大量酒精使用是台灣東部地區一項重要的健康問題，在臨床上又與合併服用抗憂鬱劑或鎮靜劑有密切相關。最常被使用的抗憂鬱劑有三或四環抗鬱劑(Tricyclic or Tetracyclic antidepressant, TCA )、選擇性血清素再吸收抑制劑(Selective Serotonin Reuptake Inhibitor, SSRI)和血清素及正腎上腺素再吸收抑制劑(Norepinephrine Serotonin Reuptake Inhibitor, SNRI)等，許多報告也指出血清素(serotonin, 5-HT)對免疫功能有密切的影響，而急性與慢性酒精中毒對個體的免疫功能，原本就有兩極性的不同生理作用及反應，雖然抗憂鬱劑與酒精同時服用是憂鬱症病人常見的現象，但目前卻尚未有研究指出選擇性血清素再吸收抑制劑對大量酒精使用下的個體，其免疫或生理功能上的影響如何。因此，本研究將以大鼠模式進行四階段的相關探討，分別要探討的議題是：一、了解酒精暴露量與生理及免疫作用的關係。二、了解大量酒精使用合併服用抗憂鬱劑的生理及免疫作用的影響。三、比較大量酒精使用合併服用不同類型抗憂鬱劑的生理及免疫作用差異之機轉。四、了解大量酒精使用合併服用抗憂鬱劑下心臟自主神經的調節反應。研究中以注射酒精的方式引發酒精中毒，收集心跳、血壓、體溫等生理參數，測量血液之血球檢測、生化檢測、病理切片與免疫化學組織染色，以了解SSRI藥物與酒精合併使用下的免疫影響與生理作用。
實驗鼠被分成只用SSRI組，只用酒精組(酒精5克/公斤，持續靜脈注射3小時) 或 SSRI 加酒精組(先口服SSRI再加酒精5克/公斤處理)。研究結果顯示，在酒精5克/公斤靜脈注射3小時後，血液中酒精濃度均超過100毫克/公升。腎臟功能和胰臟功能指標在SSRI加酒精組比只用酒精組低。然而，在9小時之後腫瘤壞死因子、肝功能和心臟酶素均比酒精組高。目前的結果認為，加 SSRI 的治療後對大量酒精使用具有減輕腎臟和胰臟損傷之作用，但是在9小時之後卻增加了肝臟及心臟的損傷。另外，當大量酒精使用合併服用TCA類的maprotiline、SSRI類的paroxetine和SNRI 類的duloxetine等三種不同類型藥物時，顯示都有抑制炎症反應的效果。在發炎前期3小時有最佳的抗發炎效果，因為藥物抑制作用的關係，可以監測到相對降低的IL-6和TNF-α濃度。由一系列的研究成果中，總結而言，可歸納出四個主要的發現：(一)三種類型藥物都對胰臟和腎臟等器官損傷有抑制促發炎物質的效果。(二) 三種類型藥物都對肺臟產生增加損傷的情形。(三)對於心臟和肝臟等器官損傷依藥物種類而有所差異，24小時後SSRI表現有抑制發炎、減輕損傷的效果，但是TCA及SNRI等兩種藥物則顯示有增加發炎與損傷的效果。(四)發現SSRI類的paroxetine藥物是可以改善因大量酒精暴露所引起過低心率變異性等之心臟自主神經調適能力問題，以及增加交感神經的活性。本研究結果將可提供醫護人員未來在照顧與治療憂鬱症病人時的藥物使用上的參考。

