摘要
抑郁症是一种高发病率和高致死率的精神疾患,产生了严重的社会经济负担。目前抑郁症的病理生理学机制不是很清楚。目前抗抑郁治疗,主要以单胺类递质的调控作为治疗靶点。而这种方式的治疗仅能缓解30%患者的症状。而且,临床常用的各种抗抑郁药物都存在着各种副作用和疗效延迟效应。
针灸疗法属于传统中医疗法,具有整体调节的特点,动物实验研究和临床报道均表明针灸治疗抑郁症的有效性,与传统药物治疗相比,它可以避免药物长期应用的毒副作用,而且是整体多靶点治疗。电针虽然抗抑郁有效,但具体作用机制不明。近年来随着分子生物学技术的深入研究,发现抑郁症的发病与信号通路有一定相关性。
基于上述考虑,我们选择慢性应激抑郁动物模型对电针抗抑郁的分子机制进行一定探究。选择与抑郁症密切相关的两条信号通路,运用多种方法对信号通路的上下游指标进行检测,并选择作用较为明显的信号通路进行阻断剂实验,以期发现电针抗抑郁的可能作用途径,并比较电针在生理状态下与病理状态下的作用不同。
研究方法和结果:
1.建立慢性应激抑郁模型,并采用Open-field test、糖水实验、体质量测量来综合评价模型复制是否成功。造模结束后,模型组大鼠旷场试验的水平穿越格数格、竖立次数次、糖水实验消耗量、体质量增加量均显著低于空白组(P<0.05);与模型组相比,旷场试验的水平穿越格数、竖立次数、糖水实验消耗量、体质量增加变化,电针组均显著高于模型组(P<0.05);而电针组与百优解组上述指标之间没有差异(P>0.05)。
2.在模型复制成功的基础上,进行了流式细胞技术Annexin V-FITC/PI双染法、PI单染法检测大鼠海马神经元凋亡率。Annexin V-FITC/PI双染法结果显示:模型组应激第21天海马神经元凋亡率高于空白组(P<0.05);电针组、百优解组均低于模型组(P<0.05);电针组低于百优解组(P<0.05)。PI单染法检测结果显示:模型组与空白组之间没有显著差异(P>0.05);而电针组与模型组之间有显著性差异(P<0.05);百优解组与电针组之间差异不显著(P>0.05)。
3.在模型复制的基础上,并结合流式细胞结果,我们进行了电针抗细胞凋亡的机制探究;运用荧光定量PCR方法对大鼠海马组织Bcl-2mRNA、BadmRNA的表达检测。结果显示:Bcl-2mRNA表达电针组较模型组为高(P<0.05),模型组与百优解组之间没有差异(P>0.05)。BadmRNA的表达各组之间没有差异,但是模型组的Bad表达有增高趋势,电针组和百优解组均有下降趋势。
4.cAMP-PKA信号通路与抑郁症的神经再生和细胞凋亡密切相关。因此,我们选择了该通路的关键指标进行检测;放射免疫法对海马组织中cAMP含量的检测;采用免疫组化法对PICA的表达进行检测;采用Western blotting方法对CREB的含量进行检测。结果显示:cAMP含量模型组大鼠海马组织中最低,空白组最高,二者之间有显著性差异(P<0.05);电针组、百优解组大鼠海马组织cAMP含量较模型组高,并与模型组有显著性差异(P<0.05);电针组与百优解组大鼠海马组织中的cAMP含量之间没有差异(P>0.05)。大脑皮质中各组之间的PKA表达之间没有差异;海马组织中,百优解组与模型组之间PICA的表达有显著性差异(P<0.05)。皮质CREB的含量电针组较模型组有一定升高,但是差异不显著(P>0.05)。海马CREB的含量:以百优解组最高,但是各组之间没有显著性差异。
5.ERK信号通路与抑郁症的发病关系密切,参与了抑郁症的神经再生和细胞凋亡机制。因此我们对该通路的关键指标进行了探究。采用Western blotting方法对该通路的上下游指标进行了检测。结果显示:各组大鼠海马组织和皮质组织中Ras、c-raf、p-c-raf、ERK蛋白含量之间差异不显著。皮质组织中电针组p-ERK的水平和百优解组的p-ERK水平明显增高,均与模型组相比较有显著性差异(P<0.05)。同时模型组较空白组p-ERK水平为低(P<0.05)。而在海马组织中检测的结果显示:模型组的p-ERK水平较空白组低(P<0.05);电针组较模型组为高(P<0.05)。但是药物组虽然较模型组有增高趋势,但是两组之间无显著性差异(P>0.05)。皮质中电针组RSK的水平较模型组为高,与模型组相比较有显著性差异(P<0.05);而且模型组与空白组之间有显著性差异(P<0.05)。百优解组与模型组相比较没有差异(P>0.05)。海马中电针组与百优解组均有升高趋势,但是统计学上与模型组之间无显著性差异(P>0.05)。
6.通过对与抑郁症发病密切相关的两条信号通路的检测,我们发现电针对ERK信号通路效果较好,因此,我们选择对ERK通路的关键点ERK进行了阻断剂研究,选用了慢性强迫游泳应激模型,结合动物行为学测试评价阻断剂的效果和电针抗抑郁的作用机制。结果显示:应激处理第7天,模型组与空组之间相比较体质量有极显著性差异(P<0.01)。应激处理第13天,模型组的体质量与空白组相比较有显著性差异(P<0.05);模型组的体质量变化与电针组之间有显著性差异(P<0.05);PD98059组大鼠体质量与电针组之间也有显著性差异(P<0.05)。第13天的测试结果中可见模型组较空白组的水平穿越格数、竖立次数明显下降,二组之间有极显著性差异(P<0.01);同时电针组较PD98059组、模型组均有显著性差异(P<0.05)。竖立次数电针+PD98059组与电针组有显著性差异(P<0.05)。大鼠皮质和海马中ERK水平各组之间没有显著性差异。皮质中的p-ERK电针组较模型组为高,二组之间有显著性差异(P<0.05);电针+PD98059组的p-ERK较电针组为低,二组之间有显著性差异(P<0.05);海马中,各组之间没有显著性差异。皮质中BDNF各组之间没有显著性差异。海马中电针+PD98059组的BDNF较电针组为低,二组之间有显著性差异(P<0.05);电针组的BDNF较模型组为高,二组有显著性差异(P<0.05)。
结论:
1.行为学测试结果提示慢性应激可以引起大鼠的活动量降低和探究行为减少,体质量增加量减少;而电针干预可以改善慢性应激抑郁大鼠行为学表现;证明模型复制成功且电针干预慢性应激抑郁模型有效。
2.流式细胞的检测结果提示模型组大鼠海马细胞凋亡较电针组、百优解组严重;电针干预可以减低海马细胞凋亡;同时也表明慢性应激可以引起海马组织细胞凋亡发生。
3.大鼠海马组织Bcl-2mRNA、BadmRNA表达的检测结果提示慢性应激可引起细胞凋亡相关基因的改变,而电针抗慢性应激抑郁与增加抗凋亡基因Bcl-2mRNA的表达和抑制促凋亡基因BadmRNA的表达有一定关系。
4.慢性应激模型大鼠海马组织中cAMP含量低于电针组、百优解组,提示电针、药物干预可以对cAMP产生积极作用;百优解组PKA海马表达明显高于模型组,而电针组与模型组没有差异;同时,CREB的含量各组之间有没有差异。由此,我们认为慢性应激可减低海马组织中cAMP的含量,减少PKA的表达,而百优解可起到相反的作用;电针对该通路的影响与药物不同,产生较少作用。
5.慢性应激可以一定程度上引起大鼠脑内ERK通路表达抑制,而电针可以起到相反作用。电针主要活化ERK通路上的关键指标ERK,从而对下游产生影响而发挥抗调亡和抗抑郁作用。电针干预、药物干预均能对该通路产生一定影响,尤其以电针的作用较为明显。
6.阻断剂实验中,动物所表现出来的探究行为和体质量变化表明慢性强迫游泳实验模型复制成功;磷酸化ERK的变化以及下游与神经再生密切相关的蛋白BDNF的检测结果提示:电针对ERK通路的确有影响,而且这种作用可以被PD98059一定程度上所阻断。
Depression is a mental disorder with high prevalence and mortality,resulting in massive socioeconomic burden.The pathophysiology mechanism of depression has been poorly understood.Nowdays it is most porpular therapeutic target to modulate monoaminergic neurotransmission.But this therapeutic method only just alleviate the symptoms of 30%patients.Furthermore,all the antidepressant drugs exist side effects and lag period for their clinical effects.
