Ueno Ken-Ichi, Togashi Hiroko, Matsumoto Machiko, Ohashi Satoshi, Saito Hideya, Yoshioka Mitsuhiro
Department of Pharmacology, Hokkaido University Graduate School of Medicine, Kita-15, Nishi-7, Kita-ku, Sapporo 060-8638, Japan.
J Pharmacol Exp Ther. 2002 Jul;302(1):95-100. doi: 10.1124/jpet.302.1.95.
The objective of the present study was to elucidate the role of nicotine in impairment of spontaneous alternation behavior of juvenile stroke-prone spontaneously hypertensive rats (SHRSP), an animal model of attention deficit hyperactivity disorder (ADHD). Spontaneous alternation behavior assessed by a Y-maze task was significantly lower, and total arm entries were significantly higher in SHRSP than in genetic control Wistar-Kyoto rats. Nicotine (0.1-1 mg/kg, s.c.) dose dependently improved the spontaneous alternation deficit without affecting total arm entries in SHRSP. Nicotine-induced (1 mg/kg, s.c.) improvement was significantly abolished by the centrally acting nicotinic acetylcholine receptor (nAChR) antagonist mecamylamine (1 mg/kg, i.p.), but not by peripherally acting hexamethonium (5 mg/kg, i.p.), suggesting that nicotine-induced improvement is mediated via central nAChR. The alpha4beta2 nAChR antagonist dihydro-beta-erythroidine (3-10 mg/kg, i.p.) dose dependently counteracted nicotine-induced improvement of spontaneous alternation in SHRSP, whereas the alpha7 nAChR antagonist methyllycaconitine (3-10 mg/kg, i.p.) did not. In addition, the alpha4beta2 nAChR agonist RJR-2403 (N-methyl-4-(3-pyridinyl)-3-butene-1-amine; 1-10 mg/kg, s.c.) dose dependently and significantly improved the spontaneous alternation deficit. These findings revealed that nicotine improved spontaneous alternation behavior in SHRSP via the activation of alpha4beta2, but not alpha7, nAChR. Thus, the alpha4beta2 nAChR mechanism might be responsible for the spontaneous alternation deficit in juvenile SHRSP, an animal model of ADHD. This evidence indicates the possibility that selective alpha4beta2 nAChR agonists might be useful for treating attentional dysfunction in ADHD.
本研究的目的是阐明尼古丁在易患中风的自发性高血压幼鼠（SHRSP）自发交替行为受损中的作用，SHRSP是一种注意力缺陷多动障碍（ADHD）的动物模型。通过Y迷宫任务评估的自发交替行为在SHRSP中显著低于基因对照Wistar-Kyoto大鼠，而总臂进入次数则显著更高。尼古丁（0.1 - 1 mg/kg，皮下注射）剂量依赖性地改善了SHRSP的自发交替缺陷，而不影响总臂进入次数。尼古丁诱导的（1 mg/kg，皮下注射）改善被中枢作用的烟碱型乙酰胆碱受体（nAChR）拮抗剂美加明（1 mg/kg，腹腔注射）显著消除，但未被外周作用的六甲铵（5 mg/kg，腹腔注射）消除，这表明尼古丁诱导的改善是通过中枢nAChR介导的。α4β2 nAChR拮抗剂二氢-β-刺桐碱（3 - 10 mg/kg，腹腔注射）剂量依赖性地抵消了尼古丁诱导的SHRSP自发交替改善，而α7 nAChR拮抗剂甲基lycaconitine（3 - 10 mg/kg，腹腔注射）则没有。此外，α4β2 nAChR激动剂RJR - 2403（N - 甲基 - 4 -（3 - 吡啶基）- 3 - 丁烯 - 1 - 胺；1 - 10 mg/kg，皮下注射）剂量依赖性地显著改善了自发交替缺陷。这些发现表明，尼古丁通过激活α4β2而非α7 nAChR改善了SHRSP的自发交替行为。因此，α4β2 nAChR机制可能是导致ADHD动物模型幼龄SHRSP自发交替缺陷的原因。这一证据表明，选择性α4β2 nAChR激动剂可能对治疗ADHD的注意力功能障碍有用。
