title: Anxiolytic-like and anxiogenic-like effects of nicotine are regulated via diverse action at β2*nicotinic acetylcholine receptors.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  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
  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.
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.
authors.forename: S M
authors.initials: SM
authors.lastname: Anderson
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.
authors.forename: D H
authors.initials: DH
authors.lastname: Brunzell
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D001007:Anxiety / Q000139:chemically induced* / Q000235:genetics; D001384:Azetidines / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects*; D004079:Dihydro-beta-Erythroidine / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009538:Nicotine / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D018733:Nicotinic Antagonists / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology; D011978:Receptors, Nicotinic / Q000187:drug effects* / Q000235:genetics
chemical_list: D014151:Anti-Anxiety Agents; D001384:Azetidines; D004079:Dihydro-beta-Erythroidine; D009538:Nicotine; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D011725:Pyridines; D011978:Receptors, Nicotinic; C426745:5-iodo-3-(2-azetidinylmethoxy)pyridine