Addiction - Differential role of nicotinic acetylcholine receptor subunits in physical and affective nicotine withdrawal signs (2008)

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J Pharmacol Exp Ther. 2008 Jan 9; [Epub ahead of print]

Jackson KJ, Martin BR, Changeux JP, Damaj MI.
It has been suggested that the negative effects associated with nicotine withdrawal promote continued tobacco use and contribute to the high relapse rate of smoking behaviors. Thus, it is important to understand the receptor-mediated mechanisms underlying nicotine withdrawal to aid in the development of more successful smoking cessation therapies. The effects of nicotine withdrawal are mediated through nAChRs; however the role of the different nAChRs subtypes in nicotine withdrawal remains unclear. Therefore, we used mecamylamine-precipitated, spontaneous, and conditioned place aversion withdrawal models to measure physical and affective signs of nicotine withdrawal in various nAChR knock-out mice. beta2, alpha7, and alpha5 nAChR knock-out male mice were chronically exposed to nicotine through surgically implanted osmotic mini pumps and 14 days later they were assessed for withdrawal signs. Our results show a loss of affective signs of withdrawal such as anxiety-related behavior and aversion in beta2 knock-out mice, while alpha7 and alpha5 knock-out mice displayed a loss of physical withdrawal signs such as hyperalgesia and somatic signs respectively. These results suggest that beta2-containing nAChRs are involved in the affective signs of nicotine withdrawal, while non-beta2 containing nAChRs are more closely associated with physical signs of nicotine withdrawal; thus the nAChR subtype composition plays an important role in the development of nicotine withdrawal.

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