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 β4 subunit in tolerance development and nicotinic binding site levels following chronic nicotine treatment was investigated. Mice differing in expression of the β4 nAChR subunit [wild-type (β4++), heterozygote (β4+−) and null mutant (β4−−)] were chronically treated for 10 days with nicotine (0, 0.5, 1.0, 2.0 or 4.0 mg/kg/hr) by constant intravenous infusion. Chronic nicotine treatment elicited dose-dependent tolerance development. β4−− mice developed significantly more tolerance than either β4++ or β4+− mice which was most evident following treatment with 4.0 mg/kg/hr nicotine. Subsets of [125I]-epibatidine binding were measured in several brain regions. Deletion of the β4 subunit had little effect on initial levels of cytisine-sensitive [125I]-epibatidine binding (primarily α4β2-nAChR sites) or their response (generally increased binding) to chronic nicotine treatment. In contrast, β4 gene-dose-dependent decreases in expression 5IA-85380 resistant [125I]-epibatidine binding sites (primarily β4*-nAChR) were observed. While these β4*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 β2−− mice (less tolerance) to that of β4−− mice (more tolerance) supports a differential role for these receptor subtypes in regulating tolerance following chronic nicotine treatment.

Insights Into Nicotinic Receptor Signaling in Nicotine Addiction: Implications for Prevention and Treatment

“…Although β4 KO mice showed few somatic signs of nicotine withdrawal or hyperalgesia after nicotine withdrawal [ 109 , 172 , 182 ] other studies reported that different β4* nAChR subtypes are involved in NA and SC, and α3β4* nAChRs are postulated to be the main contributors to tolerance [ 178 , 181 ]. Moreover, β4* nAChR KO mice display a dose-dependent tolerance during chronic nicotine treatment [ 185 ]. In particular, β4-null mutant (β4 – ) mice develop more significant tolerance than either β4 wild-type (β4 ++ ) or β4 heterozygote (β4 +− ) mice [ 185 ].…”

“…Moreover, β4* nAChR KO mice display a dose-dependent tolerance during chronic nicotine treatment [ 185 ]. In particular, β4-null mutant (β4 – ) mice develop more significant tolerance than either β4 wild-type (β4 ++ ) or β4 heterozygote (β4 +− ) mice [ 185 ]. These data indicate that β4* nAChRs are the critical response mediators and are resistant to both acute and chronic nicotine administration [ 185 ].…”

CHRNA5 rs16969968 and CHRNA3 rs578776 polymorphisms are associated with multiple nicotine dependence phenotypes in Bangladeshi smokers

“…Being an intron variant, CHRNB4 rs11072768 polymorphism has been found to be associated with smoking cessation, CPD [ 12 , 43 ] as well as lung cancer [ 45 ]. Molecular study performed on B4 subunit null mice reported an increased tolerance development after chronically treated with nicotine [ 67 ], which might lead to neuroadaptation and subsequently to ND. Surprisingly, our analysis could not identify any association of rs11072768 with any of the investigated smoking-related phenotypes.…”

No evidence of a role of the β4 subunit of the nicotinic acetylcholine receptor in alcohol-related behaviors

“…Additionally, we report no significant differences with our behaviors of interest and the usefulness of this deletion could be in question. However, studies with nicotine behaviors using knockout animals generated from the same mouse colony and tested contemporaneously to this study have reported differences in nicotine tolerance [52]. …”