Diverse strategies targeting α7 homomeric and α6β2*heteromeric nicotinic acetylcholine receptors for smoking cessation

Preclinical studies suggest that a diversity of nicotinic acetylcholine receptors (nAChRs) with different sensitivities to nicotine may contribute to tobacco addiction. Using rodent intravenous nicotine self-administration as a preclinical model with good predictive validity for therapeutic efficacy for tobacco cessation, investigators have identified heteromeric alpha 6 beta 2* and homomeric alpha 7 nAChRs as promising novel therapeutic targets to promote smoking abstinence (*denotes possible assembly with other subunits). The data suggest that diverse strategies that target these subclasses of nAChRs, namely inhibition of alpha 6 beta 2* nAChRs and stimulation of alpha 7 nAChRs, will support tobacco cessation. alpha 6 beta 2* nAChRs, members of the high-affinity family of beta 2* nAChRs, function similarly to alpha 4 beta 2* nAChRs, the primary target of the FDA-approved drug varenicline, but have a much more selective neuroanatomical pattern of expression in catecholaminergic nuclei. Although activation of beta 2* nAChRs facilitates nicotine self-administration, stimulation of alpha 7 nAChRs appears to negatively modulate both nicotine reinforcement and beta 2* nAChR function in the mesolimbic dopamine system. Although challenges and caveats must be considered in the development of therapeutics that target these nAChR subpopulations, an accumulation of data suggests that alpha 7 nAChR agonists, partial agonists, or positive allosteric modulators and alpha 6 beta 2* nAChR antagonists, partial agonists, or negative allosteric modulators may prove to be effective therapeutics for tobacco cessation.