白香丹胶囊对肝气逆证大鼠海马GABA_B受体表达及其G蛋白偶联的离子通道和信号通路的影响
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摘要
目的：检测肝气逆证模型大鼠海马GABABR1、GABABR2、AC、KIR3.2、pERK1/2、ERK1/2、pCREB、CREB、BDNF、NPY表达的变化，探讨调肝方药白香丹胶囊对肝气逆证的部分中枢干预机制。
方法：大鼠随机分为正常组、模型组、白香丹胶囊组(0.2g.kg-1)、巴氯芬组(0.008g.kg-1)，采用“社会隔离结合居住入侵”方法制备肝气逆证大鼠模型，药物组按相应剂量灌胃给药7天，每日1次。通过糖水偏好实验、旷场实验和高架十字迷宫实验进行模型评价，采用免疫荧光技术检测各组大鼠海马GABABR1、GABABR2和AC、KIR3.2、BDNF、NPY的表达与分布，Western blot检测各组大鼠海马GABABR1、GABABR2、AC、KIR3.2、pERK1/2、ERK1/2、pCREB、CREB、BDNF、NPY蛋白表达变化。
结果：居住入侵后，与正常组比较，模型组体重降低（P<0.05），糖水偏好系数降低（P<0.05），旷场实验得分增高（P<0.05），高架十字迷宫实验HD、OE+CE、RE值增高（P<0.05），OE％和OT％降低（P<0.05），海马GABABR1、GABABR2、AC、KIR3.2、pERK1/2、pCREB、BDNF、NPY表达均降低（P<0.05），ERK、CREB蛋白表达无差异（P>0.05）。与模型组比较，白香丹胶囊组体重和糖水偏好系数增高（P<0.05），巴氯芬组体重和糖水偏好系数无差异（P>0.05）；与模型组比较，白香丹胶囊组和巴氯芬组旷场实验得分降低（P<0.05）、HD、OE+CE和RE值降低（P<0.05），OE％和OT％升高（P<0.05），海马GABABR1、GABABR2、AC、KIR3.2、pERK1/2、pCREB、BDNF、NPY表达均升高（P<0.05），ERK、CREB表达无差异（P>0.05）。
结论：肝疏泄失常导致肝气逆证的微观机制与海马GABAB受体G蛋白偶联的离子通道功能和信号通路传导紊乱有关，改善海马GABAB受体G蛋白偶联的离子通道功能和信号通路传导紊乱可能是白香丹胶囊平肝理气的分子生物学机制之一。
Objective: To detect the expression of GABABR1, GABABR2, KIR3.2, AC,pERK1/2, ERK1/2, pCREB, CREB, BDNF and NPY in hippocampus of rats withanger-out emotion, to explore the intervention mechanism of Baixiangdan Capsule teatingGan-qi invasion syndrome.
Methods: The Wistar rats were divided into normal group,modle group,Baixiangdancapsule group(0.2g.kg-1) and baclofen group(0.008g.kg-1). The anger-out emotion ratmodels were established with a social isolation plus resident intruder stress.The rats wereevaluated by sucrose intake, the open field and elevated plus-maze tests.The expression ofGABABR1, GABABR2, KIR3.2, AC, pERK1/2, ERK1/2, pCREB, CREB, BDNF and NPYin hippocampus were detected by immunoflourescence and Western blot.
Results: Compared with normal group, modle group had the lower sucroseintake(P<0.05), the higher total score of open field tests(P<0.05), the lower open arm entrypercent(OE％)(P<0.05), the lower open arm time percent (OT％)(P<0.05), the higherhead dipping(HD)(P<0.05) of elevated plus-maze tests and the lower expression ofGABABR1, GABABR2, KIR3.2, AC, pERK1/2, pCREB, BDNF and NPY inhippocampus(P<0.05). Compared with modle group, Baixiangdan capsule and baclofendecreased the total score of open field tests(P<0.05), decreased HD(P<0.05), increased theOE％and OT％of elevated plus-maze tests(P<0.05), increased the expression ofGABABR1, GABABR2, KIR3.2, AC, pERK1/2, pCREB, BDNF and NPY in hippocampus(P<0.05).
Conclusion: The lower expression of GABABR, KIR3.2, AC, pERK1/2, pCREB,BDNF and NPY in hippocampus may have close relationship with anger-out emotion andGan-qi invasion syndrome. Increasing the expression and the function of GABABR inhippocampus maybe one of the mechanism of flatting Gan-qi or the antianxiety effect ofBaixiangdan capsule.
方法：大鼠随机分为正常组、模型组、白香丹胶囊组(0.2g.kg-1)、巴氯芬组(0.008g.kg-1)，采用“社会隔离结合居住入侵”方法制备肝气逆证大鼠模型，药物组按相应剂量灌胃给药7天，每日1次。通过糖水偏好实验、旷场实验和高架十字迷宫实验进行模型评价，采用免疫荧光技术检测各组大鼠海马GABABR1、GABABR2和AC、KIR3.2、BDNF、NPY的表达与分布，Western blot检测各组大鼠海马GABABR1、GABABR2、AC、KIR3.2、pERK1/2、ERK1/2、pCREB、CREB、BDNF、NPY蛋白表达变化。
结果：居住入侵后，与正常组比较，模型组体重降低（P<0.05），糖水偏好系数降低（P<0.05），旷场实验得分增高（P<0.05），高架十字迷宫实验HD、OE+CE、RE值增高（P<0.05），OE％和OT％降低（P<0.05），海马GABABR1、GABABR2、AC、KIR3.2、pERK1/2、pCREB、BDNF、NPY表达均降低（P<0.05），ERK、CREB蛋白表达无差异（P>0.05）。与模型组比较，白香丹胶囊组体重和糖水偏好系数增高（P<0.05），巴氯芬组体重和糖水偏好系数无差异（P>0.05）；与模型组比较，白香丹胶囊组和巴氯芬组旷场实验得分降低（P<0.05）、HD、OE+CE和RE值降低（P<0.05），OE％和OT％升高（P<0.05），海马GABABR1、GABABR2、AC、KIR3.2、pERK1/2、pCREB、BDNF、NPY表达均升高（P<0.05），ERK、CREB表达无差异（P>0.05）。
结论：肝疏泄失常导致肝气逆证的微观机制与海马GABAB受体G蛋白偶联的离子通道功能和信号通路传导紊乱有关，改善海马GABAB受体G蛋白偶联的离子通道功能和信号通路传导紊乱可能是白香丹胶囊平肝理气的分子生物学机制之一。
Objective: To detect the expression of GABABR1, GABABR2, KIR3.2, AC,pERK1/2, ERK1/2, pCREB, CREB, BDNF and NPY in hippocampus of rats withanger-out emotion, to explore the intervention mechanism of Baixiangdan Capsule teatingGan-qi invasion syndrome.
Methods: The Wistar rats were divided into normal group,modle group,Baixiangdancapsule group(0.2g.kg-1) and baclofen group(0.008g.kg-1). The anger-out emotion ratmodels were established with a social isolation plus resident intruder stress.The rats wereevaluated by sucrose intake, the open field and elevated plus-maze tests.The expression ofGABABR1, GABABR2, KIR3.2, AC, pERK1/2, ERK1/2, pCREB, CREB, BDNF and NPYin hippocampus were detected by immunoflourescence and Western blot.
