摘要
焦虑症是由于神经调控稳态的失衡和内分泌调节紊乱所造成的一种情绪障碍性精神疾病。焦虑症的常见症状包括对未知事物的焦虑和惊恐,对不可预见事物的过分担忧,对新环境的恐惧以及运动性的显著降低。同时还伴有植物性神经紊乱等症状。由于社会竞争及工作压力的增加,焦虑与抑郁等情绪障碍性疾病发生率呈明显上升趋势,对人的正常工作与生活造成严重影响,已经引起生理心理学、神经科学、医学及社会各界的高度关注。但是,目前对焦虑症的研究多集中在行为学的研究上,对其机制的探讨,也多集中在神经调节机制和激素调控机制的独立研究上。对各种因素之间相互作用的关系研究还比较少。
已有的研究发现,谷氨酸的离子型受体α-氨基羟甲基恶噬丙酸(α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid, AMPA)受体和N-甲基-D天门冬氨酸(N-methyl-D-aspartic acid, NMDA)受体与情绪的调控有着一定的关系。这两种受体的表达对谷氨酸能神经元发挥作用及其维持整个神经系统神经元的形态、结构和功能稳定,对神经损伤的修复均有着密切的关系。谷氨酸能神经元是中枢神经中分布广泛的一种神经元,谷氨酸受体分为代谢型受体和离子型受体两大类。有关离子型受体的作用研究的比较多。研究发现,谷氨酸NMDA受体和AMPA受体在情绪行为调节中发挥着重要作用,二者相互影响,作用不同,甚至表现为相互拮抗。研究表明,而长时间较高水平的NMDA受体激活,对神经元具有一定的损伤作用,AMPA受体激活则具有保护作用。应激诱发抑郁或焦虑与NMDA受体过度激活有关。下丘脑具有神经内分泌双重功能,既是情绪调节的重要脑区,也是重要的内分泌枢纽。下丘脑分泌的加压素(arginine vasopressin, AVP)对焦虑情绪的调节具有显著的作用。AVP的V1型受体表达量的增高,使动物产生焦虑样情绪行为,抑制或者剔除V1型受体的表达,则能产生显著的抗焦虑作用。BABL/cj小鼠是先天具有焦虑情绪的小鼠,其焦虑的产生是否与体内谷氨酸及NMDA受体、AMPA受体和AVP有关?是什么样的关系?至今尚未见有系统的研究和报道。
本实验采用脑立体定位技术和脑室微量注射技术,对先天具有较高焦虑情绪的BABL/cj实验小鼠微量注射谷氨酸离子型受体激动剂及其拮抗剂和AVP,再通过敞箱实验和高架十字迷宫实验进行行为学检测,分析其焦虑样情绪行为发生与NMDA受体、AMPA受体、AVP的关系。结果显示：
1、行为学结果显示,BALB/cj小鼠与C57BL／6小鼠比较,具有明显的焦虑样行为表现。二者存在极显著性差异(P<0.01)。
2、脑室微量注射AMPA或NMDA受体阻断剂MK-801对BALB/cj小鼠具有显著的抗焦虑作用(P<0.05)；而注射NMDA、AMPA受体阻断剂]DNQX和AVP任一种,均可使小鼠的焦虑情绪加重。
3、联合注射MK-801+AVP, AVP加重焦虑的作用被MK-801抑制,表现出MK-801的抗焦虑作用。与BABL/cj正常对照组和注射AVP组比较,具有极显著性差异(P<0.01)。
以上结果说明,AMPA和NMDA受体阻断剂MK-801具有抗BABL/cj小鼠先天焦虑样行为的作用。BABL/cj小鼠的焦虑情绪产生与谷氨酸的NMDA受体过度激活有关。谷氨酸的NMDA受体与AVP在焦虑发生中有关,AVP加重BABL/cj小鼠的焦虑症状是通过NMDA受体介导的。
Anxiety neurosis is a kind of mental disease of emotional disorder which is caused by unbalanced neural regulation homeostasis and endocrine regulation disorder. The common symptoms of anxiety neurosis are the anxiety and panic over the unknown, the overcare of the unpredictable things, the fear of new circumstances and substantial reduction in locomotion, accompanied by symptoms such as excited automonic nerve. Because of competitive world and the increasing pressure from work, a clear upward trend of emotional disorders, such as anxiety and depression, is seen in recent years. These disorders seriously affected people's normal life and work., which attracts more and more attention of researchers from psychology, neuroscience, medical science and other circles of the society. But recent studies of anxiety neurosis mainly focus on behavioral science, and the studies on mechanism mostly focus on meural regulation and hormone regulation respectively. But the studies on the mutual action among mechanisms are general lacking.
