Positive allosteric modulation of α4β2 nicotinic acetylcholine receptors as a new approach to smoking reduction: evidence from a rat model of nicotine self-administration.

Abstract

The α4β2 subtype of nicotinic acetylcholine receptors (nAChRs) plays a central role in the mediation of nicotine reinforcement. Positive allosteric modulators (PAMs) at α4β2 nAChRs facilitate the intrinsic efficiency of these receptors, although they do not directly activate the receptors. α4β2 PAMs are hypothesized to reduce nicotine self-administration in subjects engaged in routine nicotine consumption. The present study tested this hypothesis using a rat model of nicotine self-administration. Male Sprague-Dawley rats were trained in daily 1-h sessions to intravenously self-administer nicotine (0.03mg/kg per infusion, free base) on a fixed-ratio 5 schedule. The effects of the α4β2 PAM desformylflustrabromine (dFBr), α4β2 agonist 5-iodo-A-85380, and acetylcholinesterase inhibitor galantamine on nicotine intake were examined. The ability of dFBr and 5-iodo-A-85380 to substitute for nicotine was also assessed. dFBr and 5-iodo-A-85380 dose-dependently reduced nicotine self-administration without changing lever responses for food. Galantamine decreased the self-administration of nicotine and food at high doses. Unlike 5-iodo-A-85380, dFBr failed to substitute for nicotine in supporting self-administration behavior. These results demonstrated the effectiveness of dFBr in reducing nicotine intake and the inability of dFBr to support self-administration behavior. These findings suggest that positive allosteric modulation of α4β2 nAChRs may be a promising target for the treatment of nicotine addiction. Moreover, α4β2 PAMs, in contrast to agonist medications, may have clinical advantages because they may have little liability for abuse because of their lack of reinforcing actions on their own.