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Role of alpha5 nicotinic acetylcholine receptors in pharmacological and behavioral effects of nicotine in mice.

ABSTRACT: Incorporation of the alpha5 nicotinic acetylcholine receptor (nAChR) subunit can greatly influence nAChR function without altering receptor number. Although few animal studies have assessed the role of the alpha5 nAChR in nicotine-mediated behaviors, recent evidence suggests an association between polymorphisms in the alpha5 nAChR gene and nicotine dependence phenotypes in humans. Thus, additional studies are imperative to elucidate the role and function of the alpha5 nAChR subunit in nicotine dependence. Using alpha5(-/-) mice, the current study aimed to examine the role of alpha5 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 alpha5 nAChR subunit deletion on expression and activity of functional nAChRs. Results show that alpha5(-/-) mice are less sensitive to the initial effects of nicotine in antinociception, locomotor activity, and hypothermia measures and that the alpha5 nAChR is involved in nicotine reward. Alternatively, alpha5(-/-) mice did not differ from wild-type littermates in sensitivity to the discriminative stimulus effects of nicotine. Furthermore, deletion of the alpha5 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 alpha5 nAChRs are involved in nicotine-mediated behaviors relevant to development of nicotine dependence.

SUBMITTER: Jackson KJ

PROVIDER: S-EPMC2912049 | biostudies-literature | 2010 Jul

REPOSITORIES: biostudies-literature

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Role of alpha5 nicotinic acetylcholine receptors in pharmacological and behavioral effects of nicotine in mice.

Jackson K J KJ Marks M J MJ Vann R E RE Chen X X Gamage T F TF Warner J A JA Damaj M I MI

The Journal of pharmacology and experimental therapeutics 20100416 1

Incorporation of the alpha5 nicotinic acetylcholine receptor (nAChR) subunit can greatly influence nAChR function without altering receptor number. Although few animal studies have assessed the role of the alpha5 nAChR in nicotine-mediated behaviors, recent evidence suggests an association between polymorphisms in the alpha5 nAChR gene and nicotine dependence phenotypes in humans. Thus, additional studies are imperative to elucidate the role and function of the alpha5 nAChR subunit in nicotine d ...[more]

PMID: 20400469

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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

Role of alpha5 nicotinic acetylcholine receptors in pharmacological and behavioral effects of nicotine in mice.

Publications

Role of alpha5 nicotinic acetylcholine receptors in pharmacological and behavioral effects of nicotine in mice.

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