| 摘要: | 許多文獻指出多巴胺 (dopamine)過多會導致多巴胺神經過度活化而產生許多類精神分裂症急性期的臨床症狀如：正性症狀（暴力、焦躁、激動、妄想）；負性症狀（社交行為障礙、認知障礙包括損傷注意力及工作記憶等）。因此本研究以methamphetamine(MA)2mg╱kg誘導精神分裂症。另外因MK- 801(dizocilpine)為NMDA接受體的拮抗劑，也已被證實可以用來誘導與精神分裂症患者的正、負性症狀。故以0.2mg╱kgMK-801 來誘導阻斷麩胺酸鹽，導致麩胺酸鹽傳遞減少，再以臨床上目前最常用的二代抗精神分裂症用藥clozapine作為正對照組。本研究以水迷宮(評估參考及工作記憶)，被動迴避儀(評估認知記憶過程)，運動量測定儀(評估動物運動量)等三個模式來評估延胡索粗抽及dl-THP對多巴胺徑路及麩胺酸鹽徑路對動物行為的影響。實驗結果顯示MA可誘導大鼠因多巴胺的過度活化而導致記憶障礙，經由延胡索粗抽物治療後，3g╱kg劑量均會改善大鼠在水迷宮的空間記憶障礙，在被動迴避儀的測試中，粗抽物在3與4g╱kg亦有改善大鼠對認知過程的記憶障礙。dl-THP(10mg╱kg,15mg╱kg)對於MA誘導的記憶障礙，也有明顯的改善。運動量的數據也顯示粗抽物及dl-THP對運動量有抑制作用，且抑制作用呈劑量依存的關係。在MK-801誘導方面，延胡索粗抽物在4g╱kg及dl-THP10mg╱kg有改善大鼠在水迷宮的空間記憶障礙。被動迴避儀的測試中，延胡索粗抽物在3g╱kg與4g╱kg及dl- THP10mg╱kg亦有改善大鼠對認知過程的記憶障礙。運動量方面，粗抽物3g╱kg及THP10mg╱kg對運動量有抑制作用。在神經化學傳導物質與病理學的相關性中，MA或MK-801給予後會增加前額葉皮質、海馬迴及紋狀體單胺濃度，THP10mg╱kg及延胡索粗抽物3g╱kg與正對照組 clozapine7.5mg╱kg在MK-801及MA誘導後可顯著減少前額葉皮質、海馬迴及紋狀體腦內單胺濃度。綜合以上結果顯示，延胡索粗抽物及 dl-THP對於MA及MK-801誘導的正性症狀及負性症狀均有改善作用，而兩條徑路的治療效果相比較發現，MK-801誘導的障礙需要更高劑量的粗抽物及dl-THP來阻斷。延胡索粗抽物及dl-THP具有抗大鼠精神分裂症作用，其抗精神分裂症機轉主要與降低前額葉皮質、海馬迴及紋狀體腦內單胺濃度有關。
Abstract Many reports show that the dopamine dysfunction leads to produce the schizophrenic-like syndromes in clinical. The most common approach to modelling dopaminergic pathophysiology in schizophrenia has been the acute challenge of a dopamine-releasing (e.g. amphetamine) agent, and examining its effects on motor behaviour, sensorimotor gating or learned associations. NMDA antagonists, such as phencyclidine (PCP) and ketamine, have been demonstrated to evoke a worsening of positive and negative symptoms of schizophrenia and induce schizophrenia-like symptoms in healthy individuals. Animals treated with NMDA antagonists, such as MK-801, exhibit several types of behavior related with a range of symptoms in schizophrenia, e.g., hyperlocomotion, decreased social behavior, impaired performance on cognitive tasks, and deficits in sensorimotor gating. In this study, we try to investigate the effects of Corydalis yuanhusuo (CY) and one of the active ingredients-dltetrahydropalmatine (d1-THP) on the methamphetamine (MA) (2mg╱kg)-and MK-801 (0.2mg╱kg)-induced schizophrenia in rats. The results showed that CY (3 and 4 g) and dl-THP(10 and 15 mg) improved memory dysfunction the same as atypical antipsychotic drugs, clozapine (7.5 and 10 mg╱kg), in each animal models. However, the ameliorating effect of CY and dl-THP on the impaired function by MK-801 needs higher dose than by MA in the model of Morris water maze. The antischizophrenic effect of CY and dl-THP may be via not only dopaminergic but also glutamatergic systems. CY and dl-THP also decreased the levels of monoamines and metabolites in the prefrontal cortex, hippocampus and striatum. Glutamatergic and dopaminergic system are highly inter-related in the prefrontal cortex. NMDA receptors modulate discharge of dopamine neurons of the ventral tegmental area. In the prefrontal cortex, dopamine directly inhibits glutamatergic pyramidal neurons. In addition, blockade of D2 receptors located on axon terminals of glutamatergic efferents to the striatum in glutamatergic release. Therefore, we suggest that CY and dl-THP possessed anti-schizophrenic function because they decreased the levels of monoamines and metabolites in the prefrontal cortex, hippocampus and striatum. |
