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研究生：	王雅慧 Wang, Ya-Hui,
論文名稱：	連續給予甲基安非他命對於K他命誘發場地制約偏好之影響 The Impact of Repeated Methamphetamine Administrations on Subsequent Ketamine-induced Conditioned Place Preference
指導教授：	游一龍 Yu, Lung
共同指導教授:	蕭雅心 Hsiao, Ya-Hsin
學位類別：	碩士 Master
系所名稱：	醫學院 - 行為醫學研究所 Institute of Behavioral Medicine
論文出版年：	2018
畢業學年度：	106
語文別：	英文
論文頁數：	32
中文關鍵詞：	K他命、甲基安非他命、多巴胺、代謝型麩胺酸受體
外文關鍵詞：	Ketamine, methamphetamine, superfusion, dopamine, mGluR5
相關次數：	點閱：130 下載：0
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藥物濫用者大多為多重藥物濫用。在台灣及東亞根據廢水、人體代謝物及緝私查獲數量的跡證顯示，甲基安非他命(Methamphetamine)和K他命(Ketamine)是目前最為普遍使用的濫用藥物，本研究目的為探討重複給予低劑量之甲基安非他命(Methamphetamine)及K他命(Ketamine)，可能會導致神經可塑性和用藥動機行為的改變。已有許多研究證據顯示甲基安非他命(Methamphetamine) (1 mg/kg)和K他命(Ketamine) (10 mg/kg)的互動效果，因此，我們推測連續給予低劑量之甲基安非他命(Methamphetamine)，會影響隨後給予的低劑量K他命(Ketamine)誘發場地制約偏好(Conditioned Place Preference)、社交行為及其神經化學基礎。首先，我發現連續改給予甲基安非他命(Methamphetamine)十天，並且等待十天戒斷後，會增強K他命(Ketamine)誘發場地制約偏好。連續改給予甲基安非他命(Methamphetamine)十天，並且等待十天戒斷後之小鼠與連續給予生理食鹽水十天，同樣也等待十天之對照組相比，連續給予甲基安非他命(Methamphetamine)並且經歷戒斷期的小鼠，在給予K他命(Ketamine)之後，表現出更低的多巴胺含量，因此推測其伏隔核組織因受K他命(Ketamine)刺激，而使多巴胺釋放量更多。連續給予甲基安非他命(Methamphetamine)並且經歷戒斷期之小鼠在社交行為的測試中沒有呈現社會互動。在海馬迴組織中，發現連續給予甲基安非他命(Methamphetamine)並且經歷戒斷期之小鼠與對照組相比，幾種相關蛋白質表現中(mGluR5, Homer2,EAAT3)，呈現出較高的mGluR5表現。MPEP(2-Methyl-6-phenylethynylpyridine)是mGluR5的拮抗劑，可阻斷甲基安非他命(Methamphetamine)戒斷後K他命(Ketamine)增強場地制約偏好(Conditioned Place Preference)，以及改變連續給予甲基安非他命(Methamphetamine)並且經歷戒斷期之小鼠社交行為。因此我認為長期給予甲基安非他命(Methamphetamine)會造成神經可塑性的改變，並經歷長時間戒斷後， K他命(Ketamine)會使其增強場地制約偏好，也會造成社交行為降低。

Methamphetamine (MA) and ketamine (KE) abuse is prevalent and devastating in local area. Many research shows that repeated low-dose MA and KE administration may render changes in neural plasticity and motivational behavior. This study was undertaken to assess whether exposure to repeated low-dose MA may facilitate the rewarding effects produced by low-dose KE, and its social interaction and neurochemical underpinnings. Mice pretreated with MA (2 mg/kg/day) or equivalent volume of saline for 10 days and 10-day withdrawal enhanced such KE conditioned place preference (CPP). In contrast to the mice undergoing the saline pretreatment and 10-days waiting period, mice pretreated with MA and withdrawal had lower dopamine contents and enhance KE-stimulated nucleus accumbens dopamine release.
Mice pretreated with MA and withdrawal regimen displayed impairment in the social interaction tests, but mice receiving the MA without withdrawal regimen did not the effect of social interaction. In hippocampal tissues, mice pretreated with MA and withdrawal regimen have greater expression in mGluR5 protein than the mice pretreated with the saline regimen. The mGluR5 antagonist MPEP prevented the MA-withdrawal regimen with KE-induced CPP and impaired social interaction performances.

Table of contents
Abstract (Chinese) ----------------------------------------------------------------------6
Abstract (English) -----------------------------------------------------------------------7
Introduction   --------------------------------------------------------------------------8-9
Materials and methods----------------------------------------------------------------10-15
2.1. Animals --------------------------------------------------------------------------10
2.2. Drugs and chemicals -----------------------------------------------------------10
2.3. Methamphetamine-induced sensitization and 
Ketamine-induced CPP---------------------------------------------------------10
2.4. Core body temperature measurement ----------------------------------------11
2.5. Three-compartment chamber test -------------------------------------------- 12
2.6. Ex vivo superfusion ------------------------------------------------------------12-13
2.7. Western immunoblotting ------------------------------------------------------14
2.8. Statistical analysis --------------------------------------------------------------15
Results ------------------------------------------------------------------------------------15-18
3.1. Repeated, 10-day MA and 10-day withdrawal regimen on locomotor activity sensitization ----------------------------------------------------------------------15
3.2. Repeated, 10-day MA and 10-day withdrawal regimen on 
KE-induced CPP -----------------------------------------------------------------15
3.3. Repeated, 10-day MA and 10-day withdrawal regimen on and the KE-challenged remaining DA content in nucleus accumbens------------------16
3.4. Repeated, 10-day MA and 10-day withdrawal regimen and 3-day KE treatment on social interaction tests ------------------------------------------16
3.5. Repeated, 10-day MA and 10-day withdrawal regimen on mGluR5 expression levels in hippocampus --------------------------------------------17
3.6. Repeated, 10-day MA and 10-day withdrawal regimen with MPEP pretreatment on the KE-induced CPP, social interaction tests ------------18
Discussion --------------------------------------------------------------------------19-20
References--------------------------------------------------------------------------20-23
List of figures
Figure 1. ----------------------------------------------------------------------------24
Figure 2. ----------------------------------------------------------------------------25-26
Figure 3. ----------------------------------------------------------------------------27
Figure 4. ----------------------------------------------------------------------------28
Figure 5. ----------------------------------------------------------------------------29
Figure 6. ----------------------------------------------------------------------------30
Figure 7. ----------------------------------------------------------------------------31-32

                                    

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校內：2023-07-01公開
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