Acupuncture belong to traditional Chinese medicine and can regulate the balance for human body.The datas,from the animal experiments and clinical reports,show that acupuncture is effective for depression.It has little side effect and can play roles on multiple targets.Although acupuncture is effective for depression,the mechanism for the efficiency is still not clear.The pathogenesis of depression may be relevant to molecular signaling pathway.
So chronic stress animal model was chosen for the study.Two signaling pathways were chosen for the mechanism study on acupuncture antidepression.The upper stream and down stream indexes were detected.At the same time,the special inhibitor was chosen for the signaling pathway.We hope to make it clear for the mechanism of acupuncture antidepression.
Methods and Results
1.Chronic stress depression animal model was established,and Open field test, sucrose intake,and body weight balance were used to evaluate the model.After stress,compared with control group rats,the model group rats'crossing numbers,rearing times,the level of sacchar-consumption,body weight changes,were apparently less than those of control group rats'(P<0.05).In comparison with model group,the crossing numbers,rearing times,body weight changes,the level of sacchar-consumption,being apparently increasing in electroacupuncture group and Prozac group(P<0.05),those indexes were not apparently differences between electroacupuncture group and Prozac group(P>0.05).
2.Annexin V-FITC/PI double staining and PI single staining flow cytometric method were used to detect the hippocampal apoptotic rates.Annexin V-FITC/PI double staining result indicated that hippocampal apoptotic rates in model group was higher than control group(P<0.05),apoptotic rates of EA group and Pozac group was lower than model group(P<0.05),EA group was more lower than Pozac group(P<0.05).PI single staining result indicated that there was no difference between model group and control group(P>0.05),apoptotic rates of EA group was signifant different from model group(P<0.05),there was no difference between Pozac group and EA group(P>0.05).
3.Real-time PCR method was used to detect Bcl-2mRNA and BadmRNA expression.The results showed that hippocampal Bcl-2mRNA expression for EA group was more higher than model group(P<0.05),there was no difference between EA group and Pozac group(P>0.05).BadmRNA expression in model group was higher than EA group and Pozac group,but the difference was not significant.
4.cAMP-PKA signaling pathway is more relative to depression.So the signaling was chosen to detect.cAMP in hippocampus was detected by radioimmunoassay method.Immunohistochemistry method was used to detect PKA expression,and Western blotting method was used to detect CREB protein.The results showed that the level of cAMP in hippocampus for model group is lower than control group(P<0.05), cAMP level for EA group and Pozac group were more higher than model group(P <0.05),there was no difference between EA group and Pozac group(P>0.05).PKA expressin in cortex was almost similar in each groups,Hippocampal PKA expression in Pozac group was stronger than model group(P<0.05).CREB protein level in cortex for EA group was higher than model group,CREB protein level hippocampus for Prozac group was higher than model group.
5.ERK is another important signaling pathway for depression.Western blotting method was used to detect ERK signaling pathway.The data showed that Ras,c-raf,p-c-raf,ERK protein level was almost similar in each groups.p-ERK level in cortex for EA group and Pozac group were higher than model group(P<0.05).p-ERK level in cortex for model group was lower than control group(P<0.05).p-ERK level in hippocampus for model group was lower than control group(P<0.05),p-ERK level for EA group was higher than model group(P<0.05).RSK protein level in cortex for EA group was higher than model group(P<0.05),and RSK level in cortex for model group was lower than control group(P<0.05),there was no difference for cortex RSK level between Pozac group and model group(P>0.05).Although RSK level in hippocampus increased for EA group and Pozac group,there was no different from model group (P>0.05).
6.Inhibitor was used to detect the ERK signaling pathway function.Chronic forced swimming stress model was established.Open field test and body weight balance were used to evaluate the model.The results showed that,compared with control group, the crossing,rearing times,body weight changes for model group was significant different on day 7(P<0.01) and day13(P<0.05).The open field test and body weight changes for EA group was more apparent.EA group and EA+PD98059group was significant different for crossing times(P<0.05).ERK level in cortex was almost similar for each group.p-ERK level in cortex of EA group was higher than model group (P<0.05) and EA+PD98059 group(P<0.05).p-ERK level in hippocampus for each group was almost similar.There were no differences for BDNF level in cortex of each group.BDNF level in hippocampus of EA group was higher than model group (P<0.05) and EA+PD98059 group(P<0.05).
Conclusions
1.The data from open field test,sucrose intake,body weight changes showed that chronic stress could cause the rats to move less,suppress body weight gain of rats, decreasing of sucrose intake,whereas electroacupuncture could improve them.
2.Flow cytometric results indicated that chronic stress could cause hippoampal apoptotic rates increasing,but electroacupuncture could decrease it.
3.Real-time PCR results indicated that chronic stress could cause Bcl-2mRNA decreasing and BadmRNA increasing in hippocampus,but electroacupuncture could reverse it.
4.Chronic stress could cause cAMP level decreasing in hippocampus,but electroacupuncutre and Pozac could reverse it.Pozac could cause PKA expression increasing under chronic stress.We thought that Pozac was more effective than electroacupuncture on cAMP-PKA signaling pathway.
