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題名 愷他命和右旋愷他命異構物對大鼠行為及神經化學的影響效果：與右旋安非他命相比較
Behavioral and Neurochemical Effects of RS-ketamine and S-ketamine in Rats: Compared with d-Amphetamine作者 王傳堯
Wang, Chuan-Yao貢獻者 廖瑞銘<br>趙知章
Liao, Ruey-Ming<br>Chao, Chih-Chang
王傳堯
Wang, Chuan-Yao關鍵詞 藥物酬賞和成癮
制約性場地偏好
行為致敏化
麩胺酸NMDA受體
多巴胺
大鼠
Drug reward and addiction
Conditioned place preference
Behavioral sensitization
Glutamate NMDA receptor
Dopamine
Rat日期 2022 上傳時間 1-Aug-2022 18:14:28 (UTC+8) 摘要 愷他命是一種非競爭性氮-甲基天門冬胺酸(N-methyl-D-aspartate)受體拮抗劑，近年來被用於治療憂鬱症，但其神經行為機制仍然有待確證，其中一項問題是有關愷他命會致使精神迷幻和藥物上癮的效果。本研究實驗一利用一種同時測量制約性場地偏好和行為致敏化的藥癮行為動物模式，針對利用消旋性愷他命 (RS-KET)、右旋性愷他命異構物 [S(+)-KET]、和安非他命 (d-AMP)，測試其藥物酬賞的行為藥理作用；實驗二以西方墨點法檢測五個腦區之麩胺酸與多巴胺相關的蛋白質、及大腦衍生神經滋養因子之表現量，分析藥物作用的神經化學機制。實驗一藉由七次間歇重複注射藥物的操弄，結果發現d-AMP組顯著引發場地偏好及行為致敏化的效果；RS-KET組及S-KET組沒有引發顯著的場地制約偏好，但有行為致敏化的反應，惟其藥效較d-AMP組弱。實驗二生化分析的結果顯示藥物影響效果包含：（1）依核和背側紋狀體之NMDA受體 （GluN1、GluN2A和GluN2B）蛋白質表現量顯著減少，（2）多巴胺相關蛋白質（D1受體、D2受體、和DAT）表現量依據腦區和藥物的不同而有差異，（3）BDNF的蛋白質表現量僅在杏仁核有增加的效應。綜合而言，相對於d-AMP引發制約性場地偏好及行為致敏化的行為藥理效果，RS-KET及S-KET的效果比較不明顯。這三種藥物之間的行為藥理差異，與不同腦區的特定蛋白質表現量變化有關。本研究顯示愷他命的藥物酬賞性質有別於心理興奮劑，這兩類藥物影響麩胺酸與多巴胺傳遞系統相關的蛋白質表現有差異，此結果可供後續探討這兩類藥物調控成癮行為的神經生物機制之用。
Ketamine is a non-competitive N-methyl-D-aspartate receptor antagonist that has recently been repurposed in depression therapy, although the underlying neurobehavioral mechanisms remain elusive. One of the key issues should be concerned is that ketamine may cause psychotic and addictive effects in its users. Thus, this study, in Experiment 1, was designed to investigate the effects of racemic ketamine [RS (+/-)-ketamine; RS-KET] and it S-isomer [S (+)-ketamine; S-KET] respectively, on a behavioral protocol combining tests of conditioned place preference (CPP) and behavioral sensitization (BS). Additionally, d-amphetamine (d-AMP) treatment was conducted as a positive control. In the Experiment 2, after completing behavioral test, the expression levels of NMDA receptor subunits, dopamine-related proteins, and brain-derived neurotrophic factor (BDNF) were analyzed by western blotting. The results of Experiment 1 showed that the d-AMP group significantly displayed CPP and BS effects following a drug treatment of 7-time intermittent repeated injections, while the RS-KET and S-KET groups did not have CPP but showed various degrees of BS. However, the magnitude of BS induced by RS-KET or S-KET was smaller than that of d-AMP. The results of Experiment 2 revealed drug effects significantly measured on (1) decreases of the protein expressions of NMDA receptor subunits (GluN1, GluN2A, and GluN2B) in both the nucleus accumbens and dorsal striatum, (2) region-dependent changes in dopamine-related proteins (D1 receptor, D2 receptor, and DAT), and (3) no change of BDNF except detecting an increase in the amygdala. Together, RS-KET and S-KET did not produce the effects of CPP and BS as profound as d-AMP on the present behavioral task. The disparity between drug treatments is related to the change of certain protein expression on specific brain area. 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國立政治大學
