Xiu Liu
A professor at the University of Mississippi Medical Center, USA
Title: New Approach for Smoking Cessation Medication Development: Positive Allosteric Modulation of the α4β2-subtype of Nicotinic Acetylcholine Receptors
Biography
Biography: Xiu Liu
Abstract
The α4β2-subtype of nicotinic acetylcholine receptors (nAChRs) plays a central role in the reinforcement of nicotine derived from tobacco smoke. Positive allosteric modulators (PAMs) at the α4β2-nAChRs facilitate the intrinsic efficiency of these receptors and thus enhance receptor activities, although they on their own do not directly activate the receptors. Therefore, these PAMs, via enhancing α4β2-nAChR responses to the agonist nicotine, are hypothesized to reduce nicotine intake in the subjects who have already engaged in routine nicotine consumption. Our recent studies used animal models of nicotine self-administration to examine the effects of the α4β2 PAMs on nicotine intake. Rats were trained in daily sessions to intravenously self-administer nicotine as a model of nicotine consumption. After establishment of stable nicotine self-administration, the effects of a α4β2 PAM desformylflustrabromine (dFBr) were examined and compared to a α4β2-selective agonist 5-iodo-A-85380. The ability of dFBr and 5-iodo-A-85380 to substitute for nicotine in maintaining self-administration behavior was also tested. Pretreatment with dFBr and 5-iodo-A-85380 dose-dependently reduced the number of nicotine infusions rats self-administered, while did not change food self-administration, indicating the specificity of these agents for nicotine intake. Unlike 5-iodo-A-85380, dFBr failed to substitute for nicotine in supporting self-administration behavior. These results demonstrated the effectiveness of α4β2 PAMs in reducing nicotine intake in the subjects engaged in regular nicotine-taking behavior and the inability of PAMs themselves to support self-administration behavior, which indicates the PAMs do not have reinforcing actions on their own. These findings suggest that positive allosteric modulation of the a4β2-nAChRs may be a promising target for the treatment of nicotine addiction. Moreover, the a4β2-PAMs, in contrast to agonist medications, may have clinical advantages due to lack of abuse liability.