Results: Compared with normal group, modle group had the lower sucroseintake(P<0.05), the higher total score of open field tests(P<0.05), the lower open arm entrypercent(OE％)(P<0.05), the lower open arm time percent (OT％)(P<0.05), the higherhead dipping(HD)(P<0.05) of elevated plus-maze tests and the lower expression ofGABABR1, GABABR2, KIR3.2, AC, pERK1/2, pCREB, BDNF and NPY inhippocampus(P<0.05). Compared with modle group, Baixiangdan capsule and baclofendecreased the total score of open field tests(P<0.05), decreased HD(P<0.05), increased theOE％and OT％of elevated plus-maze tests(P<0.05), increased the expression ofGABABR1, GABABR2, KIR3.2, AC, pERK1/2, pCREB, BDNF and NPY in hippocampus(P<0.05).
Conclusion: The lower expression of GABABR, KIR3.2, AC, pERK1/2, pCREB,BDNF and NPY in hippocampus may have close relationship with anger-out emotion andGan-qi invasion syndrome. Increasing the expression and the function of GABABR inhippocampus maybe one of the mechanism of flatting Gan-qi or the antianxiety effect ofBaixiangdan capsule.
引文
[1]徐兴国.《内经》情志病特点及治疗浅析[J].四川中医,1996,14(2):16.
[2]张保华.略谈七情病症的常用治法[J].安徽中医学院学报,1997,4(16):43.
[3]吕直.解读中医情志疾病研究[J].中医药学刊,2004,9(22):1601-1602.
[4]乔明琦,张惠云.中医情志学[M].北京:人民卫生出版社,2009,1:138-329.
[5]乔明琦,张惠云,王文燕,等.肝气逆、肝气郁两证发病与个性特征和情绪的相关性研究[J].中国中医基础医学杂志,2007,13(5):349-352
[6] Will B Bridewell,Edward C Chang. Distinguishing between anxiety,depression, andhostility: relations to anger-in, anger-out, and anger control[J]. PersonalityIndividual Difference,1997,22(4):587.
[7]严灿,徐志伟.肝主疏泄调畅情志功能的中枢神经生物学机制探索[J].中国中西医结合杂志,2005,25(5):459-461.
[8] LeDoux JE. Emotion circuits in the brain[J]. Annu Rev Neurosci,2000,23:155-184.
[9] Wu LJ, Kim SS, Zhuo M. Molecular targets of anxiety: from membrane to nucleus [J].Neurochem Res,2008,33(10):1925-1932.
[10] Herman JP, Ostrander MM, Mueller NK, et al. Limbic system mechanisms of stressregulation: hypothalamopituitary–adrenocortical axis[J]. ProgNeuropsychopharmacol Biol Psychiatry,2005,29(8):1201-1213.
[11] Jankord R, Herman JP. Limbic regulation of hypothalamo-pituitary-adrenocorticalfunction during acute and chronic stress[J]. Ann N Y Acad Sci,2008,1148:64-73.
[12] Duman RS, Monteggia LM. A neurotrophic model for stress-related mood disorders[J].Biol Psychiatry,2006,59(12):1116–1127.
[13]林谦.γ-氨基丁酸的生理功能概述[J].玉林师范学院学报,2010,31(2):62-65.
[14] Padgett CL, Slesinger PA. GABAB Receptor Coupling to G-proteins and IonChannels[J]. Adv Pharmacol,2010,58:123-147
[15] Lopes AP, da Cunha IC, Steffens SM, et al. GABAA and GABAB agonistmicroinjections into medial accumbens shell increase feeding and induce anxiolysis inan animal model of anxiety [J]. Behav Brain Res,2007,184(2):142-149.
[16] Jacobson LH,Cryan JF. Evaluation of the anxiolytic-like profile of the GABABreceptor positive modulator CGP7930in rodents [J]. Neuropharmacology，2008,54(5):854-862.
[17] Chen Y,Menendez-Roche N,Sher E.Differential modulation by the GABAB receptorAllosteric potentiator2,6-di-tert-butyl-4-(3-hy-droxy-2,2-dimethylpropyl)-phenol(CGP7930) of synaptic transmission in the rat hippocampal CA1area [J].JPharmacol Exp Ther,2006,317(3):1170-1177.
[18] Wei S, Zhang HY, Gao J, et al. Impact of social isolation and resident intruder stresson aggressive behavior in the male rat[J]. Neural Regen Res.2010,5(15):1175-1179.
[19]金曦,金冬.论情志病发病机理[J].中国中医基础医学杂志,2001,7(7)：20-21.
[20]唐国斌,许永贵.情志致病与肾阳虚之间的关系[J].长春中医学院学报,2003,19(1):9.
[21黄跃东,李泊,赵俊芳.中医情志的发生机制当议[J].福建中医学院学报,2004,14(4):43-45.
[22]陈煜辉.中医情志学科建设及情志病证临床防治框架构建探讨[D].广州中医药大学,2005.45-56.
[23]乔明琦,张惠云,王海军,等.愤怒和郁怒与经前期综合征肝气逆证肝气郁证相关性研究[J].陕西中医,2006,27(11):1359-1361.
[24] Spielberger CD.State-trait anger expression inventory: professional manual odessa[M]. Florida:Psychological Assessment Resources Inc,1988,30.
[25] Spielberger CD.State-trait anger expression inventory-2odessa[M]. Florida:Psychological Assessment Resource Inc.1999:186.
[26] Katz RJ. Animal model of depression: Pharmacological sensitivity of a hedonicdeficit [J]. Pharmacol Biochem. Behav,1982,16(6):965-968.
[27] Willner P, Towel A, Sampson D, et al. Reduction of sucrose preference by chronicunpredictable mild stress and its restoration by a tricyclic anti-depressant[J].Psychopharmacology,1987,93(3):358-364.
[28] Carola V, D'Olimpio F, Brunamonti E, et al. Evaluation of the elevated plus-mazeand open-field tests for the assessment of anxiety-related behaviour in inbredmice[J]. Behav Brain Res.2002,134(1-2):49-57.
[29] Sato I, Arima H, Ozaki N, et al. Peripherally administered baclofen reduced foodintake and body weight in db/db as well as diet-induced obese mice[J]. Brain Res,1989,498(1):99-104.
[30]程佩素.巴氯芬的临床应用进展[J].西北药学杂志,2007,22(4):217-218.
[31]王永祥,陈敏珠,徐叔云等.白芍总甙的镇痛作用[J].中国药理学与毒理学杂志,1988,2(1):6-10.
[32] Heikal OA, Akao T, Takeda S, et al. Pharmacokinetic study of paeonimetabolin I, amajor metabolite of paeoniflorin from paeony roots [J]. Biol Pharm Bull,1997,20(5):517-521.
[33] Abdel-Hafez AA, Meselhy MR, Nakamura N, et al. Anticonvulsant activity ofpaeonimetabolin-I adducts obtained by incubation of paeoniflorin and thiolcompounds with lactobacillus brevis[J]. Biol Pharm Bull,1999,22(5):491-497.
