甘草苷抗抑郁作用的主要药效及机制研究
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摘要
抑郁症(depression)属于情感性障碍(affective disorder)。主要临床表现为心境抑郁,丧失兴趣,不能体验生活中的乐趣,精力不足,主观能动性降低或丧失,自我评价较低,精神运动迟缓,甚至产生自杀观念或行为,常伴有某些躯体或生物学症状。抑郁症由于其高发而且难以根治,传统的针对单一环节、单一靶点的抗抑郁药物毒副作用比较大,费用比较高、易反复等特点,所以研究开发新的、安全有效的抗抑郁药物有很重要的社会及经济效益。
甘麦大枣汤是传统的有较好疗效的抗抑郁复方,经过拆方对比试验,以及单味药试验,表明甘草醇提取物有效。有效部位的分离及大孔吸附树脂分离,结合动物实验检测,发现50%乙醇洗脱物具有良好的抗抑郁活性。成分分析表明以甘草苷为主要成分。在前期的一系列预实验基础上,我们欲对甘草苷的药效学及机制进行探讨。
一甘草苷抗抑郁作用的药效学研究
1甘草苷对急性应激所致动物绝望行为的影响
采用小鼠悬尾和小鼠强迫游泳致小鼠行为绝望实验,观察甘草苷对小鼠悬尾不动时间和小鼠游泳不动时间的影响。结果显示甘草苷的40mg/kg、20mg/kg、10mg/kg单次给药能显著缩短小鼠的悬尾不动时间以及小鼠游泳不动时间(p<0.05)。
2甘草苷对药物诱发的抑郁动物模型的影响
2.1甘草苷对利血平化小鼠行为变化的影响
利血平通过耗竭脑内单胺类递质诱发动物的综合症状主要包括:体温下降、眼睑下垂和活动抑制。这些症状的发生与利血平降低脑内单胺类递质,尤其是5-HT。给予甘草苷溶液1h后,再给予利血平,观察各组小鼠体温下降的情况(t检验),以及各组运动不能和睁眼不能的动物只数(X2检验)。结果表明,甘草苷各剂量组可显著对抗小鼠利血平腹腔注射所引起的体温下降、显著对抗腹腔注射利血平所引起的运动不能及眼睑下垂,说明该药具有明显的对抗利血平作用。
3甘草苷对慢性应激抑郁模型大鼠的行为的影响
本研究运用慢性不可预知的应激模型(chronic unpredictable stress,CMS)和孤养两种经典方法,利用长期不可预见性的中等强度应激,造成孤养动物抑郁状态。造模期间连续灌胃给药,观察造模后药物对模型大鼠体重、蔗糖偏嗜度及行为学的影响。实验结果显示,模型组大鼠的水平穿越格数、站立次数均减少,中央格停留时间显著延长(P<0.01, P<0.05);大鼠体重增长值明显减少(P<0.01)
蔗糖溶液消耗量明显减少(P<0.01);水迷宫实验结果显示CUMS大鼠出现学习记忆障碍。这些表现说明动物表现出抑郁状态、兴趣丧失和快感缺乏,与抑郁症临床诊断中的精神运动改变、兴趣或快感的丧失有一定程度的相似性,提示大鼠抑郁模型的复制是成功的。经过三周连续给药后,与模型组相比,甘草苷的各剂量组能显著增加大鼠体重(P<0.01);蔗糖消耗量显著增多(P<0.05);open-field实验中大鼠的水平穿越格数、站立次数显著增多(P<0.05),中央格停留时间显著缩短(P<0.05);水迷宫实验中学习记忆能力得到显著改善(P<0.05)。
二甘草苷对抑郁症模型大鼠治疗作用的机理研究
1甘草苷对CUMS大鼠脑内单胺类神经递质的影响
造CUMS模型,采用高效液相色谱-电化学检测器(HPLC-ECD)对大鼠脑内海马部位的单胺类神经递质及其代谢产物进行检测。结果显示模型组大鼠海马内5-HT、NE含量显著降低,甘草苷中剂量组(20mg/kg)能显著提高5-HT、NE水平(P<0.05)。而对DA、DOPAC含量影响不明显。
2甘草苷对CUMS大鼠血清中CRO、IL-1β、IL-2、IL-6含量的影响
造CUMS模型,采用放免法对各组大鼠血清中皮质醇(CRO)、IL-1β、IL-2、IL-6含量进行检测。结果显示,模型组大鼠血清中皮质醇、IL-1β含量明显高于空白对照组。治疗后阳性给药组及甘草苷中剂量组能显著降低IL-1β、皮质醇水平(*P<0.05),且阳性给药组能升高IL-2、IL-6水平(*P<0.05),而甘草苷大剂量、小剂量与模型组比较差异不显著。
Depression is an affective disorder disease with higher outbreak rate . Tthe symptom is diverse, such as the motion low fall, appetite and sleep obstacle, cynical and suicide obsession, and so on. At present ,the synthetic chemical medicines were mainly taken as treatment to depression have been proofed that have the defects and side effects and expensive .Medicinal plants from natural resources,especially the traditional Chinese medicine have a long time experience in cure depression.
Among many traditional Chinese medicine recipes ,the classic recipe“Ganmai Dazao Decotion”showed significant antidepressant effect.And the effect element is Liquiritin.
We want to make use of the modern pharmacology to learn method evaluate Liquiritin the treatment suppresses the efficacy of medicine and possible mechanis ms of depression.
Study of Liquiritin to treat depression on pharmacodynamics
1 Effects of Liquiritin on Behavior despair of animal
1.1 Forced swimming test(FST)
The test was performed essentially as described by Porsolt et al. (1977). Mice were individually placed in a vertical glass container (20 cm high, 10 cm in diameter), containing 16cm of water maintained at 22°C–25°C. The total duration of immobility was recorded during the last 4 min of the 6min test period. The immobility time was recorded using the EthoVision video tracking system.
