Ohmura Yu, Sasamori Hitomi, Tsutsui-Kimura Iku, Izumi Takeshi, Yoshida Takayuki, Yoshioka Mitsuhiro
Department of Neuropharmacology, Hokkaido University, Graduate School of Medicine, Japan.
Hokkaido University, School of Medicine, Japan.
Pharmacol Biochem Behav. 2017 Mar;154:1-10. doi: 10.1016/j.pbb.2017.01.002. Epub 2017 Jan 10.
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.
较高的冲动性是犯罪和药物成瘾的一个风险因素。由于尼古丁给药会增强冲动性，因此必须在不同条件下确定刺激烟碱型乙酰胆碱受体（nAChRs）的戒烟辅助药物对冲动性的影响。我们的目标是：1）确认戒烟辅助药物伐尼克兰（一种α4β2 nAChR部分激动剂）与冲动性之间的关系；2）阐明伐尼克兰作用的潜在机制；3）研究不引起冲动行为的低剂量伐尼克兰是否能阻断尼古丁对冲动行为的刺激作用；4）确定给药途径是否能调节伐尼克兰对冲动行为的影响；5）确定伐尼克兰对冲动性的影响是否会因吸烟状态而改变。我们使用三选择序列反应时任务来评估大鼠的冲动性和其他认知功能。我们的研究结果如下：1）急性皮下注射伐尼克兰会以剂量依赖性方式引发冲动行为；2）向边缘下皮质微量注射α4β2 nAChR拮抗剂二氢-β-刺桐啶可阻断伐尼克兰对冲动性的影响；3）低剂量伐尼克兰根本不会减弱尼古丁对冲动行为的影响；4）口服伐尼克兰引发冲动行为的方式与皮下注射相似；5）在接受尼古丁输注8天的大鼠或停止输注后的尼古丁戒断大鼠中未观察到伐尼克兰对冲动行为的刺激作用。此外，我们发现无论是否输注尼古丁，口服伐尼克兰都能增强注意力功能。因此，虽然服用伐尼克兰对重度吸烟者或已戒烟者可能无害，但对于非吸烟者来说，就冲动性而言可能存在困难，而在注意力功能方面可能有益。
