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研究生:陳鈺婷
研究生(外文):Yu-Ting Chen
論文名稱:一氧化氮參與甲基安非他命促進大白鼠感壓反射反應之研究
論文名稱(外文):Participation of Nitric Oxide in Methamphetamine-Enhanced Baroreflex Response in the Rat.
指導教授:嚴錦城嚴錦城引用關係
指導教授(外文):Jiin-Cherng Yen
學位類別:碩士
校院名稱:國立陽明大學
系所名稱:藥理學研究所
學門:醫藥衛生學門
學類:藥學學類
論文種類:學術論文
論文出版年:2017
畢業學年度:105
語文別:中文
論文頁數:81
中文關鍵詞:甲基安非他命感壓反射反應一氧化氮
外文關鍵詞:methamphetaminebaroreflex responsenitric oxide
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中文摘要

  甲基安非他命 (Methamphetamine, METH) 在台灣是被廣泛濫用的藥品之一。先前研究發現甲基安非他命可能會促進大白鼠的感壓反射反應,然而作用位置與機轉尚不清楚。一氧化氮 (nitric oxide, NO) 被認為造成甲基安非他命在中樞神經系統之作用,亦有研究指出,壓力接受器傳入神經纖維 (baroreceptor afferents) 最初的神經末梢所位處的孤獨核區中,一氧化氮可促進大白鼠感壓反射反應。因此本研究目的為探討孤獨核內一氧化氮之機轉是否促成了甲基安非他命促進感壓反射的反應,利用成年之雄性Sprague-Dawley大鼠作為實驗材料。實驗結果顯示,甲基安非他命分佈於孤獨核神經細胞中,更進一步地,研究發現靜脈注射甲基安非他命 (1.5-3.0 mg/kg) 促進感壓反射反應,並呈劑量反應相關性,而靜脈注射或孤獨核內微量注射非選擇性NOS抑制劑 (L-NAME) 會顯著抑制甲基安非他命促進之感壓反射反應。本研究接著利用西方點墨法探究孤獨核區磷酸化NOS亞型之變化,以釐清何種NOS亞型參與了甲基安非他命促進之感壓反射反應。西方點墨法的結果分析指出,靜脈給予甲基安非他命會增加磷酸化nNOS與磷酸化eNOS之蛋白表現量,然而iNOS卻沒有增加,且孤獨核內微量注射選擇性nNOS抑制劑 (NPLA) 亦可抑制甲基安非他命促進之感壓反射反應。此外,本研究利用西方點墨法探討何種機制調節了甲基安非他命所活化的NO訊息路徑,西方點墨法結果顯示甲基安非他命會增加磷酸化Akt的表現量,且孤獨核內微量注射Akt抑制劑 (API-2) 或PI3K抑制劑 (wortmannin),也可抑制甲基安非他命所促進之感壓反射反應與增加之磷酸化nNOS表現量。由以上結果可推論,甲基安非他命可能透過孤獨核區神經細胞內PI3K/Akt-nNOS-PKG的訊息路徑,促進感壓反射反應。
英文摘要

Methamphetamine (METH) is a psychostimulant widely abused in Taiwan. Previous study revealed that METH may enhance baroreflex response (BRR). However, the site of action of METH-induced enhancement of BRR and its underlying mechanism remain unknown. Nitric oxide (NO) is suggested to contribute to the actions of METH in the central nervous system. In addition, production of NO in the nucleus tractus solitarii (NTS), the primary termination site of baroreceptor afferents, is demonstrated to enhance BRR of the rat. In this context, this study was aimed to elucidate the contribution of nitrergic mechanism in the NTS to METH-induced enhancement of BRR of the rat. Adult, male Sprague-Dawley rats were used in this study. Our results indicated that METH was distributed in the NTS neuron. Furthermore, the result showed that BRR was enhanced by intravenous injection of METH (1.5-3.0 mg/kg) in a dose dependent manner. The enhancement of BRR was significantly inhibited by pretreatment with intravenous injection or intra-NTS microinjection of L-NAME, a nonselective NO synthase (NOS) inhibitor. To further clarify the isoforms of NOS participated in METH-enhanced BRR, we then examined the phosphorylation of three isoforms of NOS in the NTS. Western blotting analysis showed that protein levels of phosphorylated neuronal NOS (nNOS) and endothelial NOS (eNOS) were increased while the level of inducible NOS (iNOS) was not elevated in NTS following administration of METH. Moreover, METH-induced enhancement of BRR was attenuated by intra-NTS microinjection of NPLA (a selective nNOS inhibitor). In addition, western blotting was used to investigate the regulatory mechanism of METH-activated NO signaling. The result showed that METH increases phosphorylation of Akt (Ser473). Besides, METH-enhanced BRR and METH-increased phosphorylation of nNOS were significantly inhibited by intra-NTS microinjection of wortmannin, PI3K inhibitor, and API-2, Akt inhibitor. In conclusion, these results suggested that METH induces enhancement of BRR via PI3K/Akt-nNOS-PKG in the NTS neuron of rats.
目錄