1.2 Tail suspension test(TST)
The grouping and drug administration matter were the same as FST .The mouse was individually suspended by its tail with a clamp (2 cm from the end )for 6min and the duration of immobility was recorded in last 5min.
2 Effect of liquiritin on induced to the medicine of the depression animal model
After administration of liquiritin for 2 days, and then give reserpine to induce depression symptoms, observe the ptosis, akinesia and hypothermia which occurred by reserpine.
3 Unpredictable Chronic stress test(CUMS )
After chronic unpredictable stress which exerted on each rat excluding the control ones for 3 weeks , we found that the liquiritin can improve the symptoms which appeared in the mod- el rats. The three doses of liquiritin 40mg/kg、20mg/kg、10mg/kg) all increased the quantity of the water wi th carbohydrate which was drunk by rats. The rat weight increment. The number of crossings- and rearings in the open field test (OF) and stop over time of central space and number of excrement were increased as well. according to our findings of water maze , Shorten the Escape l atent period of the third day and the forth day obviously, and raise to cross the Platform num- ber of times.
Study on mechanism of liquiritin on depression models in rats
1 Effects of liquiritin on monamine transmitter of inside brain in the CUMS rats
Make use of the CUMS model.And adopt HPLC-ECD measurement brain inside transmitter and it metabolizes the outcome in the rat brain by CUMS. According to our findings,show that model group showed reduced the 5-HT、NE、DA level (**P<0.01,*P<0.05),and increased the 5-HIAA、5-HIAA/5-HT、DOPAC level . After treatment of Clomipramine and middle dose of liquiritin , the level of 5-HT、NE increased ( **P<0.01, *P<0.05 ) ,but reduced the 5-HIAA、5 - HIAA/5-HT ( **P<0.01, *P<0.05).and there have no significant changes to DA and DOPAC.
2 Effects of liquiritin on COR、ACTH、IL-2、IL-6 of the blood
Make use of the CUMS model. Make use of the immunity analysis method measurement the content of the IL-2, IL-6 in plasma andACTH, COR in serums.According to our findings, Model group showed increased IL-1? and cortisol level versus normal group(P<0.05). after treatment of Clomipramine and middle dose of liquiritin ,the level of IL-1? , IL-6 and cortisol reduced to normal (P<0.05),but high and low dose have no significant changes.And in this experiment ,there has no significant change of IL-2 before and after stress .
甘麦大枣汤是传统的有较好疗效的抗抑郁复方,经过拆方对比试验,以及单味药试验,表明甘草醇提取物有效。有效部位的分离及大孔吸附树脂分离,结合动物实验检测,发现50%乙醇洗脱物具有良好的抗抑郁活性。成分分析表明以甘草苷为主要成分。在前期的一系列预实验基础上,我们欲对甘草苷的药效学及机制进行探讨。
一甘草苷抗抑郁作用的药效学研究
1甘草苷对急性应激所致动物绝望行为的影响
采用小鼠悬尾和小鼠强迫游泳致小鼠行为绝望实验,观察甘草苷对小鼠悬尾不动时间和小鼠游泳不动时间的影响。结果显示甘草苷的40mg/kg、20mg/kg、10mg/kg单次给药能显著缩短小鼠的悬尾不动时间以及小鼠游泳不动时间(p<0.05)。
2甘草苷对药物诱发的抑郁动物模型的影响
2.1甘草苷对利血平化小鼠行为变化的影响
利血平通过耗竭脑内单胺类递质诱发动物的综合症状主要包括:体温下降、眼睑下垂和活动抑制。这些症状的发生与利血平降低脑内单胺类递质,尤其是5-HT。给予甘草苷溶液1h后,再给予利血平,观察各组小鼠体温下降的情况(t检验),以及各组运动不能和睁眼不能的动物只数(X2检验)。结果表明,甘草苷各剂量组可显著对抗小鼠利血平腹腔注射所引起的体温下降、显著对抗腹腔注射利血平所引起的运动不能及眼睑下垂,说明该药具有明显的对抗利血平作用。
3甘草苷对慢性应激抑郁模型大鼠的行为的影响
本研究运用慢性不可预知的应激模型(chronic unpredictable stress,CMS)和孤养两种经典方法,利用长期不可预见性的中等强度应激,造成孤养动物抑郁状态。造模期间连续灌胃给药,观察造模后药物对模型大鼠体重、蔗糖偏嗜度及行为学的影响。实验结果显示,模型组大鼠的水平穿越格数、站立次数均减少,中央格停留时间显著延长(P<0.01, P<0.05);大鼠体重增长值明显减少(P<0.01)
蔗糖溶液消耗量明显减少(P<0.01);水迷宫实验结果显示CUMS大鼠出现学习记忆障碍。这些表现说明动物表现出抑郁状态、兴趣丧失和快感缺乏,与抑郁症临床诊断中的精神运动改变、兴趣或快感的丧失有一定程度的相似性,提示大鼠抑郁模型的复制是成功的。经过三周连续给药后,与模型组相比,甘草苷的各剂量组能显著增加大鼠体重(P<0.01);蔗糖消耗量显著增多(P<0.05);open-field实验中大鼠的水平穿越格数、站立次数显著增多(P<0.05),中央格停留时间显著缩短(P<0.05);水迷宫实验中学习记忆能力得到显著改善(P<0.05)。
二甘草苷对抑郁症模型大鼠治疗作用的机理研究
1甘草苷对CUMS大鼠脑内单胺类神经递质的影响
造CUMS模型,采用高效液相色谱-电化学检测器(HPLC-ECD)对大鼠脑内海马部位的单胺类神经递质及其代谢产物进行检测。结果显示模型组大鼠海马内5-HT、NE含量显著降低,甘草苷中剂量组(20mg/kg)能显著提高5-HT、NE水平(P<0.05)。而对DA、DOPAC含量影响不明显。
2甘草苷对CUMS大鼠血清中CRO、IL-1β、IL-2、IL-6含量的影响
造CUMS模型,采用放免法对各组大鼠血清中皮质醇(CRO)、IL-1β、IL-2、IL-6含量进行检测。结果显示,模型组大鼠血清中皮质醇、IL-1β含量明显高于空白对照组。治疗后阳性给药组及甘草苷中剂量组能显著降低IL-1β、皮质醇水平(*P<0.05),且阳性给药组能升高IL-2、IL-6水平(*P<0.05),而甘草苷大剂量、小剂量与模型组比较差异不显著。
Depression is an affective disorder disease with higher outbreak rate . Tthe symptom is diverse, such as the motion low fall, appetite and sleep obstacle, cynical and suicide obsession, and so on. At present ,the synthetic chemical medicines were mainly taken as treatment to depression have been proofed that have the defects and side effects and expensive .Medicinal plants from natural resources,especially the traditional Chinese medicine have a long time experience in cure depression.