The existed studies show that ionotropic glutamate receptors,α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) and N-methyl-D-aspartic acid (NMDA) have certain correlation with the regualtion of emotion. The expressions of the two kinds of acceptors are closely connected with damage repairof glutamate energic neurons, and they can maintain the stable forms, structures and function of the neurons in the nervous system. The nerve centre is rich in glutamate energic neurons. There are two types of glutamate receptors, metabotropic receptors and ionotropic receptor. In recent researches, there are more studies about ionotropic receptors. According to the researches, NMDA glutamate recptors and AMPA glutamate recptors play an important role in regulating emotional behaviors.Also the two acceptors antagonise and sometimes even inhibit each other.
Researches show that a considerable time of activation of NMDA aceptor at a high level may cause injury to glutamate egernic neurons in some degree. Meanwhile, the activation of AMPA aceptor can be protective. As a result, the cause of anxiety or depression is relateded to the over activation of NMDA aceptors.Hypothalamus has nerve and endocrine dual function, it is an important brain area for rmotion regulation as well as the hinge of invretion. AVP secreted by HPA Axis (hypothalamus-adenohypophysis-adrenocortical axis) remarkably regulates anxiety. With the rise of the amount of expression, V1 acceptor of AVP can promote the emergence of anxiety. But if we inhibit or knockout the expression of V1 acceptor, it will have a remarkable effect on antianxiery. BABL/cj mice have a connatural anxious emotion. Is there any relation between its anxiety and NMDA acptors, AMPA aceptors and AVP? What's their raltionship? A systemic research or report is still absent.
This experiment uses encephalic region stereotaxis and microinjection to inject the BABL/cj mice, which have connatural anxiety, with ionotropic glutamate receptor, its antagonists and AVP, as well as the conbination of them all. The mice's behaviors is tested by open-field test and elevated plus-maze test. And the expriment analyze the relation between the anxiety of the mice and NMDA acptors, AMPA aceptors and AVP.
The result showed that:
1. The result of praxiology shows that, compared with C57BL/6 mice, BALB/cj mice have obvious anxious behavior. The difference between the two is distinct.(P<0.01)
2. Microinjection of AMPA or NMDA receptor blocking pharmacon MK-801 to the ventricle of the mice has significant anxiolytic effect. (P<0.05). But the microinjection of AMPA or NMDA receptor blocking pharmacon DNQX and AVP can boost anxiety of the mice.
3 But if AMK-801 and Avp are injected at the same time, the test mice only showed the anxiolytic effect of MK-801. The function of AVP-boosting the anxiety is restrained. The comparison between normal control group and AVP injection group of the BABL/cj mice showed remarkable difference. (P<0.01)
The results above show that AMPA and NMDA receptor blocking pharmacon MK-801 has anti-anxiety effect to the BABL/cj mice with connatural anxious behavior. The anxiety of BABL/cj mice is related to the over activation of glutamate NMDA receptors. The glutamate NMDA receptors are related to AVP in the occuring of anxiety. Mediated by NMDA aceptos, AVP boosts the anxiety of BABL/cj mice.
引文
[1]许绍芬.神经生物学[M].第2版.上海：上海医科大学出版社,1999：457.
[2]陈辰,徐维平,魏伟.抑郁症的神经内分泌学研究进展[J].山东医药,2008,48(37)：110-111.
[3]Neumeister A. Tryp tophan dep letion, serotonin, and dep res2 sion:where do we stand? [J]. Psyhopharmacol Bull,2003,37(4):99.
[4]Smolders I, Clinckers R, Meurs A, Bundel DD, Portelli J, Ebinger G, Michotte Y. Direct enhancement of hippocampal dopamine or serotonin levels as a pharmacodynamic measure of combined antidepressant eanticonvulsant action [J]. Neuro pharmacology,2008,54:1017-1028.
[5]Luo DD, An SC, Zhang X. Involvement of hippocampal serotonin and neuropeptide Y in depression induced by chronic unpredicted mild stress[J]. Brain Research Bulletin,2008,77:8-12.
