G9a inhibition decreases stress-induced escalation of alcohol drinking


Technology: Inventors at MUSC have identified that NAc (nucleus accumbens) G9a is required

for stress-regulated drinking in both ethanol-dependent and non-dependent animals.

Importantly they discovered that treating mice with UNC0642 (an inhibitor of G9a) in a stressinduced

ethanol drinking assay (Figure. 1A) showed significant reduction in ethanol consumption

during first week of daily drug injections (Figure. 1B). Further, chronic UNC0642 treatment

suppressed U50,488 (kappa opiod agonist) potentiated ethanol drinking observed in control mice

(Figure. 1C). Current treatment modalities for Alcohol Use Disorders (AUDs) such as Naltrexone

and Acomprosate are used but have side effects and have very limited efficacy in AUDs.

Therefore, alternative treatment approaches are greatly needed. Since the stress system is

dysregulated in chronic substance abusers, pharmacological inhibition of G9a activity could prove

to be a useful therapeutic strategy to treat relapse vulnerability in individuals suffering from

alcohol used disorder and substance use disorder. Additional studies are explored to determine

duration of treatment to achieve maximum efficacy. 

Fig1. Systemic G9a inhibition suppresses stress-induced ethanol drinking. A) Wild-type mice were allowed to drink ethanol for 2 weeks prior to repeated, daily injections of UNC0642 (4mg/kg; i.p.) given 30 minutes prior to the 2-bottle choice sessions (Fig.1A). B) significant reduction in ethanol drinking during the first week of daily UNC0642 injections (Fig. 1B). C) chronic UNC0642 treatment suppressed U50,488- potentiated ethanol drinking observed in vehicle control mice (Fig. 1C). D) single injection of UNC0642 failed to influence stress-potentiated drinking (Fig. 1D)

Overview: Alcohol use disorder (AUD) is a chronic, relapsing disease that is difficult to treat due

in part to co-morbidities with other neuropsychiatric illnesses like stress- or anxiety-related

disorders. In addition, evidence suggests that the chronic use of abused substances, like alcohol,

can lead to the formation of lasting stress disorders produced by dysregulation of stress-response

systems in the brain. Several epigenetic enzymes, such as histone deacetylases and histone

methyl transferases, are regulated by acute or chronic exposure to abused substances and can

influence the development of AUD related behaviors. One such enzyme, G9a (also known as

euchromatic histone-lysine N-methyltransferase 2 or EHMT2), is a histone methyltransferase that

catalyzes di-methylation on lysine 9 of histone H3 (H3K9me2). H3K9me2 is typically associated

with condensed chromatin and repression of target gene expression; and G9a is a major regulator

of this histone mark in NAc neurons. Researchers at MUSC show that ethanol dependence in

mice, produced by chronic intermittent ethanol (CIE) exposure, reduced both G9a and H3K9me2

levels in the adult NAc, but not dorsal striatum. Viral-mediated reduction of G9a in the NAc had

no effects on baseline volitional ethanol drinking or escalated ethanol drinking produced by CIE

exposure; however, NAc G9a was required for stress-regulated changes in ethanol drinking,

including potentiated ethanol drinking produced by activation of the kappa opioid receptor.


Publication: Anderson, Ethan M et al. “The histone methyltransferase G9a mediates stressregulated

alcohol drinking.” Addiction biology, e13060. 19 May. 2021, doi:10.1111/adb.13060


Applications: Alcohol use disorders


Advantages: Pharmacologic inhibition of G9a could be a new approach to treat stress induced

alcohol consumption


Key Words: Alcohol used disorders, G9a, stress induced escalation

Inventors: Christopher W. Cowan and Ethan Anderson

Patent Status: Provisional filed 7.16.2020

MUSC-FRD Technology ID: P20144

Patent Information:
For Information, Contact:
Scott Davis
Associate Director, Licensing
MUSC Foundation for Research Development
Ethan Anderson
Christopher Cowan
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