[34]黄险峰,彭国平.香附的化学成分及药理研究进展[J].中药材,2003,26(1):65-68.
[35]刘国卿,王秋娟,谢卓丘.香附挥发油药理研究[J].中国药科大学学报,1989,20(1):48-50.
[36]王本祥.现代中药药理与临床[M].天津:科技翻译出版公司,2004,2:740-745.
[37] Mi XJ, Chen SW, Wang WJ, et al. Anxiolytic-like effect of paeonol in mice [J].Pharmacol Biochem Behav,2005,81(3):683-687.
[38] Bowery NG., Doble A, Hill DR, et al.(1979). Baclofen: A selective agonist for anovel type of GABA receptor[J]. Br J Pharmacol,1979,67(3):444–445.
[39] Bowery NG, Hill DR, Hudson AL, et al.Baclofen decrease neurotransmitter releasein the mammalian CNS by an action at a novel GABAreceptor[J].Nature,1980,283(5742):92-94.
[40] Pina JP, Kniazeffa J, Bineta V, et al. Activation mechanism of the heterodimericGABA(B) receptor[J].Biochem Pharmacol,2004,68(8):1565-1572.
[41] Calver AR, Medhurst AD, Robbins MJ, et al.The expression of GABAB1andGABAB2receptor subunits in the CNS differs from that in peripheral tissues.Neuroscience,2000,100(1):155-170.
[42] Billinton A, Ige AO, Wise A, et al. GABAB receptor heterodimer componentlocolization in human brain. Brain Res Mol Brain Res,2000,77(1):111-124
[43] Odagaki, Y, Nishi, N, Ozawa, H, et al. Measurement of receptor-mediated functionalactivation of G proteins in postmortem human brain membranes[J]. Brain Res,1998,789(1):84-91.
[44] Kelly MJ, Qiu J, Wagner EJ, et al.Rapid effects of estrogen on G protein coupledreceptor activation of potassium channels in the central nervous system[J].J SteroidBiochem Mol Biol.2002,83(1-5):187-193.
[45]G hwiler BH, Brown DA.GABAB-receptor-activated K+current in voltage-clamped CA3pyramidal cells in hippocampal cultures[J]. Proc Natl Acad Sci U SA,1985,82(5):1558-1562.
[46]Inoue M, Matsuo T, Ogata N.Baclofen activates voltage-dependent and4-aminopyridine sensitive K+conductance in guinea-pig hippocampal pyramidalcells maintained in vitro[J].Br J Pharmacol,1985,84(4):833-841.
[47] Misgeld U, Bijak M, Jarolimek W. A physiological role for GABAB receptors andthe effects of baclofen in the mammalian central nervous system[J]. ProgNeurobiol,1995,46(4):423-462.
[48] Kulik A, Vida I, Fukazawa Y, et al.Compartment-dependent colocalization ofkir3.2-containing K+channels and GABAB receptors in hippocampal pyramidalcells[J]. J Neurosci,2006,26(16):4289-4297
[49] Fowler CE, Aryal P, Suen KF, et al.Evidence for association of GABAB receptors withkir3channels and RGS4proteins[J].Physiol,2007,580(Pt1):51-65.
[50] Dascal N. Signalling via the G protein-activated K+channels. Cell Signal,1997,9(8):551-573.
[51] Blednov YA, Stoffel M, Chang SR, et al.GIRK2deficient mice. Evidence forhyperactivity and reduced anxiety[J]. Physiology&Behavior,2001,74,109–117.
[52] Signorini S, Liao YJ, Duncan SA, et al. Normal cerebellar development butsusceptibility to seizures in mice lacking G protein-coupled, inwardly rectifying K+channel GIRK2[J]. Proc Natl Acad Sci U S A,1997,94(3):923-927.
[53] Kulik A, Vida I, Lujan R, et al. Subcellular localization of metabotropic GABABreceptor subunits GABAB1a/b and GABAB2in the rat hippocampus[J]. J Neurosci,2003,23(35),11026–11035.
[54] Kempermann G, Kronenberg G. Deperssed new neurons-adult hippocampalneuorgenesis and a cellular plasticity hypothesis of major depression[J]. BidPsychiatry,2003,54(5):499-503.
[55] Lucassen PJ, Muner MB,Holsboer F, et al. Hippocampal apoptosis in majordepression is a minor event and absent from subareas at risk for glucocorticoidoverexposure[J]. Am J Pathol,2001,158(2):453-68.
[56] Nishikawa M, Hirouchi M, Kuriyama K. Functional coupling of gi subtype withGABAB receptor/adenylyl cyclase system: Analysis using a reconstituted systemwith purified GTP-binding protein from bovine cerebral cortex[J]. Neurochem Int,1997,31(1):21-25.
[57] Federman AD, Conklin BR, Schrader KA, et al. Hormonal stimulation of adenylylcyclase through gi-protein bg subunits[J]. Nature,1992,356(6365):159-161.
[58] Robichon A, Tinette S, Courtial C, et al.(2004). Simultaneous stimulation of GABAand beta adrenergic receptors stabilizes isotypes of activated adenylyl cyclaseheterocomplex[J]. BMC Cell Biol,2004,5:25.
[59]Mayr B, Montminy M. Transcriptional regulation by the phosphorylation-dependentfactor CREB[J]. Nat Rev Mol Cell Biol,2001,2(8):599-609.
[60] Tu, H., Rondard, P., Xu, C., et al.(2007). Dominant role of GABAB2and Gbg forGABAB receptor-mediated ERK1/2/CREB pathway in cerebellar neurons[J].Cellular Signalling,19,1996–2002.
[61]Boulton TG, Yancopoulos GD, Gregory JS, et al. An insulin-stimulated proteinkinade similar to yeast kinases involved in cell cycle control[J]. Sciences,1990,249(4964):64-67
[62] Boulton TG, Nye SH, RobbinsDJ, et al. ERKs: a family of protein serine/threoninekinases that are activated and tyrosine phosphorylated in response to insulin andNGF[J]. Cell,1991,65(4):663-675
[63] Otani N, Nawashiro H, Yano A, et al. Characteristic Phosphorylation of theExtracellular Signal regulated Kinase Pathway after Kainate-induced Seizures in theRat Hippocampus [J]. Acta Neurochir Suppl,2003;86:571-573.
[64] Yamagata Y, Jovanovic JN, Czernik AJ, et al. Bidirectional Changes in Synapsin IPhosphorylation at MAP Kinase-dependent Sites by Acute Neuronal Excitation inVivo[J]. J Neurochem,2002,80(5):835-842.
[65] Zhao W, Bianchi R, Wang M, et al. Extracellular Signal-regulated Kinase1/2IsRequired for the Induction of Group I Metabotropic Glutamate Receptor mediatedEpileptiform Discharges [J]. J Neurosci,2004,24(1):76-84.