[6]Jay TM, Rocher C, Hotte M, et al. Placticity at hippocampal to prefrontal cortex synaps sisim paired by loss of dopamine and stress:importance for psychiatric diseases [J]. Neuro Tux Res,2004,6 (3):233-236.
[7]Schutter DJ, Peper JS, Koppeschaar HP, et al. Administration of testosterone increases functional connectivity in a cortico-cortical depression circuit [J]. Neurop sychiatry Clin Neurosci,2005,17(3):372-377.
[8]Ebstein RP, LererB, Shap ira B, et all. Cyclic AMP second-messenger signal amp lification in dep ression [J]. Br J Psychiatry,1988,152:665-669.
[9]Benjamin C. Robert S. Bridges.Arginine vasopressin V1a receptor antagonist impairs maternal memory in rats [J]. Physiology & Behavior.2008.95.182-186
[10]Karen L. Bales,* Albert J. Kim.et al. Both oxytocin and vasopressin may influence alloparental behavior in male prairie voles[J] Hormones and Behavior 45 (2004) 354-361
[11]Sungho M, Carlos A, Zarate, et al. Cellular Mechanisms Underlying the Antidepressant Effects of Ketamine:Role of Amino-3-Hydroxy-5-Methylisoxazole-4-Propionic Acid Receptors [J]. Brief Report 2008,4:349-352
[12]Magdeburg, Germany. Central vasopressin administration failed to influence anxiety behavior after pinealectomy in rats. [J] Physiology & Behavior.2000 68:735-739
[13]K. Yayou, Y. Sato. et al Comparison between the central effects of CRH and AVP in steers. [J] Physiology & Behavior 2008 93:537-545
[14]Mukherjee K, Knisely A, Jacobson L. Partial glucocorticoid agonist-like effects of imipramine on hypothalamic-pituitary-adrenocortical activity, thymus weight, and hippocampal glucocorticoid receptors in male C57BL/6 mice[J]. Endocrinology, 2004,145(9):4185-4191.
[15]Selye H. Stress in Health and Disease [J] Physiology & Behavior.1976,12: 99-106.
[16]Marianne B, Florian H. Mice with Mutations in the HPA-System as Models for Symptoms of Depression [J]. Biol Psychiatry,2006,59:1104-1115.
[17]Herman JP, Cullinan WE. Neurocircuitry of stress:central control of the hypothalam-pituitary-adrenocortical axis [J]. Trends Neurosci,1997,20:78-84.
[18]Sapolsky RM, Kery LC, Mcewen BS. Glucocorticoid-sensitive hippocampal neurons are involved in terminating the adrenocortical stress response [J]. Proc Natl Acad Sci,1984,81:6174-6177.
[19]Vas A, Bernal S. Effects of chronic stress on dendritic arborization in the central and extended amygdala[J]. Brain Res,2003,965:290-294.
[20]Marianne B, Muller, Florian H. Mice with Mutations in the HPA- System as Models for Symptoms of Depression[J]. Biol Psychiatry,2006,59:1104-1115.
[21]Herman JP, Cullinan WE. Neurocircuitry of stress:central control of the hypothalam-pituitary-adrenocortical axis [J]. Trends Neurosci,1997,20:78-84.
[22]Kim JJ, Diamond DM. The stressed hippocampus, synaptic plasticity and lost memories [J]. Nat Rev Neurosei,2002; 3:453-462.
[23]王雪琦,路长林,孙学军等.侧脑室微量注射神经生长因子对实验性大鼠抑郁行为和海马神经元损伤的影响[J].中国行为医学科学,2002,11(5)：481-486.
[24]McEwen BS. Stress and hippocampal plasticity [J].Ann Rev Nerosci,1999,22: 105-122.
[25]Barr AM, Brotto LA, Phillips AG. Chronic corticosterone enhances the rewarding effects of hypothalamic self-stimulation in rats [J]. Brain Res,2000,875:196-201.
[26]Beck KD, Luine VN. Sex differences in behavioral and neurochemical profiles after chronic stress:role of housing conditions [J]. Physiol Behav,2002,75: 661-673.
[27]Kole MH, Costoli T, Koolhaas JM et al. Bidirectional shift in thecornu ammonis 3 pyramidal dendritic organization following brief stress [J]. Neuroscience,2004; 125:337-347.
[28]Kempermann G, Kronenberg G. Depressed new neurons-adult hippocampal neurogenesis and a cellular plasticity hypothesis of major depression [J]. Biol Psychiatry,2003,54:499-503.
