抑郁症相关受体、细胞因子及信号通路的研究进展

神经药理学报 ›› 2012, Vol. 2 ›› Issue (5): 24-30.

抑郁症相关受体、细胞因子及信号通路的研究进展

董栋，王蕊

华东理工大学药学院，上海市新药设计重点实验室，上海，200237，中国

出版日期:2012-10-26 发布日期:2014-06-27
通讯作者: 王蕊，女，教授，博士生导师；研究方向：神经药理学；Tel/Fax：+86-21-64250823；E-mail：ruiwang@ecust.edu.cn
作者简介:董栋，男，研究生；研究方向：神经药理学；E-mail：dongdy08@163.com
基金资助:
国家自然科学基金（No.81072627），教育部111项目（No.B07023），浦江人才计划（No.11PJ1402300），上海市科学技术委员会上海市新药设计重点实验室（No.11DZ2260600），上海市科学技术委员会重点项目（No.12431900901）

Progress of receptors, cytokine and signal pathways about depression

DONG Dong，WANG Rui

School of Pharmacy,Shanghai Key Laboratory of New Drug Design,East China University of Science and Techonolgy, Shanghai ,200237,China

Online:2012-10-26 Published:2014-06-27
Contact: 王蕊，女，教授，博士生导师；研究方向：神经药理学；Tel/Fax：+86-21-64250823；E-mail：ruiwang@ecust.edu.cn
About author:董栋，男，研究生；研究方向：神经药理学；E-mail：dongdy08@163.com
Supported by:
国家自然科学基金（No.81072627），教育部111项目（No.B07023），浦江人才计划（No.11PJ1402300），上海市科学技术委员会上海市新药设计重点实验室（No.11DZ2260600），上海市科学技术委员会重点项目（No.12431900901）

摘要/Abstract

摘要： 抑郁症是指某种不愉快的心境和一定身体器官的功能紊乱，是一种精神病理状态。迄今为止对抑郁症的治疗，及病因的研究已有一定的进展。目前的研究认为抑郁症的发生与五羟色胺系统、多巴胺等单胺类神经递质的紊乱有关，大量的文献报道了单胺类神经递质与抑郁症的发生和治疗有着密切的关系。同时，研究也发现谷氨酸、糖皮质激素等非单胺类系统也与抑郁症有密切的关系。也有大量的报道称，在抑郁症患者脑中细胞外调节蛋白激酶的活性是降低的，而且抑制该酶的活性在动物模型上可表现出类似抑郁的行为。脑源性神经营养因子在抑郁症患者及抑郁症动物模型血液中的水平与正常对照相比均有明显的下调，而且脑源性神经营养因子在抑郁动物模型上有抗抑郁的作用。本文主要对近期与抑郁症相关的受体、细胞因子及细胞通路研究进行综述。

关键词: 抑郁症, 5-HT受体, 谷氨酸受体, 细胞外调节蛋白激酶, 神经营养因子

Abstract: Depression is a mental disease with negative mood and dysfunction of organs. The study of the pathogenesis of depression has made great progress. The current research demonstrates that the disorder of serotonin system and dopamine system are related to depression; a close relationship between depression and the disorder of monoaminegic
systems has been repeatedly reported. Researchers also find that the glutamatergic system and glucocorticoid system affect the development and progress of depression. The level of brain-derived neurotrophic factor is significantly
decreased in the blood of depressed patients and animal models, and brain-derived neruotrophic factor has a therapeutic effect in animal models of depression. Extracellular signal-regulated kinase is also decreased in depressed
patients. This review summarizes the recent understanding about the receptors, cytokine and signal pathway that are thought to be involved in the pathophysiology of depression

Key words: depression, 5-HT receptor, glutamate receptor, extracellular regulated protein kinase, neurotrophic factor

董栋，王蕊. 抑郁症相关受体、细胞因子及信号通路的研究进展[J]. 神经药理学报, 2012, 2(5): 24-30.

DONG Dong，WANG Rui. Progress of receptors, cytokine and signal pathways about depression[J]. Acta Neuropharmacologica, 2012, 2(5): 24-30.

参考文献

[1] D Hoyer, G Martin. 5-HT receptor classification and nomenclature: towards a harmonization with the human genome[J]. Neuropharmacology, 1997, 36 (4-5): 419-428.