中文摘要 i
英文摘要 ii
目錄 iii
圖表目錄 v
縮寫對照 vii
壹、研究背景介紹 1
一、甲基安非他命 1
二、甲基安非他命影響動物體之心血管功能 2
三、甲基安非他命透過孤獨核促進感壓反射反應的可能性 3
四、孤獨核中一氧化氮參與感壓反射的調控 4
五、甲基安非他命可能透過增加NO產量促進感壓反射反應 5
貳、研究動機與目的 7
參、材料與方法 8
一、 實驗動物 8
二、 藥品與其他試劑材料 8
三、 動物生理實驗 11
四、 西方點墨法 13
五、 免疫組織化學染色與免疫螢光染色 15
六、 統計分析 18
七、 實驗設計 18
肆、結果 21
一、 甲基安非他命於大白鼠孤獨核區之分布情形 21
二、 甲基安非他命透過孤獨核區內的NOS促進感壓反射的反應 22
三、 PI3K/Akt參與甲基安非他命促進感壓反射的反應 24
伍、討論 26
一、 甲基安非他命於孤獨核區的分佈 27
二、 一氧化氮與甲基安非他命 28
三、 PI3K/Akt訊息路徑與甲基安非他命促進感壓反射反應之關係 29
四、 甲基安非他命透過孤獨核促進感壓反射反應的可能機轉 30
陸、結論 32
參考文獻 33
附圖 41


圖表目錄
Figure 1. 實驗流程圖 42
Figure 2. 甲基安非他命分佈於大白鼠孤獨核區 44
Figure 3. 靜脈注射之甲基安非他命分佈於孤獨核區的神經細胞上 46
Figure 4. 甲基安非他命促進感壓反射反應之劑量反應關係 48
Figure 5. 靜脈注射L-NAME可抑制甲基安非他命所造成感壓反射反應之變化 50
Figure 6. 孤獨核內微量注射L-NAME可抑制甲基安非他命所造成感壓反射反應之變化 52
Figure 7. 甲基安非他命可以增加孤獨核內nNOS磷酸化表現量 54
Figure 8. 甲基安非他命可以增加孤獨核內eNOS磷酸化表現量 56
Figure 9. 靜脈注射甲基安非他命後,孤獨核內iNOS沒有增加表現 58
Figure 10. 孤獨核內微量注射NPLA可抑制甲基安非他命所造成感壓反射反應之變化 60
Figure 11. 孤獨核內微量注射L-NIO未抑制甲基安非他命所造成感壓反射反應之變化 62
Figure 12. 甲基安非他命可能增加孤獨核內PKG表現量 64
Figure 13. 甲基安非他命可以增加孤獨核內磷酸化Akt (Ser473) 表現量 66
Figure 14. 甲基安非他命未增加孤獨核內磷酸化Akt (Thr308) 表現量 68
Figure 15. 孤獨核內微量注射wort可抑制甲基安非他命所造成感壓反射反應之變化 70
Figure 16. 孤獨核內微量注射API-2可抑制甲基安非他命所造成感壓反射反應之變化 72
Figure 17. 孤獨核內微量注射wort與API-2可抑制甲基安非他命所造成磷酸化nNOS表現量之增加 74
Figure 18. 甲基安非他命可能會透過孤獨核神經細胞中的PI3K/Akt-nNOS-PKG訊息路徑而促進感壓反射反應之示意圖。 76
Figure 19. 孤獨核內微量注射ADM22-52可抑制甲基安非他命所造成感壓反射反應之變化 78
Figure 20. 各種藥物處理後之大鼠血壓與心跳變化圖 80
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