Huang Yu-Wen, Hu Wei-Wei, Chen Zhong, Zhang Li-San, Shen Hai-Qing, Timmerman Henk, Leurs Rob, Yanai Kazuhiko
Department of Pharmacology and Neurobiology, School of Medicine, Zhejiang University, Hangzhou 310031, China.
Behav Brain Res. 2004 May 5;151(1-2):287-93. doi: 10.1016/j.bbr.2003.09.002.
This study was performed to investigate whether or not the histamine H3-antagonist clobenpropit can ameliorate spatial memory deficits induced by MK-801 (0.3 microg per site) as evaluated by an eight-arm radial maze task of rats. A bilateral intrahippocampal (i.h.) injection of clobenpropit (5, 10 microg per site, dose-dependent) markedly improved the working and reference memory deficits induced by MK-801. Its ameliorating effect was potentiated by histidine, but completely antagonized by immepip (2.5 microg per site), a selective H3-agonist. alpha-Fluoromethylhistidine (FMH, 25 microg per site), a selective histidine decarboxylase inhibitor prevented the ameliorating effect of clobenpropit on the working memory deficits induced by MK-801. In addition, the H(1-antagonist pyrilamine, but not the H2-antagonist cimetidine, also inhibited the procognitive effects of clobenpropit. Both FMH and pyrilamine did not significantly modulate the effect of clobenpropit on reference memory. Therefore, the results of this study suggest that the procognitive effects of clobenpropit in MK-801-induced working memory deficits is mediated by increasing endogenous histamine release. In addition, the ameliorating effect of clobenpropit on reference memory might be due to the increased release of neurotransmitters other than histamine.
本研究旨在通过大鼠八臂放射状迷宫任务，探讨组胺H3拮抗剂氯苯丙哌是否能改善由MK-801（每部位0.3微克）诱导的空间记忆缺陷。双侧海马内注射氯苯丙哌（每部位5、10微克，呈剂量依赖性）显著改善了由MK-801诱导的工作记忆和参考记忆缺陷。其改善作用被组氨酸增强，但被选择性H3激动剂咪哌酯（每部位2.5微克）完全拮抗。选择性组氨酸脱羧酶抑制剂α-氟甲基组氨酸（FMH，每部位25微克）可阻止氯苯丙哌对MK-801诱导的工作记忆缺陷的改善作用。此外，H1拮抗剂吡苄明而非H2拮抗剂西咪替丁也抑制了氯苯丙哌的促认知作用。FMH和吡苄明均未显著调节氯苯丙哌对参考记忆的作用。因此，本研究结果表明，氯苯丙哌在MK-801诱导的工作记忆缺陷中的促认知作用是通过增加内源性组胺释放介导的。此外，氯苯丙哌对参考记忆的改善作用可能是由于组胺以外的神经递质释放增加所致。