[2] K P Lesch, J Disselkamp-Tietze, A Schmidtke. 5-HT1A receptor function in depression: effect of chronic amitriptyline treatment[J]. J Neural Transm Gen Sect, 1990, 80 (2): 157-161.

[3] Paul R Albert. Transcriptional regulation of the 5-HT1A receptor: implications for mental illness[J]. Philos Trans R Soc Biol Sci, 2012, 367(1601): 2402-2415.

[4] Li Yan, Kasper F Raaby, Connie Sanchez, et al. Serotonergic receptor mechanisms underlying antidepressant-like action in the progesterone withdrawal model of hormonally induced depression in rats[J]. Behav Brain Res, 2013, 256: 520-528.

[5] A C Nugent, P J Carlson, E E Bain, et al. Mood stabilizer treatment increases serotonin type 1A receptor binding in bipolar depression[J]. J Psychopharmacol, 2013, 27 (10): 894-902.

[6] James W Murrough, Shannan Henry, J Hu, et al. Reduced ventral striatal/ventral pallidal serotonin1B receptor binding potential in major depressive disorder[J]. Psychopharmacology (Berl), 2011, 213 (2-3): 547-53.

[7] R C Shelton, E Sanders-Bush, D H Manier, et al. Elevated 5-HT2A receptors in postmortem prefrontal cortex in major depression is associated with reduced activity of protein kinase A[J]. Neuroscience, 2009, 158 (4): 1406-1415.

[8] Sharon Rosenzweig-Lipson, Annmarie Sabb, Gary Stack, et al. Antidepressant-like effects of the novel, selective, 5-HT2C receptor agonist WAY-163909 in rodents[J]. Psychopharmacology, 2007, 192 (2): 159-170.

[9] Li Bing-jin, Zhao Jing, Lv Jia-yin, et al. Additive antidepressant-like effects of fasting with imipramine via modulation of 5-HT2 receptors in the mice[J]. Prog Neuropsychopharmacol Biol Psychiatry, 2014, 48(3): 199-206.

[10] Laurent P Lacroix, Lee A Dawson, Jim J Hagan, et al. 5-HT6 receptor antagonist SB-271046 enhances extracellular levels of monoamines in the rat medial prefrontal cortex[J]. Synapse, 2004, 51 (2): 158-164.

[11] Herbert Y Meltzer. Serotonergic mechanisms as targets for existing and novel antipsychotics[M].Handb Exp Pharmacol, 2012, 212: 87-124.

[12] Anna Weso?owska, Agnieszka Nikiforuk. Effects of the brain-penetrant and selective 5-HT6 receptor antagonist SB-399885 in animal models of anxiety and depression[J]. Neuropharmacology, 2007, 52 (5): 1274-1283.

[13] Per Svenningsson, Eleni T Tzavara, Qi Hong-shi, et al. Biochemical and behavioral evidence for antidepressant-like effects of 5-HT6 receptor stimulation [J]. J Neurosci, 2007, 27 (15): 4201-4209.

[14] Atheir I Abbas, Peter B Hedlund, X P Huang, et al. Amisulpride is a potent 5-HT7 antagonist: relevance for antidepressant actions in vivo[J]. Psychopharmacology, 2009, 205 (1): 119-128.

[15] Anna Weso?owska, Ewa Tatarczyńska, Agnieszka Nikiforuk, et al. Enhancement of the anti-immobility action of antidepressants by a selective 5-HT7 receptor antagonist in the forced swimming test in mice[J]. Eur J Pharmacol, 2007, 555 (1): 43-47.

[16] Lindsay N Cates, Amanda J Roberts, Salvador Huitron-Resendiz, et al. Effects of lurasidone in behavioral models of depression. Role of the 5-HT7 receptor subtype[J]. Neuropharmacology, 2013, 70: 211-217.

[17] Gavin Lambert, Mats Johansson, Hans Agren, et al. Reduced brain norepinephrine and dopamine release in treatment-refractory depressive illness: evidence in support of the catecholamine hypothesis of mood disorders[J]. Arch Gen Psychiatry, 2000, 57(8): 787.

[18] Eric Dailly, Frank Chenu, Caroline E Renard, et al. Dopamine, depression and antidepressants[J]. Fundam Clin Pharmacol, 2004, 18(6): 601-607.

[19] Song Rui, Zhang Hai-ying, Li Xia, et al. Increased vulnerability to cocaine in mice lacking dopamine D3 receptors[J]. Proc Natl Acad Sci, 2012, 109(43): 17675-17680.

