Engaging Gut-to-Brain Signalling to Treat Alcohol Use Disorder

According to the 2023 National Survey on Drug Use and Health (NSDUH), 28.9 million people ages 12 and older in the United States had alcohol use disorder (AUD) in the past year. Although chronic alcohol use contributes to numerous health disorders as well as being an economic burden, there are few medications approved for treatment of AUD, and these medications are not uniformly effective and are not widely used. We now describe studies of a small molecule, novel chemical entity called Nezavist, which shows promise as a medication to treat AUD and possibly other addictive disorders. Nezavist acts as a positive allosteric modulator at a novel site on the GABA_A receptor, but pharmacokinetic analysis demonstrates that Nezavist does not enter the CNS. However, Nezavist effectively reduces relapse to chronic alcohol consumption in alcohol-dependent animals in two widely used models. An important goal of the current studies is to provide evidence for the hypothesis that Nezavist acts in the intestine to stimulate vagus nerve afferents that project to the brainstem (nucleus tractus solitarius), leading to reduced inflammation in the brain that may alleviate alcohol 'craving' during abstinence from alcohol. It is hoped that the presentation of the current results will stimulate interest in further confirmation of the mechanism of action of Nezavist, with the intent of developing a new and effective medication for treatment for AUD.