神經科學研究所
108754003資料來源 http://thesis.lib.nccu.edu.tw/record/#G0108754003 資料類型 thesis dc.contributor.advisor 廖瑞銘<br>趙知章 zh_TW dc.contributor.advisor Liao, Ruey-Ming<br>Chao, Chih-Chang en_US dc.contributor.author (Authors) 王傳堯 zh_TW dc.contributor.author (Authors) Wang, Chuan-Yao en_US dc.creator (作者) 王傳堯 zh_TW dc.creator (作者) Wang, Chuan-Yao en_US dc.date (日期) 2022 en_US dc.date.accessioned 1-Aug-2022 18:14:28 (UTC+8) - dc.date.available 1-Aug-2022 18:14:28 (UTC+8) - dc.date.issued (上傳時間) 1-Aug-2022 18:14:28 (UTC+8) - dc.identifier (Other Identifiers) G0108754003 en_US dc.identifier.uri (URI) http://nccur.lib.nccu.edu.tw/handle/140.119/141188 - dc.description (描述) 碩士 zh_TW dc.description (描述) 國立政治大學 zh_TW dc.description (描述) 神經科學研究所 zh_TW dc.description (描述) 108754003 zh_TW dc.description.abstract (摘要) 愷他命是一種非競爭性氮-甲基天門冬胺酸(N-methyl-D-aspartate)受體拮抗劑，近年來被用於治療憂鬱症，但其神經行為機制仍然有待確證，其中一項問題是有關愷他命會致使精神迷幻和藥物上癮的效果。本研究實驗一利用一種同時測量制約性場地偏好和行為致敏化的藥癮行為動物模式，針對利用消旋性愷他命 (RS-KET)、右旋性愷他命異構物 [S(+)-KET]、和安非他命 (d-AMP)，測試其藥物酬賞的行為藥理作用；實驗二以西方墨點法檢測五個腦區之麩胺酸與多巴胺相關的蛋白質、及大腦衍生神經滋養因子之表現量，分析藥物作用的神經化學機制。實驗一藉由七次間歇重複注射藥物的操弄，結果發現d-AMP組顯著引發場地偏好及行為致敏化的效果；RS-KET組及S-KET組沒有引發顯著的場地制約偏好，但有行為致敏化的反應，惟其藥效較d-AMP組弱。實驗二生化分析的結果顯示藥物影響效果包含：（1）依核和背側紋狀體之NMDA受體 （GluN1、GluN2A和GluN2B）蛋白質表現量顯著減少，（2）多巴胺相關蛋白質（D1受體、D2受體、和DAT）表現量依據腦區和藥物的不同而有差異，（3）BDNF的蛋白質表現量僅在杏仁核有增加的效應。綜合而言，相對於d-AMP引發制約性場地偏好及行為致敏化的行為藥理效果，RS-KET及S-KET的效果比較不明顯。這三種藥物之間的行為藥理差異，與不同腦區的特定蛋白質表現量變化有關。本研究顯示愷他命的藥物酬賞性質有別於心理興奮劑，這兩類藥物影響麩胺酸與多巴胺傳遞系統相關的蛋白質表現有差異，此結果可供後續探討這兩類藥物調控成癮行為的神經生物機制之用。 zh_TW dc.description.abstract (摘要) Ketamine is a non-competitive N-methyl-D-aspartate receptor antagonist that has recently been repurposed in depression therapy, although the underlying neurobehavioral mechanisms remain elusive. One of the key issues should be concerned is that ketamine may cause psychotic and addictive effects in its users. Thus, this study, in Experiment 1, was designed to investigate the effects of racemic ketamine [RS (+/-)-ketamine; RS-KET] and it S-isomer [S (+)-ketamine; S-KET] respectively, on a behavioral protocol combining tests of conditioned place preference (CPP) and behavioral sensitization (BS). Additionally, d-amphetamine (d-AMP) treatment was conducted as a positive control. In the Experiment 2, after completing behavioral test, the expression levels of NMDA receptor subunits, dopamine-related proteins, and brain-derived neurotrophic factor (BDNF) were analyzed by western blotting. The results of Experiment 1 showed that the d-AMP group significantly displayed CPP and BS effects following a drug treatment of 7-time intermittent repeated injections, while the RS-KET and S-KET groups did not have CPP but showed various degrees of BS. However, the magnitude of BS induced by RS-KET or S-KET was smaller than that of d-AMP. The