5.Chronic stress could inhibit the ERK signaling pathway,but electroacupuncture could active ERK signaling pathway under stress by phosphorate ERK and play some roles on antiapoptosis and antidepression.
6.Chronic forced swimming model could be used for inhibitor study.The results indicated that electroacupuncture could effect ERK pathway expression,and PD98059 could inhibit its function.
引文
[1]Murray CJ,Lopez AD.Alternative projections of mortality and disability by cause 1990-2020:global burden of disease study.Lancet,1997,349:1498-1504.
[2]Kessler RC,Berglund P,Dernier O,et al.Lifetime prevalence and age-of-onset distributions of DSM-Ⅳ disorders in the National Comorbidity Survey Replication.Arch Gen Psychiatry,2005,62:593-602.
[3]Sullivan PF,Neale MC,Kendler KS.Genetic epidemiology of major depression:review and meta-analysis.Am J Psychiatry 2000;157:1552.
[4]Kendler KS,Gatz M,Gardner CO,et al.A Swedish national twin study of lifetime major depression.Am J Psychiatry,2006,163:109.
[5]Hopkinson G.A genetic study of affective illness in patients over 50.Br J Psychiatry,1964,110:244.
[6]Mendlewicz J.The age factor in depressive illness:some genetic considerations.J Gerontol,1976,31:300.
[7]Blazer DG,Hybels CF.Origins of depression in later life.Psychol Med,2005,35:1241.
[8]袁勇贵,张心保,昊爱勤,等.抑郁症患者单胺类神经递质与血脂的相关性.临床精神医学杂志,2003,13(2):67-68.
[9]阚红卫,明亮.5-HTR在抑郁症发病及治疗中的作用.山东医药,2005,45(1):66-68.
[10]陈芳萍,李运曼,刘国卿.5-HT1A受体激动剂类抗抑郁药的研究与开发.药学进展,2003,27(4):213-216.
[11]Wang YM,Xu F,Gainetdinov R.R,et al.Genetic approaches to studying norepinephrine function:knockout of the mouse norepinephrine transporter gene.Biol.Psychiatryl999,46(9):1124-1130.
[12]Brunello N,Blier P,Judd LL,et al.Noradrenaline in mood and anxiety disorders:basic and clinical studies.Int.Clin.Psychopharmacol.2003,18(4):191.
[13]Gilmor M.L.,Owens M.J.,Nemeroff C.B.Inhibition of norepinephrine uptake in patients with major depression treated with paroxetine Am.J.Psychiatry 2002,159(10):1702.
[14]Svenningsson P,Chergui K,Rachleff I,et al.Alterations in 5-HT1B receptor function by pi 1 in depression-like states.Science,2006,311:77.
[15]Duman RS,Heninger GR,Nestler EJ.A molecular and cellular theory of depression.Arch Gen Psychiatry,1997,54:597.
[16]Thase ME.Molecules that mediate mood.N Engl J Med,2007,357:2400.
[17]Slattery DA,Desrayand S,Cryan JF.GABAB receptor antagonist-mediated antidepressant-like behavior is serotonin-dependent.Pharmacol Exp.Ther.2005,312(1):290.
[18]SanacoraG,Mason GF,Krystal JH.Impairment of GABAergic transmission in depression:new insights from neuroimaging studies Crit.Rev.Neurobiol.2000,14(1):23-45.
[19]Emrich HM,von Zerssen D,Kissling W,et al.Effect of sodium valproate on mania.The GABA-hypothesis of affective disorders.Arch.Psychiatr.Nervenkr.1980,229(1):1-16.
[20]Mombereau C,Kaupmann K,van der Putten H,et al.Altered response to benzodiazepine anxiolytics in mice lacking GABA B(1)receptors Eur.J.Pharmacol.2004,497(1):119.
[21]Zhou W,Mailloux AW,Jung BJ,et al.GABA(B)receptor stimulation decreases amphetamine-induced behavior and neuropeptidegene expression in the striatum.Brain Res.2004,1004:18-28.
[22]Holsboer F,Liebl R,Hofschuster E.Reapeated dexamethasone suppression test during depressive illness normalization of test result compared with clinical improvement.J.Affect Disord,1982,4(2):93-101.
[23]Carroll BJ,Martin FI,Davies B.Resistance to suppression by dexamethasone of plasma 11-O.H.C.S.levels in severe depressive illness Br.Med.J.,1968,3:285-287.
[24]Gourley SL,et al.Regionally specific regulation of ERK MAP kinase in a model of antidepressant-sensitive chronic depression.Biol Psychiatry,2007,63:353-359.
[25]Holsboer F.The corticosteroid receptor hypothesis of depression.Neuropsychopharmacology,2000,23:477-501.
[26]McQuade R,Young AH.Future therapeutic targets in mood disorders:the glucocorticoid receptor.Br J Psychiatry,2000,177:390-395.
[27]Pariante CM,Miller AH.Glucocorticoid receptors in major depression:relevance to pathophysiology and treatment.Biol Psychiatry,2001,49:391-404.
[28]Liberzon I,Krstov M,Young EA.Stress-restress:effects on ACTH and fast feedback.Psychoneuroendocrinology,1997,22(6):443.
[29]Young EA,Lopez JF,Murphy-Weinberg V,et al.Mineralocorticoid receptor function in major depression.Arch.Gen.Psychiatry,2003,60(1):24.
[30]Müller M.B.,Holsboer F.,Keck M.E.,Genetic modification of corticosteroid receptor signalling:novel insights into pathophysiology and treatment strategies of human affective disorders.Neuropeptides,2002,36(2-3):117.
[31]Reul JM,de Kloet ER.Two receptor systems for corticosterone in rat brain:microdistribution and differential occupation.Endocrinology,1985,117(6):2505-2511.
[32]Pariante CM,Miller A H.Glucocorticoid receptors in major depression:relevance to pathophysiology and treatment.Biol.Psychiatry 2001,49(5):391.
[33]Young EA,Akil H,Haskett RF,S.J.Watson,Evidence against changes in corticotroph CRF receptors in depressed patients.Biol.Psychiatry,l995,37(6):355.
[34]Duman RS.Depression:a case of neuronal life and death? Biol Psychiatry,2004,56:140-145.
[35]Castren E.Neurotrophic effects of antidepressant drugs.Curr Opin Pharmacol,2004,4:58-64.
[36]Duman RS,Nakagawa S,Malberg J.Regulation of adult neurogenesis by antidepressant treatment.Neuropsychopharmacology,2001,25:836-844.
[37]Banasr M,Soumier A,Hery M,et al.Agomelatine,a new antidepressant,induces regional changes in hippocampal neurogenesis.Biol Psychiatry,2006,59(11):1087-1096.