[66] Lonze BE, Ginty DD. Function and regulation of CREB family transcription factorsin the nervous system[J]. Neuron,2002,35(4):605-623
[67] Hayward P Presenilin dysfunction leads to memory and plasticit defects[J]. LancetNeurol,2004,3(6):327
[68] Kandel ER.Themolecularbiology ofmemory storage: a dialogue between“genes andsynapses”[J]. Science,2001,94(5544):1030-1038
[69] Yang BH, Son H Kim SH, et a1. Phosphorylation of ERK and CREB in culturedhippocampalneurons after and haloperidol risperidone administration[J]. Psych ClinNeurosci,2004,58(3):262-267
[70] Walton MR,Dragunow M.Is CREB a key to neuronal survival [J]. Trends Neurosci,2000,23(2):48-53.
[71] Nakagawa S,Kim J E, Lee R, et a1.Regulation of neurogenesis in adult mousehippocampus by cAMP and the cAMP response element-binding protein[J]. Neurosci,2002,22(9):3673-3682
[72] Graves L, Dalvi A, Lucki I, et al.Behavioral analysis of CREB alpha delta mutationon a B6/129F1hybrid background[J].Hippocampus,2002;12(1):18-26.
[73] Valverde O, Mantamadiotis T, Torrecilla M, et al.Modulation of anxiety-likebehavior and morphine dependence in CREB-deficient mice [J].Neuropsychopharmacology2004,29(6):1122–1133
[74] Pandey SC.Anxiety and alcohol abuse disorders: a common role for CREB and itstarget, the neuropeptide Y gene [J].Trends Pharmacol Sci,2003,24(9):456–460.
[75] Pandey SC, Roy A, Zhang H,et al. Partial deletion of the cAMP responseelement-binding protein gene promotes alcohol-drinking behaviors [J]. J Neurosci,2004,24(21):5022-5030
[76] Wallace DL, Han MH, Graham DL, et al. CREB regulation of nucleus accumbensexcitability mediates social isolation–induced behavioral deficits[J]. Nat Neurosci.2009,12(2):200-209.
[77] An L,Zhang YZ,Yu NJ,Liu XM,, et al. The total flavonoids extracted fromXiaobuxin-Tang up-regulate the decreased hippocampal neurogenesis andneu-rotrophic molecules expression in chronically stressed rats[J].ProgNeuropsychopharmacol Biol Psychiatry2008;32(6):1484-1490.
[78] Barde Y A, Edger D, Thoenen H. Purification of a new neurotrophic factorfrommammalian brain[J].EMBO J,1982,1(5):549-553.
[79] Frustaci A, Pozzi G, Gianfagna F, et al.Meta-analysis of the brainderivedneurotrophic factor gene (BDNF) Val66Metpolymorphism in anxiety disorders andanxiety-related personality traits[J]. Neuropsychobiology,2008,58(3/4):163-170.
[80] Yoshimura R, Ikenouchi-Sugita A, Hori H, et al. Brain-derived neu-rotrophic factor(BDNF)and mood disorder[J]. Nihon Shinkei Seishin Yakurigaku Zasshi，2010,30(5/6):81-184.
[81] Dunham JS, Deakin J F, Miyajima F, et al. Expression of hippocampal brain-derivedneurotrophic factor and its receptors in Stanley consortium brains[J]. J Psychiatr Res,2009,43(14):1175-1184.
[82] Park DI, Kim HG, Jung WR, et al. Mecamylamine attenuates dexamethasone-induced anxiety-like behavior in association with brain derived neurotrophic factorupregulation in rat brains[J]. Neuropharmacology,2011,61(1/2):276-282.
[83] Tatemoto K, Carlquist M, Mutt V. Neuropeptide Y-a novel brain peptide withstructural similarities to peptide YY and panereatie polypeptide[J].Nature,1982,296(5858):659-660.
[84] Palmiter RD, Erickson JC, Hollopeter G, et al. Life without neuropeptide Y[J].Recent Prog Horm Res,1998,53:163-199.
[85] Heilig M, S derpalm B, Engel JA, et al.Centrally administered neuropeptide Y(NPY) produces anxiolytic-like effects in animal anxiety models[J].Psychopharmacology,1989,98(4):524–529.
[86] Heilig M, McLeod S, Koob GK, et al. Anxiolytic-like effect of neuropeptide Y(NPY), but not other peptides in an operant conflict test[J]. Regul Pept,1992,41(1):61-69.
[87] Pich EM, Agnati LF, Zini I, et al. Neuropeptide Y produces anxiolytic effects inspontaneously hypertensive rats[J]. Peptides,1993,14(5):909-12.
[88] Thorsell A, Michalkiewicz M, Dumont Y, et al. Behavioral insensitivity to restraintstress, absent fear suppression of behavior and impaired spatial learning intransgenic rats with hippocampal neuropeptide Y overexpression[J]. Proc Natl AcadSci U S A,2000,97(23):12852-12857.
[89] Carvajal CC, Vercauteren F, Dumont Y, et al. Aged neuropeptide Y transgenic ratsare resistant to acute stress but maintain spatial and non-spatial learning[J]. BehavBrain Res,2004,153(2):471-480.
[90] Heilig M, McLeod S, Brot M, et al. Anxiolytic-like action of neuropeptideY:mediation by Y1receptors in amygdala, and dissociation from food intakeeffects[J]. Neuropsychopharmacology,1993,8(4):357–363.
[91] Broqua P, Wettstein JG, Rocher MN, et al. Behavioral effects of neuropeptide Yreceptor agonists in the elevated plus-maze and fear-potentiated startleprocedures[J]. Behav Pharmacol1995;6:215-222.
[92] Karlsson RM, Choe JS, Cameron HA, et al. The neuropeptide Y Y1receptor subtypeis necessary for the anxiolytic-like effects of neuropeptide Y, but not theantidepressant-like effects of fluoxetine, in mice[J]. Psychopharmacology,2008,195(4):547-557.
[93] Wahlestedt C, Pich EM, Koob GF, et al. Modulation of anxiety and neuropeptideY-Y1receptors by antisense oligodeoxynucleotides. Science1993;259:528-31
[94] Heilig M. Antisense inhibition of neuropeptide Y (NPY)-Y1receptor expressionblocks the anxiolytic-like action of NPY in amygdala and paradoxically increasesfeeding[J]. Regul Pept,1995,59(2):201-205
[95] Kask A, Rago L, Harro J. Anxiogenic-like effect of the neuropeptide Y Y1receptorantagonist BIBP3226: antagonism with diazepam[J]. Eur J Pharmacol,1996,317(2-3):R3-4
[96] Rasmusson AM, Hauger RL,Morgan CA, et al. Low baseline andyohimbine-stimulated plasma neuropeptide Y (NPY) levels in combat-relatedPTSD[J]. Biol Psychiatry,2000,47(6):526-539.
[97] Yehuda R, Brand S, Yang RK. Plasma neuropeptide Y concentrations in combatexposed veterans: relationship to trauma exposure, recovery from PTSD, andcoping[J]. Biol Psychiatry,2006,59(7):660-663.
[98] Sah R, Ekhator NN, Strawn JR, et al. Low cerebrospinal fluid neuropeptide Yconcentrations in posttraumatic stress disorder[J]. Biol Psychiatry,2009,66(7):705-707.
