# Role of glucocorticoid receptor-mediated mRNA decay in alcohol dependence

> **NIH NIH R21** · SCRIPPS RESEARCH INSTITUTE, THE · 2023 · $259,735

## Abstract

SUMMARY
Pharmacological inhibition of glucocorticoid receptor (GR) signaling can efficiently reduce alcohol intake and
seeking in rodent and primate models of heavy alcohol drinking, as well as in human subjects with an alcohol
use disorder (AUD). Despite the wealth of evidence supporting the therapeutic potential of GR inhibition for the
treatment of AUD, the molecular mechanism mediating this effect remains unknown. Aside from acting as a
transcriptional regulator, GR can bind a subset of mRNAs in the cytoplasm and elicit their rapid degradation
upon ligand binding – a process called GR-mediated mRNA decay (GMD). Intriguingly, we demonstrated that
the endoribonuclease RIDA, a critical component of the GMD complex, is among the most significantly
upregulated proteins in the mouse medial prefrontal cortex (mPFC) during abstinence following a history of
excessive alcohol drinking. The present project will test the hypothesis that hyperactive GMD contributes to
alcohol intake escalation and underlies the ability of GR antagonism to reduce alcohol drinking in mice withdrawn
from chronic intermittent alcohol vapor inhalation. A first aim will be to determine whether abstinence increases
GMD activity in excessive alcohol drinkers. To do so, we will first determine the identity of mRNAs bound to GR
in mPFC samples from alcohol-naïve mice and test whether GR activation causes their rapid degradation. We
will then examine the effect of alcohol withdrawal on these potential GMD substrates and the ability of GR
inhibition to prevent it. A second aim will be to determine whether blocking GMD in the mPFC via local RIDA
knockdown, which will not impact GR transcriptional activity, can replicate the effect of GR antagonism on
excessive alcohol consumption and cognitive impairment. Our approach capitalizes on our expertise in modeling
AUD in mice and manipulating gene expression in small brain regions, combined with access to state-of-the-art
core resources for RNA sequencing and bioinformatic analysis. The proposed work will enhance our
understanding of the molecular mechanisms driving alcohol intake escalation and memory deficits in mice, as
well as the mechanism of action of GR antagonists. It will probe for the first time the relevance of GMD in the
brain and may identify a new molecular target for the treatment of AUD and other GR-related neurological and
psychiatric disorders.

## Key facts

- **NIH application ID:** 10811212
- **Project number:** 1R21AA030807-01A1
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** Candice Contet
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $259,735
- **Award type:** 1
- **Project period:** 2023-09-20 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10811212

## Citation

> US National Institutes of Health, RePORTER application 10811212, Role of glucocorticoid receptor-mediated mRNA decay in alcohol dependence (1R21AA030807-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10811212. Licensed CC0.

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