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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 劉秉慧(Biing-Hui Liu) | |
dc.contributor.author | Yu-Ching Hsiao | en |
dc.contributor.author | 蕭宇晴 | zh_TW |
dc.date.accessioned | 2021-05-20T00:49:31Z | - |
dc.date.available | 2023-08-31 | |
dc.date.available | 2021-05-20T00:49:31Z | - |
dc.date.copyright | 2020-09-01 | |
dc.date.issued | 2020 | |
dc.date.submitted | 2020-08-17 | |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/8168 | - |
dc.description.abstract | K他命濫用為全球面臨之公衛議題,K他命可能經由阻斷N-甲基-D-天門冬胺酸受體(N-methyl-D-aspartate receptor, NMDA receptor)導致成癮。本研究欲釐清調節NMDA受體功能的藥物是否能降低獲取K他命的動機及尋求K他命的再犯反應,測試藥物包括肌胺酸,D-絲胺酸,和L-4-fluorophenylglycine (L-4FPG);其中肌胺酸是甘胺酸轉運蛋白1抑制劑並且作用於 NMDA受體甘胺酸結合位點,D-絲胺酸為NMDA受體甘胺酸結合位點之內生性共同致效劑,L-4FPG是中性胺基酸轉運蛋白alanine-seine-cysteine transporter(ASCT)抑制劑,藉由抑制D-絲胺酸再回收以提高突觸間隙D-絲胺酸的濃度,因此三種測試藥物均可以調節NMDA受體的功能。本研究首先利用大鼠自我給藥系統訓練Sprague-Dawley公鼠按壓壓桿以獲得靜脈K他命輸注(0.5 mg/kg/infusion),當訓練穩定後進行以下實驗:(1)在累進比率時程下,測試分別給予肌胺酸(30及100 mg/kg)、D-絲胺酸(30及100 mg/kg)或L-4FPG (0.3及1 mg/kg)對於K他命靜脈內自我給藥大鼠之劑量依賴反應。(2)測試在線索(cue)或K他命誘發的再犯試驗前,急性給予肌胺酸(30及100 mg/kg)、D-絲胺酸(30及100 mg/kg)或L-4FPG (1及3 mg/kg)之劑量依賴反應。(3)測試在消除階段給予肌胺酸(100 mg/kg)、D-絲胺酸(100 mg/kg)或L-4FPG (3 mg/kg)是否可以促進消去形成,並利用線索或K他命誘發的再犯試驗來測試藥物效果。結果顯示,於累進比率時程下急性前給予肌胺酸(100 mg/kg)、D-絲胺酸(100 mg/kg)或L-4FPG(1 mg/kg)皆會降低大鼠按壓壓桿的次數(lever presses)、斷點數值(breakpoint)以及所獲得的藥物輸注次數(number of infusions),與此相同的抑制效果也存在於線索及K他命誘導再犯試驗中,不過,於誘導再犯試驗中,L-4FPG的用量須提高至3 mg/kg才有顯著差異;此外,於消除階段給予此三種藥物,只能防止線索誘發再犯反應但是不能促進消除。此三種藥物均不影響壓桿取得食物粒的實驗以及運動活性。本研究結果顯示,肌胺酸、D-絲胺酸及L-4FPG可能具有防止K他命成癮的渴藥及復發的潛力,並為未來臨床研究奠立基礎。 | zh_TW |
dc.description.abstract | Ketamine abuse is a worldwide public health problem. Ketamine may cause addiction through blocking the phencyclidine (PCP) binding site of N-methyl-D-aspartate (NMDA) receptors. The present study examined whether the drugs with NMDA receptors-modulation ability could attenuate the motivation and reinstatement of ketamine-seeking behavior. Sarcosine is a glycine transporter 1 inhibitor and works on the glycine binding site of NMDA receptor. D-serine is an endogenous NMDA receptor co-agonist at the glycine binding site. L-4-fluorophenylglycine (L-4FPG) is a neutral amino acid transporter ASCT (Alanine/Serine/Cysteine-preferring Transporter) inhibitor by blocking the reuptake of D-serine in the synaptic cleft. In the present study, male Sprague-Dawley rats were trained to press an active lever for self-administration (SA) of intravenous ketamine (0.5 mg/kg/infusion), and then subjected to the following three experiments. Experiment 1 is to assess the dose-dependent effects of acute treatment of sarcosine (30 and 100 mg/kg), D-serine (30 and 100 mg/kg), and L-4FPG (0.3and 1 mg/kg) on the self-administration