[99] Morgan CA III, Wang S, Southwick SM, et al. Plasma neuropeptide-Yconcentrations in humans exposed to military survival training[J]. Biol Psychiatry,2000,47(10):902-909.
[100]Zhou Z, Zhu G, Hariri AR, et al. Genetic variation in human NPY expression affectsstress response and emotion[J]. Nature,2008,452(7190):997-1001.
[101]Sommer WH, Lidstrom J, Sun H, et al. Human NPY promoter variationrs16147:T>C as a moderator of prefrontal NPY gene expression and negativeaffect[J]. Hum Mutat,2010,31(8):E1594-608.
[102]Amstadter AB, Koenen KC, Ruggiero KJ, et al.NPY Moderates the Relationbetween Hurricane Exposure and Generalized Anxiety Disorder in anEpidemiologic Sample of Hurricane-Exposed Adults[J]. Depress Anxiety,2010,27(3):270-275.
[103]Chance WT, Sheriff S, Peng F, et al. Antagonism of NPY-induced feedingbypretreatment with cyclic AMP response element binding protein antisenseoligonucleotide[J]. Neuropeptides,2000,34(3-4):167-172.
[104]Sheriff S, Dayal R, Kasckow J, et al. NPY upregulates genes containing cyclic AMPresponse-element in human neuoblastoma cell lines bearing Y1and Y2receptors:involvement of CREB[J]. Regul Pept,1998,75-76:309-318.
[105]Sheriff S, Chance WT, Fischer JE, et al.Neuropeptide Y treatment and fooddeprivation increase cyclic AMP response-element-binding in rat hypothalamus[J].Mol Pharmacol,1997,51(4):597-604.
[106]Sheriff S, F Qureshy A, T Chance W, et al. Predominant role by CaM kinase inNPY-Y1receptor signaling: involvement of CREB[J]. Peptides,2002,23(1):87-96.
[107]Rios M, Fan G, Fekete C, et al. Conditional deletion of brain-derived neurotrophicfactor in the postnatal brain leads to obesity and hyperactivity[J]. Mol Endocrinol,2001,15(10):1748-1757.
[108]Impey S, Obrietan K, Storm DR. Making new connections: role of ERK/MAPkinase signaling in neuronal plasticity[J]. Neuron,1999,23(1):11-14.
[109]Barnea A, Roberts J.(2001) Induction of functional and morphological expressionof neuropeptide Y (NPY) in cortical cultures by brain-derived neurotrophic factor(BDNF): evidence for a requirement for extracellular-regulated kinase(ERK)-dependent and ERK independent mechanisms[J]. Brain Res,2001,919(1):57-69.
[110]Inoue T, Inui A, Okita M,et al. The effect of neuropeptide Y on thehypothalamic-pituitary-adrenal axis in the dog[J].Nihon Naibunpi Gakkai Zasshi,1990,66(6):607-18.
[111]Krysiak R, Obuchowicz E, Herman ZS. Interactions between the neuropeptide Ysystem and the hypothalamic-pituitary-adrenal axis[J]. Eur J Endocrinol,1999,140(2):130-136.
[112]H usler A, Monnet G, Peter O.Involvement of GABAB receptors in the regulationof the hypothalamo-pituitary-adrenocortical (HPA) axis in rats[J]. J SteroidBiochem Mol Biol,1993,46(6):767-771.
[113]Shinohara M, Kariya T.Etiology of affective disorders[J]. Nihon Rinsho,1994,52(5):1142-1146.
[114]Colmers WF, Pittman QJ.Presynaptic inhibition by neuropeptide Y and baclofen inhippocampus: insensitivity to pertussis toxin treatment[J]. Brain Res,1989,498(1):99-104.
[115]Bleakman D, Harrison NL, Colmers WF, et al.Investigations into neuropeptideY-mediated presynaptic inhibition in cultured hippocampal neurones of the rat[J]. BrJ Pharmacol,1992,107(2):334-340.
[116]Larhammar D.Structural diversity of receptors for neuropeptide Y, peptide YY andpancreatic polypeptide[J]. Regul Pept,1996,65(3):165-74.
[117] Sun QQ, Huguenard JR, Prince DA.Neuropeptide Y receptors differentiallymodulate G-protein-activated inwardly rectifying K+channels andhigh-voltage-activated Ca2+channels in rat thalamic neurons[J]. J Physiol,2001,531(Pt1):67-79.
[2]张保华.略谈七情病症的常用治法[J].安徽中医学院学报,1997,4(16):43.
[3]吕直.解读中医情志疾病研究[J].中医药学刊,2004,9(22):1601-1602.
[4]乔明琦,张惠云.中医情志学[M].北京:人民卫生出版社,2009,1:138-329.
[5]乔明琦,张惠云,王文燕,等.肝气逆、肝气郁两证发病与个性特征和情绪的相关性研究[J].中国中医基础医学杂志,2007,13(5):349-352
[6] Will B Bridewell,Edward C Chang. Distinguishing between anxiety,depression, andhostility: relations to anger-in, anger-out, and anger control[J]. PersonalityIndividual Difference,1997,22(4):587.
[7]严灿,徐志伟.肝主疏泄调畅情志功能的中枢神经生物学机制探索[J].中国中西医结合杂志,2005,25(5):459-461.
[8] LeDoux JE. Emotion circuits in the brain[J]. Annu Rev Neurosci,2000,23:155-184.
[9] Wu LJ, Kim SS, Zhuo M. Molecular targets of anxiety: from membrane to nucleus [J].Neurochem Res,2008,33(10):1925-1932.
[10] Herman JP, Ostrander MM, Mueller NK, et al. Limbic system mechanisms of stressregulation: hypothalamopituitary–adrenocortical axis[J]. ProgNeuropsychopharmacol Biol Psychiatry,2005,29(8):1201-1213.
[11] Jankord R, Herman JP. Limbic regulation of hypothalamo-pituitary-adrenocorticalfunction during acute and chronic stress[J]. Ann N Y Acad Sci,2008,1148:64-73.
[12] Duman RS, Monteggia LM. A neurotrophic model for stress-related mood disorders[J].Biol Psychiatry,2006,59(12):1116–1127.
[13]林谦.γ-氨基丁酸的生理功能概述[J].玉林师范学院学报,2010,31(2):62-65.
[14] Padgett CL, Slesinger PA. GABAB Receptor Coupling to G-proteins and IonChannels[J]. Adv Pharmacol,2010,58:123-147
[15] Lopes AP, da Cunha IC, Steffens SM, et al. GABAA and GABAB agonistmicroinjections into medial accumbens shell increase feeding and induce anxiolysis inan animal model of anxiety [J]. Behav Brain Res,2007,184(2):142-149.
[16] Jacobson LH,Cryan JF. Evaluation of the anxiolytic-like profile of the GABABreceptor positive modulator CGP7930in rodents [J]. Neuropharmacology，2008,54(5):854-862.
[17] Chen Y,Menendez-Roche N,Sher E.Differential modulation by the GABAB receptorAllosteric potentiator2,6-di-tert-butyl-4-(3-hy-droxy-2,2-dimethylpropyl)-phenol(CGP7930) of synaptic transmission in the rat hippocampal CA1area [J].JPharmacol Exp Ther,2006,317(3):1170-1177.
