 10/25/2023
Academic Unit: Neurology; Psychiatry; Critical Care; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Neuroscience and Pharmacology; Internal Medicine
Record Identifier: 9984511956102771

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