[38]Malberg JE,Eisch AJ,Nestler EJ,et al.Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus.Neurosci,2000,20:9104-9110.
[39]Duman RS,Monteggia LM.A neurotrophic model for stress-related mood disorders.Biol Psychiatry,2006,59:1116-1127.
[40]Monteggia LM,et al.Essential role of brain-derived neurotrophic factor in adult hippocampal function.Proc Natl Acad Sci,2004,101:10827-10832.
[41]Shirayama Y,Chen AC,Nakagawa S,et al.Brain-derived neurotrophic factor produces antidepressant effects in behavioral models of depression.J Neurosci,2002,22:3251-3261.
[42]Monteggia LM,et al.Brain-derived neurotrophic factor conditional knockouts show gender differences in depression-related behaviors.Biol Psychiatry,2007,61:187-197.
[43]Chen B,Dowlatshahi D,MacQueen GM,et al.Increased hippocampal BDNF immunoreactivity in subjects treated with antidepressant medication.Biol Psychiatry,2001b,50:260-265.
[44]Dwivedi Y,Rizavi HS,Conley RR,et al.Altered gene expression of brain-derived neurotrophic factor and receptor tyrosine kinase B in postmortem brain of suicide subjects.Arch Gen Psychiatry,2003b,60:804-815.
[45]Huang EJ,Reichardt LF.Neurotrophins:roles in neuronaldevelopment and function.Annu Rev Neurosci,2001,24:677-736.
[46]Hunsberger JG,et al.Antidepressant actions of the exercise-regulated gene VGF.Nature Med.2007,13:1476-1482.
[47]Warner-Schmidt JL,Duman RS.VEGF is an essential mediator of the neurogenic and behavioral actions of antidepressants.Proc Natl Acad Sci,2007,104:4647-4652.
[48]Wang JW,David DJ,Monckton JE,et al.Chronic fluoxetine stimulates maturation and synaptic plasticity of adult-born hippocampal granule cells.J Neurosci,2008b,28:1374-1384.
[49]Czeh B,Michaelis T,Watanabe T,et al.Stress-induced changes in cerebral metabometabolites,hippocampal volume,and cell proliferation are prevented by antidepressant treatment with tianeptine.Proc Natl Acad Sci,2001,98:12796-12801.
[50]Malberg JE,Duman RS.Cell proliferation in adult hippocampus is decreased by inescapable stress:reversal by fluoxetine treatment.Neuropsychopharmacology,2003,28:1562-1571.
[51]Dranovsky A,Hen R.Hippocampal neurogenesis:regulation by stress and antidepressants.Biol Psychiatry,2006,59:1136-1143.
[52]Dowlatshahi D,MacQueen GM,Wang JF,et al.Increased temporal cortex CREB concentrations and antidepressant treatment inmajor depression.Lancet,1998,352:1754-1755.
[53]Dowlatshahi D,MacQueen GM,Wang JF,et al.G protein-coupled cyclic AMP signaling in postmortem brain of subjects with mood disorders:effects of diagnosis,suicide,and treatment at the time of death.J Neurochem,1999,73:1121-1126.
[54]Cowburn RF,Marcusson JO,Eriksson A,et al.Adenylyl cyclase activity and G-protein subunit levels in postmortem frontal cortex of suicide victims.Brain Res,1994,633:297-304.
[55]Perez J,Tardito D,Mori S,et al.Abnormalities of cAMP signaling in affective disorders:implication for pathophysiology and treatment.Bipolar Disord,2000,2:27-36.
[56]Duman R.Novel therapeutic approaches beyond the serotonin receptor.Biol Psychiatry,1998,44:324-335.
[57]Kamenetsky M,Middelhaufe S,Bank EM,et al.Molecular details of cAMP generation in mammalian cells:a tale of two systems.J Mol Biol,2006,362:623-639.
[58]Brandon EP,Idzerda RL,McKnight GS.PKA isoforms,neural pathways,and behaviour:making the connection.Curr Opin Neurobiol,1997,7:397-403.
[59]Donati RJ,Rasenick MM.G protein signaling and the molecular basis of antidepressant action.Life Sci,2003,73:1-17.
[60]Nestler EJ,Terwilliger RZ,Duman RS.Chronic antidepressant administration alters the subcellular distribution of cyclic AMP-dependent protein kinase in rat frontal cortex.J Neurochem,1989,53:1655-1657.
[61]Perez J,Tinelli D,Brunello N,et al.cAMP-dependent phosphorylation of soluble and crude microtubule fractions of rat cerebral cortex after prolonged desmethylimipramine treatment.Eur J Pharmacol,1989,172:305-316.
[62]Thome J,Sakai N,Shin K,et al.cAMP response element-mediated gene transcription is upregulated by chronic antidepressant treatment.J Neurosci,2000,20:4030-4036.
[63]Tiraboschi E,Tardito D,Kasahara J,et al.Selective phosphorylation of nuclear CREB by fluoxetine is linked to activation of CaMK IV and MAPkinase cascades.Neuropsychopharm,2004b,29:1831-1840.
[64]Deogracias R,Espliguero G,Iglesias T,et al.Expression of the neurotrophin receptor trkB is regulated by the cAMP/CREB pathway in neurons.Mol Cell Neurosci,2004,26:470-480.
[65]Fukuchi M,Tabuchi A,Tsuda M.Transcriptional regulation of neuronal genes and its effect on neural functions:cumulative mRNA expression of PACAP and BDNF genes controlled by calcium and cAMP signals in neurons.J Pharmacol Sci,2005,98:212-218.
[66]McCauslin CS,Heath V,Colangelo AM,et al.CAAT/Enhancer-binding Protein(delta)and cAMP-response Element-binding Protein Mediate Inducible Expression of the Nerve Growth Factor Gene in the Central Nervous System.J Biol Chem,2006,281:17681-17688.
[67]Thomas MJ,Umayahara Y,Shu H,et al.Identification of the cAMP response element that controls transcriptional activation of the insulin-like growth factor-Ⅰ gene by prostaglandin E2 in osteoblasts.J Biol Chem,1996,271:21835-21841.
[68]Tanimoto K,Yoshida E,Mita S,et al.Human activin betaA gene.Identification of novel 5' exon,functional promoter,and enhancers.J Biol Chem,1996,271:32760-32769.
[69]Pugazhenthi S,Miller E,Sable C,et al.Insulin-like growth factor-I induces bcl-2 promoter through the transcription factor cAMP-response element-binding protein.J Biol Chem,1999,274:27529-27535.
[70]Duman CH,Schlesinger L,Kodama M,et al.A role for MAPK signaling in behavioral models of depression and antidepressant treatment.Biol Psych,2007,61:661-670.