[18] Wei S, Zhang HY, Gao J, et al. Impact of social isolation and resident intruder stresson aggressive behavior in the male rat[J]. Neural Regen Res.2010,5(15):1175-1179.
[19]金曦,金冬.论情志病发病机理[J].中国中医基础医学杂志,2001,7(7)：20-21.
[20]唐国斌,许永贵.情志致病与肾阳虚之间的关系[J].长春中医学院学报,2003,19(1):9.
[21黄跃东,李泊,赵俊芳.中医情志的发生机制当议[J].福建中医学院学报,2004,14(4):43-45.
[22]陈煜辉.中医情志学科建设及情志病证临床防治框架构建探讨[D].广州中医药大学,2005.45-56.
[23]乔明琦,张惠云,王海军,等.愤怒和郁怒与经前期综合征肝气逆证肝气郁证相关性研究[J].陕西中医,2006,27(11):1359-1361.
[24] Spielberger CD.State-trait anger expression inventory: professional manual odessa[M]. Florida:Psychological Assessment Resources Inc,1988,30.
[25] Spielberger CD.State-trait anger expression inventory-2odessa[M]. Florida:Psychological Assessment Resource Inc.1999:186.
[26] Katz RJ. Animal model of depression: Pharmacological sensitivity of a hedonicdeficit [J]. Pharmacol Biochem. Behav,1982,16(6):965-968.
[27] Willner P, Towel A, Sampson D, et al. Reduction of sucrose preference by chronicunpredictable mild stress and its restoration by a tricyclic anti-depressant[J].Psychopharmacology,1987,93(3):358-364.
[28] Carola V, D'Olimpio F, Brunamonti E, et al. Evaluation of the elevated plus-mazeand open-field tests for the assessment of anxiety-related behaviour in inbredmice[J]. Behav Brain Res.2002,134(1-2):49-57.
[29] Sato I, Arima H, Ozaki N, et al. Peripherally administered baclofen reduced foodintake and body weight in db/db as well as diet-induced obese mice[J]. Brain Res,1989,498(1):99-104.
[30]程佩素.巴氯芬的临床应用进展[J].西北药学杂志,2007,22(4):217-218.
[31]王永祥,陈敏珠,徐叔云等.白芍总甙的镇痛作用[J].中国药理学与毒理学杂志,1988,2(1):6-10.
[32] Heikal OA, Akao T, Takeda S, et al. Pharmacokinetic study of paeonimetabolin I, amajor metabolite of paeoniflorin from paeony roots [J]. Biol Pharm Bull,1997,20(5):517-521.
[33] Abdel-Hafez AA, Meselhy MR, Nakamura N, et al. Anticonvulsant activity ofpaeonimetabolin-I adducts obtained by incubation of paeoniflorin and thiolcompounds with lactobacillus brevis[J]. Biol Pharm Bull,1999,22(5):491-497.
[34]黄险峰,彭国平.香附的化学成分及药理研究进展[J].中药材,2003,26(1):65-68.
[35]刘国卿,王秋娟,谢卓丘.香附挥发油药理研究[J].中国药科大学学报,1989,20(1):48-50.
[36]王本祥.现代中药药理与临床[M].天津:科技翻译出版公司,2004,2:740-745.
[37] Mi XJ, Chen SW, Wang WJ, et al. Anxiolytic-like effect of paeonol in mice [J].Pharmacol Biochem Behav,2005,81(3):683-687.
[38] Bowery NG., Doble A, Hill DR, et al.(1979). Baclofen: A selective agonist for anovel type of GABA receptor[J]. Br J Pharmacol,1979,67(3):444–445.
[39] Bowery NG, Hill DR, Hudson AL, et al.Baclofen decrease neurotransmitter releasein the mammalian CNS by an action at a novel GABAreceptor[J].Nature,1980,283(5742):92-94.
[40] Pina JP, Kniazeffa J, Bineta V, et al. Activation mechanism of the heterodimericGABA(B) receptor[J].Biochem Pharmacol,2004,68(8):1565-1572.
[41] Calver AR, Medhurst AD, Robbins MJ, et al.The expression of GABAB1andGABAB2receptor subunits in the CNS differs from that in peripheral tissues.Neuroscience,2000,100(1):155-170.
[42] Billinton A, Ige AO, Wise A, et al. GABAB receptor heterodimer componentlocolization in human brain. Brain Res Mol Brain Res,2000,77(1):111-124
[43] Odagaki, Y, Nishi, N, Ozawa, H, et al. Measurement of receptor-mediated functionalactivation of G proteins in postmortem human brain membranes[J]. Brain Res,1998,789(1):84-91.
[44] Kelly MJ, Qiu J, Wagner EJ, et al.Rapid effects of estrogen on G protein coupledreceptor activation of potassium channels in the central nervous system[J].J SteroidBiochem Mol Biol.2002,83(1-5):187-193.
[45]G hwiler BH, Brown DA.GABAB-receptor-activated K+current in voltage-clamped CA3pyramidal cells in hippocampal cultures[J]. Proc Natl Acad Sci U SA,1985,82(5):1558-1562.
[46]Inoue M, Matsuo T, Ogata N.Baclofen activates voltage-dependent and4-aminopyridine sensitive K+conductance in guinea-pig hippocampal pyramidalcells maintained in vitro[J].Br J Pharmacol,1985,84(4):833-841.
[47] Misgeld U, Bijak M, Jarolimek W. A physiological role for GABAB receptors andthe effects of baclofen in the mammalian central nervous system[J]. ProgNeurobiol,1995,46(4):423-462.
[48] Kulik A, Vida I, Fukazawa Y, et al.Compartment-dependent colocalization ofkir3.2-containing K+channels and GABAB receptors in hippocampal pyramidalcells[J]. J Neurosci,2006,26(16):4289-4297
[49] Fowler CE, Aryal P, Suen KF, et al.Evidence for association of GABAB receptors withkir3channels and RGS4proteins[J].Physiol,2007,580(Pt1):51-65.
[50] Dascal N. Signalling via the G protein-activated K+channels. Cell Signal,1997,9(8):551-573.
[51] Blednov YA, Stoffel M, Chang SR, et al.GIRK2deficient mice. Evidence forhyperactivity and reduced anxiety[J]. Physiology&Behavior,2001,74,109–117.
[52] Signorini S, Liao YJ, Duncan SA, et al. Normal cerebellar development butsusceptibility to seizures in mice lacking G protein-coupled, inwardly rectifying K+channel GIRK2[J]. Proc Natl Acad Sci U S A,1997,94(3):923-927.
[53] Kulik A, Vida I, Lujan R, et al. Subcellular localization of metabotropic GABABreceptor subunits GABAB1a/b and GABAB2in the rat hippocampus[J]. J Neurosci,2003,23(35),11026–11035.
[54] Kempermann G, Kronenberg G. Deperssed new neurons-adult hippocampalneuorgenesis and a cellular plasticity hypothesis of major depression[J]. BidPsychiatry,2003,54(5):499-503.
