臺灣博碩士論文加值系統

2,5-二甲氧基-4-乙硫基苯乙胺（2, 5 – dimethoxy – 4 – ethylthiophenethylamine, 2C-T-2）為苯環上官能基改變之苯乙胺（phenethylamine）衍生物，為一種精神活化藥物（psychoactive drugs）；精神活化藥物服用後可影響腦部功能，造成服用者知覺、心情、認知與行為改變，長期濫用會影響多項生理功能。先前研究中，小鼠單次口服2C-T-2會導致小鼠脾臟細胞在活化狀況下nitric oxide（NO）產生的下降，NO與免疫系統的防禦力有關，但有關2C-T-2對免疫生理活性的影響尚無相關文獻報導。本研究的目的是以小鼠灌食模式，評估單次或多次2C-T-2餵食對小鼠免疫活性的影響，並進一步探討在2C-T-2對免疫系統的神經內分泌調控的機制。研究結果顯示，小鼠口服2C-T-2卅分鐘後即可在血液中被偵測，約6小時在血液中便達到殘餘量的最低點，2C-T-2同時可促進血漿中皮質固酮（conrticosterone）的濃度增加。在單次餵食2C-T-2的結果顯示，2C-T-2的餵食會抑制周邊血中總白血球的數目，同時也抑制白血球吞噬的活性，而2C-T-2也會抑制脾臟B與T淋巴球在活化狀態下細胞增生與NO釋放，並在餵食後2小時呈現最大抑制的反應；另外2C-T-2也顯著抑制LPS刺激分泌的細胞激素IL-1β、IL-6與TNF-α分泌量與Con A刺激分泌的細胞激素IFN-γ、IL-4與IL-10的分泌量，但2C-T-2顯著促進TGF-β1與IL-2分泌增加。在多次餵食實驗結果顯示，2C-T-2不會顯著改變周邊血總白血球數目，對脾臟B與T淋巴球在活化狀態下細胞增生僅呈現些微抑制現象，而在多次餵食下IL-1β、IL-6、TNF-α、IL-4與IL-2分泌量皆會下降，但對IFN-γ與IL-10的分泌量並無影響。在探討2C-T-2所造成免疫活性抑制機制的結果顯示，將不同劑量的2C-T-2與巨噬細胞株、脾臟初代細胞與純化出T細胞進行體外共同培養的實驗結果顯示，2C-T-2之免疫抑制作用並非藥物直接作用細胞所導致；接著在餵食藥物前30分鐘腹腔施打交感神經抑制劑（nadolol）與興奮劑（epinephrine），發現NO釋放的抑制現象可因為藥物的施打而減弱。綜合以上所得， 2C-T-2攝食可造成小鼠免疫活性的抑制，而此抑制作用與神經內分泌的調控有關。

2C-T-2 (2,5–dimethoxy–4–ethylthio- phenethylamine), a psychoactive drug, is a ring-substituted phenethylamine derivative that exerts psychological effects including changes in mood, cognition, and behavior. It had been reported that psychoactive drugs caused the health problems if there were abused intake. The previously studies indicated that oral intake 2C-T-2 suppressed the nitric oxide production of mitogen-stiumated splenocytes in mice. However, little information is available concerning its bioactivity and immunomodulatory activity. In this study, the metabolic kinetic and immunomodulatory effects of 2C-T2 after single or repeated oral intake are examined and characterized used the mice animal model. In addition, the neuroendocrine-mediated mechanism(s) of 2C-T-2-induced immunosuppression was also examined. Results indicated that the level of 2C-T-2 in the peripheral blood was firstly detected at 30 minutes after intake, and 6 hours later, the level of 2C-T-2 was metabolic clear and less than detectable amount. In parallel, 2C-T-2 oral intake also increased the level of corticosterone in blood plasma. The results of single intake 2C-T-2 on immune activities indicated that 2C-T-2 induced the decrease the distribution of T, B, and NK cell populations in peripheral blood. And the ability of phagocytosis in leukocytes was suppressed significantly after 2C-T-2 oral intake 6 hours. 2C-T-2 also induced the suppression of mitogen-stimulated proliferation and nitric oxide in spleen and thymus. In addition, the production of IL-1β, IL-6, TNF-α, IFN-γ, IL-4, and IL-10 cytokines from LPS or Con A-stimulated splenocytes were significantly decreased after 2C-T-2 oral intake. However, 2C-T-2 intake significantly increased the IL-2 and TGF-β1 production. Repeated 2C-T-2 intake induced the immunosuppression on production of nitric oxide, IL-1β, IL-6, TNF-α, IL-4, IL-10, and TGF-β1, but no change on leukocytes subpopulation number, proliferation and production of IL-2 and IFN-γ. Furthermore, in this study, we observed that in vitro exposure to 2C-T-2 did not alter LPS-stimulated nitric oxide production. This data indicate that the ability of 2C-T-2 to suppress the production of nitric oxide and cytokine production is not due to a direct action on immune cells. Interestingly, administrated nodolol, a β-adrenoceptor blockade, or epinephrine attenuated the decrease in nitric oxide production induced by 2C-T-2 oral intake. In summary, these data demonstrate that 2C-T-2 intake induce the suppression effect on immune activities of mice. However, further studies are needed to elucidate the exact mechanisms that underlie 2C-T-2 induced suppression of nitric oxide and cytokine production.

中文摘要………………………………………………………………...…………..1
英文摘要……..………………………………………………………….…………..2
第一章 研究背景
第一節 精神活化藥物（psychoactive drugs）………………………..…….3
第二節 2C-T-2與2C衍生物.…………….…………………….……………6
第三節 精神活化藥物的藥性作用………………………………………...…11
第四節 免疫與神經內分泌的交互作用…………………………………...…12
第二章 研究動機與目的………….……..…….........................15
第三章 實驗材料與方法
第一節 實驗設計…………….………………………....……….........…...16
第二節 實驗材料…………….………………………...………….......…...…19
第三節 實驗藥品………….………………………..…………........…...….21
第四節 實驗試劑......................................... …...….22
第五節 實驗儀器..........................................…...….26
第六節 實驗方法..........................................…...….28
第四章 結果
第一節 2C-T-2代謝與藥物動力學……………..……………..……..…........34
第二節 單次餵食2C-T-2之小鼠整體免疫活性的評估……..……...……....35
第三節多次餵食2C-T-2之小鼠活體免疫活性的分析.…………………........38
第四節 2C-T-2抑制NO產生作用機制探討.............................41
第五章 討論...................................................45
第六章 總結...................................................51
參考文獻…....................................................52

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