[29]Sousa N, Lukoyanov NV, MadeiraMD et al. Reorganization of the morphology of hippocampal neurites and synapses after stress-induced damage correlates with behavioral imp rovement[J]. Neuro science,2000; 97:253-266.
[30]Sandi C, Davies HA, Cordero MI et al. Rapid reversal of stress induced loss of synapses in CA3 of rat hippocampus following water maze training [J]. Eur J Neurosci,2003,17:2447-2456.
[31]Sapolsky RM. The possibility of neurotoxicity in the hippocampus in major depression:a primer on neuron death [J]. Biol Psychiatry,2000; 48:755-765.
[32]Moghaddam B, BolinaoML, Stein-Behrens B et al. Glucocorticoids mediate the stress-induced extracellular accumulation of glutamate [J]. Brain Res,1994,655: 251-254.
[33]Arborelius L, Owens MJ, Plotsky PM et al. The role of corticotropin-releasing factor in depression and anxiety disorders [J]. Endocrinology,1999,160:1-12.
[34]Nibuya M, Takahashi M, Russell DS. Repeated stress increases catalytic TrkB mRNA in rat hippocampus [J]. Neurosci Lett,1999,267:81-84.
[35]Bowman RE, Beck KD, Luine VN. Chronic stress effects on memory:sex differences in performance and monoaminergic activity [J]. Horm Behav,2003,43: 48-59.
[36]Katz RJ. Animal model of depression:Pharmacological sensitivity of a hedonic deficit [J]. Pharmacol Biochem. Behav,1982,16,965-968.
[37]Willner P, Towell A, Sampson D, etal. Reduction of sucrose preference by chronic unpredictable mild stress, and its restoration by a tricycles antidepressant[J]. Psychopharmacology 1987,93(3):358-364.
[38]Matthews K., Forbes N., Reid I.C. Sucrose consumption as an hedonic measure following chronic unpredictable mild stress [J]. Physiol.Behav,1995,57: 241-248.
[39]American Psychiatric Association. DSM-III Diagnostic and statistical manual of psychiatric disorders,1994,4
[40]Mccarthy MM, Felzenber E, Robbins A, et al. Infusion of diazepam and all opregnanolone into the midbrain central gray facilitate open-field behavior and sexual receptivity in female rats [J]. Horm Behavior,1995,29:279-295.
[41]Porsolt RD, Lepichon M, Jalfre M, et al. Dpression:A new animal model sensitive to antidepressant treatment [J]. Nature,1977,226(5604):730-732.
[42]郑婵颖,罗建红,赵卉.AMPA受体的内化及其分子机制[J].细胞生物学杂志,2004,26(3)：216-220.
[44]Koloski NA, Talley NJ, Boyce PM. Epidemiology and health care seeking in the functional GI disorders:apopulation-based study [J]. Am J Gastroenterol,2002, 97(9):2290-2299.
[45]Vyas A, Bernal S, Chattarji S. Effects of chronic stress on dendritic arborization in the central and extended amygdale [J]. Brain Res,2003,965:290-294.
[46]Arborelius L, OwensMJ, Plotsky PM et al. The role of corticotrop-in-releasing factor in dep ression and anxiety disorders [J]. J Endocrinol,1999,160:1-12.
[47]Stanghellini V, Malagelada JR, Zinsmeister AR, Go VLW, Kao PC. Effect of opiate and adrenergic blockers on the gut motor response to the centrally acting stimuli[J]. Gast roenterol,1984,87:1104-1113.
[48]Thompson DG, Richelson E, Malagelada JR. Perturbation of gastric emptying and duodenal motility through the central neurons system. Gast roenterol,1982,83: 1200-1206.
[49]Monnikes H, Schmidt BG, Raybould HE, at el. CRF in the paraventricular nucleus mediates gastric and colonic motor response to restraint stress [J]. A m J Physiol, 1992;262:G137-G143
[50]Kim JJ, Diamond DM. The stressed hippocampus, synap tic plasticity and lostmemories [J]. Nat Rev Neurosei,2002,3:453-462
[51]Monnikes H, Tebbe CJ, Hildebrand TM. Role of stress in gastrointestinal disorders: evidence for stress-induced alterations in gastrointestinal motility and sensitivity [J]. Dig Dis,2001,19(3):201-211.
