Role of α5 Nicotinic Acetylcholine Receptors in Pharmacological and Behavioral Effects of Nicotine in Mice

Abstract

Incorporation of the ␣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 ␣5 nAChR in nicotine-mediated behaviors, recent evidence suggests an association between polymorphisms in the ␣5 nAChR gene and nicotine dependence phenotypes in humans. Thus, additional studies are imperative to elucidate the role and function of the ␣5 nAChR subunit in nicotine dependence. Using ␣5(Ϫ/Ϫ) mice, the current study aimed to examine the role of ␣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 ϩ efflux and 125 I-epibatidine binding assays were conducted to examine the effect of ␣5 nAChR subunit deletion on expression and activity of functional nAChRs. Results show that ␣5(Ϫ/Ϫ) mice are less sensitive to the initial effects of nicotine in antinociception, locomotor activity, and hypothermia measures and that the ␣5 nAChR is involved in nicotine reward. Alternatively, ␣5(Ϫ/Ϫ) mice did not differ from wild-type littermates in sensitivity to the discriminative stimulus effects of nicotine. Furthermore, deletion of the ␣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 ␣5 nAChRs are involved in nicotine-mediated behaviors relevant to development of nicotine dependence.

Differential Roles of α6β2* and α4β2* Neuronal Nicotinic Receptors in Nicotine- and Cocaine-Conditioned Reward in Mice

“…This is consistent with the necessity of b2* nAChRs for nicotine reward and reinforcement in the CPP and self-administration procedures in rodents (Corrigall et al, 1994;Picciotto et al, 1998;Maskos et al, 2005;Pons et al, 2008;Walters et al, 2006). A similar phenotype was observed with nicotine-induced CPP at high doses in the a5 KO mouse (Jackson et al, 2010). Although a5 and a6 are co-expression in the substantia nigra and VTA, no direct evidence suggests co-assembly of these two subunits.…”

CHRNA3 rs1051730 Genotype and Short-Term Smoking Cessation

“…One possibility is that individuals with one or more copies of the T allele may be more resistant to the aversive side effects of nicotine, as shown in recent studies of nAChR a5 knockout mice (Jackson et al, 2010), and may therefore be able to tolerate higher doses of NRT. Conceivably, nicotine derived from combinations of smoking and NRT, or different combinations of NRTs, might thus provide different dose-response relationships for individuals with nAChRs encoded by haplotypes with these variants at this locus.…”

Acetylcholine Receptor (AChR) α5 Subunit Variant Associated with Risk for Nicotine Dependence and Lung Cancer Reduces (α4β2)2α5 AChR Function

“…Knockout of ␣5 subunits increases nicotine reward and decreases aversion to high doses of nicotine (Jackson et al, 2010). A PAM could provide genetically based personalized medical therapy for those with the ␣5 Asn 398 variant when combined with nicotine replacement therapy using nicotine or varenicline.…”

“…The ␣5 subunit plays a key role in attention circuitry (Bailey et al, 2010). An ␣4␤2␣5 AChR PAM might enhance nicotinic antinociception (Jackson et al, 2010). A PAM would specifically enhance the impact of ACh, especially where volume transmission is mediated by low concentrations of ACh.…”