Among many traditional Chinese medicine recipes ,the classic recipe“Ganmai Dazao Decotion”showed significant antidepressant effect.And the effect element is Liquiritin.
We want to make use of the modern pharmacology to learn method evaluate Liquiritin the treatment suppresses the efficacy of medicine and possible mechanis ms of depression.
Study of Liquiritin to treat depression on pharmacodynamics
1 Effects of Liquiritin on Behavior despair of animal
1.1 Forced swimming test(FST)
The test was performed essentially as described by Porsolt et al. (1977). Mice were individually placed in a vertical glass container (20 cm high, 10 cm in diameter), containing 16cm of water maintained at 22°C–25°C. The total duration of immobility was recorded during the last 4 min of the 6min test period. The immobility time was recorded using the EthoVision video tracking system.
1.2 Tail suspension test(TST)
The grouping and drug administration matter were the same as FST .The mouse was individually suspended by its tail with a clamp (2 cm from the end )for 6min and the duration of immobility was recorded in last 5min.
2 Effect of liquiritin on induced to the medicine of the depression animal model
After administration of liquiritin for 2 days, and then give reserpine to induce depression symptoms, observe the ptosis, akinesia and hypothermia which occurred by reserpine.
3 Unpredictable Chronic stress test(CUMS )
After chronic unpredictable stress which exerted on each rat excluding the control ones for 3 weeks , we found that the liquiritin can improve the symptoms which appeared in the mod- el rats. The three doses of liquiritin 40mg/kg、20mg/kg、10mg/kg) all increased the quantity of the water wi th carbohydrate which was drunk by rats. The rat weight increment. The number of crossings- and rearings in the open field test (OF) and stop over time of central space and number of excrement were increased as well. according to our findings of water maze , Shorten the Escape l atent period of the third day and the forth day obviously, and raise to cross the Platform num- ber of times.
Study on mechanism of liquiritin on depression models in rats
1 Effects of liquiritin on monamine transmitter of inside brain in the CUMS rats
Make use of the CUMS model.And adopt HPLC-ECD measurement brain inside transmitter and it metabolizes the outcome in the rat brain by CUMS. According to our findings,show that model group showed reduced the 5-HT、NE、DA level (**P<0.01,*P<0.05),and increased the 5-HIAA、5-HIAA/5-HT、DOPAC level . After treatment of Clomipramine and middle dose of liquiritin , the level of 5-HT、NE increased ( **P<0.01, *P<0.05 ) ,but reduced the 5-HIAA、5 - HIAA/5-HT ( **P<0.01, *P<0.05).and there have no significant changes to DA and DOPAC.
2 Effects of liquiritin on COR、ACTH、IL-2、IL-6 of the blood
Make use of the CUMS model. Make use of the immunity analysis method measurement the content of the IL-2, IL-6 in plasma andACTH, COR in serums.According to our findings, Model group showed increased IL-1? and cortisol level versus normal group(P<0.05). after treatment of Clomipramine and middle dose of liquiritin ,the level of IL-1? , IL-6 and cortisol reduced to normal (P<0.05),but high and low dose have no significant changes.And in this experiment ,there has no significant change of IL-2 before and after stress .
引文
[1] 龚绍鳞主编.抑郁症.第二版,北京:人民卫生出版社,2003,1.
[2] Altar C.A. Neurotrophins and Depression. Trends Pharmacol. Sci., 1999, 20(2):59-61.
[3] Harold I. Kaplan ,Benjamin J Sadock. Comprehensive textbook of psychiat ry[M]/ IV VoL I Fourthed Baltimore/ London WILL IAMS & WIL KINS ,1985 :760～833.
[4] 库保善. neuropsycho-pharmacology .北京大学医学出版社. 189.
[5] Kevin M. Malone ,Christine Wafernaux ,Gretchen L Haas ,et al. Cigareefle snloking ,suicidal behavior ,and seratonin function in major disorders [J ] . Am J Psychiatry ,2003 ,160 :773～779.
[6] 江三多等.遗传与精神疾病.北京:科学出版社,1998.94-130.
[7] 吕秋军 主编《新药药理学研究方法》(Methodology of New Drug Research in Pharmacology). 化学工业出版社.178.
[8] Schildkraut J J .The caetchoalmine hypothesis of affective disorders:are view of supporitng evdience [J Am J Psychairty,1965,122:509-512.
[9] Delgado, P.L., 2000. Depression: the case for a monoamine deficiency. The Journal of Clinical Psychiatry 61, 7–11.
[10]Yen Kuang Yang, , Tzung Lieh Yeh, Greater availability of dopamine transporters in patients with major depression — A dual-isotope SPECT study Psychiatry Research: Neuroimaging 162 (2008) 230–235.
