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研究生:黃立宗
研究生(外文):Li-Chung Hwang
論文名稱:神經系統成癮性藥物對[18F]FDOPA在大鼠體內動態分佈之影響
論文名稱(外文):Effect of psychostimulants on pharmacokinetics of [18F]FDOPA in rats by quantitative autoradiography
指導教授:黃正仲黃正仲引用關係
指導教授(外文):Jeng-Jong Hwang
學位類別:碩士
校院名稱:國立陽明大學
系所名稱:放射醫學科學研究所
學門:醫藥衛生學門
學類:醫學技術及檢驗學類
論文種類:學術論文
論文出版年:2004
畢業學年度:92
語文別:中文
中文關鍵詞:氟-18-多巴定量自動放射顯影術古柯鹼甲基安非他命K他命
外文關鍵詞:[18F]FDOPAquantitative autoradiographycocainemethamphetamineketamine
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多種神經系統成癮性藥物(psychostimulants)的作用機轉已被證實和多巴胺神經系統(dopaminergic neurosystem)有關。而核醫放射製劑6-[18F]-fluoro-L-DOPA ([18F]FDOPA) 已被廣泛運用於偵測生物體內多巴胺神經元(dopaminergic neuron)內多巴胺的生合成代謝情況。本研究以定量自動放射顯影術(quantitative autoradiography, QARG) 結合微正子發射斷層掃描儀(microPET)來定量分析急性給予神經成癮性藥物對[18F]FDOPA在大鼠腦部多巴胺神經系統吸收之影響。
本實驗所採用的是Sprague-Dawley (SD)公鼠(250±25克)。每隻大鼠在尾靜脈注射[18F]FDOPA (37 MBq)之前的一個小時,都先以灌食的方式給予carbidopa (28 mg/kg)。在打完[18F]FDOPA之後的0.25、0.5、1及2小時犧牲大鼠做顯微自動放射顯影術(microautoradiography)及定量自動放射顯影術。微正子發射斷層掃描造影也採用相同的時間點。
在控制組中,不論是定量自動放射顯影術或是微正子發射斷層掃描都顯示在[18F]FDOPA給予之後的2個小時有最好的紋狀體/額狀皮質(striatum/frontal cortex, S/FC)比率,顯微自動放射顯影術也得到相似的結果。在神經系統成癮性藥物後處理的實驗組分別在靜脈注射[18F]FDOPA 1.5小時後給予古柯鹼(5-25 mg/kg, i.v.)、甲基安非他命(5-50 mg/kg, i.v.)或是K他命(5-60 mg/kg, i.p.)。而經古柯鹼(20 mg/kg)、甲基安非他命(40 mg/kg)及K他命(40 mg/kg)後處理(post-treatment)大鼠其2小時腦部紋狀體/額狀皮質比率較控制組分別顯著地減少48%、61%和73% (P < 0.001)。而在藥物前處理 (pre-treatment)的大鼠腦部紋狀體/額狀皮質比率,相較於同劑量的後處理組都有顯著的增加,分別較控制組減少了40%、38% 及27%。
本研究結果顯示,後處理低劑量的古柯鹼、甲基安非他命及K他命在抑制[18F]FDOPA的吸收上都可以發現在急性給予時有劑量依隨效應(dose-dependent effect),而在高劑量的範圍,則出現抑制飽和的現象;前處理低劑量的神經系統成癮性藥物同樣有劑量依隨效應,而抑制飽和的高劑量點在甲基安非他命及K他命則提前出現。在本實驗所採用的三種神經系統成癮性藥物,以K他命對紋狀體吸收[18F]FDOPA有最大的抑制效果,依次為甲基安非他命和古柯鹼。
利用高解析度(25 μm)的定量自動放射顯影術配合微正子發射斷層掃描(解析度 1-2 mm)來評估神經系統成癮性藥物對於生物體腦部神經傳導物質合成代謝、轉運體或受體之影響,本研究同時也顯示定量自動放射顯影術不但可以在藥物動力學上量測腦部各區之積聚比率,也可以有效地量化動物接受核醫藥物後,其腦部各區域的放射活度(radioactivity),這是截至目前為止,其他造影方法所達不到的。
The effects and the mechanisms of the several psychostimulants on the dopaminergic neurosystem have been studied. 6-[18F]-fluoro-L-DOPA ([18F]FDOPA), a radiopharmaceutical, has been used to detect the biochemical activities of dopaminergic neurons. In this study, the effects of acute administration of psychostimulants on dopamine neuron system of Sprague-Dawley rat brain before or after [18F]FDOPA injection were investigated using quantitative autoradiography (QARG) in combination with micro positron emission tomography (microPET).
Male Sprague-Dawley (SD) rats (250±25 grams) were used in this study. All rats were given carbidopa (28 mg/kg) by gavage 1 hr prior to intravenous injection (i.v.) of [18F]FDOPA (37 MBq). The rats were sacrificed at 0.25, 0.5, 1 and 2 hrs after [18F]FDOPA injection to acquire the striatum to frontal cortex (S/FC) ratio by microautoradiography and QARG. MicroPET imaging was also performed at the same time points.
In the control group, both QARG and microPET showed that the S/FC ratio at 2 hours after [18F]FDOPA injection was the highest. In addition, the highest density of silver grams was also found in the striatum 2 hours after [18F]FDOPA injection from microautoradiography. For drug post-treated groups, rats were administrated with cocaine (5-25 mg/kg, i.v.), methamphetamine (5-50 mg/kg, i.v.) or ketamine (5-60 mg/kg, i.p.) 1.5 hours after [18F]FDOPA injection. And all rats were sacrificed with chloroform 30 min after drug administration. The striatum to frontal cortex ratio at 2 hours in cocaine (20 mg/kg), methamphetamine (40 mg/kg) and ketamine (40 mg/kg) post-treated group were significantly (P < 0.001) reduced to 52%, 39% and 27% of the control, respectively, assayed by QARG. In pre-treated group, the striatum to frontal cortex ratio at 2 hours in cocaine (20 mg/kg), methamphetamine (40 mg/kg) and ketamine (40 mg/kg) were reduced to 60%, 62% and 73% of the control.
The effect of psychostimulants on [18F]FDOPA uptake all showed the dose-dependent manner at the lower dose range. At high dose range (> or = 40 mg/kg), ketamine showed the highest inhibition capability following by methamphetamine and cocaine.
High resolution (25 μm) quantitative autoradiography combined with microPET (resolution 1-2 mm) is very valuable for the evaluation of the effect of the psychostimulants on the biosynthesis/metabolism, neurotransporter or neuroreceptor. Quantitative autoradiography is not only good for the assay of the uptake ratio in pharmacokinetics, but also for the calculation of radioactivity in various regions of the brain.
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