results of Experiment 2 revealed drug effects significantly measured on (1) decreases of the protein expressions of NMDA receptor subunits (GluN1, GluN2A, and GluN2B) in both the nucleus accumbens and dorsal striatum, (2) region-dependent changes in dopamine-related proteins (D1 receptor, D2 receptor, and DAT), and (3) no change of BDNF except detecting an increase in the amygdala. Together, RS-KET and S-KET did not produce the effects of CPP and BS as profound as d-AMP on the present behavioral task. The disparity between drug treatments is related to the change of certain protein expression on specific brain area. These results indicate the differential characteristics of drug reward between ketamine and psychostimulant which could be associated with different patterns of protein expressions involved in the glutamate and dopamine transmission systems, highlighting the neurobiological mechanisms of drug reward and addiction underlying these drugs to be unfolded in future study. en_US dc.description.tableofcontents 中文摘要 I英文摘要 II表次 VI圖次 VII第一章、緒論 1一、前言 1二、愷他命的臨床運用 1三、藥物酬賞相關的動物行為模式 2（一）制約性場地偏好 (CPP) 2（二）行為致敏化 (BS) 4四、愷他命相關的神經化學反應 4（一）酬賞動機相關的腦區 5（二）麩胺酸 (Glutamate; Glu) 受體及功能 5（三）多巴胺 (Dopamine; DA) 受體及功能 6（四）大腦衍生神經滋養因子 (brain-dervied neurotrophic factor; BDNF) 7五、研究目的 8第二章、材料與方法 9一、實驗動物 9二、藥物 9三、行為實驗測試儀器 9（一）場地制約箱 9（二）行為致敏箱 10四、行為藥理實驗程序 10（一）制約性場地偏好 (Conditioned place preference; CPP) 10（二）行為致敏化 (Behavioral sensitization; BS) 11五、行為藥理學實驗設計 11六、西方墨點法 (Western blot) 12七、統計分析 15第三章、結果 16ㄧ、藥物引發之成癮相關行為變化 16二、藥物引發蛋白質表現量變化 17（一）GluN1、GluN2及GluN2B蛋白質表現量之檢測結果 17（二）D1受體、D2受體及DAT蛋白質表現量之檢測結果 18（三）BDNF蛋白質表現量之檢測結果 19三、行為數據與蛋白質含量的統計相關分析結果 19第四章、討論 21一、藥物引發CPP與BS之行為反應 21二、藥物對NMDA受體之次單元的影響 23三、藥物對DA相關蛋白質的影響 25四、藥物對BDNF的影響 26五、行為數據及生化分析結果的相關分析 26六、結論 27參考文獻 29附表 37附圖 44 zh_TW dc.format.extent 12488915 bytes - dc.format.mimetype application/pdf - dc.source.uri (資料來源) http://thesis.lib.nccu.edu.tw/record/#G0108754003 en_US dc.subject (關鍵詞) 藥物酬賞和成癮 zh_TW dc.subject (關鍵詞) 制約性場地偏好 zh_TW dc.subject (關鍵詞) 行為致敏化 zh_TW dc.subject (關鍵詞) 麩胺酸NMDA受體 zh_TW dc.subject (關鍵詞) 多巴胺 zh_TW dc.subject (關鍵詞) 大鼠 zh_TW dc.subject (關鍵詞) Drug reward and addiction en_US dc.subject (關鍵詞) Conditioned place preference en_US dc.subject (關鍵詞) Behavioral sensitization en_US dc.subject (關鍵詞) Glutamate NMDA receptor en_US dc.subject (關鍵詞) Dopamine en_US dc.subject (關鍵詞) Rat en_US dc.title (題名) 愷他命和右旋愷他命異構物對大鼠行為及神經化學的影響效果：與右旋安非他命相比較 zh_TW dc.title (題名) Behavioral and Neurochemical Effects of RS-ketamine and S-ketamine in Rats: Compared with d-Amphetamine en_US dc.type (資料類型) thesis en_US dc.relation.reference (參考文獻) Abiero A, Custodio RJP, Botanas CJ, Ortiz DM, Sayson VL, Kim M, Lee HJ, Yoon S, Lee YS, Cheong JH, Kim HJ (2021) 1-Phenylcyclohexan-1-amine hydrochloride (PCA HCl) alters mesolimbic dopamine system accompanied by neuroplastic changes: A neuropsychopharmacological evaluation in rodents. 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