[11] 马欢, 抑郁症病因病机研究探析. 辽宁中医杂志2005:32 (6): 537-538.
[12] 修丽娟,魏品康,从痰论治抑郁症相关理论探讨.中国中医药信息杂志 2007, 14( 3):78-79.
[13] 同[11]
[14] 曲 淼,唐启盛.抑郁症与中医“郁证”的关系探讨.北京中医药大学学报,2004,27(1):11-13.
[15] 韩 毳,李晓泓.抑郁症与中医肝脏关系探讨.山东中医杂志,2001,20(5):326.
[16] 邝曼露,论“神经衰弱”从肝辨治 Journal of Clinical and Experimental M edicine Vol. 5, N o. 2 Feb. 2006:186-188.
[1] Baldessarini RJ. The basis for amine hypotheses in affective disorder: A critical evaluation. Arch Gen Psychiatry. 1975;32:1087-1093.
[2] Charney DS. Monoamine dysfunction and the pathophysiology and treatment of depression. J Clin Psychiatry. 1998;59(suppl 14):11–14
[3] Violetta klimek, Jane E. Schenck, Hui Han, et al. Dopaminergic abnormalities in amygdaloid nuclei in major depression: A postmortem study. Biol Psychiatry.2002;52:740–748.
[4] [Kempermann G, Kronenberg G. Depressed new neurons--adult hippocampal neurogenesis and a cellular plasticity hypothesis of major depression. Biol Psychiatry. 2003;54(5):499-503.
[5]Invernizzi RW,Garattini S.2004.Role of presynaptic alpha2-adrenoceptors in antidepressant action:recent findings from microdialysis studies.Prog Neuropsychopharmacol Biol Psychiatry 28(5):819-827.
[6] 成令忠,钟翠平.现代组织学.上海科学技术文献出版社.P420
[7] Megumi Adachi, Michel Barrot, Selective Loss of Brain-Derived Neurotrophic Factor in the Dentate Gyrus Attenuates Antidepressant Efficacy,BIOL PSYCHIATRY 2008;63:642–649
[8]Heuser, Bettina Weber-Hamann, Jürgen Kratzsch. Resistin and adiponectin in major depression: The association with free cortisol and effects of antidepressant treatment.Journal of Psychiatric Research.2007,Volume 41,344-350.
[9] Yvette I, Sheline, M ilan S, et al. Depression duration but not age predicts hippocampal volume loss in medically healthy woman w ith recurrent major depression [ J ]. J N euro sci,1999, 19 (12) : 5034-5043.
[10] Jing-Wen Wang, Alex Dranovsky, and René Hen,The When and Where of BDNF and the Antidepressant Response,BIOL PSYCHIATRY
[11] Angelucci F,et al:Neuropeptides,2003;37(1):51-56.
[12] Saarelainen T, Hendolin P, Lucas G, Koponen E, Sairanen M, MacDonald E, et al. (2003): Activation of the TrkB neurotrophin receptor is induced by antidepressant drugs and is required for antidepressant-induced behavioral effects. J Neurosci 23:349 –357
[13] Monteggia LM, Barrot M, Powell CM, Berton O, Galanis V, Gemelli T, et al.(2004): Essential role of brain-derived neurotrophic factor in adult hippocampal function. Proc Nat Acad Sci U S A 101:10827–10832.
[14] Chen ZY, Jing D, Bath KG, Ieraci A, Khan T, Siao CJ, et al. (2006): Genetic variant BDNF (Val66Met) polymorphism alters anxiety-related behavior. Science 314:140 –143.
[15] 彭贵军.国外医学精神病学分册.2004,31(3): 152-154.
[16] Pezet S, Malcangio M. Brain-derived neurotrophic factor as a drug target for CNS disorders. Expert Opin Ther Targets. 2004 Oct;8(5):391-9.
[17] Bateman A, Singh A, Kral T. Solomon S. The immune hypothalamic pituitary adrenal axis. Endocr Rev. 1989;10:92-112.
[18] Johan H, M alinW , PaulM , et al. Electroconvulsive seizures increase h ippocampal neurogenesis after ch ronic co rtico sterone treatment [J ]. Eur J N euro sci, 2002, 16 (2) : 28-32.
[19] Ader R., ed. Psychoncuroimmunology. New York: Academic Press; 1981.[Brian E. Leonard, Cai Song. Stress and the immune system in the etiology of anxiety and depression. Pharmacology Biochemistry and Behavior. 1996;54(1):299-303.
[20] Marta Kubera,et al. International Journal of Im-munopharmacology, 1998;20:781-789.][ 祖蓓蓓.抑郁症与免疫抑制. 国外医学精神病学分册 2004, 31( 2) : 97-99.
[21] Maes M,Meltzer H,Scharpe S,et al. Relationships between lower plasm a ltryptophan levels and immune-inflammatory variables in depression. Psychiatry Res,1993,49:151.
[22] Nibuya M,Nestler EJ,Duman RS.Chronic Antidepressant Administration Increases the Expression of cAMP Response Element Binding Protein (CREB) in Rat Hippocampus[J].J Neurosci,1996,16(7):2365-2372.
[23] Duman RS.Novel therapeutic approaches beyond the serotonin receptor[J].Biol Psychiatry,1998,44(5):324-335.
[24] Kempemann G. Regulation of adult hippocampal neurogenensis-implications for novel theories of major depression. Bipolar Disord ,2002,4:17-33.
[25] Duman RS, Malberg JE, Nakagawa S. Regulation of adult neyrogenesis by psychotropic drugs and stress ,J Pharmacol Exp Ther,2001 ,299:401-407.
[26] Kempemann G, Kuhn HG, Gage FH. More hippocampal neurons in adult mice living an enriched environment . Nature ,1997,386:493-495.
