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系統識別號 U0026-3007201914582300
論文名稱(中文) 探討杏仁核中蛋白磷酸酶和蛋白激酶在甲基安非他命相關記憶去穩定性過程的角色
論文名稱(英文) The roles of protein phosphatase and protein kinase in the destabilization of methamphetamine-related memory in amygdala
校院名稱 成功大學
系所名稱(中) 藥理學研究所
系所名稱(英) Department of Pharmacology
學年度 107
學期 2
出版年 108
研究生(中文) 黃柏融
研究生(英文) Po-Jung Huang
電子信箱 frank960631@gmail.com
學號 s26064060
學位類別 碩士
語文別 英文
論文頁數 46頁
口試委員 指導教授-簡伯武
口試委員-陳柏熹
口試委員-蕭雅心
中文關鍵字 甲基苯丙胺  再固化  杏仁核  紋狀體富集蛋白酪氨酸磷酸酶  去穩定化 
英文關鍵字 Methamphetamine  Reconsolidation  Amygdala  Striatal-enriched protein tyrosine phosphatase  destabilization 
學科別分類
中文摘要 藥物成癮是一種強迫性的尋求藥物的行為,其特徵是慢性複發性疾病。重複的甲基安非他命給藥可以在甲基安非他命配對環境線索和甲基安非他命的獎賞效應之間產生強烈的聯想記憶。記憶的再固化過程涉及環境線索引起的去穩定化和再穩定化過程,以便更新為新的記憶。重新激活的記憶去穩定化後,會透過基因表達依賴的再固化程來重新穩定。場地制約偏好模式是藥物成癮的標準臨床前行為模型。場地制約偏好模式是將與特定環境配對成癮藥物跟不同且缺乏獎勵藥物的環境配對並誘導正增強效應。以前的研究表明記憶去穩定化過程的機制是含有NR2B次單的N-甲基-D-天冬氨酸受體活化導致鈣離子內流,激活鈣調神經磷酸酶和蛋白脫磷酸化酵素1,導致麩氨酸受體次單位GluR1-Ser845(p-GluR1-Ser845)的去磷酸化並且產生麩氨酸受體內吞作用所導致的。早期研究表明,N-甲基-D-天冬氨酸受體的刺激通過鈣調神經磷酸酶 蛋白脫磷酸化酵素1途徑促進紋狀體富集蛋白酪氨酸磷酸酶的去磷酸化和活化。 紋狀體富集蛋白酪氨酸磷酸酶的活化誘導含有NR2B次單的N-甲基-D-天冬氨酸受體和含有GluR2次單的麩氨酸受體內吞作用。然而,這些現象仍需要在甲基安非他命相關記憶的去穩定化過程進行研究。此外,我們已經證明在基底外側杏仁核中甲基安非他命誘導的場地制約偏好記憶恢復刺激鈣調神經磷酸酶活性,導致紋狀體富集蛋白酪氨酸磷酸酶的去磷酸化和活化。此外,我們已經證明甲基安非他命誘導的場地制約偏好的記憶恢復會刺激鈣調神經磷酸酶活性,導致紋狀體富集蛋白酪氨酸磷酸酶的去磷酸化和活化。我們的假設是記憶提取後會誘導紋狀體富集蛋白酪氨酸磷酸酶的激活,導致麩氨酸受體次單位GluR1-Ser845(p-GluR1-Ser845)的去磷酸化,隨後造成突觸麩氨酸受體的內吞作用,最終形成藥物記憶的去穩定化過程。在甲基安非他命相關的記憶提取測試之後處理茴香黴素會破壞記憶再固定過程,然後破壞了藥物相關的記憶。我們發現茴香黴素誘導的甲基安非他命相關記憶破壞會被紋狀體富集蛋白酪氨酸磷酸酶的抑製劑(TC-2153)所阻斷,並且具有劑量梯度的趨勢。為了確定作用腦區,我們在基底外側杏仁核中微量注射紋狀體富集蛋白酪氨酸磷酸酶的抑製劑也會阻斷了茴香黴素所誘導的甲基安非他命相關記憶破壞。此外,我們還發現紋狀體富集蛋白酪氨酸磷酸酶的抑製劑會逆轉茴香黴素誘導的麩氨酸受體次單位GluR1-Ser845的去磷酸化和樹突棘的數量降低。這些現象表明,紋狀體富集蛋白酪氨酸磷酸酶活化後使麩氨酸受體次單位GluR1-Ser845去磷酸化,從而引發麩氨酸受體的內吞作用和麩氨酸受體記憶的去穩定化過程。
英文摘要 Drug addiction is a compulsive drug-seeking behavior characterized by chronically relapsing disorders. Repeated methamphetamine (MeAM) administration can develop an intense associative memory between MeAM-paired cues and the rewarding effects of MeAM. Reconsolidation of memory involves retrieval-induced destabilization and restabilization processes in order to update as new memory. Reactivated memory is destabilized and then restabilized through gene expression-dependent reconsolidation. Retrieval-induced destabilization renders memories susceptible to disruption. The conditioned place preference (CPP) paradigm is a standard preclinical behavioral model of drug addiction which involves addiction and addiction-related memory. The CPP procedure is paired a particular environment with addiction drugs, followed by pairing different environments with the absence of the reward drug and induces positive reinforcing effects. Previous studies revealed that NR2B-containing NMDAR activation leading to Ca2+ influx that activated calcineurin (CaN) and protein phosphatase 1 (PP1), resulting in dephosphorylation of p-GluR1-Ser845 and subsequently AMPA receptors (AMPARs) endocytosis involves the mechanism of memory destabilization. Previous study showed that stimulation of glutamate NMDAR promotes dephosphorylation and activation of striatal-enriched protein tyrosine phosphatase (STEP) via a calcineurin/PP1 pathway. Activation of STEP induced endocytosis of NR2B containing-NMDARs and GluR2 containing-AMPARs. However, these phenomena still need to be investigated in destabilization of MeAM-related memory. Moreover, We have showed that MeAM-induce CPP memory retrieval stimulates calcineurin activity resulting in the dephosphorylation and activation of STEP. Our hypothesis is that MeAM memory retrieval induces STEP activated, leading to p-GluR1-Ser845 dephosphorylated, subsequently synaptic AMPARs endocytosis, and then the destabilization of drug memory in the basolateral amygdala (BLA). Anisomycin (ANI) treatment after the MeAM-associated memory retrieval test disrupted reconsolidation and then disrupted drug-associated memory. We found ANI induced MeAM-related CPP memory loss was blocked by STEP inhibitor TC-2153 in a dose-dependent manner. To determine the site of action, ANI-mediated disruption of MeAM memory was also blocked by microinjecting STEP inhibitor TC-2153 in the BLA. Furthermore, we also found that STEP inhibitor reverses ANI-induced decrease phosphorylation of GluR1-Ser845 and the number of dendritic spines. These phenomena indicated that activation of STEP dephosphorylate p-GluR1-Ser845 to elict APMPARs endocytosis and destabilization of MeAM-related memory.
論文目次 中文摘要Abstract in Chinese....I
英文摘要Abstract in English...IV
誌謝...VII
Content...IX
圖表檢索List of Figures...X
縮寫檢索表Abbreviations...XII
Introduction...1
The Aims of the Research...9
Materials and Methods...12
Results...18
Discussion...23
References...26
Figures and Legend...38
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