[71]Adams JP,Sweatt JD.Molecular Psychology:Roles for the ERK MAP kinase Cascade in Memory.Annu Rev Pharmacol Toxicol,2002,42:135-163.
[72]Mercier G,Lennon AM,Renouf B,et al.MAP kinase activation byfluoxetine and its relation to gene expression in cultured rat astrocytes.J Mol Neurosci,2004,24:207-216.
[73]Kodama M,Russell DS,Duman RS.Electroconvulsive seizures increase the expression of MAP kinase phosphatases in limbic regions of rat brain.Neuropsychopharm,2005,30:360-371.
[74]Bhat RV,Engber TM,Finn JP,et al.Region-specific targets of p42/p44MAPK signaling in rat brain.J Neurochem,1998,70:558-571.
[75]Sweatt JD.The neuronal MAP kinase cascade:a biochemical signal integration system subserving synaptic plasticity and memory.J Neurochem,2001,76:1-10.
[76]Colucci-D'Amato L,Perrone-Capano C,di Porzio U.Chronic activation of ERK and neurodegenerative diseases.Bioessays,2003,5:1085-1095.
[77]Brunet A,Datta SR,Greenberg ME.Transcription-dependentand-independent control of neuronal survival by the PI3K-Akt signaling pathway.Curr Opin Neurobiol,2001,11(3):297-305.
[78]Neri LM,Borgatti P,Capitani S,et al.The nuclear phosphoinositide 3-kinase/AKT pathway:a new second messenger system.Biochim Biophys Acta,2002,1584(2-3):73-80.
[79]Evans DL,Ten Have TR,Douglas SD,et al.Association of depression with viral load,CD8 T lymphocytes,and natural killer cells in women with HIV infection.Am J Psychiatry 2002,159(10):1752-1759.
[80]Leserman J.HIV disease progression:depression,stress,and possible mechanisms.Biol Psychiatry 2003,54(3):295-306.
[81]Kubera M,Symbirtsev A,Basta-Kaim A,et al.Effect of chronic treatment with imipramine on interleukin 1 and interleukin 2 production by splenocytes obtained from rats subjected to a chronic mild stress model of depression.Pol J Pharmacol 1996,48(5):503-506.
[82]Zorrilla EP,Luborsky L,McKay JR,et al.The relationship of depression and stressors to immunological assays:a meta-analytic review.Brain Behav Immun 2001,15(3):199-226.
[83]Maes M,Scharpe S,Meltzer HY,et al.Relationships between interleukin-6 activity,acute phase proteins,and function of the hypothalamic-pituitary-adrenal axis in severe depression.Psychiatry Res 1993,49(1):11-27.
[84]Anisman H,Ravindran AV,Griffiths J,et al.Endocrine and cytokine correlates of major depression and dysthymia with typical or atypical features.Mol Psychiatry 1999,4:182-188.
[85]Kim YK,Suh IB,Kim H,et al.The plasma levels of interleukin-12 in schizophrenia,major depression,and bipolar mania:e?ects of psychotropic drugs.Mol Psychiatry 2002,7(10):1107-1114.
[86]MacsM,Bosnians E,De Jongh R,et al.Increased serum IL-6 and IL-1 receptor antagonist concentrations in major depression and treatmentresistant depression.Cytokine,1997,9(11):853-858.
[1]吕梅,王玲玲.针刺治疗抑郁症选穴频次的分析.针灸临床杂志,2003,19(8):15.
[2]姜风莲.针刘治疗老年期抑郁症.河南中医,1997,17(6):373.
[3]杨卓欣,虢周科.针刺治疗抑郁症的临床疗效观察.针灸临床杂志,2003,19(8):28-29.
[4]吴北燕.针灸治疗抑郁症.四川中医,1996,14(9):53.
[5]杨秀娟,刘向,罗和春,等.针刺奇经穴为主治疗抑郁症临床观察.中医杂志,1992,33(3):36-38.
[6]魏晓萍,齐盛.醒神开四关治疗更年期抑郁症38例.四川中医,2003,21(9):84-85.
[7]任建宁.耳针治疗抑郁症50例.河南中医,2005,25(2):75.
[8]赵秀敏.背俞穴穴位注射配合针刺治疗郁证.中国中医药信息杂志,2001,8(12):78.
[9]黄巍.心理加水针治方郁证临床分析.山西中医,1996,12(3):40.
[10]叶国传.针刺治疗抑郁症36例.上海针灸杂志,2000,19(6):30.
[11]王寅.针灸治疗脑卒中后抑郁失眠临床疗效评价.中国针灸,2004,24(6):7.
[12]李小军.头穴为主治疗中风后抑郁症临床研究.上海针灸杂志,2004,23(7):5.
[13]罗和春.新电针疗法治疗抑郁症研究进展的启示.中国中西医结合杂志,2000,20(11):806-807.
[14]康波,张平根,熊生财,等.电针与阿米替林治疗抑郁症对照观察.中国针灸,2002,22(6):383-384.
[15]淑沙尼克,图娅.电针与百优解对照治疗抑郁症的临床观察.针刺研究,2006,31(4):242-243.
[16]韩毳,罗和春,李晓泓,等.电针与麦普替林治疗抑郁症患者的对照研究.中国中西医结合杂志,2002,22(7):512-514.
[17]罗和春,沈渔邮,贾云奎,等.电针治疗133例抑郁症患者临床疗效观察.中西医结合杂志,1988,8(2):77-80.
[18]段冬梅,图娅.不同联合方案治疗60例轻、中度抑郁症的疗效分析.中国药业,2007,16(21):45-46.
[19]金花,玄吉龙.电针治疗抑郁症的增效作用.临床精神医学杂志,2007,17(6):379.
[20]吴爱群,党瑞山,周强,等.电针足三里对慢性不可预见性抑郁症大鼠多器官损伤的作用及其机制.解剖学杂志,2007,30(5):538-541.
[21]张春平,黄光远,陈志兴.电针与帕罗西汀治疗抑郁症的临床对照研究.实用医学杂志,2007,23(18):2949-2950.
[22]王秀芬,张新平.电针治疗抑郁症及其对血浆促肾上腺皮质激素和皮质醇的影响.四川中医,2007,25(4):102-103.
[23]钟文红.电针与阿米替林治疗抑郁状态对照观察.临床精神医学杂志,2006,16(6):335.
[24]汪冰霞,周树平,孙鸿辉.电针合并抗抑郁剂治疗抑郁症的临床观察.北京中医,2003,22(2):5-7.
[25]董子平.电针治疗抑郁症101例.中国针灸,2001,21(1):6-8.
[26]杨冲英.电针百会印堂穴治疗抑郁症临床玩察.天津中医,1998,15(3):124.
[27]张洪,何竟.电针治疗抑郁症的疗效观察.上海针灸杂志,2002,21(5):
[28]杨坤英.电针百会印堂穴治疗抑郁症临床观察.天津中医,1998,15(6):124.