[27] Heilig M,Zachrisson O ,Thorsell A ,et al .Decreased cerebrospinal f luid neuropeptide Y(NPY)in patients with treatmen trefractory unipolar major depression:preliminary evidence of rassocaiiton with prepro NPY gene polymorphism [J ] . Psychiatr Res,2004 Mar-Apr,38 ( 2 ):113-121.
[28] 刘耀文编译. 脑神经肽 Y 系统:治疗焦虑症、抑郁症及酒精依赖的候选靶标. 国外医学药学分册. 2004,31( 6):348-349.
[1] Taylor AT,Spruill WJ,Longe RL ,et al .2001.Improved health-related quality of life with SSRIs and other antidepressants .Pharmacotherapy 21(2):189-194.
[2] Versiani M,Mehilane L,et al.1999.Reboxetine,a unique selective NRI,prevents relapse and recurrence in long-term treatment of major depressive disorder.J Clin Psychiatry 60(6):400-406.
[3] Kavirajan H .2004.Venlafaxine and SSRI remission data revisited.Br J Psychiatry 184:452-453
[4] Boer T. The pharmacologic profile of mirtazapine[J].J clin Psychiatry, 1996,57(suppl 4):19.
[5] BLIERP ,GOBBIG ,HADDJERIN ,et a l ,Impact of substance P Recepot ranatgonism on the serotonin and norepniephrnie sysetms : relevance to the antidepressan/tanxiolytic response [J ] . J Psych-iatry Neurosci,2004 May,29( 3 ):208-218.
[6] 军事医学科学院毒物药物研究所. 刘耀文编译. 脑神经肽 Y 系统:治疗焦虑症、抑郁症及酒精依赖的候选靶标. 国外医学药学分册, 2004,31(6):348-349.
[7] 刘忠纯,罗小年,王高华. 促肾上腺皮质激素释放因子与抑郁症.. 国外医学精神病学分册.
[8] 张迎春,何红玲.中药治疗抑郁焦虑症的研究述要 .中医药学刊 2005,23 (4): 764-765.
[9] Dar A. 槟榔乙醇提取物对啮齿动物的抗抑郁作用[J ] . 国外医学·中医药分册,1998 ,20(3) :47.
[10] 李亚明,陈红梅.石菖蒲对行为绝望动物抑郁模型的抗抑郁作用[J ] . 中药材,2001 ,24(1) :40～41.
[11] 翁深宏,程自立,王高华. 刺五加胶囊治疗抑郁症的临床对照研究[J ] . 湖北中医杂志,2001 ,23(6) :8～9.
[12] Molodavkin GM, Aldarmaa Zh , Voronina T A , et al. Khim -Farm Zh ,1998 ,32(4) :35.
[13] 熊元君. 新疆三种金丝桃属植物中金丝桃素含量测定[ J ]. 中草药, 2003, 33 (9) : 100-102.
[14] 郑丽,刘国卿. 贯叶连翘醇提物对单胺氧化酶与单胺递质的影 响[ J ]. 中国药科大学学报, 2002, 33 (2) : 138-141.
[15] 王斌,刘天培. 柴胡皂甙加强氟西汀在强迫游泳模型上的抗抑郁作用[J ] . 中草药,1997 ,28(12) :729.
[16] 日本大村典子. 国外医学中医中药分册,2005, 27 (5): 311.
[17] 金国琴,张学礼.甘麦大枣汤加味对抑郁症大鼠海马 cAMP- 蛋白激酶 A 途径的影响. 上海中医药大学学报 第 20 卷 第 4 期 2006 年 12 月 73-76.
[18] 刘屏,汪进良 开心散类方配伍及抗抑郁作用研究.中华中医药杂志,2005,20(5): 279-280.
[19] 郑晓鹤,洪婴,王献坤. 越菊保和丸的抗抑郁作用研究.时珍国医国药,2005 ,16(9):865-866.
[20] 傅强,马世平 半夏厚朴汤抗抑郁作用研究.中国天然药物, 2005 ,3 (2): 112-115.
[21] 尾崎哲,黄欣. 小建中汤的抗抑郁作用[J ] . 国外医学:中医中药分册,1993 ,15(5) :7～9.
[22] 张有志,聂惠民,张德昌,等. 柴胡加龙骨牡蛎汤等经方治疗抑郁症的动物行为学研究[J ] . 中国中医基础医志,2001 ,7(7) :30～32.
[1] 朱兴族. 罗质璞 编.神经药理学新论.人民卫生出版社.1-2 页
[2] Tanaka S; Kuwait Y; Tabitha M. Isolation of monoamine oxidize inhibitors from Glycyrrhizin realness roots and the structure-activity relationship. Planta.Med. 1987, 53(1): 5-8.
[3] Porsolt RD, Le Pichon M.Depression : a new animal model sesentive to antidepressant treatments .Nature,1977,266:730.
[4] Steru L,Chermat R,Thierry B ,Simon P .The tail suspension test :a new method for screening antidepressants in mice. Psychopharmacology(Berl),1985,85:367.
[5] Katz RJ.Animal model of depression: pharmacological sensitivity of ahedonic deficit .Pharmacol Biochem Behav ,1982,16:965.
[6] Overstreet DH.The Flinders sensitive line rats: a genetic animal model of depression ,Neurosci Biobehav Rev,1933,17:51.
[7] Roth KA ,Katz RJ . Further studies on a novel animal model of de-pression :Therapeutic effects of a tricyclic antidepressant [J ] . Neu- rosci Biobehav Rev ,1981 ,5(2) :253-258.
[8] Morris R.Development of a water-maze procedure for studying spatial learning in the rat.J Neurosci Methods,1984,11:47.
[9]吴俊芳主编,现代神经科学研究方法.中国协和医科大学出版社.696-697.
