本文關(guān)鍵詞： 抑郁 海馬 NMDA受體 谷氨酸代謝型受體 喹啉酸 谷氨酸　出處：《陜西師范大學(xué)》2013年碩士論文　論文類型：學(xué)位論文

【摘要】：抑郁(depression)是一種伴隨著高致殘率、高死亡率,并且具有周期長、易反復(fù)等特點的疾病。隨著社會壓力增加,抑郁癥患者數(shù)量日趨增長,該病給個人和社會帶來的負擔(dān)也隨之加重。因此,盡快研究清楚抑郁發(fā)病機制就顯得尤為重要。已有的研究證明,5-羥色胺(5-hydroxytryptamine,5-HT)在抑郁的發(fā)生中扮演著重要角色,臨床對于抑郁癥的治療也是基于改善5-HT水平而進行,但5-HT失調(diào)并不能完全解釋抑郁癥的全部表現(xiàn)。研究發(fā)現(xiàn)應(yīng)激使得海馬谷氨酸(glutamic acid,Glu)釋放量增加,其N-甲基-D-天冬氨酸(N-methyl-D-aspartic acid,NMDA)受體過度激活可能是抑郁發(fā)生原因之一,該受體拮抗劑具有顯著的抗抑郁作用。此外,在應(yīng)激性抑郁中代謝型谷氨酸受體mGluRl含量也增多,其拮抗劑AIDA同樣能顯著削弱由應(yīng)激引起的抑郁樣行為。喹啉酸(quinolinic acid, QUIN)是色氨酸代謝產(chǎn)物之一,在中樞神經(jīng)系統(tǒng)中僅由小膠質(zhì)細胞產(chǎn)生,它是NMDA受體的激動劑,與多種神經(jīng)類疾病及神經(jīng)退行性疾病都可能相關(guān)。有研究報道,抑郁癥病人尿中促進QUIN產(chǎn)生的色氨酸代謝產(chǎn)物3-羥基犬尿氨酸(3-hydroxykynurenine,3HK)含量明顯升高。由此推斷,色氨酸代謝失調(diào)導(dǎo)致5-HT的下降和QUIN的升高很可能均與抑郁發(fā)生相關(guān)。在色氨酸代謝異常時,5-HT就會減少,而QUIN增加,QUIN不但可以過度激活NMDA受體和代謝型谷氨酸受體引起神經(jīng)損傷,還能抑制膠質(zhì)細胞對谷氨酸的重吸收及谷氨酰胺合成酶的表達,加劇中樞神經(jīng)系統(tǒng)興奮性毒的作用。然而,有關(guān)抑郁發(fā)生機制及治療策略研究多集中于5-HT的變化,而對于QUIN在應(yīng)激性抑郁發(fā)生中的作用及作用機制并不完全清楚。 海馬因其自身特點被廣泛作為研究抑郁癥的主要區(qū)域,但海馬QUIN是否有參與應(yīng)激性抑郁,它與Glu及其受體之間的關(guān)系并不清楚。為了探討慢性應(yīng)激性抑郁樣行為發(fā)生過程中海馬膠質(zhì)細胞釋放的QUIN的作用,以及它與Glu及其受體的關(guān)系,本研究通過建立慢性不可預(yù)見性溫和應(yīng)激(chronic unpredictable mild stress,CUMS)性抑郁模型,海馬單側(cè)微量注射QUIN,QUIN抑制劑Ro61-8048,NMDA受體拮抗劑MK-801和mGluRl拮抗劑AIDA,檢測大鼠體重變化率,并通過糖水偏愛測試、曠場實驗和懸尾實驗等進行行為學(xué)表現(xiàn)測驗,采用高效液相色譜法(high-performance liquid chromatography,HPLC)和酶聯(lián)免疫吸附(enzyme linked immunosorbent assay,ELISA)法分別檢測海馬內(nèi)Glu水平及其QUIN含量,運用Western blot方法檢測NMDA受體和mGluRl的變化。研究結(jié)果如下： 1、CUMS誘發(fā)大鼠表現(xiàn)出明顯的抑郁樣行為,且海馬Glu和QUIN含量、NMDA受體的NR2B亞基和mGluR1受體表達水平顯著升高。 2、正常大鼠海馬微量注射QUIN也表現(xiàn)出明顯抑郁樣行為,且Glu含量明顯升高,NMDA受體的NR2B亞基和mGluRl表達水平顯著升高。 3、CUMS誘發(fā)的抑郁樣行為可被QUIN抑制劑Ro61-8048顯著改善,且海馬中Glu含量也顯著降低,同時NMDA受體的NR2B亞基和mGluRl表達水平與CUMS(?)相比也明顯降低。 4、CUMS引起的抑郁樣行為可被海馬注射NMDA受體拮抗劑MK-801和mGluRl拮抗劑AIDA顯著改善,且其海馬中Glu含量也明顯降低,同時MK-801和AIDA對海馬注射QUIN所引起的抑郁樣行為也起到改善作用,并能降低由QUIN引起的Glu含量的升高。 以上結(jié)果表明,CUMS引起海馬小膠質(zhì)細胞產(chǎn)生和釋放QUIN增加,QUIN既可提高NR2B和mGluRl表達,也可以通過NMDA受體和代謝型谷氨酸受體途徑使Glu含量增多,產(chǎn)生興奮性神經(jīng)毒,導(dǎo)致抑郁樣行為發(fā)生。
[Abstract]:Depression (depression) is accompanied by a high morbidity, high mortality, and has a long cycle, easy to repeated and other characteristics of the disease. With the increasing social pressure, the growing number of patients with depression, the disease brought to the personal and social burden will be heavier. Therefore, it is particularly important to study the pathogenesis of depression is clear as soon as possible. Previous studies have demonstrated that serotonin 5- (5-hydroxytryptamine, 5-HT) plays an important role in the occurrence of depression in clinical treatment for depression, but also improve the level of 5-HT and 5-HT based, but can not fully explain the disorder of depression. The study found that all stress glutamate (glutamic acid, Glu) increased release of. The N- methyl -D- aspartate (N-methyl-D-aspartic acid, NMDA) receptor activation might be one of the reasons for depression, the receptor antagonists have remarkable antidepressant effect Use. In addition, in stress-induced depression of metabotropic glutamate receptor mGluRl content also increased, the antagonist AIDA can significantly weaken the depression like behavior caused by stress. Quinolinic acid (quinolinic acid QUIN) is one of the tryptophan metabolites in the central nervous system is only produced by microglia, it is NMDA receptor agonist, with a variety of neurological diseases and neurodegenerative diseases are likely related. Studies have reported that patients with depression and promote urinary tryptophan