Differential Roles of the \(\alpha\)4\(\beta\)2 and \(\alpha\)7 Nicotinic Acetylcholine Receptors in Nicotine Addiction: Implications in Smoking Cessation Medication Development

Abstract

Nicotine exerts its reinforcing actions via activating the nicotinic acetylcholine receptors (nAChRs). In tobacco smoking, exposure to the environmental stimuli (cues) previously conditioned to nicotine reinforcement critically contributes to the high relapse rates in abstinent smokers. Research including findings from our own laboratory has suggested critical and differential roles of the two major nAChR subtypes, the \(\alpha\)4\(\beta\)2- and \(\alpha\)7-containing receptors that accounts for about 95% of the whole nAChR population in brain, in the process of tobacco smoking addiction development and cue-triggered relapse after a period of abstinence. In specific, our laboratory studies using rat models of smoking and relapse demonstrated that antagonism of the \(\alpha\)4\(\beta\)2 but not \(\alpha\)7 subtype effectively reduced on-going nicotine self-administration, indicating attenuation of nicotine reinforcement, whereas, blockade of the \(\alpha\)7 but not \(\alpha\)4\(\beta\)2 subtype prevented cue-induced relapse to nicotine-seeking behavior in abstinent subjects. These research observations provide support for the continued effort to test cholinergic agents aiming at the \(\alpha\)4\(\beta\)2 nAChRs for reducing or stopping smoking. However, this work suggests that, in order to prevent smoking relapse in abstinent smokers triggered by exposure to environmental cues, targeting at the \(\alpha\)7 nAChRs’ activity would be a promising strategy.