[1]Borsini F,Voltera G,Meli A. Does the Behavioral Despair Test easure.Physiology&Bhavior,2003,(38):385.
[2] Tanaka S; Kuwai Y; Tabata M. Isolation of monoamine oxidase inhibitors from Glycyrrhiza uralensis roots and the structure-activity relationship. Planta.Med. 1987, 53(1): 5-8.
[3]Katz RJ,Roth KA,Carroll BJ (1981).Acute and chronic stress effects on open field activity in the rat:implication for a model of depression. Neurosci Biobehav Rev 5(2):247-251.
[4] V.Butterweck,A.Wall,et al. Effects of the total extract and fractions of Hypericum in animal assays for antidepressant activity.Pharmacopsychiat. (1997)(Supplement) 117-124.
[5] Morris RGM,Garrud P,Rawlins JNP,Place navigation impaired in rats with hippocampal lesions.Nature, 1982,297:681-683.
[6] 李云峰,罗质璞.应激诱发抑郁症机制的进展[J].生理科学进展,2002,33(2):142-144.
[7] Young EA,Lopez JF,Murphy-Weinberg V,et alM.ineralocorticoid receptor function in major depression[J]A.rch Gen Psychiatry,2003,60(1):24-28.
[8] Joels M,Karst H,Alfarez D,et alE.ffects of chronic stress on structure and cell function in rat hippocampus and hypothala-mus[J]S.tress,2004,7(4):221-231.
[9] Karten YJ,Nair SM,van Essen L,et al.Long -term exposure to high corticosterone levels attenuates serotonin responses in rat CA1 neurons[J].Proc Natl Acad Sci USA,1999,96(23):13456-13461.
[10] Young,E.A;Akil,H:Changes in releasability of ACTH and beta-endorphin with chronic stress[J]. Neuro- peptides 5:545-548;1985.
[11] Young, E.A;Akil,H:Paradoxical effect of corticosteroids on pituitary ACTH/beta-endorphin release inst ressed animals[J].Psychoneurodndocrinology 13:217-323;1988.
[12] Cotter Paul A, Mulligan Owen F, Papadopoulos Andrew.Vasoconstrictor response to topical beclomethasone in major depression[J]. Psychoneuroen- docrinology,2002,27(4):475-487.
[2] Altar C.A. Neurotrophins and Depression. Trends Pharmacol. Sci., 1999, 20(2):59-61.
[3] Harold I. Kaplan ,Benjamin J Sadock. Comprehensive textbook of psychiat ry[M]/ IV VoL I Fourthed Baltimore/ London WILL IAMS & WIL KINS ,1985 :760～833.
[4] 库保善. neuropsycho-pharmacology .北京大学医学出版社. 189.
[5] Kevin M. Malone ,Christine Wafernaux ,Gretchen L Haas ,et al. Cigareefle snloking ,suicidal behavior ,and seratonin function in major disorders [J ] . Am J Psychiatry ,2003 ,160 :773～779.
[6] 江三多等.遗传与精神疾病.北京:科学出版社,1998.94-130.
[7] 吕秋军 主编《新药药理学研究方法》(Methodology of New Drug Research in Pharmacology). 化学工业出版社.178.
[8] Schildkraut J J .The caetchoalmine hypothesis of affective disorders:are view of supporitng evdience [J Am J Psychairty,1965,122:509-512.
[9] Delgado, P.L., 2000. Depression: the case for a monoamine deficiency. The Journal of Clinical Psychiatry 61, 7–11.
[10]Yen Kuang Yang, , Tzung Lieh Yeh, Greater availability of dopamine transporters in patients with major depression — A dual-isotope SPECT study Psychiatry Research: Neuroimaging 162 (2008) 230–235.
[11] 马欢, 抑郁症病因病机研究探析. 辽宁中医杂志2005:32 (6): 537-538.
[12] 修丽娟,魏品康,从痰论治抑郁症相关理论探讨.中国中医药信息杂志 2007, 14( 3):78-79.
[13] 同[11]
[14] 曲 淼,唐启盛.抑郁症与中医“郁证”的关系探讨.北京中医药大学学报,2004,27(1):11-13.
[15] 韩 毳,李晓泓.抑郁症与中医肝脏关系探讨.山东中医杂志,2001,20(5):326.
[16] 邝曼露,论“神经衰弱”从肝辨治 Journal of Clinical and Experimental M edicine Vol. 5, N o. 2 Feb. 2006:186-188.
[1] Baldessarini RJ. The basis for amine hypotheses in affective disorder: A critical evaluation. Arch Gen Psychiatry. 1975;32:1087-1093.
[2] Charney DS. Monoamine dysfunction and the pathophysiology and treatment of depression. J Clin Psychiatry. 1998;59(suppl 14):11–14
[3] Violetta klimek, Jane E. Schenck, Hui Han, et al. Dopaminergic abnormalities in amygdaloid nuclei in major depression: A postmortem study. Biol Psychiatry.2002;52:740–748.
[4] [Kempermann G, Kronenberg G. Depressed new neurons--adult hippocampal neurogenesis and a cellular plasticity hypothesis of major depression. Biol Psychiatry. 2003;54(5):499-503.
[5]Invernizzi RW,Garattini S.2004.Role of presynaptic alpha2-adrenoceptors in antidepressant action:recent findings from microdialysis studies.Prog Neuropsychopharmacol Biol Psychiatry 28(5):819-827.
[6] 成令忠,钟翠平.现代组织学.上海科学技术文献出版社.P420
[7] Megumi Adachi, Michel Barrot, Selective Loss of Brain-Derived Neurotrophic Factor in the Dentate Gyrus Attenuates Antidepressant Efficacy,BIOL PSYCHIATRY 2008;63:642–649
[8]Heuser, Bettina Weber-Hamann, Jürgen Kratzsch. Resistin and adiponectin in major depression: The association with free cortisol and effects of antidepressant treatment.Journal of Psychiatric Research.2007,Volume 41,344-350.