[20] Gian Marco Leggio, Vincenzo Micale, Filippo Drago. Increased sensitivity to antidepressants of D3 dopamine receptor-deficient mice in the forced swim test (FST)[J]. Eur Neuropsychopharmacol, 2008, 18(4): 271-277.

[21] Xing Bo, Liu Peng, Jiang Wen-hui, et al. Effects of immobilization stress on emotional behaviors in dopamine D3 receptor knockout mice[J]. Behavioural brain research, 2013, 243(15): 261-266.

[22] J Hirvonen, J Hietala, J Kajander. Effects of antidepressant drug treatment and psychotherapy on striatal and thalamic dopamine D2/3 receptors in major depressive disorder studied with raclopride PET[J]. J Psychopharmacol, 2011, 25(10): 1329-1336.

[23] Anteneh M Feyissa, Agata Chandran, Craig A Stockmeier, et al. Reduced levels of NR2A and NR2B subunits of NMDA receptor and PSD-95 in the prefrontal cortex in major depression[J]. Prog Neuropsychopharmacol Biol Psychiatry, 2009, 33 (1): 70-75.

[24] Luis E B Bettio, Mauricio P Cunha, Josiane Budni, et al. Guanosine produces an antidepressant-like effect through the modulation of NMDA receptors, nitric oxide–cGMP and PI3K/mTOR pathways[J]. Behavioural Brain Research, 2012, 234(2): 137-148.

[25] Li Nan-xin, Lee Bo-young, Liu Rong-Jian, et al. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists[J]. Science, 2010, 329 (5994): 959-964.

[26] Rodrigo Machado-Vieira, Giacomo Salvadore, Nancy DiazGranados, et al. Ketamine and the next generation of antidepressants with a rapid onset of action[J]. Pharmacol Ther, 2009, 123 (2): 143-150.

[27] Anita E Autry, Megumi Adachi, Elena Nosyreva, et al. NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses[J]. Nature, 2011, 475 (7354): 91-95.

[28] S Chourbaji, M Vogt, F Fumagalli, et al. AMPA receptor subunit 1 (GluR-A) knockout mice model the glutamate hypothesis of depression[J]. The FASEB Journal, 2008, 22 (9): 3129-3134.

[29] Malgorzata Wolak, Agata Siwek, Bernadeta Szewczyk, et al. Involvement of NMDA and AMPA receptors in the antidepressant-like activity of antidepressant drugs in the forced swim test[J]. Pharmacol Rep, 2013, 65(991): 991-997.

[30] Y Tizabi, B H Bhatti, K F Manaye, et al. Antidepressant-like effects of low ketamine dose is associated with increased hippocampal AMPA/NMDA receptor density ratio in female Wistar–Kyoto rats[J]. Neuroscience, 2012, 213(28): 72-80.

[31] Alessandro Barbon, Luca Caracciolo, Cesare Orlandi, et al. Chronic antidepressant treatments induce a time-dependent up-regulation of AMPA receptor subunit protein levels[J]. Neurochem Int, 2011, 59 (6): 896-905.

[32] I V Belozertseva, T Kos, P Popik, et al. Antidepressant-like effects of mGluR1 and mGluR5 antagonists in the rat forced swim and the mouse tail suspension tests[J]. Eur Neuropsychopharmacol, 2007, 17 (3): 172-179.

[33] Agnieszka Pa?ucha-Poniewiera, Andrzej Pilc. Involvement of mGlu5 and NMDA receptors in the antidepressant-like effect of acamprosate in the tail suspension test[J]. Prog Neuropsychopharmacol Biol Psychiatry, 2012, 39(1): 102-106.

[34] Gene G Kinney, Julie A O'Brien, Wei Lemaire, et al. A novel selective positive allosteric modulator of metabotropic glutamate receptor subtype 5 has in vivo activity and antipsychotic-like effects in rat behavioral models[J]. J Pharmacol Exp Ther, 2005, 313 (1): 199-206.

[35] Agnieszka Pa?ucha-Poniewiera, Piotr Brański, Tomasz Lenda, et al. The antidepressant-like action of metabotropic glutamate 7 receptor agonist N, N′-bis (diphenylmethyl)-1, 2-ethanediamine (AMN082) is serotonin-dependent[J]. J Pharmacol Exp Ther, 2010, 334(3): 1066-1074.

