海马神经元型一氧化氮合酶神经元再生通路介导5-羟色胺类抗抑郁药作用

中国临床药理学与治疗学 ›› 2013, Vol. 18 ›› Issue (3): 252-257.

海马神经元型一氧化氮合酶神经元再生通路介导5-羟色胺类抗抑郁药作用

吴海银, 张晶

南京医科大学药学院药理教研室,南京 210000,江苏

收稿日期:2012-10-15 修回日期:2013-01-02 出版日期:2013-03-26 发布日期:2013-04-02
通讯作者: 张晶,通信作者,女,博士,讲师,研究方向:基础药理学、神经再生与抑郁症。Tel: 15850517835 E-mail: jingzhang@njmu.edu.cn
作者简介:吴海银,女,本科,助教,研究方向:基础药理学与药效学、神经再生与抑郁症。Tel: 15950536316 E-mail: haiyinwu@njmu.edu.cn

Hippocampal nNOS-neuronal regeneration pathways mediates the effect of 5-serotonin antidepressive drugs

WU Hai-yin, ZHANG Jing

Department of Pharmacology, School of Pharmacy, Nanjing Medicine University, Nanjing 210000, Jiangsu, China

Received:2012-10-15 Revised:2013-01-02 Online:2013-03-26 Published:2013-04-02

摘要/Abstract

摘要： 目的: 研究5-羟色胺类抗抑郁药的作用机制。方法: 将经典5-羟色胺类抗抑郁药氟西汀及选择性5-HT1A受体激动剂8-OH-DPAT,通过立体定位特异性注射到野生型和神经元型一氧化氮合酶(nNOS)敲除型小鼠海马部位,通过Brdu免疫组化和新奇摄食抑制试验、强迫游泳试验、悬尾试验等抑郁行为学检测,观察神经元再生的变化情况和抗抑郁效果。结果: 氟西汀和8-OH-DPAT通过nNOS上调海马神经元再生,发挥抗抑郁作用。结论: 海马nNOS-神经元再生通路介导5-羟色胺类抗抑郁药的抗抑郁作用。

关键词: 抑郁症, 氟西汀, 选择性5-HT1A受体激动剂, 神经元再生, 神经元型一氧化氮合酶

Abstract: AIM: To explore the antidepressive mechanism of serotonin reuptake inhabitor and selective 5-HT1A receptor agonist.METHODS: Fluoxetine, a serotonin reuptake inhibitor, and 8-OH-DPAT, a selective 5-HT1A receptor agonist, were infused into the dentate gyrus (DG) of bilateral hippocampus of nNOS knockout and wild-type mice by stereotactic surgery. Brdu immunohistochemisty was performed to detect neurogenesis as well as novelty suppressed feeding test, forced swimming test and tail suspending test were used to measure depression-related behavior.RESULTS: Both selective infusion of fluoxetine and 8-OH-DPAT into hippocampus up-regulated neurogenesis and generated antidepressant- like effect, which were dependent on the function of nNOS.CONCLUSION: nNOS-neurogenesis cascade in the hippocampus mediates the antidepressive effect of serotonin reuptake inhabitor and selective 5-HT1A receptor agonist.

Key words: Depession, Fluoxetine, Selective 5-HT1A receptor agonist, Neurogenesis, nNO

中图分类号:

R965.2

吴海银, 张晶. 海马神经元型一氧化氮合酶神经元再生通路介导5-羟色胺类抗抑郁药作用[J]. 中国临床药理学与治疗学, 2013, 18(3): 252-257.

WU Hai-yin, ZHANG Jing. Hippocampal nNOS-neuronal regeneration pathways mediates the effect of 5-serotonin antidepressive drugs[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2013, 18(3): 252-257.

参考文献

[1] 许莉莉, 张惠云. 5-HT1A受体及其与抑郁症相关性的研究进展[J]. 中国医药导报, 2012, 9(3): 16-18.
[2] 夏金校, 姚华华, 王一冰, 等. 艾司西酞普兰联合小剂量阿立哌唑治疗伴躯体症状抑郁症的研究[J]. 中国临床药理学与治疗学, 2011, 16( 8): 929-932.
[3] 陈鹏宇, 胡泽卿. 5-羟色胺能系统在抑郁症中的研究进展[J]. 神经疾病与精神卫, 2008, 8(4): 325- 327.
[4] 陈嘉, 董文心. 抗抑郁药物对海马神经元保护作用的研究进展[J]. 中国新药杂志, 2008, 17(8): 441-445.
[5] 刘国卿,主编. 抗精神失常药-抗抑郁症药[M]. 药理学.2版.中国医药科技出版社, 2009:152-156.
[6] 刘艳梅, 祁红, 陈红专. 抗抑郁药的信号转导机制[J]. 中国临床药理学与治疗学, 2004, 9(12): 1321-1326.
[7] Santarelli L, Saxe M, Gross C, et al. Requirement of Hippocampal Neurogenesis for the Behavioral Effects of Antidepressants[J]. Science, 2003, 301(5634): 805-809.
[8] Zhu DY, Zhou L. Neuoronal nitric oxide synthase: structrre, subcellular localization, regulation, and clinical implications[J]. Nitric Oxide, 2009, 20(4): 223-230.
[9] Bodnoff SR, Suranyi-Cadotte B, Aitken DH, et al. The effects of chronic antidepressant treatment in an animal model of anxiety[J]. Psychopharmacology (Berl), 1988, 95(3): 298-302.
[10] Kodama M, Fujioka T, Duman RS. Chronic olanzapine or fluoxetine administration increase cell proliferation in hippocampus and prefrontal cortex of adult rat[J]. Biol Psychiatry, 2004, 56 (8): 570-580.
[11] Zheng F, Adelsberger H, Müller MR, et al. Activing tunes GABA ergic neurotransmission and modulates anxiety-like behavior[J]. Mol Psychiatry, 2009, 14(3): 332-346.
[12] Zhu DY, Liu SH, Sun HS, et al. Expression of inducible nitric oxide synthase after focal cerebral ischemia stimulates neurogenesis in the adult rodent dentate gyrus[J]. J Neurosci, 2003, 23 (1): 223-229.
[13] Van Praag H, Schinder AF, Christie BR, et al. Functional neurogenesis in the adult hippocampus[J]. Nature, 2002, 415: 1030-1034.
[14] Gould E, Reeves AJ, Graziano MS, et al. Neurogenesis in the neocortex of adult primates[J]. Science, 1999, 286(5439): 548-552.
[15] Horner PJ, Gage FH. Regenerating the damaged central nervous system[J]. Nature, 2000, 407: 963-970.
[16] Neumeister A, Wood S, Bonne O, et al. Reduced hippocampal volume in unmedicated, remitted patients with major depression versus control subjects[J]. Biol Psychiatry, 2005, 57(8): 935-937.