Nicotinic acetylcholine receptors containing the α4 subunit are critical for the nicotine-induced reduction of acute voluntary ethanol consumption

Recently, we investigated the molecular mechanisms of the smoking cessation drug varenicline, a nicotinic acetylcholine receptor (nAChR) partial agonist, in its ability to decrease voluntary ethanol intake in mice. Previous to our study, other labs had shown that this drug can decrease ethanol consumption and seeking in rat models of ethanol intake. Although varenicline was designed to be a high affinity partial agonist of nAChRs containing the alpha 4 and beta 2 subunits (designated as alpha 4 beta 2*), at higher concentrations it can also act upon alpha 3 beta 2*, alpha 6*, alpha 3 beta 4* and alpha 7 nAChRs. Therefore, to further elucidate the nAChR subtype responsible for varenicline-induced reduction of ethanol consumption, we utilized a pharmacological approach in combination with two complimentary nAChR genetic mouse models, a knock-out line that does not express the alpha 4 subunit (alpha 4 KO) and another line that expresses alpha 4* nAChRs hypersensitive to agonist (the Leu9'Ala line). We found that activation of alpha 4* nAChRs was necessary and sufficient for varenicline-induced reduction of alcohol consumption. Consistent with this result, here we show that a more efficacious nAChR agonist, nicotine, also decreased voluntary ethanol intake, and that alpha 4* nAChRs are critical for this reduction.