Differential Roles of alpha 6 beta 2*and alpha 4 beta 2*Neuronal Nicotinic Receptors in Nicotine- and Cocaine-Conditioned Reward in Mice

Mesolimbic alpha 6* nicotinic acetylcholine receptors (nAChRs) are thought to have an important role in nicotine behavioral effects. However, little is known about the role of the various alpha 6*-nAChRs subtypes in the rewarding effects of nicotine. In this report, we investigated and compared the role of alpha 6*-nAChRs subtypes and their neuro-anatomical locus in nicotine and cocaine reward-like effects in the conditioned place preference (CPP) paradigm, using pharmacological antagonism of alpha 6 beta 2* nAChRs and genetic deletion of the alpha 6 or alpha 4 subunits in mice. We found that alpha 6 KO mice exhibited a rightward shift in the nicotine dose-response curve compared with WI littermates but that alpha 4 KO failed to show nicotine preference, suggesting that alpha 6 alpha 4 beta 2*-nAChRs are involved. Furthermore, alpha 6 beta 2* nAChRs in nucleus accumbens were found to have an important role in nicotine-conditioned reward as the intra-accumbal injection of the selective alpha 6 beta 2* alpha-conotoxin MII [H9A; L15A], blocked nicotine CPP. In contrast to nicotine, alpha 6 KO failed to condition to cocaine, but cocaine CPP in the alpha 4 KO was preserved. Intriguingly, a-conotoxin MII [H9A; L15A], blocked cocaine conditioning in alpha 4 KO mice, implicating alpha 6 beta 2* nAChRs in cocaine reward. Importantly, these effects did not generalize as alpha 6 KO showed both a conditioned place aversion to lithium chloride as well as CPP to palatable food. Finally, dopamine uptake was not different between the alpha 6 KO or WT mice. These data illustrate that the subjective rewarding effects of both nicotine and cocaine may be mediated by mesolimbic alpha 6 beta 2* nAChRs and that antagonists of these receptor subtypes may exhibit therapeutic potential.