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研究生:吳小華
研究生(外文):Shiao-Hua Wu
論文名稱:積核中第二型鈣離子/鈣制素依存型蛋白質激酶在甲基安非他命誘發大白鼠產生制約性場地偏好學習表現中所扮演的角色
論文名稱(外文):Calcium /calmodulin-dependent protein kinase in Ⅱnucleus accumbens is involved in methamphetamine-induced conditioned place preference
指導教授:潘懷宗潘懷宗引用關係
指導教授(外文):Wynn H. T. Pan
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:2004
畢業學年度:92
語文別:中文
論文頁數:58
中文關鍵詞:第二型鈣離子/鈣制素依存型蛋白質激酶制約性場地偏好學習甲基安非他命積核
外文關鍵詞:CaMKⅡconditioned place preferencemethamphetaminenucleus accumbens
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許多的文獻報告指出海馬迴及杏仁核中的CaMKⅡ蛋白質參與調控精神刺激劑所誘發的制約性場地偏好行為。積核這個傳統被認為和藥物迴饋作用相關的核區,近年來也被發現其參與記憶的提取過程。
本篇論文利用甲基安非他命(1mg/kg) 誘發動物產生制約性場地偏好,藉以探討和藥物相關連結的環境刺激是否藉由改變積核中CaMKⅡ的活性進而調控制約性場地偏好的行為表現。
結果顯示動物在經過八天共四次的甲基安非他命制約性訓練,在偏好測試前積核雙側給予CaMKⅡ蛋白質抑制劑KN-93 (5μg/side)可以觀察到動物的偏好行為表現受到抑制。而當動物在受到和藥物相關連結的的環境刺激後(此時並未給與甲基安非他命),其積核中的CaMKⅡ蛋白質活性和沒有受到環境刺激的動物相較有明顯下降的情形,但CaMKⅡ蛋白質總量則沒有變化,顯示動物在表現偏好行為時會消耗大量活化的CaMKⅡ蛋白質。除此之外,積核雙側給予CaMKⅡ蛋白質抑制劑KN-93 的確可以使CaMKⅡ蛋白質活性下降,而給完抑制劑並做完偏好測試觀察,發現並不會使得蛋白質活性下降趨勢更明顯,因此我們認為CaMKⅡ蛋白質所調控的下游訊息傳遞須要足夠的活化量才能啟動。進一步在積核雙側事先給予NMDA 接受器的拮抗劑L-AP-5 (0.2μg/side) 發現動物的偏好行為有減弱的現象,但對於積核中的CaMKⅡ蛋白質活性下降的情形則沒有影響。
由以上實驗結果顯示,和藥物相關聯結的環境刺激會藉由消耗積核中的CaMKⅡ蛋白質活性及活化NMDA 接受器進而調控甲基安非他命所誘發的制約性場地偏好行為表現。
Previous studies have shown that calcium/calmodulin- dependent protein kinase (CaMKⅡ ) in hippocampus and amygdala play a critical role inpsychostimulant-induced conditioned place preference (CPP). Since the nucleus accumbens (NAc) plays an important role in behavior activation, appetitive motivation and memory retrieval. Therefore, we attempted to investigate the role of CaMKⅡ in NAc in methamphetamine (MA; 1mg/kg)–induced CPP expression in this study.
Our results showed that intra-accumben infusion of CaMKⅡ protein inhibitor KN-93 (5µg/per side) could abolished MA-induced CPP expression and the activity of CaMKⅡ (phosphorylation CaMKⅡ/total amount CaMKⅡ) significantly decreased in NAc after CPP test as compared to the rats without CPP test. It seems to us that conditioned stimuli could enhance calcium-dependent neurotransmitter release by exhausting phoshorylated CaMKⅡprotein. Additionally, after intra-accumbens infusion of KN-93, we observed a decrease of CaMKⅡ activity in NAc so that the MA-induced CPP expression was abolished. However even did the CPP test after infusion of KN-93 into NAc could not further decrease the CaMKⅡ activity. It meant that CaMKⅡinvolved signaling could not be started until having enough activity ofCaMKⅡ. Furthermore, L-AP-5 (0.2µg/site), an NMDA receptor antagonist, was infused into NAc before CPP test, and then both the activity of CaMKⅡand CPP expression were monitored. The results showed that intra-accumbens infusion of L-AP-5 could attenuate MA-induced CPP expression with a decrease of CaMKⅡ activity, which decrease is the same as the control group.
These results, taken together, indicate that the CaMKⅡ protein and the NMDA receptor in NAc were both involved in MA-induced CPP expression.
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