Anxiolytic-like and anxiogenic-like effects of nicotine are regulated via diverse action at β2*nicotinic acetylcholine receptors.

BACKGROUND AND
PURPOSE: Nicotine dose-dependently activates or preferentially desensitizes β2 subunit containing nicotinic ACh receptors (β2*nAChRs). Genetic and pharmacological manipulations assessed effects of stimulation versus inhibition of β2*nAChRs on nicotine-associated anxiety-like phenotype. EXPERIMENTAL APPROACH: Using a range of doses of nicotine in β2*nAChR subunit null mutant mice (β2KO; backcrossed to C57BL/6J) and their wild-type (WT) littermates, administration of the selective β2*nAChR agonist, 5I-A85380, and the selective β2*nAChR antagonist dihydro-β-erythroidine (DHβE), we determined the behavioural effects of stimulation and inhibition of β2*nAChRs in the light-dark and elevated plus maze (EPM) assays. KEY
RESULTS: Low-dose i.p. nicotine (0.05 mg·kg(-) 1) supported anxiolysis-like behaviour independent of genotype whereas the highest dose (0.5 mg·kg(-1) ) promoted anxiogenic-like phenotype in WT mice, but was blunted in β2KO mice for the measure of latency. Administration of 5I-A85380 had similar dose-dependent effects in C57BL/6J WT mice; 0.001 mg·kg(-1) 5I-A85380 reduced anxiety on an EPM, whereas 0.032 mg·kg(-1) 5I-A85380 promoted anxiogenic-like behaviour in both the light-dark and EPM assays. DHβE pretreatment blocked anxiogenic-like effects of 0.5 mg·kg(-1) nicotine. Similarly to DHβE, pretreatment with low-dose 0.05 mg·kg(-1) nicotine did not accumulate with 0.5 mg·kg(-1) nicotine, but rather blocked anxiogenic-like effects of high-dose nicotine in the light-dark and EPM assays. CONCLUSIONS AND IMPLICATIONS: These studies provide direct evidence that low-dose nicotine inhibits nAChRs and demonstrate that inhibition or stimulation of β2*nAChRs supports the corresponding anxiolytic-like or anxiogenic-like effects of nicotine. Inhibition of β2*nAChRs may relieve anxiety in smokers and non-smokers alike.