[52]Sobhani I, Buyse M, Goiot H, et al. Vagal stimulation rapidly increases leptin secretion in human stomach [J]. Gastroenterology,2002,122 (2):259-263.
[53]Chua AS, Keeling PW, Dinan TG. Role of cholecystokinin and central serotonergic receptors in functional dyspepsia[J]. World J Gastroenterol,2006,12(9): 1329-1335.
[54]Watanabe Y, Gould E, McEwen BS. Stress induces atrophy of apical dendrites of hippocampal CA3 pyramidal neurons [J]. Brain Research,1992,588(2):341-345.
[55]Rajkoska G. Postmortem studies in mood disorders indicate altered numbers of neurons and glial cells [J]. Biological Psychiatry,2000,48(8):766-777.
[56]Jarrett ME, Burr RL, Cain KC, et al. Anxiety and depression are related to autonomic nervous systemfunction in women with irritable bowel syndrome [J]. Dig Dis Sci,2003,48:386-394.
[57]acobs BL. Adult brain neurogenesis and depression[J]. Brain Behav Immun,2002, 16:602-609
[58]Jiang WR, Xu SR, Cai YY, at el. Experimental Study on Chronic Stress in Pathogenesis of Chronic Gastritis[J]. Chinese General Practice,2008,11 (9B): 1638-1640.
[59]Neumeister A. Tryptophan depletion, serotonin, and depression:where do we stand? [J].Psychopharmacol Bull,2003,37(4):99-115.
[60]Boyd C, Abraham S, Kellow J. Psychological features are important predictors of functional gastrointestinal disorders in patients with eating disorders [J].Scand J Gastroenterol,2005,40(8):929-935.
[61]Cann PA, Read NW, Cammack J, et al. Psychological stress and the passage of a standard meal through the stomach and small intestine in man[J]. Gut,1983,24(3): 236-240.
[62]Drossman DA. Gastrointestinal illness and the biopaychosocial model [J]. J Clin Gastroenterol.1996,22(4):252-254.
[63]Hang TT. Wilhelmsen I. Ursin H. et al. What are the real problems for patients with functional dyspepsia?[J]. Scand J Gastroenterol,1995,30(2):97-100.
[64]Talley NJ, Howell S, Poulton R. The irritable bowel syndrome and psychiatric disorders in the community:is there a link?[J] Am J Gastroenterol,2001,96: 1072-1079.
[65]Mayer EA, CraskeM, Naliboff BD. Depression, anxiety, and the gastrointestinal system[J]. J Clin Psychiatry,2001,62(Suppl8):28-36.
[66]Kim JJ, Diamond DM. The stressed hippocampus, synap tic plasticity and Iostmemories [J]. Nat Rev Neurosei,2002,3:453-462.
[67]Moghaddam B, BolinaoML, Stein2BehrensB et al. Glucocorticoids mediate the stress-induced extracellular accumulation of glutamate [J].Brain Res,1994,655: 251-254.
[68]Jackson JL, O'Malley PG, Tomkins G, et al. Treatment of functional gastrointestinal disorders with antidepressant medications:a meta-analysis [J]. Am J Med,2000,108 (1):65-72.
[69]Gerson CD, Gerson MJ. A collaborative health care model for the treatment of irritable bowel syndrome[J]. Clin Gastroenterol Hepatol,2003,1(16):446-452.
[70]Yang BH, Zhen YP, Gao ZS, at el. Antidepressants in the treatment of functional dyspepsia [J]. Chin. J. Dig.2001,21 (4):226-228.
[71]Sarles JC, Delecourt P, Devaux MA, et al. In vivo effect of 13 Leu motilin activity of the rabbit sphincter of oddi[J]. Horm Metab Res,1981,13 (6):340-342.
[72]Peeters TL, Janssens J, Vantrappen G. Somatostatin and the interdigestive migrating motor complex in man [J]. Regul Pept,1983,5(3):209-217.
[73]Peeters TL, BormansV, Vantrappen G. Comparison of motilin binding to crude homogenates of human and canine gastrointestinal smooth muscle tissue[J]. Regul Pept,1988,23 (2):171-182.
[74]K. Yayou, Y. Sato. et al Comparison between the central effects of CRH and AVP in steers. [J] Physiology & Behavior 2008 93:537-545
[75]Lu Y, Guan ZM, Wu Q, Hou YL, Zhao RP. Effect of motilin on electric motility of hippocampal neurons in rats[J]. Medical Recap itulate,2009,15(1):135-137.