motivation which is determined by the breakpoint according to during the progressive ratio (PR) schedule. Experiment 2 is to evaluate the acute effects of sarcosine (30 and 100 mg/kg), D-serine (30 and 100 mg/kg), and L-4FPG (1 and 3 mg/kg) on the cue-induced and ketamine priming-induced reinstatement of ketamine seeking behaviors. Experiment 3 is to examine the repeated administration of sarcosine (100 mg/kg), D-serine (100 mg/kg), and L-4FPG (3 mg/kg) during extinction on the cue-induced and ketamine priming-induced reinstatement of ketamine seeking behaviors. Our data demonstrated that sarcosine (100 mg/kg), D-serine (100 mg/kg) and L-4FPG (1 mg/kg) significantly decreased the lever presses, breakpoint and number of infusions for ketamine and attenuated the cue-induced and ketamine priming-induced ketamine seeking behavior; however, the dose of L-4FPG must be increased to 3 mg/kg to show significant difference on reinstatement. Additionally, administration of these three compounds during extinction only prevented cue-induced reinstatement of ketamine-seeking behavior but did not facilitate the extinction. These three drugs had no effect on food self-administration and locomotor activity in the present study. Our findings suggest that sarcosine, D-serine, and L-4FPG have the anti-craving and anti-relapse potential for treatment of ketamine addiction, laying the groundwork for future clinical research. | en |
dc.description.provenance | Made available in DSpace on 2021-05-20T00:49:31Z (GMT). No. of bitstreams: 1 U0001-1708202012445700.pdf: 2016789 bytes, checksum: 0c31c899ec26b7e4d1497a0f67d17fa0 (MD5) Previous issue date: 2020 | en |
dc.description.tableofcontents | 壹、介紹 1 一、 K他命 (ketamine) 1 二、 K他命與成癮 5 三、肌胺酸 (Sarcosine) 10 四、 D-絲胺酸 (D-serine) 11 五、 L-4-氟苯基甘胺酸 (L-4-fluorophenylglycine, L-4FPG) 12 貳、實驗假說 14 參、研究動機與目的 16 肆、實驗材料、方法及結果 17 一、實驗動物 17 二、實驗藥品配置 17 三、實驗方法及流程 19 四、實驗數據分析 26 五、實驗結果 27 伍、討論 35 陸、結論 39 柒、參考資料 40 捌、圖表 52 | |
dc.language.iso | zh-TW | |
dc.title | NMDA受體調節劑對大鼠K他命自我給藥之影響 | zh_TW |
dc.title | Effects of NMDA receptor modulators on ketamine self-administration in rats | en |
dc.type | Thesis | |
dc.date.schoolyear | 108-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 陳慧諴(Hwei-Hsien Chen),詹銘煥(Ming-Huan Chan),姚皓傑(Hau-Jie Yau) | |
dc.subject.keyword | K他命,自我給藥,消除,再犯反應,復發, | zh_TW |
dc.subject.keyword | ketamine,self-administration,extinction,reinstatement,relapse, | en |
dc.relation.page | 66 | |
dc.identifier.doi | 10.6342/NTU202003723 | |
dc.rights.note | 同意授權(全球公開) | |
dc.date.accepted | 2020-08-17 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 毒理學研究所 | zh_TW |
dc.date.embargo-lift | 2023-08-31 | - |
顯示於系所單位: | 毒理學研究所 |
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