G9a inhibition reduces stress-potentiated alcohol drinking in both male and female mice: Implications for safe and effective pharmacological therapeutics for alcohol use disorder

Alcohol Clin Exp Res (Hoboken). 2026 Mar;50(3):e70277. doi: 10.1111/acer.70277.

ABSTRACT

BACKGROUND: Alcohol use disorder (AUD) is a chronic, relapsing disease that is difficult to treat, and current therapies are not effective for many patients. Clinical studies show that stress increases heavy alcohol consumption and that stress is a predominant factor in rates of relapse. As such, pharmacotherapies that reduce stress-related alcohol drinking might be beneficial clinically. We recently showed that viral vector-mediated reduction of the epigenetic enzyme G9a (also known as euchromatic histone-lysine N-methyltransferase 2 or EHMT2) in the nucleus accumbens blocks stress-potentiated alcohol drinking. In addition, repeated systemic administration of the G9a inhibitor UNC0642 also reduces stress-potentiated alcohol drinking, suggesting that G9a inhibitors might be effective for treating AUD.

METHODS: Here, we further investigated the potential for UNC0642 to be used clinically to treat AUD. We first tested the effective dose of UNC0642 in multiple models of alcohol consumption in both male and female mice. We also tested half-life, oral bioavailability, maximum tolerated dose, and many measures of behavioral toxicity.

RESULTS: We found that UNC0642 is effective at reducing stress-potentiated alcohol consumption in both male and female mice at lower doses than we previously reported, and we re-confirmed the anxiolytic-like effects of UNC0642. We also found that UNC0642 has a long half-life in vivo, is orally bioavailable, is within an acceptable toxicity range for therapeutic use, and does not produce behavioral inhibition in many standard preclinical assessments, including locomotor activity, open field, Y-maze, rotarod, fear conditioning, sucrose self-administration, or sucrose-seeking.

CONCLUSIONS: Together, our studies suggest that G9a inhibitors could be effective, safe, and novel AUD therapeutics that reduce stress and dependence-related high levels of alcohol drinking in AUD patients.

PMID:41802857 | DOI:10.1111/acer.70277