[76]Nakazato M, Murakami N, Date Y, et al. A role for ghrelin in thecentral regulation of feeding [J]. Nature,2001,409 (6817):194-198.
[77]Pietranera L, Saravia F, Gonzalez Deniselle MC, et al. Abnormalities of the hippocampus are similar in deoxycorticosterone acetate-salt hypertensive rats and spontaneously hypertensive rats[J]. J Neuroendocrinol,2006,18:466-474.
[78]Korf ES, White LR, Scheltens P, et al. Midlife blood p ressure and the risk of hippocampal atrophy:the Honolulu Asia Aging Study [J]. Hypertension,2004,44: 29-34.
[79]Smith DC, Modglin AA, Roosevelt RW, et al. Electrical stimulation of the vagus nerve enhances cognitive and motor recovery following moderate fluid percussion injury in the rat [J]. J Neurotrauma,2005,22:1485-1502]
[80]Sapolsky RM, Krey LC, Mcewen BS. Glucocorticoid-sensitive hippocampal neurons are involved in terminating the adrenocortical stress response [J]. Proc Natl Acad Sci,1984,81:6174-6177.
[81]Forraya MI, Gyslingb K. Role of noradrenergic projections to the bed nucleus of the striaterminalis in the regulation of the hypothalamic-pituitary-adrenal axis [J]. Brain Res Rev,2004,47:145-160.
[82]Herman JP, Ostrander MM, Mueller NK, et al. Limbic system mechanisms of stress regulation:Hypothalamo-pituitary-adrenocortical axis [J]. Prog Neurop sychopharmacol Biol Psychiatry,2005,29:1201-1213.
[83]Furukawa H, Singh SK, Mancusso R, Gouaux E. Subunit arrangement and function in NMDA recep tors[J]. N ature,2005,438(7065):185-192.
[84]Yan J, Wang CA, Ye AL, at el. The effect of stress on behaviors and Glutamate levels of four brain regions[J]. Acta Psychologica Sinica,1995,27:422-426.
[85]Moghaddam B, Bolinao ML, Stein-Behrens B, at el. Glucocorticoids mediate the stress-induced extracellular accumulation of glutamate [J]. Brain Res,1994,655 (1-2):251-254.
[86]Berk M, Plein H, Ferreira D. Platelet glutamate receptor supersensitivity in major depressive disorder [J]. Clin Neuropharmacol,2001,24 (3):129-132.
[87]Law AJ, Deakin JF. Asymmetrical reductions of hippocampal NMDAR1 glutamate receptor mRNA in the psychoses[J]. Neuro-report,2001,12 (13):2971-2974.
[88]Vyas A, Bernal S, Chattarji S. Effects of chronic stress on dendritic arborization in the central and extended amygdale [J]. Brain Res,2003,965:290-294.
[89]Goldsmith DR, Wagstaff A J, Ibbotson T, Perry CM. Lamotrigine:a review of its use in bipolar disorder [J]. D rugs,2003,63(19):2029-2050.
[90]Papp M, Moryl E. Antidepressant activity of non-competitive and competitive NMDA receptor antagonists in a chronic mild stress model of depression[J]. Euro J Pharmacology,1994,263(1-2):1-7.
[91]Dawson TM. Nitric oxide:a brake for bad behavior. Mol. Psychiatry [J].1996,1 (1):9-10.
[92]Svenningsson P, Tzavara ET, Witkin JM, et al. Involvement of striatal and extrastriatal DARPP-32 in biochemical and behavioral effects of fluoxetine (prozac) [J]. Proc Natl Acad Sci USA,2002,99 (5):3182-3187.
[93]Legutko B, Li X, Skolnick P. Regulation of BDNF expression in primary neuron culture by LY392098, a novel AMPA receptor potentiator[J]. N europharm acology,2001,40 (8):1019-1027.
[94]Svensson TH. Brain noradrenaline and the mechanisms of action of antidepressant drugs[J]. Acta Psychiatry Scand Suppl,2000,402(1):18-27.
[95]Paul IA, Skolnick P. Glutamate and depression:clinical and preclinical studies [J]. Ann NY Acad Sci,2003,1003:250-272.
[96]Maeng S, Zarate CA, Du J, at el. Cellular mechanisms underling the antidepressant effects of ketamine:role of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors. Bio Psychiatry 2008,63:349-352.