metabolites of 3- hydroxy kynurenic acid produced by QUIN (3-hydroxykynurenine, 3HK) was significantly increased. Thus, tryptophan metabolism disorder lead to elevated 5-HT drop and QUIN is likely to happen. And depression in abnormal tryptophan metabolism, 5-HT will be reduced, and the increase of QUIN, QUIN can not only excessive activation of NMDA receptors and metabotropic glutamate receptors induced by nerve injury, also The expression can inhibit the reabsorption of glutamine synthetase and glutamate on glial cells, increased central nervous system excitability toxicity. However, changes related to depression of mechanism and treatment strategy focused on 5-HT, and for QUIN in stress-induced depression in the role and the mechanism is not entirely clear.
The hippocampus is widely due to its own characteristics as the main research area of depression, but whether QUIN is involved in stress in hippocampus of depression and its relationship with Glu and its receptor is not clear. In order to investigate the release of hippocampal glial cells of chronic stress-induced depression like behavior during the process of the role of QUIN and its relationship with Glu and its receptor. In this study, through the establishment of chronic unpredictable mild stress (chronic unpredictable mild stress, CUMS) of hippocampus of depression model, unilateral microinjection of QUIN inhibitor, QUIN Ro61-8048, NMDA receptor antagonist MK-801 and mGluRl antagonist AIDA, weight change detection rate in rats, and the sucrose preference test, open field test and tail suspension test such behavior tests, using high performance liquid chromatography (HPLC high-performance liquid chromatography) and enzyme-linked immunosorbent assay (enzyme linked immunosorbent assay The level of Glu in the hippocampus and the content of QUIN were detected by ELISA). The changes of NMDA receptor and mGluRl were detected by Western blot. The results were as follows:
1, CUMS induced depressive behavior in rats, and the content of Glu and QUIN in the hippocampus, and the level of NR2B subunit and mGluR1 receptor expression of NMDA receptor significantly increased.
2, the microinjection of QUIN in the hippocampus of normal rats also showed significant depressive behavior, and the Glu content increased significantly, and the NR2B subunit and mGluRl expression level of NMDA receptor increased significantly.
3, CUMS induced depressive behavior can be significantly improved by QUIN inhibitor Ro61-8048, and the content of Glu in hippocampus is also significantly reduced. Meanwhile, the expression of NR2B subunit and mGluRl of NMDA receptor is also significantly lower than that of CUMS.
4, depression like behavior induced by CUMS can be injected into the hippocampus of NMDA receptor antagonist MK-801 and mGluRl antagonist AIDA significantly improved, and the content of Glu in the hippocampus were significantly decreased, while MK-801 and AIDA depression like behavior caused by QUIN injection into the hippocampus also play a role in improving, and can reduce the increase of Glu content caused by QUIN the.
The above results indicate that CUMS increases the production and release of QUIN from hippocampal microglia. QUIN can not only increase the expression of NR2B and mGluRl, but also increase Glu content through NMDA receptor and metabotropic glutamate receptor pathway, resulting in excitatory neurotoxicity, leading to depressive like behavior.

【學(xué)位授予單位】：陜西師范大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2013
【分類號】：R749.4

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本文編號：1493129