發(fā)布時(shí)間：2018-05-21 01:37

  本文選題：氯胺酮 + 抑郁��； 參考：《南京大學(xué)》2013年碩士論文

【摘要】：目的：新近臨床研究及動物實(shí)驗(yàn)均證實(shí)全身麻醉藥氯胺酮具有快速有效的抗抑郁作用,然而,氯胺酮的抗抑郁作用機(jī)制仍不清楚。同時(shí),研究表明氯胺酮可致精神分裂樣表現(xiàn),其作用機(jī)制可能為氯胺酮導(dǎo)致微清蛋白(Parvalbumin, PV)中間神經(jīng)元表達(dá)PV和谷氨酸脫羧酶67(Glutamate decarboxylase67, GAD67)下降,使其對谷氨酸信號傳導(dǎo)去抑制,增強(qiáng)了錐體細(xì)胞興奮性,從而使大腦皮層興奮,產(chǎn)生精神分裂樣表現(xiàn)。鑒于氯胺酮抗抑郁時(shí)谷氨酸信號亦增強(qiáng),我們推測氯胺酮使PV中間神經(jīng)元抑制功能下調(diào)是其抗抑郁的重要機(jī)制。本研究探討PV中間神經(jīng)元在氯胺酮抗抑郁及致精神分裂樣表現(xiàn)中的作用,同時(shí)觀察PV中間神經(jīng)元、谷氨酸(Glutamic acid, Glu)及γ-氨基丁酸(Gamma-aminobutyric acid, GAB A)在氯胺酮抗抑郁作用及致精神分裂樣表現(xiàn)中的不同變化。 方法：采用強(qiáng)迫游泳實(shí)驗(yàn)(Forced swimming test, FST)建立大鼠急性抑郁模型；氯胺酮30mg/kg連續(xù)5天腹腔注射建立精神分裂樣表現(xiàn)模型。結(jié)合工具藥氯胺酮、夾竹桃麻素(Apocynin, Nox2抑制劑,能夠逆轉(zhuǎn)氯胺酮導(dǎo)致的PV和GAD67表達(dá)減少)及GABA進(jìn)行干預(yù)。觀察FST不動時(shí)間、敞箱實(shí)驗(yàn)(Open field test,OFT)自主活動評分、刻板行為評分等大鼠行為學(xué)改變。行為學(xué)測試結(jié)束后,取大鼠前額皮層,采用免疫熒光雙標(biāo)法檢測前額皮層PV和GAD67蛋白的表達(dá),生化方法及ELISA法檢測大鼠前額皮層Glu和GABA含量。 結(jié)果：與生理鹽水相比,氯胺酮10mg/kg給藥后0.5h,大鼠FST不動時(shí)間減少,前額皮層PV及GAD67蛋白表達(dá)的下降,Glu含量增加,GABA含量下降(P0.05)；給藥后2h,不動時(shí)間仍減少(P0.05),但生化改變均恢復(fù)(P0.05)。夾竹桃麻素及GABA預(yù)處理阻斷了氯胺酮的抗抑郁作用(P0.05),這兩種藥物單獨(dú)應(yīng)用并未影響不動時(shí)間。精神分裂樣表現(xiàn)模型中最后一次氯胺酮30mg/kg給藥后0.5h,大鼠自主活動增強(qiáng),刻板行為評分增高,PV及GAD67蛋白表達(dá)下降,大鼠前額皮層Glu含量增加,GABA含量下降(P0.05)；給藥后2h,行為學(xué)差異無統(tǒng)計(jì)學(xué)意義(P0.05),而生化指標(biāo)改變?nèi)晕椿謴?fù)(P0.05)。最后一次氯胺酮30mg/kg給藥后0.5h,大鼠前額皮層Glu含量高于10mg/kg單次給藥(P0.05),而GABA含量、PV及GAD67蛋白表達(dá)無統(tǒng)計(jì)學(xué)意義(P0.05)；給藥后2h, Glu含量高于、GABA含量低于、PV及GAD67蛋白表達(dá)低于10mg/kg單次給藥(P0.05)。 結(jié)論：PV中間神經(jīng)元功能下調(diào)在氯胺酮抗抑郁及致精神分裂中均發(fā)揮重要作用,這可能與其介導(dǎo)的Glu信號系統(tǒng)去抑制有關(guān)。在氯胺酮抗抑郁及致精神分裂樣表現(xiàn)中,PV中間神經(jīng)元功能下調(diào)與Glu信號系統(tǒng)去抑制的程度及持續(xù)時(shí)間不同。
[Abstract]:Objective: recent clinical studies and animal experiments have confirmed that ketamine has a rapid and effective antidepressant effect. However, the antidepressant mechanism of ketamine is still unclear. At the same time, it has been shown that ketamine can induce schizophrenia, and its mechanism may be that ketamine induces the decrease of PV expression and glutamate decarboxylase 67(Glutamate decarboxylase67 (GAD67) in the interneuron of microalbumin Parvalbumin (PVV), which can inhibit the transduction of glutamate signal. It enhances the excitability of pyramidal cells, which excites the cerebral cortex and produces schizophrenic manifestations. In view of the increase of glutamate signal during ketamine antidepressant, we speculate that ketamine down-regulates the inhibitory function of PV intermediate neurons, which is an important antidepressant mechanism of ketamine. The purpose of this study was to investigate the role of PV intermediate neurons in ketamine antidepressant and schizophrenic manifestations, and to observe the role of PV intermediate neurons in antidepressant and schizophrenic manifestations. Different changes of Glutamic acid (Gluid) and Gamma-aminobutyric acid, GAB A) in antidepressant and schizophrenic manifestations of ketamine. Methods: a rat model of acute depression was established by forced swimming test, FST) and ketamine 30mg/kg was injected intraperitoneally for 5 days to establish a schizophreniform model. Combined with Ketamine, Apocyninine, Nox2 inhibitor, can reverse the decreased expression of PV and GAD67 induced by ketamine) and GABA intervention. FST immobility time, open field test score, stereotypical behavior score and other behavioral changes in rats were observed. The expression of PV and GAD67 protein in prefrontal cortex was detected by immunofluorescence double labeling method, and the contents of Glu and GABA in prefrontal cortex were detected by biochemical method and ELISA method. Results: compared with normal saline, the immobility time of FST decreased and the expression of PV and GAD67 protein decreased in prefrontal cortex of rats at 0.5 h after administration of ketamine 10mg/kg. The antidepressant effect of ketamine was blocked by the pretreatment of diosgenin and GABA. The two drugs alone did not affect the immobility time. At 0.5 h after administration of ketamine 30mg/kg in the schizophreniform model, the autonomic activity increased and the stereotypical behavior score increased and the expression of PV and GAD67 decreased. The content of Glu in prefrontal cortex of rats was increased and the content of Glu was decreased (P0.05A), but there was no significant difference in behavior at 2 h after administration, but the change of biochemical indexes was still not recovered (P0.05). At 0.5 h after administration of ketamine 30mg/kg, the content of Glu in prefrontal cortex of rats was higher than that in single dose of 10mg/kg (P0.05), while the expression of GABA in PV and GAD67 was not statistically significant, and at 2 h after administration, the content of Glu was higher than that of GABA-GABA and the expression of GAD67 protein was lower than that of single dose of 10mg/kg. Conclusion the down-regulation of the function of the intermediate neurons in the PV may play an important role in the antidepressant and schizophrenia induced by ketamine, which may be related to the inhibition of the Glu signaling system mediated by Ketamine. In ketamine antidepressant and schizophrenic manifestations, the down-regulation of the function of PV intermediate neurons is different from the degree and duration of deinhibition of Glu signal system.
【學(xué)位授予單位】：南京大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2013
【分類號】：R749

【參考文獻(xiàn)】

相關(guān)期刊論文 前2條

1 周志強(qiáng);楊春;楊建軍;徐建國;;氯胺酮抗抑郁的研究進(jìn)展[J];臨床麻醉學(xué)雜志;2011年03期

2 焦彬;徐亞輝;劉鐵橋;;氯胺酮的抗抑郁作用及其機(jī)制[J];中國藥物依賴性雜志;2011年04期

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本文編號：1917180