甲苯是被廣泛使用的有機溶劑，因為便宜、易取得而常被濫用。吸食甲苯後會造成類似給予Ketamine與MK-801等N-methyl-D-aspartate (NMDA)受體拮抗劑造成的行為異常，如：認知記憶損傷、社交互動缺失以及運動協調障礙等。從電生理研究得知甲苯可以抑制NMDA受體調節的電流，本研究使用三室社交試驗測試甲苯是否類似NMDA受體拮抗劑會造成社交行為缺失，並釐清一個結合在NMDA受體甘胺酸結合位點的部分致效劑二甲基甘胺酸(N,N-dimethylglycine, DMG)是否可以減緩急性和青春期暴露甲苯誘發的行為異常。急性與青春期暴露甲苯在三室社交試驗顯示會造成社交能力以及社交新穎性損傷。DMG可以減緩給予一劑甲苯所誘發之社交缺失、長期認知記憶損傷以及運動協調障礙。除了減緩甲苯誘發之運動不協調不受影響外，DMG改善認知及社交能力缺失的效果會因為預先給予甘胺酸結合位點抑制劑(7-chlorokynureic acid, 7-CK, 1 mg/kg)而消失。為了測試DMG在青春期暴露甲苯的影響，將滿五週齡之小鼠在出生後38-40天以腹腔注射分別給予玉米油或甲苯(600 mg/kg)，出生後41-42天與45-49天給予甲苯(750 mg/kg)。DMG (30或100 mg/kg)則是在給予甲苯前30分鐘以同時給予的方式，或是在甲苯停藥後14天，連續給予14天的方式給藥。接著進行三室社交試驗、新物體辨識能力試驗、社交互動行為試驗以及運動活性能力試驗，以及給予5-HT2A受體致效劑1-[2,5-dimethoxy-4-iodophenyl]-2-aminopropane (DOI) 觀察小鼠頭部抽搐反應。結果顯示DMG可以預防和改善青春期暴露甲苯所誘發之社交缺失、長期認知記憶損傷以及DOI誘發之頭部抽搐反應，但對於運動活性能力沒有影響。這些結果顯示DMG可以減輕且改善急性與青春期暴露甲苯所造成之行為異常，顯示DMG對於在職業性或蓄意暴露甲苯的人們是有益的。

Toluene is a widely used and common abused organic solvent because it is readily available and inexpensive. Inhalation of toluene results in behavioral disturbances including cognitive memory impairments, social deficits and motor incoordination. These effects are similar to those induced by N-methyl-D-aspartate (NMDA) receptor antagonists, such as ketamine, PCP or MK-801. As toluene inhibits NMDA receptor-mediated currents, the present study examined whether toluene, similar to NMDA receptor antagonists, impaired social behaviors in the three-chamber social test and determine if N,N-dimethylglycine (DMG), a derivative of the amino acid glycine and a NMDA receptor glycine binding site partial agonist, could reduce the acute or adolescent toluene exposure-induced behavioral aberrations. Acute and adolescent toluene exposure impaired sociability and social novelty in the three-chamber social test. DMG could reduce social deficits, cognitive memory impairments and motor incoordination induced by one injection of toluene. In addition, the beneficial effects of DMG on toluene-induced cognitive and social deficits were disappeared by the pre-treatment of NMDA receptor glycine binding site inhibitor, 7-chlorokyureic acid (7-CK, 1 mg/kg, i.p.). To test the effects of DMG on adolescent exposure, mice were exposed to toluene (600 mg/kg, i.p.) during postnatal days (PN) 38–40 and toluene (750 mg/kg, i.p.) during PN41–42 and PN45–49. DMG (30 or 100 mg/kg, i.p.) was either co-treated with toluene or given 14 days after toluene withdrawal for 14 days. The three-chamber social test, novel object recognition task, social interaction test and locomotor activity test were monitored. Further, these mice were administered with 1-[2,5-dimethoxy-4-iodophenyl]-2-aminopropane (DOI), a 5-HT2A agonist, to induce head twitch responses. Pretreatment and subsequent treatment of DMG reduced the social deficits, memory impairments and DOI-induced head twitch responses, but not locomotor activity in adolescent toluene-exposed mice. These results revealed that DMG could ameliorate behavioral disturbances induced by toluene, either acute or during and after adolescent exposure, suggesting DMG might be beneficial to those who occupationally or intentionally exposed to toluene.

摘要 i
Abstract ii
目錄 v
圖表目錄 vi
壹、 背景介紹 1
一、 甲苯 1
1. 甲苯吸收與代謝 1
2. 甲苯神經毒性 2
3. 甲苯的作用機制 4
二、 二甲基甘胺酸 8
貳、 研究動機與實驗目的 10
參、 實驗設計 12
肆、 研究目標 13
伍、 實驗材料與方法 14
一、 實驗動物 14
二、 藥品配製 14
三、 實驗儀器 15
四、 實驗流程 15
五、 實驗方法 19
陸、 實驗數據分析 22
柒、 實驗結果 23
一、 甲苯對於小鼠三室社交試驗劑量效應的影響 23
二、 DMG是否可以減緩小鼠急性暴露甲苯所誘發之行為異常 24
三、 7-CK對於DMG減緩小鼠急性暴露甲苯所誘發之行為異常的影響 25
四、 同時給予DMG與青春期甲苯暴露是否可以減緩小鼠持久性行為異常 27
五、 同時給予DMG與青春期甲苯暴露是否可以減緩小鼠對DOI的高敏感性 29
六、 DMG是否可以減緩小鼠青春期暴露甲苯所誘發之持久性行為異常 29
七、 DMG是否可以減緩青春期甲苯暴露小鼠對DOI的高敏感性 32
捌、 討論 33
一、 DMG對於急性暴露甲苯所誘發之行為異常 34
二、 DMG對於青春期暴露甲苯所誘發之持久性行為異常 36
玖、 結論 39
壹拾、 參考文獻 40
壹拾壹、 圖表 49

中文部分
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