title: Varenicline provokes impulsive action by stimulating α4β2 nicotinic acetylcholine receptors in the infralimbic cortex in a nicotine exposure status-dependent manner.
abstract: Higher impulsivity is a risk factor for criminal involvement and drug addiction. Because nicotine administration enhances impulsivity, the effects of stop-smoking aids stimulating nicotinic acetylcholine receptors (nAChRs) on impulsivity must be determined in different conditions. Our goals were 1) to confirm the relationship between varenicline, a stop-smoking aid and α4β2 nAChR partial agonist, and impulsivity, 2) to elucidate the mechanisms underlying the effects of varenicline, 3) to examine whether a low dose of varenicline that does not evoke impulsive action could block the stimulating effects of nicotine on impulsive action, 4) to determine whether the route of administration could modulate the effects of varenicline on impulsive action, and 5) to determine whether the effects of varenicline on impulsivity could be altered by smoking status. We used a 3-choice serial reaction time task to assess impulsivity and other cognitive functions in rats. Our findings are as follows: 1) acute subcutaneous (s.c.) injection of varenicline evoked impulsive action in a dose-dependent manner; 2) the effects of varenicline on impulsivity were blocked by the microinjection of dihydro-β-erythroidine, a α4β2 nAChR antagonist, into the infralimbic cortex; 3) the low dose of varenicline did not attenuate the effects of nicotine on impulsive action at all; 4) oral administration of varenicline evoked impulsive action in a similar manner to s.c. injection; and 5) the stimulating effects of varenicline on impulsive action were not observed in rats that received nicotine infusion for 8days or nicotine-abstinent rats after discontinuing infusion. Additionally, we found that oral varenicline administration enhanced attentional function whether nicotine was infused or not. Thus, although varenicline administration could be harmless to heavy smokers or ex-smokers, it could be difficult for non-smokers with respect to impulsivity, whereas it may be beneficial with respect to attentional function.
authors.affiliation: Department of Neuropharmacology, Hokkaido University, Graduate School of Medicine, Japan. Electronic address: gwd0701@yahoo.co.jp.
authors.forename: Yu
authors.initials: Y
authors.lastname: Ohmura
authors.affiliation: Hokkaido University, School of Medicine, Japan.
authors.forename: Hitomi
authors.initials: H
authors.lastname: Sasamori
authors.affiliation: Department of Neuropharmacology, Hokkaido University, Graduate School of Medicine, Japan; Department of Neuropsychiatry, Keio University, School of Medicine, Tokyo, Japan; Research Fellow of Japan Society for the Promotion of Science, Japan.
authors.forename: Iku
authors.initials: I
authors.lastname: Tsutsui-Kimura
authors.affiliation: Department of Neuropharmacology, Hokkaido University, Graduate School of Medicine, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Izumi
authors.affiliation: Department of Neuropharmacology, Hokkaido University, Graduate School of Medicine, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Yoshida
authors.affiliation: Department of Neuropharmacology, Hokkaido University, Graduate School of Medicine, Japan.
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Yoshioka
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001066:Appetite / Q000187:drug effects; D004079:Dihydro-beta-Erythroidine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D055103:Hypodermoclysis; D007175:Impulsive Behavior / Q000187:drug effects*; D065726:Limbic Lobe / Q000187:drug effects*; D008297:Male; D008845:Microinjections; D009538:Nicotine / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology; D051381:Rats; D011978:Receptors, Nicotinic / Q000187:drug effects*; D000068580:Varenicline / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology*
chemical_list: D018722:Nicotinic Agonists; D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2; D004079:Dihydro-beta-Erythroidine; D009538:Nicotine; D000068580:Varenicline
keywords: Attention; Champix; Chantix; Impulsive behavior; Tobacco