臺灣博碩士論文加值系統

許多藥物成癮研究中，發現心理依賴較生理依賴難以治療，其中原因在於心理依賴牽涉古典制約學習，無法以生理依賴治療方式戒除，只能採用成癮藥物之拮抗劑來降低求藥行為，近期研究顯示古典制約中消弱大腦機制研究，可能為心理依賴治療帶來新的契機。因此，本研究將利用古典制約學習中消弱動物模型，試圖研究消弱之現象及大腦神經機制，研究目的如下：1.以地區性制約偏好學習典範，建立成癮藥物之制約及消弱動物行為模型。2.以c-Fos與p-ERK免疫組織染色的方法，來量測制約期與消弱期的大腦神經機制，包括前額葉皮質區包括，前邊緣皮質區(prelimbic cortex, PrL)及下邊緣皮質區(infralimbic cortex, IL)、中間段杏仁核(central amygdala, CeA)、島葉皮質區(insular cortex, IC)、邊緣皮質區(perhirihal cortex, PR)。3. 以p-ERK免疫組織染色的方法，來量測制約期與消弱期的大腦神經機制，包括IL、PrL、CeA、IC以及PR。
研究結果於動物行為模型方面透過腹腔施打1.5mg/ml劑量甲基安非他命(methamphetamine, MAMPH)，確實可產生地區性制約偏好學習效果，也能產生消弱之現象。此外，腦內蛋白質與核區方面，結果顯示，在制約期，IL、PrL、CeA、PR等核區，對於施打甲基安非他命組，都顯著增加c-FOS與p-ERK的表現量，但是IC核區這兩種蛋白質均無顯著差異。在消弱期，c-Fos蛋白在IL、PrL、CeA、IC及PR五個核區的表現量，施打甲基安非他命組都有顯著增加效果。但是，甲基安非他命組，p-ERK蛋白質在IL、PrL、CeA及PR四個核區有顯著增加表現量，但是IC無顯差異。這些核區分別參與制約期與消弱期的結果，可能助於瞭解成癮藥物制約與消弱階段在特定腦內核區蛋白質調控的機制，並且根據此結果可能發展相關治療法，使藥物成癮的回流現象降低。

The important symptoms of methamphetamine addiction include psychological dependence and physical dependence. However, psychological dependence is harder for treatments compared to those of physical dependence. The psychological dependence involves the classical conditioning. The intoxification approach cannot reduce psychological dependence although the treatment is a better way that it can antagonize the toxic effect of the plasma for drug abusers. Recently, a growing body of data has shown that the neural mechanism research regarding extinction might provide some insights for a novel treatment to drug addiction, particularly in psychological dependence. Therefore, the purposes of the present study were firstly to develop extinction on the conditioned place preference (CPP) learning in rats. Second, the study further investigated the neural substrates of CPP extinction including the insular cortex (IC), perhirihal cortex (PR), central amygdala (CeA), prelimbic cortex (PrL), and infralimbic cortex (IL) in the animal model by a way of immunohistochemical staining with c-Fos and p-ERK proteins. The results indicated that (a). CPP conditioning and extinction have been established in animal model. (b). On conditioning phase, the c-Fos and p-ERK overexpressions occurred at IL, PrL, CeA, and PR; however, the c-Fos of the IC was not active. (c). On extinction, the c-Fos overexpressions occurred at IL, PrL, CeA, IC, and PR. The p-ERK was active in IL, PrL, CeA, and PR, but the p-ERK was not active in IC on extinction. The present findings may offer some implications for the clinic treatment of drug addiction and reduce the drug relapse.

目錄
摘要 ............................................................................................................................... I
Abstract ........................................................................................................................ II
誌謝 ............................................................................................................................ III
簡寫對照表 ................................................................................................................ IV
目錄 .............................................................................................................................. V
圖目錄 ....................................................................................................................... VII
表目錄............................................................................................................. . VIII
第壹章 緒論 ....................................................................................................... 1
第一節 研究背景.................................................................................................. 1
第二節 研究動機.................................................................................................. 2
第貳章 文獻探討 ............................................................................................... 3
第一節 古典制約學習.......................................................................................... 3
第二節 消弱.......................................................................................................... 4
第三節 地區性制約偏好學習.............................................................................. 6
第四節 多巴胺系統.............................................................................................. 7
第五節 消弱的大腦神經機制.............................................................................. 8
第六節 制約學習典範與消弱.............................................................................. 9
第七節 c-Fos與p-ERK蛋白質腦內神經機轉與制約學習典範 .................... 14
第八節 研究目的................................................................................................ 16
第參章 研究方法 ............................................................................................. 17
第一節 研究架構與假設.................................................................................... 17
第二節 實驗動物................................................................................................ 18
第三節 實驗藥品................................................................................................ 19
第四節 研究工具................................................................................................ 20
第五節 實驗設計................................................................................................ 23
第六節 統計方法................................................................................................ 26
第肆章 實驗結果 ............................................................................................. 27
第伍章 討論 ..................................................................................................... 32
第陸章 實驗建議與侷限 ................................................................................. 36

圖目錄
圖1 研究架構圖 ........................................................................................................ 51
圖2 地區性制約偏好學習箱 .................................................................................... 52
圖3 實驗1流程圖 .................................................................................................... 53
圖4 實驗2流程圖 .................................................................................................... 54
圖5 實驗3流程圖 .................................................................................................... 55
圖6 目標腦組織核區選定位置 ................................................................................ 56
圖7 實驗1行為數據分析結果 ................................................................................ 57
圖8 實驗2-1行為數據分析結果(conditioning phase) .......................................... 58
圖9 實驗2-1 IHC數據分析結果(conditioning phase) .......................................... 59
圖10 實驗2-1 c-Fos IHC Staining效果(conditioning phase) ............................... 60
圖11 實驗2-2行為數據分析結果(extinction phase) ............................................. 61
圖12 實驗2-2 IHC數據分析結果(extinction phase) ............................................ 62
圖13 實驗2-2 c-Fos IHC Staining效果(extinction phase).................................... 63
圖14 實驗3-1行為數據分析結果(conditioning phase) ........................................ 64
圖15 實驗3-1 IHC數據分析結果(conditioning phase) ........................................ 65
圖16 實驗3-1 p-ERK IHC Staining效果(conditioning phase)............................ 66
圖17 實驗3-2行為數據分析結果(extinction phase) ............................................. 67
圖18 實驗3-2 IHC數據分析結果(extinction phase) ............................................ 68
圖19 實驗3-2 p-ERK IHC Staining效果(extinction phase)................................. 69

表目錄
表1 制約學習典範與消弱學習之研究 .................................................................... 70
表2 腦內核區c-Fos參與調控之階段 ..................................................................... 71
表3 腦內核區p-ERK參與調控之階段 .................................................................. 72

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