Role of alpha 5 Nicotinic Acetylcholine Receptors in Pharmacological and Behavioral Effects of Nicotine in Mice

Abstract

Incorporation of the alpha 5 nicotinic acetylcholine receptor ( nAChR) subunit can greatly influence nAChR function without altering receptor number. Although few animal studies have assessed the role of the alpha 5 nAChR in nicotine-mediated behaviors, recent evidence suggests an association between polymorphisms in the alpha 5 nAChR gene and nicotine dependence phenotypes in humans. Thus, additional studies are imperative to elucidate the role and function of the alpha 5 nAChR subunit in nicotine dependence. Using alpha 5(-/-) mice, the current study aimed to examine the role of alpha 5 nAChRs in the initial pharmacological effects of nicotine, nicotine reward using the conditioned place preference model, and the discriminative effects of nicotine using a two-lever drug discrimination model. (86)Rb(+) efflux and (125)I-epibatidine binding assays were conducted to examine the effect of alpha 5 nAChR subunit deletion on expression and activity of functional nAChRs. Results show that alpha 5(-/-) mice are less sensitive to the initial effects of nicotine in antinociception, locomotor activity, and hypothermia measures and that the alpha 5 nAChR is involved in nicotine reward. Alternatively, alpha 5(-/-) mice did not differ from wild-type littermates in sensitivity to the discriminative stimulus effects of nicotine. Furthermore, deletion of the alpha 5 nAChR subunit resulted in a statistically significant decrease in function in the thalamus and hindbrain, but the decreases noted in spinal cord were not statistically significant. Receptor number was unaltered in all areas tested. Taken together, results of the study suggest that alpha 5 nAChRs are involved in nicotine-mediated behaviors relevant to development of nicotine dependence.