[29]张平根,康波,钟旗,等.电针与阿米替林治疗抑郁症的对照观察.江西中医药,2002,33(3):62.
[30]王辉,于恩庆,赵军,等.电针治疗129例精神科常见病疗效分析.针灸临床杂志,1999(1):42.
[31]罗和春,沈渔邮,周东丰,等.盲法对照电针与阿米替林治疗抑郁症疗效分析.中国神经精神科杂志,1985,18(5):273.
[32]罗和春,贾云奎,詹丽.电针与阿米替林治疗抑郁症疗效比较.(日文)Japanese J of Psychiatric Treatment,1986,(1):3.
[33]罗和春.电针治疗抑郁症临床观察与实验室研究.北京医科大学学报,1987,19(1):4.
[34]罗和春,沈渔邮,贾云奎,等.电针治疗133抑郁症患者临床疗效观察.中西医结合杂志,1988,8(2):17.
[35]Luo HC,Shen YC,Zhou DF,et al.A Comparative Study of the treatment Depression by Eectroacupuncture and Amitriptyline.Acupuncture the Scientific International J,1990,(2):123.
[36]陈光,周东丰,沈渔邮,等.抑郁症神经内分泌功能及其对电针治疗反应的研究.北京医科大学学报,1992,24(5):401-403.
[37]朱明清.中国头皮针.广州:广东科技出版社,1993:62.
[38]罗和春.电针治疗抑郁症临床观察与实验研究.北京医科大学报,1987,19(1):45-47.
[39]徐虹,孙忠人,李丽萍,等.针刺治疗抑郁症及其对患者下丘脑-垂体-肾上腺轴的影响.中国针灸,2004,24(2):78-79.
[40]范肖冬.对内源性抑郁症病人淋巴细胞β-肾上腺素受体功能的观察.中华神经精神科杂志,1992,25(6):322-324,382.
[41]钱瑞琴,张春英,杨宇,等.电针与舒血宁联合治疗对抑郁症患者免疫功能的影响.中国实验方剂学杂志,2001,7(3):56-57.
[42]韩毳,王磊,李晓泓,等.电针对抑郁症患者血清细胞因子的影响.中国行为医学科学,2002,11(3):277-279.
[43]杜元灏,李桂平,颜红,等.调神疏肝针法治疗郁证的临床研究.中国针灸,2005,25(3):151.
[44]段冬梅,图娅,陈利平,等.电针对抑郁症患者不同脑区的影响:磁共振研究.2009,29(2):139-143.
[45]黄泳,唐安戊,李求实,等.头电针对抑郁症脑功能成像的影响.上海针灸杂志,2004,23(7):5-7.
[46]俞瑾,李晓艳,曹小定,等.电针合用抗抑郁药能明显减少小鼠强迫游泳实验中的静止时间.针刺研究,2002,27(2):119-123.
[47]卢峻,时宇静,金智秀,等.不同频率电针对模型大鼠抗抑郁效应的比较研究.北京中医药大学学报,2003,26(6):83-84.
[48]时宇静,卢峻,贾宝辉,等.电针对抑郁模型大鼠糖水摄入量和性行为的影响及机理研究.针刺研究,2006,31(1):27-30.
[49]贾宝辉,李志刚,时宇静,等.电针对慢性应激模型大鼠行为学及HPA轴相关激素的影响.针刺研究,2004,29(4):252-256.
[50]孙华,张有志.针灸百会和足三里穴对抑郁模型小鼠和大鼠行为的影响.针灸临床杂志,2003,19(2):47-49.
[51]史榕荇,秦丽娜,吴茜,等.电针对慢性应激模型大鼠行为学及海马谷氨酸含量影响的研究.北京中医药大学学报,2007,30(3):177-180.
[52]Jair Guilherme dos Santos Jr,Kawano F,Nishida MM,et al.Antidepressive-like effects of electroacupuncture in rats.Physiol Behav,2008,93(1-2):155-159.
[53]金光亮,苏晶,丁世芹,等.电针百会、印堂穴对大鼠行为及脑内单胺类递质的影响.中国行为医学科学,2000,9(3):164.
[54]邱艳明,时宇静,图娅.电针印堂、百会对获得性无助大鼠不同脑区内单胺类神经递质的影响.北京中医药大学学报,2002,25(6):54-56.
[55]韩毳,李晓泓,郭顺根,等.电针对抑郁大鼠中枢及外周单胺类抻经递质的影响.中医药学刊,2004,22(1):185-186,188.
[56]金光亮,周东丰,苏晶.电针对慢性应激抑郁模型大鼠脑单胺类神经递质的影响.中华精神科杂志,1999,32(4):220-221.
[57]李丽萍,兰敬昀,华金双,等.针刺百会和太冲穴对慢性应激抑郁模型大鼠下丘脑-垂体-肾上腺轴的影响.中医药学报,2006,33(2):52-53.
[58]韩毳,李晓泓,李学武,等.电针“百会”“三阴交”穴对慢性应激抑郁模型大鼠HPA轴的影响.北京中医药大学学报,2001,24(3):74-76.
[59]史榕荇,吴茜,秦丽娜,等.电针百会、印堂对慢性应激模型大鼠体重及HPA轴影响的研究.针灸临床杂志,2007,23(1):50-53.
[60]孙冬玮,王珑.针刺对慢性应激抑郁模型大鼠HPA轴的影响.上海针灸杂志,2007,26(2):32.
[61]时宇静,卢峻,费宇彤,等.电针对抑郁状态模型大鼠性行为及血清睾酮、黄体生成素水平的影响。北京中医药大学学报,2006,29(5):318-320.
[62]沈鲁平,金光亮,范建华,等.抗抑郁处理对慢性应激大鼠海马鸟苷酸结合蛋白表达的影响.中华精神科杂志,2002,35(1):25-27.
[63]卢峻,时宇静,费宇彤,等.电针对抑郁症模型大鼠脑磷酸化cAMP反应元件结合蛋白表达的影响.中国中医基础医学杂志,2006,12(5):380-382.
[64]李海燕,周东丰,宋煜青,等.电针和氟西汀治疗抑郁症对血小板蛋白激酶C 的影响.中国心理卫生杂志,2004,18(10):668-691.
[1]Murua VS,Gomez RA,Andrea ME,et al.Shuttle 2 box deficits induced by chronic variable stress:Reversal by imipramine administration.Pharmacol Biochem &Behav,1991,38:125.
[2]许晶,李晓秋.慢性应激抑郁模型的建立与评价.中国行为医学科学,2003,12:14-17.
[3]Katz RJ,Roth KA,Carroll B.Acute and chronic stress effects on open-field activity in the rat:Implications for a model of depression.Neurosci Biobehav Rev,1981,5:247.
