Role of glucocorticoid receptor-mediated mRNA decay in alcohol dependence

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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contributes to alcohol intake escalation and underlies the ability of GR antagonism to reduce alcohol drinking in mice withdrawn from chronic intermittent alcohol vapor inhalation.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.