Partial Agonists of the α3β4*Neuronal Nicotinic Acetylcholine Receptor Reduce Ethanol Consumption and Seeking in Rats

Alcohol use disorders (AUDs) impact millions of individuals and there remain few effective treatment strategies. Despite evidence that neuronal nicotinic acetylcholine receptors (nAChRs) have a role in AUDs, it has not been established which subtypes of the nAChR are involved. Recent human genetic association studies have implicated the gene cluster CHRNA3-CHRNA5-CHRNB4 encoding the alpha 3, alpha 5, and beta 4 subunits of the nAChR in susceptibility to develop nicotine and alcohol dependence; however, their role in ethanol-mediated behaviors is unknown due to the lack of suitable and selective research tools. To determine the role of the alpha 3, and beta 4 subunits of the nAChR in ethanol self-administration, we developed and characterized high-affinity partial agonists at alpha 3 beta 4 nAChRs, CP-601932, and PF-4575180. Both CP-601932 and PF-4575180 selectively decrease ethanol but not sucrose consumption and operant self-administration following long-term exposure. We show that the functional potencies of CP-601932 and PF-4575180 at a3b4 nAChRs correlate with their unbound rat brain concentrations, suggesting that the effects on ethanol self-administration are mediated via interaction with alpha 3 beta 4 nAChRs. Also varenicline, an approved smoking cessation aid previously shown to decrease ethanol consumption and seeking in rats and mice, reduces ethanol intake at unbound brain concentrations that allow functional interactions with alpha 3 beta 4 nAChRs. Furthermore, the selective alpha 4 beta 2* nAChR antagonist, DH beta E, did not reduce ethanol intake. Together, these data provide further support for the human genetic association studies, implicating CHRNA3 and CHRNB4 genes in ethanol-mediated behaviors. CP-601932 has been shown to be safe in humans and may represent a potential novel treatment for AUDs. Neuropsychopharmacology (2011) 36, 603-615; doi:10.1038/npp.2010.191; published online 3 November 2010