Differential expression of the beta4 neuronal nicotinic receptor subunit affects tolerance development and nicotinic binding sites following chronic nicotine treatment.

ABSTRACT: The role of neuronal nicotinic acetylcholine receptors (nAChR) containing the ?4 subunit in tolerance development and nicotinic binding site levels following chronic nicotine treatment was investigated. Mice differing in expression of the ?4-nAChR subunit [wild-type (?4(++)), heterozygote (?4(+-)) and null mutant (?4(--))] were chronically treated for 10 days with nicotine (0, 0.5, 1.0, 2.0 or 4.0mg/kg/h) by constant intravenous infusion. Chronic nicotine treatment elicited dose-dependent tolerance development. ?4(--) mice developed significantly more tolerance than either ?4(++) or ?4(+-) mice which was most evident following treatment with 4.0mg/kg/h nicotine. Subsets of [(125)I]-epibatidine binding were measured in several brain regions. Deletion of the ?4 subunit had little effect on initial levels of cytisine-sensitive [(125)I]-epibatidine binding (primarily ?4?2-nAChR sites) or their response (generally increased binding) to chronic nicotine treatment. In contrast, ?4 gene-dose-dependent decreases in expression 5IA-85380 resistant [(125)I]-epibatidine binding sites (primarily ?4*-nAChR) were observed. While these ?4*-nAChR sites were generally resistant to regulation by chronic nicotine treatment, significant increases in binding were noted for habenula and hindbrain. Comparison of previously published tolerance development in ?2(--) mice (less tolerance) to that of ?4(--) mice (more tolerance) supports a differential role for these receptor subtypes in regulating tolerance following chronic nicotine treatment.

SUBMITTER: Meyers EE 

PROVIDER: S-EPMC4336781 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature