N-甲基甘膠酸在大鼠強迫游泳測驗中的類抗憂鬱效果是否有劑量相關與持續性---從行為面向到細胞層次

中國醫藥大學機構典藏 China Medical University Repository, Taiwan > 台中附設醫院 > 研究計畫 > Item 310903500/25452

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题名:	N-甲基甘膠酸在大鼠強迫游泳測驗中的類抗憂鬱效果是否有劑量相關與持續性---從行為面向到細胞層次 The Dose-Dependent and Sustained Antidepressant-Like Effects of Sarcosine in the Forced Swim Test in Rats---From Behaviors to Cellular Level
作者:	黃智佳;藍先元
贡献者:	中國醫藥大學附設醫院精神科
关键词:	N-甲基甘膠酸;N-甲基天門冬胺酸鹽受器;AMPA 受器;動物模式;強迫游泳試驗;憂鬱症;sarcosine;NMDA receptor;AMPA receptor;animal model;forced swim test;depression
日期:	2009-07
上传时间:	2010-09-02 17:48:13 (UTC+8)
摘要:	憂鬱症是種常見的精神疾病，其終身盛行率高達50%。目前雖然憂鬱症狀可以使用藥物而獲得改善，但其中有高達60%的患者並無法完全痊癒或有明顯的服藥副作用。現在對於憂鬱症的疾病機轉主要有單胺類異常的假設，而目前治療憂鬱症的抗憂鬱劑亦是依據此假設而來的。最近對於憂鬱症的病理成因開始有人提出N-methyl-D-asparate (NMDA) receptor 異常的假設，而這新的假設或理論或許可對不滿意目前的抗憂鬱劑病患帶來新的希望。我們之前亦發現給予N-甲基甘膠酸(sarcosine - glycine transporter-1 inhibitor)同樣也可改善強制游泳測試所造成的憂鬱行為，此類致效劑確實也同樣具有類似抗憂鬱的效果。至今目前研究仍未闡明及釐清sarcosine 的類抗憂鬱作用是否有劑量相關與持續性。此外，對於相關腦區各部位中的形態學研究及蛋白質與分子層次的探討則所知有限。因此，本研究計畫利用單純憂鬱症動物模式-強制游泳測試造成憂鬱行為後，進一步施予不同劑量的阻斷glycine transporter-1 之藥物sarcosine 結合憂鬱症動物模式- 強制游泳測試之實驗模式，之後再給予NMDA 與AMPA receptors 的拮抗劑，再利用組織化學、免疫細胞化學、西方免疫墨點法及RT-PCR 等方法，預計分三年的實驗期，分別觀察與憂鬱症腦區密切相關的海馬迴及前額葉內，於不同存活時程下，神經細胞免疫表型與相關化學分子之活性表現。本實驗所得之成果無疑的將增進吾人對憂鬱症病理變化衍生過程中所參與及扮演功能角色之瞭解，進一步亦將對研究NMDA receptor 拮抗劑及致效劑與憂鬱症病理機轉等相關議題上，提供一更完整且詳實的參考資料。也冀望有關NMDA receptor 拮抗劑及致效劑與憂鬱症病理機轉之相關形態學及分子生物學研究能提供未來學術及臨床上使用精神科藥物研究之參考，進而有助於神經生物學上對憂鬱症病理機轉相關衍生過程有更深一層的認識，同時希望有助於研發新一代的憂鬱症的治療方法。 Major depression is a common disorder, with a life time prevalence of about 15 %, perhaps as high as 50 % when bipolar and chronic minor depression were included. While most depressive symptoms are eliminated by the current pharmacological treatments, as many as 50-60% of patients have incomplete recovery or significant side effects. Current antidepressant pharmacological treatments are hypothesized act through monoamine receptor hypothesis. However, in addition to monoamine receptor hypothesis, another hypothesis for the pathophysiology of depression implicated to the N-methyl-D-aspartate(NMDA) receptor which may providing additional benefits for resistant to the current antidepressant. In our preliminary study, we found sarcosine (glycine transporter-1 inhibitor) 560 mg/kg exerts antidepressant-like effect in rats. Nevertheless, until now, no studies focus on the dose-dependent and sustained effect of sarcosine. Additionally, the implication morphological, and molecular level of brain regions related with mood modulation and such neo-antidepressant have not yet been well explored. In order to elucidate and test the action of NMDA receptor on the pathogenesis of depression, we conducted this study to investigate the impact sarcosine after administrating different dosage in the Porsolt swim test, a behavioral model of depression. Additional biochemical and behavioral experiments were undertaken to determine whether the antidepressant-like properties of sarcosine involve α-amino-3- hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor throughput. Finally, we hope our finding can improve the efficacy of anti-depression treatment.
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