[9] Yvette I, Sheline, M ilan S, et al. Depression duration but not age predicts hippocampal volume loss in medically healthy woman w ith recurrent major depression [ J ]. J N euro sci,1999, 19 (12) : 5034-5043.
[10] Jing-Wen Wang, Alex Dranovsky, and René Hen,The When and Where of BDNF and the Antidepressant Response,BIOL PSYCHIATRY
[11] Angelucci F,et al:Neuropeptides,2003;37(1):51-56.
[12] Saarelainen T, Hendolin P, Lucas G, Koponen E, Sairanen M, MacDonald E, et al. (2003): Activation of the TrkB neurotrophin receptor is induced by antidepressant drugs and is required for antidepressant-induced behavioral effects. J Neurosci 23:349 –357
[13] Monteggia LM, Barrot M, Powell CM, Berton O, Galanis V, Gemelli T, et al.(2004): Essential role of brain-derived neurotrophic factor in adult hippocampal function. Proc Nat Acad Sci U S A 101:10827–10832.
[14] Chen ZY, Jing D, Bath KG, Ieraci A, Khan T, Siao CJ, et al. (2006): Genetic variant BDNF (Val66Met) polymorphism alters anxiety-related behavior. Science 314:140 –143.
[15] 彭贵军.国外医学精神病学分册.2004,31(3): 152-154.
[16] Pezet S, Malcangio M. Brain-derived neurotrophic factor as a drug target for CNS disorders. Expert Opin Ther Targets. 2004 Oct;8(5):391-9.
[17] Bateman A, Singh A, Kral T. Solomon S. The immune hypothalamic pituitary adrenal axis. Endocr Rev. 1989;10:92-112.
[18] Johan H, M alinW , PaulM , et al. Electroconvulsive seizures increase h ippocampal neurogenesis after ch ronic co rtico sterone treatment [J ]. Eur J N euro sci, 2002, 16 (2) : 28-32.
[19] Ader R., ed. Psychoncuroimmunology. New York: Academic Press; 1981.[Brian E. Leonard, Cai Song. Stress and the immune system in the etiology of anxiety and depression. Pharmacology Biochemistry and Behavior. 1996;54(1):299-303.
[20] Marta Kubera,et al. International Journal of Im-munopharmacology, 1998;20:781-789.][ 祖蓓蓓.抑郁症与免疫抑制. 国外医学精神病学分册 2004, 31( 2) : 97-99.
[21] Maes M,Meltzer H,Scharpe S,et al. Relationships between lower plasm a ltryptophan levels and immune-inflammatory variables in depression. Psychiatry Res,1993,49:151.
[22] Nibuya M,Nestler EJ,Duman RS.Chronic Antidepressant Administration Increases the Expression of cAMP Response Element Binding Protein (CREB) in Rat Hippocampus[J].J Neurosci,1996,16(7):2365-2372.
[23] Duman RS.Novel therapeutic approaches beyond the serotonin receptor[J].Biol Psychiatry,1998,44(5):324-335.
[24] Kempemann G. Regulation of adult hippocampal neurogenensis-implications for novel theories of major depression. Bipolar Disord ,2002,4:17-33.
[25] Duman RS, Malberg JE, Nakagawa S. Regulation of adult neyrogenesis by psychotropic drugs and stress ,J Pharmacol Exp Ther,2001 ,299:401-407.
[26] Kempemann G, Kuhn HG, Gage FH. More hippocampal neurons in adult mice living an enriched environment . Nature ,1997,386:493-495.
[27] Heilig M,Zachrisson O ,Thorsell A ,et al .Decreased cerebrospinal f luid neuropeptide Y(NPY)in patients with treatmen trefractory unipolar major depression:preliminary evidence of rassocaiiton with prepro NPY gene polymorphism [J ] . Psychiatr Res,2004 Mar-Apr,38 ( 2 ):113-121.
[28] 刘耀文编译. 脑神经肽 Y 系统:治疗焦虑症、抑郁症及酒精依赖的候选靶标. 国外医学药学分册. 2004,31( 6):348-349.
[1] Taylor AT,Spruill WJ,Longe RL ,et al .2001.Improved health-related quality of life with SSRIs and other antidepressants .Pharmacotherapy 21(2):189-194.
[2] Versiani M,Mehilane L,et al.1999.Reboxetine,a unique selective NRI,prevents relapse and recurrence in long-term treatment of major depressive disorder.J Clin Psychiatry 60(6):400-406.
[3] Kavirajan H .2004.Venlafaxine and SSRI remission data revisited.Br J Psychiatry 184:452-453
[4] Boer T. The pharmacologic profile of mirtazapine[J].J clin Psychiatry, 1996,57(suppl 4):19.
[5] BLIERP ,GOBBIG ,HADDJERIN ,et a l ,Impact of substance P Recepot ranatgonism on the serotonin and norepniephrnie sysetms : relevance to the antidepressan/tanxiolytic response [J ] . J Psych-iatry Neurosci,2004 May,29( 3 ):208-218.
[6] 军事医学科学院毒物药物研究所. 刘耀文编译. 脑神经肽 Y 系统:治疗焦虑症、抑郁症及酒精依赖的候选靶标. 国外医学药学分册, 2004,31(6):348-349.
[7] 刘忠纯,罗小年,王高华. 促肾上腺皮质激素释放因子与抑郁症.. 国外医学精神病学分册.
[8] 张迎春,何红玲.中药治疗抑郁焦虑症的研究述要 .中医药学刊 2005,23 (4): 764-765.
[9] Dar A. 槟榔乙醇提取物对啮齿动物的抗抑郁作用[J ] . 国外医学·中医药分册,1998 ,20(3) :47.
