Varenicline is a high affinity partial agonist at α4β2* nAChRs, low affinity partial agonist at α3β4*, α3β2*, α6β2* nAChRs, and a low affinity agonist at α7 nAChRs (Coe et al., 2005). Acute varenicline administration decreases nicotine and ethanol induced increases in dopamine release in the nucleus accumbens (Ericson et al., 2009) and reduces ethanol intake in rodents (Kamens et al., 2010; Steensland et al., 2007) as well as alcohol self-administration in humans (McKee et al., 2009). Consistent with our previous findings (Steensland et al., 2007), we show that varenicline decreases baseline ethanol as well as reduces nicotine-induced increase in 20% self-administration. However, varenicline did not reduce nicotine-induced increases in ethanol intake below its effects on ethanol intake alone. This suggests that varenicline-insensitive nAChRs or non-nicotinic receptors as suggested by Ericson (2000) may also mediate the effects of nicotine to increase ethanol self-administration. Taken together, our data suggests that nAChRs play an essential role in ethanol self-administration and that varenicline may prove to be an effective treatment for the co-administration of ethanol and nicotine.
