The role of various nicotinic receptor subunits and factors influencing nicotine conditioned place aversion

Affective nicotine withdrawal symptoms are of major motivational significance in contributing to relapse and continued tobacco use; thus, it is important to understand the molecular and receptor-mediated mechanisms that mediate affective withdrawal behaviors. Previous work using the conditioned place aversion (CPA) model has shown that nicotine withdrawal is associated with a negative affective state, and place aversion to previously neutral environmental stimuli represents a motivational component in the maintenance of drug use. Thus, the purpose of this study was to evaluate the role of genotype, sex, and age and to extend previous studies examining the role of various nicotinic receptor subtypes in the development of nicotine withdrawal aversion using the CPA model. Mice were chronically treated with nicotine and conditioned for two days with various nicotinic receptor antagonists. The major findings showed that mecamylamine and dihydro-β-erythroidine (DHβE), but not hexamethonium or methyllycaconitine citrate (MLA), precipitated significant aversion in the CPA model. This pharmacological data support our previous knockout mouse data suggesting that nicotine CPA is mediated by central β2-containing nicotinic receptors, but not α7 nicotinic receptors. Further, we show that sex and age are contributing factors to the development of nicotine CPA. Overall, the results of our study provide some insight into pharmacological and behavioral factors involved in the development of an aversive motivational component associated with nicotine withdrawal.