Enhancement of alcohol aversion by the nicotinic acetylcholine receptor drug sazetidine-A

The prevalence of alcohol use disorders (AUDs) has steadily increased in the United States over the last 30 years. Alcohol acts on multiple receptor systems including the nicotinic acetylcholine receptors (nAChRs), which are known to mediate alcohol consumption and reward. We previously reported that the preclinical drug sazetidine-A, a nAChR agonist, reduces alcohol consumption without affecting nicotine consumption in C57BL/6J mice. Here, we found that sazetidine-A enhances the expression of alcohol aversion without affecting the expression or acquisition of conditioned alcohol reward in C57BL/6J mice. Microinjection of sazetidine-A into the ventral midbrain targeting the ventral tegmental area (VTA) reduced binge alcohol consumption, implicating the neurocircuitries in this region in mediating the effects of sazetidine-A. Furthermore, sazetidine-A-induced reduction in alcohol consumption was mediated by non-4 containing nAChRs, as sazetidine-A reduced binge alcohol consumption in both 4 knock-out and wild-type mice. Finally, we found that in mice pre-treated with sazetidine-A, alcohol induced Fos transcript within Th-expressing but not Gad2-expressing neurons in the VTA as measured by increased Fos transcript expression. In summary, we find that sazetidine-A acts on non-4 nAChRs to enhance the expression of alcohol aversion, which may underlie the reduction in alcohol consumption induced by sazetidine-A. Elucidating the identity of non-4 nAChRs in alcohol aversion mechanisms will provide a better understanding the complex role of nAChRs in alcohol addiction and potentially reveal novel drug targets to treat AUDs.