[36] Stefania R Bradley, Jason M Uslaner, Rose B Flick, et al. The mGluR7 allosteric agonist AMN082 produces antidepressant-like effects by modulating glutamatergic signaling[J]. Pharmacol Biochem Behav, 2012, 101(1): 35-40.

[37] Vilma Gabbay, Rachel G Klein, Y Katz, et al. The possible role of the kynurenine pathway in adolescent depression with melancholic features[J]. Journal of child psychology and psychiatry, 2010, 51 (8): 935-943.

[38] Pierre Blier, Gabriella Gobbi, N Haddjeri, et al. Impact of substance P receptor antagonism on the serotonin and norepinephrine systems: relevance to the antidepressant/anxiolytic response[J]. J Psychiatry Neurosci, 2004, 29 (3): 208-218.

[39] Liliane J Dableh, Kiran Yashpal, Joseph Rochford, et al. Antidepressant-like effects of neurokinin receptor antagonists in the forced swim test in the rat[J]. European J Pharmacol, 2005, 507 (1): 99-105.

[40] Carmine M Pariante, Stafford L Lightman. The HPA axis in major depression:classical theories and new developments[J].Trends in neurosciences, 2008, 31(9): 464-468.

[41] Jose M Pérez-Ortiz, Maria S García-Gutiérrez, Francisco Navarrete, et al. Gene and protein alterations of FKBP5 and glucocorticoid receptor in the amygdala of suicide victims[J]. Psychoneuroendocrinology, 2013, 38(8): 1251-1258.

[42] 彭军波, 季丽莉, 金雪花, 等. 糖皮质激素注射建立小鼠行为抑郁症模型[J]. 解剖学研究, 2012, 34(2): 86-88.

[43] Gianluigi Guidotti, Francesca Calabrese, Calabrese Anacker, et al. Glucocorticoid receptor and FKBP5 expression is altered following exposure to chronic stress: Modulation by antidepressant treatment[J]. Neuropsychopharmacology, 2013, 38(4): 616-627.

[44] Y Dwivedi, H S Rizavi, R C Roberts, et al. Reduced activation and expression of ERK1/2 MAP kinase in the post‐mortem brain of depressed suicide subjects[J]. J Neurochem, 2001, 77 (3): 916-928.

[45] Qi Xiao-li, Lin Wen-juan, Wang Dong-lin, et al. A role for the extracellular signal-regulated kinase signal pathway in depressive-like behavior[J]. Behavioural Brain Res, 2009, 199 (2): 203-209.

[46] Gilles Mercier, Anna M Lennon, Benjamin Renouf, et al. MAP kinase activation by fluoxetine and its relation to gene expression in cultured rat astrocytes[J]. J Mol Neurosci, 2004, 24 (2): 207-216.

[47] Maya First, Irit Gil-Ad, Michal Taler, et al. The effects of reboxetine treatment on depression-like behavior, brain neurotrophins, and ERK expression in rats exposed to chronic mild stress[J]. J Mol Neurosci, 2013, 50(1): 88-97.

[48] Eero Castren. Neurotrophic effects of antidepressant drugs[J]. Curr Opin Pharmacology, 2004, 4 (1): 58-64.

[49] Felicien Karege, Guido Bondolfi, Nicola Gervasoni, et al. Low brain-derived neurotrophic factor (BDNF) levels in serum of depressed patients probably results from lowered platelet BDNF release unrelated to platelet reactivity[J]. Biological psychiatry, 2005, 57 (9): 1068-1072.

[50] 操军, 王俊, 况利, 等. 抑郁症自杀未遂患者血浆脑源性神经营养因子水平及相关分析[J]. 中国神经精神疾病杂志, 2013, 39(10): 597-601.

[51] Alessandra Berry, Veronica Bellisario, Sara Capoccia, et al. Social deprivation stress is a triggering factor for the emergence of anxiety-and depression-like behaviours and leads to reduced brain BDNF levels in C57BL/6J mice[J]. Psychoneuroendocrinology, 2012, 37(6): 762-772.

[52] F Angelucci, S Brene, A Mathe. BDNF in schizophrenia, depression and corresponding animal models[J]. Molecular Psychiatry, 2005, 10 (4): 345-352.

[53] Laura L Hurley, Luli Akinfiresoye, Evaristus Nwulia, et al. Antidepressant-like effects of curcumin in WKY rat model of depression is associated with an increase in hippocampal BDNF[J]. Behav Brain Res, 2013, 239(15): 27-30.