[55] Lucassen PJ, Muner MB,Holsboer F, et al. Hippocampal apoptosis in majordepression is a minor event and absent from subareas at risk for glucocorticoidoverexposure[J]. Am J Pathol,2001,158(2):453-68.
[56] Nishikawa M, Hirouchi M, Kuriyama K. Functional coupling of gi subtype withGABAB receptor/adenylyl cyclase system: Analysis using a reconstituted systemwith purified GTP-binding protein from bovine cerebral cortex[J]. Neurochem Int,1997,31(1):21-25.
[57] Federman AD, Conklin BR, Schrader KA, et al. Hormonal stimulation of adenylylcyclase through gi-protein bg subunits[J]. Nature,1992,356(6365):159-161.
[58] Robichon A, Tinette S, Courtial C, et al.(2004). Simultaneous stimulation of GABAand beta adrenergic receptors stabilizes isotypes of activated adenylyl cyclaseheterocomplex[J]. BMC Cell Biol,2004,5:25.
[59]Mayr B, Montminy M. Transcriptional regulation by the phosphorylation-dependentfactor CREB[J]. Nat Rev Mol Cell Biol,2001,2(8):599-609.
[60] Tu, H., Rondard, P., Xu, C., et al.(2007). Dominant role of GABAB2and Gbg forGABAB receptor-mediated ERK1/2/CREB pathway in cerebellar neurons[J].Cellular Signalling,19,1996–2002.
[61]Boulton TG, Yancopoulos GD, Gregory JS, et al. An insulin-stimulated proteinkinade similar to yeast kinases involved in cell cycle control[J]. Sciences,1990,249(4964):64-67
[62] Boulton TG, Nye SH, RobbinsDJ, et al. ERKs: a family of protein serine/threoninekinases that are activated and tyrosine phosphorylated in response to insulin andNGF[J]. Cell,1991,65(4):663-675
[63] Otani N, Nawashiro H, Yano A, et al. Characteristic Phosphorylation of theExtracellular Signal regulated Kinase Pathway after Kainate-induced Seizures in theRat Hippocampus [J]. Acta Neurochir Suppl,2003;86:571-573.
[64] Yamagata Y, Jovanovic JN, Czernik AJ, et al. Bidirectional Changes in Synapsin IPhosphorylation at MAP Kinase-dependent Sites by Acute Neuronal Excitation inVivo[J]. J Neurochem,2002,80(5):835-842.
[65] Zhao W, Bianchi R, Wang M, et al. Extracellular Signal-regulated Kinase1/2IsRequired for the Induction of Group I Metabotropic Glutamate Receptor mediatedEpileptiform Discharges [J]. J Neurosci,2004,24(1):76-84.
[66] Lonze BE, Ginty DD. Function and regulation of CREB family transcription factorsin the nervous system[J]. Neuron,2002,35(4):605-623
[67] Hayward P Presenilin dysfunction leads to memory and plasticit defects[J]. LancetNeurol,2004,3(6):327
[68] Kandel ER.Themolecularbiology ofmemory storage: a dialogue between“genes andsynapses”[J]. Science,2001,94(5544):1030-1038
[69] Yang BH, Son H Kim SH, et a1. Phosphorylation of ERK and CREB in culturedhippocampalneurons after and haloperidol risperidone administration[J]. Psych ClinNeurosci,2004,58(3):262-267
[70] Walton MR,Dragunow M.Is CREB a key to neuronal survival [J]. Trends Neurosci,2000,23(2):48-53.
[71] Nakagawa S,Kim J E, Lee R, et a1.Regulation of neurogenesis in adult mousehippocampus by cAMP and the cAMP response element-binding protein[J]. Neurosci,2002,22(9):3673-3682
[72] Graves L, Dalvi A, Lucki I, et al.Behavioral analysis of CREB alpha delta mutationon a B6/129F1hybrid background[J].Hippocampus,2002;12(1):18-26.
[73] Valverde O, Mantamadiotis T, Torrecilla M, et al.Modulation of anxiety-likebehavior and morphine dependence in CREB-deficient mice [J].Neuropsychopharmacology2004,29(6):1122–1133
[74] Pandey SC.Anxiety and alcohol abuse disorders: a common role for CREB and itstarget, the neuropeptide Y gene [J].Trends Pharmacol Sci,2003,24(9):456–460.
[75] Pandey SC, Roy A, Zhang H,et al. Partial deletion of the cAMP responseelement-binding protein gene promotes alcohol-drinking behaviors [J]. J Neurosci,2004,24(21):5022-5030
[76] Wallace DL, Han MH, Graham DL, et al. CREB regulation of nucleus accumbensexcitability mediates social isolation–induced behavioral deficits[J]. Nat Neurosci.2009,12(2):200-209.
[77] An L,Zhang YZ,Yu NJ,Liu XM,, et al. The total flavonoids extracted fromXiaobuxin-Tang up-regulate the decreased hippocampal neurogenesis andneu-rotrophic molecules expression in chronically stressed rats[J].ProgNeuropsychopharmacol Biol Psychiatry2008;32(6):1484-1490.
[78] Barde Y A, Edger D, Thoenen H. Purification of a new neurotrophic factorfrommammalian brain[J].EMBO J,1982,1(5):549-553.
[79] Frustaci A, Pozzi G, Gianfagna F, et al.Meta-analysis of the brainderivedneurotrophic factor gene (BDNF) Val66Metpolymorphism in anxiety disorders andanxiety-related personality traits[J]. Neuropsychobiology,2008,58(3/4):163-170.
[80] Yoshimura R, Ikenouchi-Sugita A, Hori H, et al. Brain-derived neu-rotrophic factor(BDNF)and mood disorder[J]. Nihon Shinkei Seishin Yakurigaku Zasshi，2010,30(5/6):81-184.
[81] Dunham JS, Deakin J F, Miyajima F, et al. Expression of hippocampal brain-derivedneurotrophic factor and its receptors in Stanley consortium brains[J]. J Psychiatr Res,2009,43(14):1175-1184.
[82] Park DI, Kim HG, Jung WR, et al. Mecamylamine attenuates dexamethasone-induced anxiety-like behavior in association with brain derived neurotrophic factorupregulation in rat brains[J]. Neuropharmacology,2011,61(1/2):276-282.
[83] Tatemoto K, Carlquist M, Mutt V. Neuropeptide Y-a novel brain peptide withstructural similarities to peptide YY and panereatie polypeptide[J].Nature,1982,296(5858):659-660.
[84] Palmiter RD, Erickson JC, Hollopeter G, et al. Life without neuropeptide Y[J].Recent Prog Horm Res,1998,53:163-199.
[85] Heilig M, S derpalm B, Engel JA, et al.Centrally administered neuropeptide Y(NPY) produces anxiolytic-like effects in animal anxiety models[J].Psychopharmacology,1989,98(4):524–529.
[86] Heilig M, McLeod S, Koob GK, et al. Anxiolytic-like effect of neuropeptide Y(NPY), but not other peptides in an operant conflict test[J]. Regul Pept,1992,41(1):61-69.
[87] Pich EM, Agnati LF, Zini I, et al. Neuropeptide Y produces anxiolytic effects inspontaneously hypertensive rats[J]. Peptides,1993,14(5):909-12.