[10] 李亚明,陈红梅.石菖蒲对行为绝望动物抑郁模型的抗抑郁作用[J ] . 中药材,2001 ,24(1) :40～41.
[11] 翁深宏,程自立,王高华. 刺五加胶囊治疗抑郁症的临床对照研究[J ] . 湖北中医杂志,2001 ,23(6) :8～9.
[12] Molodavkin GM, Aldarmaa Zh , Voronina T A , et al. Khim -Farm Zh ,1998 ,32(4) :35.
[13] 熊元君. 新疆三种金丝桃属植物中金丝桃素含量测定[ J ]. 中草药, 2003, 33 (9) : 100-102.
[14] 郑丽,刘国卿. 贯叶连翘醇提物对单胺氧化酶与单胺递质的影 响[ J ]. 中国药科大学学报, 2002, 33 (2) : 138-141.
[15] 王斌,刘天培. 柴胡皂甙加强氟西汀在强迫游泳模型上的抗抑郁作用[J ] . 中草药,1997 ,28(12) :729.
[16] 日本大村典子. 国外医学中医中药分册,2005, 27 (5): 311.
[17] 金国琴,张学礼.甘麦大枣汤加味对抑郁症大鼠海马 cAMP- 蛋白激酶 A 途径的影响. 上海中医药大学学报 第 20 卷 第 4 期 2006 年 12 月 73-76.
[18] 刘屏,汪进良 开心散类方配伍及抗抑郁作用研究.中华中医药杂志,2005,20(5): 279-280.
[19] 郑晓鹤,洪婴,王献坤. 越菊保和丸的抗抑郁作用研究.时珍国医国药,2005 ,16(9):865-866.
[20] 傅强,马世平 半夏厚朴汤抗抑郁作用研究.中国天然药物, 2005 ,3 (2): 112-115.
[21] 尾崎哲,黄欣. 小建中汤的抗抑郁作用[J ] . 国外医学:中医中药分册,1993 ,15(5) :7～9.
[22] 张有志,聂惠民,张德昌,等. 柴胡加龙骨牡蛎汤等经方治疗抑郁症的动物行为学研究[J ] . 中国中医基础医志,2001 ,7(7) :30～32.
[1] 朱兴族. 罗质璞 编.神经药理学新论.人民卫生出版社.1-2 页
[2] Tanaka S; Kuwait Y; Tabitha M. Isolation of monoamine oxidize inhibitors from Glycyrrhizin realness roots and the structure-activity relationship. Planta.Med. 1987, 53(1): 5-8.
[3] Porsolt RD, Le Pichon M.Depression : a new animal model sesentive to antidepressant treatments .Nature,1977,266:730.
[4] Steru L,Chermat R,Thierry B ,Simon P .The tail suspension test :a new method for screening antidepressants in mice. Psychopharmacology(Berl),1985,85:367.
[5] Katz RJ.Animal model of depression: pharmacological sensitivity of ahedonic deficit .Pharmacol Biochem Behav ,1982,16:965.
[6] Overstreet DH.The Flinders sensitive line rats: a genetic animal model of depression ,Neurosci Biobehav Rev,1933,17:51.
[7] Roth KA ,Katz RJ . Further studies on a novel animal model of de-pression :Therapeutic effects of a tricyclic antidepressant [J ] . Neu- rosci Biobehav Rev ,1981 ,5(2) :253-258.
[8] Morris R.Development of a water-maze procedure for studying spatial learning in the rat.J Neurosci Methods,1984,11:47.
[9]吴俊芳主编,现代神经科学研究方法.中国协和医科大学出版社.696-697.
[1]Borsini F,Voltera G,Meli A. Does the Behavioral Despair Test easure.Physiology&Bhavior,2003,(38):385.
[2] Tanaka S; Kuwai Y; Tabata M. Isolation of monoamine oxidase inhibitors from Glycyrrhiza uralensis roots and the structure-activity relationship. Planta.Med. 1987, 53(1): 5-8.
[3]Katz RJ,Roth KA,Carroll BJ (1981).Acute and chronic stress effects on open field activity in the rat:implication for a model of depression. Neurosci Biobehav Rev 5(2):247-251.
[4] V.Butterweck,A.Wall,et al. Effects of the total extract and fractions of Hypericum in animal assays for antidepressant activity.Pharmacopsychiat. (1997)(Supplement) 117-124.
[5] Morris RGM,Garrud P,Rawlins JNP,Place navigation impaired in rats with hippocampal lesions.Nature, 1982,297:681-683.
[6] 李云峰,罗质璞.应激诱发抑郁症机制的进展[J].生理科学进展,2002,33(2):142-144.
[7] Young EA,Lopez JF,Murphy-Weinberg V,et alM.ineralocorticoid receptor function in major depression[J]A.rch Gen Psychiatry,2003,60(1):24-28.
[8] Joels M,Karst H,Alfarez D,et alE.ffects of chronic stress on structure and cell function in rat hippocampus and hypothala-mus[J]S.tress,2004,7(4):221-231.
[9] Karten YJ,Nair SM,van Essen L,et al.Long -term exposure to high corticosterone levels attenuates serotonin responses in rat CA1 neurons[J].Proc Natl Acad Sci USA,1999,96(23):13456-13461.
[10] Young,E.A;Akil,H:Changes in releasability of ACTH and beta-endorphin with chronic stress[J]. Neuro- peptides 5:545-548;1985.
[11] Young, E.A;Akil,H:Paradoxical effect of corticosteroids on pituitary ACTH/beta-endorphin release inst ressed animals[J].Psychoneurodndocrinology 13:217-323;1988.
[12] Cotter Paul A, Mulligan Owen F, Papadopoulos Andrew.Vasoconstrictor response to topical beclomethasone in major depression[J]. Psychoneuroen- docrinology,2002,27(4):475-487.