Diverse strategies targeting ?7 homomeric and ?6?2* 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 ?6?2* and homomeric ?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 ?6?2* nAChRs and stimulation of ?7 nAChRs, will support tobacco cessation. ?6?2* nAChRs, members of the high-affinity family of ?2* nAChRs, function similarly to ?4?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 ?2* nAChRs facilitates nicotine self-administration, stimulation of ?7 nAChRs appears to negatively modulate both nicotine reinforcement and ?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 ?7 nAChR agonists, partial agonists, or positive allosteric modulators and ?6?2* nAChR antagonists, partial agonists, or negative allosteric modulators may prove to be effective therapeutics for tobacco cessation.
?7 nicotinic smoking cessation drug development ?6 nicotine dependence