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研究生:李俊學
研究生(外文):Jyun-Syue Li
論文名稱:利用正子斷層造影方法研究ADHD動物模式大腦血清素系統
論文名稱(外文):Exploring Brain Serotonergic System in ADHD Animal Model Using Positron Emission Tomography Imaging
指導教授:馬國興馬國興引用關係鄭澄意李宜勲
指導教授(外文):Kuo-Hsing MaCheng-Yi ChengI-Hsun Li
口試委員:馬國興鄭澄意李宜勲薛晴彥劉江川
口試委員(外文):Kuo-Hsing MaCheng-Yi ChengI-Hsun LiChyng-Yann ShiueJiang-Chuan Liu
口試日期:2014-05-14
學位類別:碩士
校院名稱:國防醫學院
系所名稱:生物及解剖學研究所
學門:生命科學學門
學類:生物訊息學類
論文種類:學術論文
論文出版年:2014
畢業學年度:102
語文別:中文
論文頁數:47
中文關鍵詞:過動症血清素正子斷層造影
外文關鍵詞:ADHDSerotoninPositron emission tomography imaging
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注意力不足過動症 (Attention-deficit/hyperactivity disorder, ADHD),是一種發生在兒童精神和行為障礙的疾病。患者的症狀包括注意力不集中、衝動、多動。過動症主要發生在學齡的兒童,症狀可能會持續到成年。目前過動症的病理及生理機制尚未明瞭。根據文獻記載,血清素系統的異常可能與ADHD症狀有相關聯性。在本實驗中,我們利用開放式行為測試(Open field test)、 [18F]-Altanserin (專一性結合於血清素接受器) 放射性藥物搭配使用正子斷層造影 (Positron Emission Tomography, PET) 以及免疫組織化學染色在過動症大鼠研究以下議題:1.建立 [18F]-Altanserin在大鼠腦中的分布情形與最大專一攝取率的時間 2.過動症的病理與生理的機制 3. 過動症大鼠4-[18F]-Altanserin造影技術的有效性。結果顯示,開放式行為測試SHR與WKY大鼠比較,SHR大鼠出現過動症的行為表現。PET動態影像造影結果顯示,在額葉皮質與紋狀體[18F]-Altanserin最大專一攝取率時間為90-120分鐘之間。此外,SHR WKY 大鼠的造影結果互相比較,SHR大鼠各腦區的4-[18F]-Altanserin專一攝取率數值較高。免疫化學染色結果則顯示血清素2A接受器 (Serotonin 2A receptor)、酪胺酸氫化酶 (Tyrosine hydroxylase) 在SHR大鼠的額葉皮質與紋狀體表現量大於WKY大鼠;多巴胺轉運體 (Dopamine transpoter) 則是WKY大鼠表現量大於SHR大鼠。本實驗的血清素2A受體免疫染色結果跟PET造影結果相符。根據以上結果,發現血清素系統在ADHD中扮演相當重要的角色,而[18F]-Altanserin/PET在開發治療ADHD的新藥上可能可以提供有用之訊息。
Attention-deficit/hyperactivity disorder (ADHD) is a psychiatric and behavior disorder that often occurred in children. Symptoms of ADHD include inattention, impulsivity, and hyperactivity which affected mainly on child and the symptoms may persist into adulthood. Based on previous studies, we hypothesized that alterations of serotonin receptor may be involved in ADHD. To address this issue, we used open-field test, immunohistochemical staining, and [18F] Altanserin (targeting to 5-HT2A receptor) coupled with animal positron emission tomography (animal-PET) imaging to investigate the following issues: 1) Establishment of the maximum binding period of [18F] Altanserin in rat brain. 2) The possible mechanism of the ADHD pathophysiology. 3) Validity of the imaging techniques ADHD rat models. Data showed that ADHD rat model displayed hyperactive behavior compared to control rat in open-field test. In the results of PET imaging, the regions of interest (ROIs) were drawn according to rat brain atlas and dynamic data showed that the maximum binding period of [18F] Altanserin was between 90-120 min. Moreover, SHR (spontaneous ADHD model) showed higher [18F] Altanserin uptakes in various brain regions than those of WKY rat (control group). The data of immunohistochemical staining of 5-HT2A receptor was comparable with those of micro-PET images. With this study the roles of monoaminergic system in ADHD may be well understood and the [18F] Altanserin/PET may be feasible to evaluate the drug therapeutic effects in ADHD.
正文目錄………………………………………………………………I
圖目錄…………………………………………………………………IV
中文摘要…………………………………………………………………V
英文摘要………………………………………………………………VII
第一章、 緒言……………………………………………………………1
第一節、 注意力不足過動症理論概述………………………1
1. 病理生理學……………………………………………2
2. 神經發育學……………………………………………2
3. 毒物學…………………………………………………2
4. 神經傳導………………………………………………3
5. 基因遺傳………………………………………………3
第二節、 血清素系統…………………………………………5
1. 血清素生合成…………………………………………5
2. 血清素系統中樞神經投射路徑………………………6
3. 血清素異常相關疾病…………………………………7
4. 核子醫學造影技術……………………………………8
5. 血清素2A受體之正子造影技術……………………8
第二章、 實驗目的……………………………………………………10
第三章、 材料與方法…………………………………………………11
第一節、 實驗流程……………………………………………11
第二節、 麻醉用藥物…………………………………………11
第三節、 開放式空間行為測試………………………………12
第四節、 正子斷層造影………………………………………12
第五節、 影像資料分析………………………………………13
第六節、 免疫組織化學染色…………………………………14
第四章、 結果
第一節、 比較WKY及SHR在開放空間活動量……………16
第二節、 觀察[18F]Altanserin在WKY與SHR腦中各腦區結合情況與造影活性之比較…………………………17
第三節、 以免疫組織化學染色觀察WKY與SHR腦部各腦區血清素2A受體數量………………………………18
第四節、 以免疫組織化學染色觀察WKY與SHR腦部紋狀體酪胺酸羥化酶數量…………………………………19
第五節、 以免疫組織化學染色觀察WKY與SHR腦部紋狀體多巴胺轉運體數量…………………………………20

第五章、 討論
第一節、 SH大鼠與注意力不足過動症之關係……………28
第二節、 多巴胺系統與ADHD關係…………………………29
第三節、 血清素2A受體與ADHD關係……………………31
第四節、 ADHD血清素系統與多巴胺系統之關係…………31
第六章、 結論…………………………………………………………34
第七章、 參考資料……………………………………………………35

圖目錄
頁碼
圖一:WKY與SHR開放空間行為測式…………………………………21
圖二:[ 18F]-Altanserin正子斷層造影影像與MRI影像………………22
圖三: [ 18F]-Altanserin正子斷層動態造影影像量化與比較…………23
圖四: [ 18F]-Altanserin正子斷層靜態造影影像量化與比較…………24
圖五:血清素2A受體免疫組織化學染色灰階顯微照片與各腦區光學密度量化比較…………………………………………………………25
圖六:酪胺酸羥化酶免疫組織化學染色灰階顯微照片與紋狀體光學密度量化比較…………………………………………………………26
圖七:多巴胺轉運體免疫組織化學染色灰階顯微照片與紋狀體光學密度量化比較…………………………………………………………27


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