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 2 subunit containing nicotinic ACh receptors (2*nAChRs). Genetic and pharmacological manipulations assessed effects of stimulation versus inhibition of 2*nAChRs on nicotine-associated anxiety-like phenotype. Experimental Approach Using a range of doses of nicotine in 2*nAChR subunit null mutant mice (2KO; backcrossed to C57BL/6J) and their wild-type (WT) littermates, administration of the selective 2*nAChR agonist, 5I-A85380, and the selective 2*nAChR antagonist dihydro--erythroidine (DHE), we determined the behavioural effects of stimulation and inhibition of 2*nAChRs in the light-dark and elevated plus maze (EPM) assays. Key Results Low-dose i.p. nicotine (0.05mg center dot kg(-)1) supported anxiolysis-like behaviour independent of genotype whereas the highest dose (0.5mg center dot kg(-1)) promoted anxiogenic-like phenotype in WT mice, but was blunted in 2KO mice for the measure of latency. Administration of 5I-A85380 had similar dose-dependent effects in C57BL/6J WT mice; 0.001mg center dot kg(-1) 5I-A85380 reduced anxiety on an EPM, whereas 0.032mg center dot kg(-1) 5I-A85380 promoted anxiogenic-like behaviour in both the light-dark and EPM assays. DHE pretreatment blocked anxiogenic-like effects of 0.5mg center dot kg(-1) nicotine. Similarly to DHE, pretreatment with low-dose 0.05mg center dot kg(-1) nicotine did not accumulate with 0.5mg center dot 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 2*nAChRs supports the corresponding anxiolytic-like or anxiogenic-like effects of nicotine. Inhibition of 2*nAChRs may relieve anxiety in smokers and non-smokers alike.