[88] Thorsell A, Michalkiewicz M, Dumont Y, et al. Behavioral insensitivity to restraintstress, absent fear suppression of behavior and impaired spatial learning intransgenic rats with hippocampal neuropeptide Y overexpression[J]. Proc Natl AcadSci U S A,2000,97(23):12852-12857.
[89] Carvajal CC, Vercauteren F, Dumont Y, et al. Aged neuropeptide Y transgenic ratsare resistant to acute stress but maintain spatial and non-spatial learning[J]. BehavBrain Res,2004,153(2):471-480.
[90] Heilig M, McLeod S, Brot M, et al. Anxiolytic-like action of neuropeptideY:mediation by Y1receptors in amygdala, and dissociation from food intakeeffects[J]. Neuropsychopharmacology,1993,8(4):357–363.
[91] Broqua P, Wettstein JG, Rocher MN, et al. Behavioral effects of neuropeptide Yreceptor agonists in the elevated plus-maze and fear-potentiated startleprocedures[J]. Behav Pharmacol1995;6:215-222.
[92] Karlsson RM, Choe JS, Cameron HA, et al. The neuropeptide Y Y1receptor subtypeis necessary for the anxiolytic-like effects of neuropeptide Y, but not theantidepressant-like effects of fluoxetine, in mice[J]. Psychopharmacology,2008,195(4):547-557.
[93] Wahlestedt C, Pich EM, Koob GF, et al. Modulation of anxiety and neuropeptideY-Y1receptors by antisense oligodeoxynucleotides. Science1993;259:528-31
[94] Heilig M. Antisense inhibition of neuropeptide Y (NPY)-Y1receptor expressionblocks the anxiolytic-like action of NPY in amygdala and paradoxically increasesfeeding[J]. Regul Pept,1995,59(2):201-205
[95] Kask A, Rago L, Harro J. Anxiogenic-like effect of the neuropeptide Y Y1receptorantagonist BIBP3226: antagonism with diazepam[J]. Eur J Pharmacol,1996,317(2-3):R3-4
[96] Rasmusson AM, Hauger RL,Morgan CA, et al. Low baseline andyohimbine-stimulated plasma neuropeptide Y (NPY) levels in combat-relatedPTSD[J]. Biol Psychiatry,2000,47(6):526-539.
[97] Yehuda R, Brand S, Yang RK. Plasma neuropeptide Y concentrations in combatexposed veterans: relationship to trauma exposure, recovery from PTSD, andcoping[J]. Biol Psychiatry,2006,59(7):660-663.
[98] Sah R, Ekhator NN, Strawn JR, et al. Low cerebrospinal fluid neuropeptide Yconcentrations in posttraumatic stress disorder[J]. Biol Psychiatry,2009,66(7):705-707.
[99] Morgan CA III, Wang S, Southwick SM, et al. Plasma neuropeptide-Yconcentrations in humans exposed to military survival training[J]. Biol Psychiatry,2000,47(10):902-909.
[100]Zhou Z, Zhu G, Hariri AR, et al. Genetic variation in human NPY expression affectsstress response and emotion[J]. Nature,2008,452(7190):997-1001.
[101]Sommer WH, Lidstrom J, Sun H, et al. Human NPY promoter variationrs16147:T>C as a moderator of prefrontal NPY gene expression and negativeaffect[J]. Hum Mutat,2010,31(8):E1594-608.
[102]Amstadter AB, Koenen KC, Ruggiero KJ, et al.NPY Moderates the Relationbetween Hurricane Exposure and Generalized Anxiety Disorder in anEpidemiologic Sample of Hurricane-Exposed Adults[J]. Depress Anxiety,2010,27(3):270-275.
[103]Chance WT, Sheriff S, Peng F, et al. Antagonism of NPY-induced feedingbypretreatment with cyclic AMP response element binding protein antisenseoligonucleotide[J]. Neuropeptides,2000,34(3-4):167-172.
[104]Sheriff S, Dayal R, Kasckow J, et al. NPY upregulates genes containing cyclic AMPresponse-element in human neuoblastoma cell lines bearing Y1and Y2receptors:involvement of CREB[J]. Regul Pept,1998,75-76:309-318.
[105]Sheriff S, Chance WT, Fischer JE, et al.Neuropeptide Y treatment and fooddeprivation increase cyclic AMP response-element-binding in rat hypothalamus[J].Mol Pharmacol,1997,51(4):597-604.
[106]Sheriff S, F Qureshy A, T Chance W, et al. Predominant role by CaM kinase inNPY-Y1receptor signaling: involvement of CREB[J]. Peptides,2002,23(1):87-96.
[107]Rios M, Fan G, Fekete C, et al. Conditional deletion of brain-derived neurotrophicfactor in the postnatal brain leads to obesity and hyperactivity[J]. Mol Endocrinol,2001,15(10):1748-1757.
[108]Impey S, Obrietan K, Storm DR. Making new connections: role of ERK/MAPkinase signaling in neuronal plasticity[J]. Neuron,1999,23(1):11-14.
[109]Barnea A, Roberts J.(2001) Induction of functional and morphological expressionof neuropeptide Y (NPY) in cortical cultures by brain-derived neurotrophic factor(BDNF): evidence for a requirement for extracellular-regulated kinase(ERK)-dependent and ERK independent mechanisms[J]. Brain Res,2001,919(1):57-69.
[110]Inoue T, Inui A, Okita M,et al. The effect of neuropeptide Y on thehypothalamic-pituitary-adrenal axis in the dog[J].Nihon Naibunpi Gakkai Zasshi,1990,66(6):607-18.
[111]Krysiak R, Obuchowicz E, Herman ZS. Interactions between the neuropeptide Ysystem and the hypothalamic-pituitary-adrenal axis[J]. Eur J Endocrinol,1999,140(2):130-136.
[112]H usler A, Monnet G, Peter O.Involvement of GABAB receptors in the regulationof the hypothalamo-pituitary-adrenocortical (HPA) axis in rats[J]. J SteroidBiochem Mol Biol,1993,46(6):767-771.
[113]Shinohara M, Kariya T.Etiology of affective disorders[J]. Nihon Rinsho,1994,52(5):1142-1146.
[114]Colmers WF, Pittman QJ.Presynaptic inhibition by neuropeptide Y and baclofen inhippocampus: insensitivity to pertussis toxin treatment[J]. Brain Res,1989,498(1):99-104.
[115]Bleakman D, Harrison NL, Colmers WF, et al.Investigations into neuropeptideY-mediated presynaptic inhibition in cultured hippocampal neurones of the rat[J]. BrJ Pharmacol,1992,107(2):334-340.
[116]Larhammar D.Structural diversity of receptors for neuropeptide Y, peptide YY andpancreatic polypeptide[J]. Regul Pept,1996,65(3):165-74.
[117] Sun QQ, Huguenard JR, Prince DA.Neuropeptide Y receptors differentiallymodulate G-protein-activated inwardly rectifying K+channels andhigh-voltage-activated Ca2+channels in rat thalamic neurons[J]. J Physiol,2001,531(Pt1):67-79.