關鍵詞：憂鬱症、三或四環抗鬱劑、選擇性血清再吸收抑制劑、血清素及正腎上腺素再吸收抑制劑、大量酒精使用、免疫功能、心率變異性、自主神經調節

Heavy alcohol use is a major health problem in eastern Taiwan, which is often used together with antidepressant or sedation. TCA (Tricyclic or Tetracyclic antidepressant), SSRI (Selective Serotonin Reuptake Inhibitor) and SNRI (Norepinephrine Serotonin Reuptake Inhibitor) are the most common antidepressants prescribed in Taiwan. The immunology and physiology during acute alcohol intoxication are different from those during chronic alcohol intoxication. Although combined use of alcohol and antidepressant are common in clinical scenario, little is known about the effects of antidepressants on immunology and physiology during heavy alcohol use.
This study explored the effects of antidepressants on immunology and physiology in rats during heavy alcohol use. To reach this aim, immune and physiological responses at different alcohol dosages, and effects of TCA, SSRI and SNRI during heavy alcohol use were examined. In addition, to explore the effects of SSRI on cardiac autonomic regulation under heavy alcohol exposure.Alcohol intravenous infusion was used to induce heavy alcohol use in the conscious rats and the indicators included heart rate, blood pressure, body temperature, blood CBC, blood chemistry analysis, pathological stain, and immunohistologicalchemistry stain (IHC stain).
Rats were randomized to SSRI, alcohol (EtOH 5 g/kg, a constant intravenous infusion for 3 hours) and SSRI+alcohol (SSRI oral intake followed by EtOH 5 g/kg) group. The renal and pancreas function of SSRI+alcohol group were lower than those of the alcohol group in the early stage. After 9 hours, however, liver and heart function o fthe SSRI+alcohol group were higher than those of the alcohol group. These findings indicated that SSRI treatment decreased renal and pancreas damage soon after heavy alcohol use, but increased liver and heart injury when the intoxication prolonged. Maprotiline (TCA), Paroxetine (SSRI) and Duloxetine (SNRI) demonstrated anti-inflammatory effects during heavy alcohol use, most effective at the first 3 hours of inflammation. I concluded that during heavy alcohol use, TCA, SSRI and SNRI demonstrated an anti-inflammatory effect on pancreas and kidney and had injury effect on lung but had diverse contributions on heart and liver damage. SSRI increased sympathetic activity and demonstrated an improvable effect on the over-low HRV, induced by the heavy alcohol exposure. SSRI demonstrated an anti-inflammatory effect on heart and liver 24 hours after heavy alcohol use, but TCA and SNRI enhanced the inflammation. The findings may be used as references when treating depression patients exposed to heavy alcohol use.


Keywords: depression, tricyclic or tetracyclic antidepressant, selective serotonin reuptake inhibitor, norepinephrine serotonin reuptake inhibitor, heavy alcohol use, immunology function, heart rate variability, cardiac autonomic regulation