[1]李云峰,罗质璞.抑郁症发病机制及治疗药物.北京:人民卫生出版社,2004:1-20.
[2]李文迅,韩焱晶,陶娟,等.电针对抑郁模型大鼠海马神经元凋亡的影响.中国中医药信息杂志,2005,12:33-35.
[1]Arantes-Goncalves F,Coelho R.Depression and treatment.Apoptosis,neuroplasticity and antidepressants.Acta Med Port,2006,19(1):9-20.
[2]Kosten TA,Galloway MP,Duman RS,et al.Repeated unpredictable stress and antidepressants differentially regulate expression of the bcl-2 family of apoptotic genes in rat cortical,hippocampal,and limbic brain structures.Neuropsychopharmacology,2008,33(7):1545-1558.
[3]Chen SJ,Kao CL,Chang YL,et al.Antidepressant administration modulates neural stem cell survival and serotoninergic differentiation through bcl-2.Curr Neurovasc Res,2007,4(1):19-29.
[1]Duman RS,Malberg JE,Nakagawa S,et al.Regulation of adultneurogenesis by psychotropic drugs and stress.J Phar-macolExp Ther,2001,299:401-407.
[1]Duman CH,Schlesinger L,Kodama M,et al.A role for MAPK signaling in behavioral models of depression and antidepressant treatment.Biol Psych,2007,61:661-670.
[2]Weeber EJ,Sweatt JD.Molecular neurobiology of human cognition.Neuron,2002,33:845-848.
[3]Huang EJ,Reichardt LF.Neurotrophins:roles in neuronal development and function.Annu Rev Neurosci,2001,24:677-736.
[1]Porsolt RD,LePichon M,Jalfre M.Depression:A new animal model sensitive to anti-depressant treatment.Nature,1977,266:730-732.
[1]Keller MB,Hirschfeld RM,Demyttenaere K,et al.Optimizing outcomes in depression:focus on antidepressant compliance.Int Clin Psychopharmacol,2002,17:265-271.
[2]米希塔梁·淑沙尼克,图娅.电针与百优解对照治疗抑郁症的临床观察.针刺研究,2006,31(4):242-243.
[3]段冬梅,图娅,陈利平.电针与百优解对伴躯体症状抑郁症有效性的评价.中国针灸,2008,28(3):167-170.
[4]Li YF,Luo ZP.Research progress in mechanisms of stress induced depression.Prog Physiol Sci,2002,33(2):142-144.
[5]Lee AL,Ogle WO,Sapolsky RM.Stress and depression:possible links to neuron death in the hippocampus.Bipolar Disord,2002,4(2):117-128.
[6]D'Sa C,Duman RS.Antidepressants and neuroplasticity.Bipolar Disord,2002,4(3):183-194.
[7]Li YF,Yuan L,Yang M,et al.Protective effect of oligosaccharides extracted fromMorinda officinalisagainst the corticosterone-induced lesion in PC12 cells.China J Chin Mater Med,2000,25(9):551-555.
[8]Li YF,Luo ZP.Protection of buspirone on cultured PC12 cells lesioned by corticosterone.Chin J Pharmacol Toxicol,2001,15(5):333-336.
[9]Adams JP,Sweatt JD.Molecular Psychology:Roles for the ERKMAP kinase Cascade in Memory.Annu Rev Pharmacol Toxicol,2002,42:135-163.
[10]Thomas GM,Huganir RL.MAPK cascade signalling and synaptic plasticity.Nat Rev Neurosci,2004,5(3):173-183.
[11]Xu Z,Wang BR,Ding YQ,et al.Extracellular signal-regulated kinases1/2 in neurons of the dorsal motor nucleus of the vagus nerve and nucleus of the solitary tract are activated by noxious visceral stimulus in mice.Neurosci Lett.2002,13,334(2):103-106.
[12]Harro J,Tonissaar M,Eller M,et al.Chronic variable stress and partial 5-HT denervation by parachloroamphetamine treatment in the rat:effects on behavior and monoamine neurochemistry.Brain Research,2001,899:227-239.
[13]Solomon DA,Keller MB,Leon AC,et al.Multiple recurrences of major depressive disorder.Am J Psychiatry,2000,157(2):229-233.
[14]Reid L,Forbes NF,Stewart C,et al.Chronicmild stress and depressive disorder:a useful new model? Psychopharmacology,1997,134:365-367.
[15]Vry LD,Schreiber R.The chronic mild stress depression model:future dvelopments from a drug discovery perspective.Psychopharmacology,1997,134:349-350.
[16]Willner P.Validity,reliability and utility of the chronic mild stressmodel of depression:a 10-year review and evaluation.Psychopharmacology,1997,134:319-329.
[17]徐叔云.药理实验方法学.北京:人民卫生出版社,1994:641.
[18]郭德玉,陈铁玉,李斌,等.不同年龄大鼠学习记忆能力及旷场行为比较.中国实验动物学报,1998,6:19-23.
[19]Harro J,Tonissaar M,Eller M,et al.Chronic variable stress and partial 5-HT denervation by parachloroamphetamine treatment in the rat:effects on behavior and monoamine neurochemistry.Brain Research,2001,899:227-239.
[20]Naranjoa CA,Tremblaye LK,Bustob UE.The role of the brain reward system in depression.Progress in Neuro-Psychopharmacology and Biological Psychiatry,2001,25(4):781-823.
[21]Gronli J,Murison R,Bjorvatn B,et al.Chronic mild stress affects sucrose intake and sleep in rats.Behavioural Brain Research,2004,150(1-2):139-147.
[22]Hayley S,Poulter MO.The pathogenesis of clinical depression:stressor and cytokine-induced alterations of neuroplasticity.Neuroscience,2005,135:659-678.
[23]Lucassen PJ,Heine VM,Muller MB,et al.Stress,depression and hippocampal apoptosis.CNS Neurol Disord Drug Targets,2006,5:531-546.
[24]Arantes-Goncalves F,Coelho R.Depression and treatment.Apoptosis,neuroplasticity and antidepressants.Acta Med Port,2006,19:9-20.
[25]Silva R,Mesquita AR,Bessa J,et al.Lithium blocks stress-induced changes in depressive-like behavior and hippocampal cell fate:the role of glycogen-synthase-kinase-3beta.Neuroscience,2008,152:656-669.
[26]Vermes L,Haanen C,Stefens-Nakken H,et al.Anovel sasay for apoptosis.Flowcytometric detection of phosphatidylserine expression on early apoptotic cells using 1 fuorescein labeled AnnexinV.Immunot Methods,1995,184(1):39-51.
[27]郑骏年,谢叔良,陈家存,等.流式细胞术定量检测细胞凋亡三种方法的比较研究.中国免疫学杂志,1999,15:467-469.
[28]郑骏年.细胞凋亡检测方法研究进展.国外医学临床生物化学与检验学分册,1999.20:124-126.