[97]Cunha GM, Bezerra PJ, Saldanha MD,et al. Pentoxifylline Improves Learning and Memory in Glutamate-Lesioned Rats [J]. Pharmacol Biochem Behav,2000,66(4): 687-694.
[98]Yoshihara T, Ichitani Y. Hippocampal N-methyl-D-aspartate receptor-mediated encoding and retrieval processes in spatial working memory:delay-interposed radial maze performance in rats [J]. Neuroscience,2004,129:1-10.
[99]Hung YW, Chen Z, Hu WW, at el. Facilitating effect of histamine on spatial memory deficits induced by dizocilpine as evaluated by 8-arm radial maze in SD rats [J]. Acta Pharmacol 2003,24(12):1270-1276.
[100]Zarrindast MR, Lashgari R, Rezayof A, at el. NMDA receptors of dorsal hippocampus are involved in the acquisition, but not in the expression of morphine-induced place preference [J]. Eur J Pharmacology 2007,568:192-198.
[101]Raybould HE, Roberts ME, Dockray GI. Reflex decreases in intragastric pressure in response to intragastric pressure in response tocholecystokinin in rats [J]. Am J Physiol Gastrointest Liver Physiol.1987; 253:165-170.
[102]Sapolsky RM. Why stress is bad for your brain [J]. Science 1996,273:749-750.
[103]Hou Q. Psychological stress damage of cerebral hippocampus and depression[J]. Chin J Clin Rehabil,2005,9:174-176.
[104]Berton O, Nestler EJ. New approaches to antidepressant drug discovery:beyond monoamines [J]. Nat Rew Neurosci,2006,7(2):137-151.
[105]Nestler EL, Michel B, Dileone RJ, at el. Neurobiology of depression[J]. Neuron 2002,34(1):13-25.
[106]Fumagalli F, Molteni R, Racagni G, Riva MA. Stress during development:impact on neuroplasticity and relevance to psychopathology [J]. Prog Neurobiol 2007, 81(4):197-217.
[107]Frank P. MacMaster, Yousha Mirza, et al. Amygdala and Hippocampal Volumes in Familial Early Onset Major Depressive Disorder[J]. Biol Psychiatry 2008,63: 385-390.
[108]Margaret C, McKinnon, Kaan Yucel, at el. A meta-analysis examining clinical predictors of hippocampal volume in patients with major depressive disorder [J]. J Psychiatry Neurosci 2009;34(1):41-54.
[109]Skolnick P. Antidepressants for the new millennium[J]. European Journal of Pharmacology,1999,375:31-40.
[110]Brewer LD, Thibault O, Staton J, at el. Increased vulnerability of hippocampal neurons with age in culture:Temporal association with increases in NMD A receptor current, NR2A subunit expression and recruitment of L-type calcium channels [J]. Brain Research,2007,1151:20-31.
[111]Brewer LD, Thibault O, Staton J, at el. Increased vulnerability of hippocampal neurons with age in culture:temporal association with increase in NMDA receptor current, NR2A subunit expression and recruitment of L-type calcium channels [J]. Brain Res 2007,1151:20-31.
[112]Legutko B, Li X, Skolnick P. Regulation of BDNF expression in primary neuron culture by LY392098, a novel AMPA receptor-potentiator [J]. Neuropharmacology 2001,40(8):1019-1027.
[113]Skolnick P, Legutko B, Li X, Bymaster FP. Current perspectives on the development of non-biogenic amine based antidepressants. Pharmacol Res 2001, 43(5):411-423.
[114]Zarate CA Jr, Singh JB, Carlson PJ, at el. A randomized trial of an N-methyl-D-asparate antagonist in treatment resistant major depression[J]. Arch Gen Psychiatry,2006,63(8):856-864.
[115]Petrenko AB, Yamakura T, Baba H, at el. The role of N-methyl-D-aspartate(NMDA) receptors in pain:a review [J]. Anesth Analg, 2003,97(4):1108-1116.
[116]Levy RL, Olden KW, Naliboff BD, at el. Psychosocial aspects of the functional gastrointestinal disorders[J]. Gastroentrology 2006,130(5):1447-1458.
[117]Bennett EJ, Piesse C, Palmer K, at el. Functional gastrointestinal disorders: psychological, social, and somatic features. Gut 1998,42(3):414-420.
[118]Grover M, Drossman DA. Psychotropic agents in functional gastrointestinal disorders[J]. Current Opinion in Pharmacology,2008,8:715-723.