目錄
上網授權書
論文口試委員會審定書
致謝辭…………………………………………………………………………I
中文摘要………………………………………………………………………II
英文摘要………………………………………………………………………IV
縮寫表…………………………………………………………………………VI
第一章 前言 ........................................1
第一節 研究背景與動機 ................................1
第二節 研究問題與目的 ................................2
第三節 名詞解釋 .....................................4
第二章 文獻查證 .....................................6
第一節 流行病學 .....................................6
第二節 酒精對免疫功能與生理的影響 ......................7
第三節 憂鬱症和免疫功能的關聯 .........................9
第四節 常用抗憂鬱劑種類 ..............................10
第五節 抗憂鬱劑對免疫功能的影響 .......................12
第六節 抗憂鬱劑與酒精的相關...........................13
第七節 心率變異性對免疫功能的影響......................14
第八節 常用動物模式 .................................15
第三章 材料與方法......................................18
第一節 實驗材料......................................18
第二節 實驗流程......................................19
第三節 酒精及藥物給予模式..............................19
第四節 檢驗項目......................................20
第五節 統計分析......................................21
第六節 實驗分組......................................22
第四章 結果與討論......................................24
第一節 建立大量酒精使用的動物模式.......................24
第二節 探討抗憂鬱劑在大量酒精使用下動物的生理作用..........39
第三節 比較多種類型抗憂鬱劑在大量酒精使用動物模式中的作用差異..........52
第四節 探討SSRI類型抗憂鬱劑在大量酒精使用下心臟自主神經功能的調節反應...63
第五章 總結論與未來研究方向 ......................................75
參考文獻 ........................................................80
圖表目錄
圖 1大量酒精使用之實驗流程…………………………………………………………………95
圖 2、大量酒精使用前後服用SSRI抗憂鬱劑之實驗流程…………………………………96
圖 3、比較大量酒精使用後服用三種類型抗憂鬱劑之實驗流程…………………………97
圖 4、服用抗憂鬱劑後大量酒精使用之實驗流程…………………………………………98
圖 5、不同酒精劑量下ETOH濃度變化……………………………………………………99
圖 6、不同酒精劑量下平均動脈壓MAP變化………………………………………………99
圖 7、不同酒精劑量下GOT變化……………………………………………………………100
圖 8、不同酒精劑量下GPT變化……………………………………………………………100
圖 9、不同酒精劑量下BUN變化……………………………………………………………101
圖 10、不同酒精劑量下Cre變化…………………………………………………………101
圖 11、不同酒精劑量下CPK變化…………………………………………………………102
圖 12、不同酒精劑量下LDH變化…………………………………………………………102
圖 13、不同酒精劑量下Amylase變化……………………………………………………103
圖 14、不同酒精劑量下血糖Glucose變化………………………………………………103
圖 15、不同酒精劑量下，3小時間隔之血中TNF-α濃度………………………………………104
圖 16、不同酒精劑量下，3小時間隔之血中IL-10濃度………………………………………104
圖 17、不同酒精劑量下，BALF液中TNF-α濃度………………………………………………105
圖 18、不同酒精劑量下，BALF液中IL-10濃度………………………………………………105
圖 19、不同酒精劑量下，肝臟和肺臟的病理切片檢查及損傷評估……………………………106
圖 20、大量酒精使用前後服用SSRI抗憂鬱劑，ETOH濃度變化………………………………107
圖 21、大量酒精使用前後服用SSRI抗憂鬱劑，GOT變化……………………………………108
圖 22、大量酒精使用前後服用SSRI抗憂鬱劑，GPT變化……………………………………108
圖 23、大量酒精使用前後服用SSRI抗憂鬱劑，BUN變化……………………………………109
圖 24、大量酒精使用前後服用SSRI抗憂鬱劑，Creatinine變化…………………………109
圖 25、大量酒精使用前後服用SSRI抗憂鬱劑，CPK變化……………………………………110
圖 26、大量酒精使用前後服用SSRI抗憂鬱劑，LDH變化……………………………………110
圖 27、大量酒精使用前後服用SSRI抗憂鬱劑，Amylase變化……………………………111
圖 28、大量酒精使用前後服用SSRI抗憂鬱劑，3 小時之血中TNF-α濃度………………112
圖 29、大量酒精使用前後服用SSRI抗憂鬱劑，3小時之血中IL-6濃度…………………112
圖 30、大量酒精使用後服用抗憂鬱劑下，血中TNF-α濃度………………………………113
圖 31、大量酒精使用後服用抗憂鬱劑下，血中IL-6濃度…………………………………113
圖 32、大量酒精使用後服用抗憂鬱劑下，肝臟、腎臟、胰臟和肺臟等器官病理切片分析……114
國 33、大量酒精使用後服用三種類型抗憂鬱劑下，血中ETOH濃度變化…………………………115
圖 34、大量酒精使用後服用三種類型抗憂鬱劑下，BALF-WBC變化……………………………116
圖 35、大量酒精使用後服用三種類型抗憂鬱劑下，BALF-PLT變化……………………………116
圖 36、大量酒精使用後服用三種類型抗憂鬱劑下，GOT變化……………………………………117
圖 37、大量酒精使用後服用三種類型抗憂鬱劑下，GPT變化……………………………………117
圖 38、大量酒精使用服用三種類型抗憂鬱劑下，BUN變化………………………………………118
圖 39、大量酒精使用服用三種類型抗憂鬱劑下，Cre變化………………………………………118
圖 40、大量酒精使用後服用三種類型抗憂鬱劑下，CPK變化……………………………………119
圖 41、大量酒精使用後服用三種類型抗憂鬱劑下，LDH變化……………………………………119
圖 42、大量酒精使用後服用三種類型抗憂鬱劑下，Amylase變化………………………………120
圖 43、大量酒精使用後服用三種類型抗憂鬱劑下，Lipase變化………………………………120
圖 44、大量酒精使用後服用三種類型抗憂鬱劑下，血中TNF-α濃度……………………………121
圖 45、大量酒精使用後服用三種類型抗憂鬱劑下，血中IL-6濃度………………………………121
圖 46、比較在大量酒精使用後服用三種類型抗憂鬱劑下，心臟、肝臟、肺臟、胰臟和腎臟等器官的損傷變化………………………………………122
圖47、服用抗憂鬱劑後大量酒精使用下，血中酒精濃度BAC變化…………………………123
圖48、服用抗憂鬱劑後大量酒精使用下，平均動脈壓MAP變化……………………………123
圖49、服用抗憂鬱劑後大量酒精使用下，心跳速率HR變化…………………………………124
圖50、服用抗憂鬱劑後大量酒精使用下，心率變異量SDNN(HRV)變化……………………124
圖51、服用抗憂鬱劑後大量酒精使用下，相對心率變異量CVNN變化………………………125
圖52、服用抗憂鬱劑後大量酒精使用下，RMSSD變化………………………………………125
圖53、服用抗憂鬱劑後大量酒精使用下，低頻功率LF變化…………………………………126
圖54、服用抗憂鬱劑後大量酒精使用下，高頻功率HF變化…………………………………126
圖55、服用抗憂鬱劑後大量酒精使用下，低頻與高頻功率的比值LF/HF變化……………127

附表1、Definitions of Alcoholic Drinking…………………………………………………………………128
受稿論文 …………………………………………………………………………………………129

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