[29]Wilcox ME,Yang W,Senger D,et al.Reovirus as an oncolytic agent against experimental human malignant gliomas.Natl Cancer Inst,2001,93:903-912.
[30]李文迅,韩焱晶,陶娟,等.电针对抑郁模型大鼠海马神经元凋亡的影响.中国中医药信息杂志,2005,12:33-35.
[31]Chen SJ,Kao CL,Chang YL,et al.Antidepressant administration modulates neural stem cell survival and serotoninergic differentiation through bcl-2.Curr Neurovasc Res,2007,4(1):19-29.
[32]Hara A,Hirose Y,Wang A,et al.Localization of Bax and Bcl2 proteins,regulators of programmed cell death,in the human centralnervous system.Virchows Arch,1996,429:249-253.
[33]Kramer BC,Mytilineou C.Alterations in the cellular distribution of bcl-2,bcl-x and bax in the adult rat substantia nigra following striatal 6-hydroxydopamine lesions.J Neurocytol,2004,33:213-223.
[34]HuangYY,Peng CH,Yang YP,et al.Desipra-mine activated Bcl-2 expression and inhibited lipopolysaccharide-induced apoptosis in hippocampus-derived adult neural stem cells.J Pharmacol Sci,2007,104:61-72.
[35]Li XB,Inoue T,Koyama T.Effect of chronic treatment with the protein kinase C inhibitor staurosporine on the acquisition and expression of contextual fear conditioning.Eur J Pharmacol,2002,441:151-155.
[36]Bai O,Zhang H,Li XM.Antipsychotic drugs clozapin and olanzapine upregulate bcl-2 mRNA and protein in rat frontal cortex and hippocampus.Brain Res,2004,1010:81-86.
[37]Luo C,Xu H,Li XM.Post-stress changes in BDNF and Bcl-2 immuno-reactivities in hippocampal neurons:effect of chronic administration of olanzapine.Brain Res,2004,1025:194-202.
[38]Hayley S,Poulter MO.The pathogenesis of clinical depression:stressor-and cytokine-induced alterations of neuroplasticity.Neuroscience,2005,135(3):659-678.
[39]王丽,章军建,刘涛.PKA-CREB信号转导通路在大鼠慢性脑缺血所致认知功能障碍中的作用.中国临床神经科学,2006,14(5):449-452.
[40]Tardito D,Perez J,Tiraboschi E,et al.Signaling pathways regulating gene expression,neuroplasticity,and neurotrophic mechanisms in the action of antidepressants:a critical overview.Pharmacol Rev,2006,58:115-134.
[41]Carlezon WA Jr,Duman RS,Nestler EJ.The many faces of CREB.Trends Neurosci,2005,28:436-445.
[42]Nibuya M,Nestler EJ,Duman RS.Chronic antidepressant administration increases the expression of cAMP response element binding protein(CREB )in rat hippocampus.J Neurosci,1996,16:2365-2372.
[43]Newton SS,Thome J,Wallace TL,et al.Inhibition of cAMP response element-binding protein or dynorphin in the nucleus accumbens produces an antidepressant-like effect.J Neurosci,2002,22:10883-10890.
[44]Shelton R C.Cellular mechanisms in the vulnerability to depression and response to antidepressants.Psychiatr Clin North Am,2000,23:713-729.
[45]Tardito D,Perez J,Tiraboschi E,et al.Signalling pathways regulating gene expression,neuroplasticity,and neurotrophic mechanisms in the actionof antidepressants:a critical overview.Pharmacol Rev,2006,58:115-134.
[46]Nestler EJ,Terwilliger RZ,Duman RS.Chronic antidepressant administration alters the subcellular distribution of cyclic AMP-dependent protein kinase in rat frontal cortex.J Neurochem,1989,53:1644-1647.
[47]Chen A C,Shirayama Y,Shin K H,et al.Expression of the cAMP response element binding protein(CREB) in hippocampus produces an antidepressant effect.Biol Psychiatry,2001 a,9:753-762.
[48]Pliakas AM,Carlson RR,Neve RL,et al.Altered responsiveness to cocaine and increased immobility in the forced swim test associated with elevated cAMP response element-binding protein expression in nucleus accumbens.J Neurosci,2001,21:7397-7403.
[49]Adams JP,Sweatt JD.Molecular Psychology.Roles for the ERK MAP kinase Cascade in Memory.Annu Rev Pharmacol Toxicol,2002,42:135-163.
[50]Amato LC.Chronic activation of ERK and neurodegenerative diseases.BioEssays,2003,25:1085-1095.
[51]Duman CH,Schlesinger L,Kodama M,et al.A role for MAPK signaling in behavioral models of depression and antidepressant treatment.Biol Psych,2007,61:661-670.
[52]Weeber EJ,Sweatt JD.Molecular neurobiology of human cognition.Neuron,2002,33:845-848.
[53]Huang EJ,Reichardt LF.Neurotrophins:roles in neuronal development and function.Annu Rev Neurosci,2001,24:677-736.
[54]Meller E,Shen C,Nikolao TA,et al.Region-specific effects of acute and repeated restraint stress on the phosphorylation of mitogen-activated protein kinase.Brain Res,2003,979:57-64.
[55]Sasaguri K,Kikuchi M,Hori N,et al.Suppression of stress immobilization-induced phosphorylation of ERK1/2 by biting in the rat hypothalamic paraventricular nucleus.Neurosci Lett,2005,383:160-164.
[56]Shen CP,Tsimberg Y,Salvadore C,et al.Activation of Erk and JNK MAPK pathways by acute swim stress in rat brain regions.BMC Neurosci,2004,5:36.
[57]Trentani A,Kuipers SD,Ter Horst GJ,et al.Selective chronic stress-induced in vivo ERK1/2 hyperphosphorylation in medial prefrontocortical dendrites:Implications for stress-related cortical pathology? Eur J Neurosci,2002,15:1681-1691.
[58]Duman CH,Schlesinger L,Kodama M,et al.A role for MAP kinase signaling in behavioralmodels of depression and antidepressant treatment.Biol Psychiatry,2007,61:661-670.
[59]Duman RS.Role of neurotrophic factors in the etiology and treatment of mood disorders.Neuromol Med.2004,5:11-25.
[60]Duman RS,Monteggia LM.A neurotrophic model for stress-related mood disorders.Biol Psychiatry.2006,59:1116-1127.
[61]Dias B.G.,Banerjee S.B.,Duman R.S,et al.Differential regulation of brain derived neurotrophic factortranscripts by antidepressant treatments in the adult rat brain.Neuropharmacology.2003,45:553-563.
[62]Shirayama Y,Chen A.C.,Nakagawa S.,et al.Brain-derived neurotrophic factor produces antidepressant effects in behavioral models of depression.J.Neurosci.2002,22:3251-3261.