# Regulator of G protein Signaling-12 (RGS12) as a target for SUD therapeutics development

> **NIH NIH U18** · WEST VIRGINIA UNIVERSITY · 2021 · $222,568

## Abstract

For cocaine use disorder and methamphetamine use disorder, there are presently no FDA-approved
medications for their treatment. These substance use disorders (SUDs) are thought to arise from persistent
pathophysiologic changes in CNS synaptic transmission caused by initial exposure to these substances. Such
initial exposures lead to heightened dopamine levels in the brain’s reward circuitry (a key event in establishing
long-term drug-seeking behavior). We recently discovered that mice lacking expression of Regulator of G protein
Signaling type-12 (RGS12) are attenuated in their normal hyperlocomotion elicited by acute cocaine or
methamphetamine administration. RGS12 is the most complex member of this protein superfamily, containing
five different functional domains that affect both heterotrimeric G protein-dependent and -independent signaling
cascades. The Target Development Level currently assigned to RGS12 is Tbio. Without a pharmacological
inhibitor to RGS12 (which would elevate this protein to the level of Tchem), we have performed genetic studies to
discern the molecular functions of RGS12 within neuronal circuitry and the potential utility of reducing RGS12
function toward ameliorating disease states. We observe increased dopamine transporter (DAT) expression and
dopamine uptake within the ventral striata, but not dorsal striata, of RGS12-deficient mouse strains. The most
likely direct target for RGS12’s action is the presynaptic kappa opioid receptor (KOR), as activation of this GPCR
is known to attenuate striatal dopaminergic tone. Given that Oprk1 (KOR) and Rgs12 mRNAs exhibit
considerable overlap in their CNS expression patterns, it is likely that the increased DAT expression / function
and reduced hyperlocomotion to psychostimulants exhibited by RGS12-null mice are both caused by removal of
a critical negative influence on signaling downstream of KOR activation. RGS12 loss was also seen to attenuate
KOR-induced conditioned place aversion (CPA) in mice. Based on our newly published data, we hypothesize
that RGS12 modulates the output of dynorphin/KOR signaling both to dopamine reuptake and to behavioral
responses of analgesia and aversion. To advance the Tbio target RGS12 as a novel SUD drug discovery target,
we propose to test in mice whether reducing RGS12 function blunts cocaine-induced withdrawal sequelae and/or
blunts the reinstatement of drug-seeking behavior after cocaine self-administration. Inhibiting RGS12 function in
the adult mouse brain, by tamoxifen-induced Cre recombinase-mediated excision of Rgs12, is predicted to
diminish dopamine-dependent reward upon acute re-exposure to drug, and to shape the dynorphin signaling
(that is heightened during withdrawal) away from dysphoria and towards beneficial analgesia. Upon establishing
proof-of-principle observations that RGS12 inhibition (via genetic means) helps to ameliorate withdrawal
symptoms and blunt drug-seeking behaviors, we will be able to more robustly justify parallel h...

## Key facts

- **NIH application ID:** 10107085
- **Project number:** 1U18DA052497-01
- **Recipient organization:** WEST VIRGINIA UNIVERSITY
- **Principal Investigator:** Vincent Setola
- **Activity code:** U18 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $222,568
- **Award type:** 1
- **Project period:** 2020-12-01 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10107085

## Citation

> US National Institutes of Health, RePORTER application 10107085, Regulator of G protein Signaling-12 (RGS12) as a target for SUD therapeutics development (1U18DA052497-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10107085. Licensed CC0.

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