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Reduced ?4 subunit expression in ?4+- and ?4+- /?2+- nicotinic acetylcholine receptors alters ?4?2 subtype up-regulation following chronic nicotine treatment.

ABSTRACT: BACKGROUND AND PURPOSE:Genomic analysis has shown many variants in both CHRNA4 and CHRNB2, genes which encode the ?4 and ?2 subunits of nicotinic ACh receptors (nAChR) respectively. Some variants influence receptor expression, raising the possibility that CHRNA4 variants may affect response to tobacco use in humans. Chronic exposure to nicotine increases expression of nAChRs, particularly ?4?2-nAChRs, in humans and laboratory animals. Here, we have evaluated whether the initial level of receptor expression affects the increase in expression. EXPERIMENTAL APPROACH:Mice differing in expression of ?4 and/or ?2 nAChR subunits were chronically treated with saline, 0.25, 1.0 or 4.0 mg·kg-1 ·h-1 nicotine. Brain preparations were analysed autoradiographically by [125 I]-epibatidine binding, immunoprecipitation and Western blotting. KEY RESULTS:Immunochemical studies confirmed that most of the [3 H]-epibatidine binding corresponds to ?4?2*-nAChR and that increases in binding correspond to increases in ?4 and ?2 proteins. Consistent with previous reports, the dose-dependent increase in nAChR in wild-type mice following chronic nicotine treatment, measured with any of the methods, reached a maximum. Although receptor expression was reduced by approximately 50% in ?2+- mice, the pattern of response to chronic treatment resembled that of wild-type mice. In contrast, both ?4+- and ?4+- /?2+- exhibited relatively greater up-regulation. Consistent with previous reports, ?4?2?5-nAChR did not increase in response to nicotine. CONCLUSIONS AND IMPLICATIONS:These results indicate that mice with reduced expression of the ?4 nAChR subunit have a more robust response to chronic nicotine than mice with normal expression of this subunit. LINKED ARTICLES:This article is part of a themed section on Nicotinic Acetylcholine Receptors. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.11/issuetoc.

SUBMITTER: Moretti M

PROVIDER: S-EPMC5980142 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Reduced α4 subunit expression in α4<sup>+-</sup> and α4<sup>+-</sup> /β2<sup>+-</sup> nicotinic acetylcholine receptors alters α4β2 subtype up-regulation following chronic nicotine treatment.

Moretti Milena M Fasoli Francesca F Gotti Cecilia C Marks Michael J MJ

British journal of pharmacology 20170801 11

<h4>Background and purpose</h4>Genomic analysis has shown many variants in both CHRNA4 and CHRNB2, genes which encode the α4 and β2 subunits of nicotinic ACh receptors (nAChR) respectively. Some variants influence receptor expression, raising the possibility that CHRNA4 variants may affect response to tobacco use in humans. Chronic exposure to nicotine increases expression of nAChRs, particularly α4β2-nAChRs, in humans and laboratory animals. Here, we have evaluated whether the initial level of ...[more]

PMID: 28585241

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Project description:Nicotine leads to both activation and desensitization (inactivation) of nicotinic acetylcholine receptors (nAChRs). This study tested the hypothesis that nicotine and a selective antagonist of ?2*nAChRs would have similar effects on affective behavior. Adult C57BL/6J male mice were tested in a conditioned emotional response (CER) assay which evaluates the ability of an aversive stimulus to inhibit goal-directed behavior. Mice lever-pressed for a saccharin reinforcer according to a variable schedule of reinforcement during sessions in which two presentations of a compound light/tone conditioned stimulus (CS) co-terminated with a 0.1 or 0.3 mA, 0.5 s footshock unconditioned stimulus (US). During testing in the absence of the US, mice received doses of i.p. nicotine (0, 0.0032, 0.01, 0.032, 0.1 mg/kg) or a selective ?2 subunit containing nAChR (?2*nAChR) antagonist dihydro-beta-erythroidine (0, 0.1, 0.3, 1.0, 3.0 mg/kg DH?E). There was a dose-dependent effect of nicotine revealing that only low doses (0.01, 0.032 mg/kg) increased CER suppression ratios (SR) in these mice. DH?E also dose-dependently increased SR at the 3 mg/kg dose. In ethological measures of fear-/anxiety-like behavior, these doses of nicotine and DH?E significantly reduced digging behavior in a marble burying task and 0.3 mg/kg DH?E promoted open-arm activity in the elevated plus maze. Doses of nicotine and DH?E that altered affective behavior had no effect on locomotor activity. Similar to previous reports with anxiolytic drugs, low dose nicotine and DH?E reversed SR in a CER assay, decreased digging in a marble burying assay and increased open arm activity in the elevated plus maze. This study provides evidence that inactivation of ?2*nAChRs reduces fear-like and anxiety-like behavior in rodents and suggests that smokers may be motivated to smoke in part to desensitize their ?2*nAChRs. These data further identify ?2*nAChR antagonism as a potential therapeutic strategy for relief of negative affect and anxiety.

Dataset Information

Reduced ?4 subunit expression in ?4+- and ?4+- /?2+- nicotinic acetylcholine receptors alters ?4?2 subtype up-regulation following chronic nicotine treatment.

Publications

Reduced α4 subunit expression in α4<sup>+-</sup> and α4<sup>+-</sup> /β2<sup>+-</sup> nicotinic acetylcholine receptors alters α4β2 subtype up-regulation following chronic nicotine treatment.

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