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系統識別號 U0026-0108201615360700
論文名稱(中文) 探討利莫那班和不同的提取-消除行為程序對於古柯鹼相關記憶之調控作用
論文名稱(英文) The modulatory effects of rimonabant and retrieval-extinction procedures on cocaine-associated memory in mice
校院名稱 成功大學
系所名稱(中) 心理學系
系所名稱(英) Department of Psychology
學年度 104
學期 2
出版年 105
研究生(中文) 張恆愛
研究生(英文) Heng-Ai Chang
學號 U76034017
學位類別 碩士
語文別 英文
論文頁數 88頁
口試委員 口試委員-曾淑芬
口試委員-許桂森
口試委員-游一龍
指導教授-胡書榕
中文關鍵字 古柯鹼  第一型大麻素受體  利莫那班  性別差異  提取-消除程序  場地制約偏好 
英文關鍵字 Cocaine  CB1 receptor  Rimonabant  Sex difference  Retrieval-extinction procedure  Conditioned place preference (CPP) 
學科別分類
中文摘要 古柯鹼復發的問題目前還沒有任何根治的方法。由於我們身體的內生性大麻素系統對於調控負責藥物上癮機制的酬賞系統扮演重要的角色,例如古柯鹼的成癮,許多研究認為第一型大麻素受體是未來發展治療古柯鹼濫用一個重要目標。此外,研究者認為藉由干擾記憶再穩固化歷程,藥物相關記憶可以被重新改寫。因此本研究目的旨在探討第一型大麻素受體對於公母鼠古柯鹼相關記憶的調控效果及其機制,並藉由以「提取-消除」程序為基礎的不同行為操弄程序,來觀察其對於公鼠古柯鹼相關記憶的影響。本研究使用場地制約偏好作為藥物相關記憶的動物模型來研究古柯鹼記憶的不同歷程。研究結果顯示,第一型大麻素受體拮抗劑/反向促進劑利莫那班對於促進公鼠古柯鹼相關記憶的穩固化歷程是透過第一型大麻素受體以及提升血液中皮質固醇來達成。然而在母鼠身上,利莫那班並沒有促進古柯鹼相關記憶穩固化。在公鼠身上,單獨阻斷代謝型麩醯胺酸受體5 (mGluR5) 能促進古柯鹼記憶的穩固化。然而代謝型麩醯胺酸受體5 (mGluR5) 並沒有和利莫那班共同產生協同性促進作用。為了檢視雌激素與第一型大麻素受體對於古柯鹼相關記憶的調控作用,我們使用去除性腺的母鼠作為研究對象。研究顯示利莫那班在去除性腺的母鼠身上能夠促進古柯鹼記憶的穩固化,如同我們先前在公鼠發現的效果。此外,在去除性腺的母鼠身上,單獨給予雌激素也能促進古柯鹼記憶的穩固化;然而當利莫那班和雌激素同時作用在去除性腺的母鼠身上時,反而損害了古柯鹼記憶的穩固化。對於去除性腺的母鼠而言,阻斷代謝型麩醯胺酸受體5 (mGluR5) 並不會影響古柯鹼記憶的穩固化歷程。接著我們採用三種不同的行為操弄程序並檢視它們消除古柯鹼相關記憶的效果,這三種行為程序分別是:消除程序、提取-消除程序以及和前者相反的消除-提取程序。結果顯示這三種行為程序的操弄對於破壞古柯鹼相關記憶並沒有顯著差異的影響。此外,這些不同行為程序的效果仰賴於所使用古柯鹼之劑量而有所不同。這些行為操弄能夠長時間阻斷高劑量古柯鹼所引發的記憶,然而對於低劑量古柯鹼建立的記憶,只有短暫壓抑的效果。總結來說,對公鼠而言,第一型大麻素受體藉由影響皮質固醇的釋放來調節古柯鹼相關記憶的穩固化。而在母鼠身上,雌激素主導了由第一型大麻素受體調控的古柯鹼相關記憶。這些結果顯示性別差異存在於第一型大麻素受體調控古柯鹼記憶的效果當中。最後,以不同的行為程序來操弄古柯鹼相關記憶的效果以及記憶再穩固化歷程的理論仍有待更深入的研究。
英文摘要 There are no effective pharmacological medications to treat cocaine relapse thus far. Since the endocannabinoid system plays an important role in modulating the reward system, which is responsible for cocaine addiction, the cannabinoid CB1 receptors are considered a promising target to treat cocaine addiction. On the other hand, some researchers believe that drug memory can be re-written via interfering memory reconsolidation. Therefore, the objectives of this study are to examine the role of the CB1 receptors in cocaine-associated memory in both sexes of C57BL/6N mice and to explore the efficacy of different retrieval-extinction behavioral procedures to eliminate cocaine-associated memory in male mice. We used conditioned place preference (CPP) as an animal model of drug-associated memory to verify the effects of pharmacological and behavioral manipulations in different memory processes. We found that the facilitating effect of a CB1 receptor antagonist/inverse agonist rimonabant on memory consolidation of cocaine-induced CPP was mediated by the CB1 receptors and by the elevated plasma level of corticosterone in male wild-type mice. However, there was no facilitating effect of rimonabant on cocaine CPP memory in female wild-type mice. Blockade of mGluR5 per se also facilitated cocaine memory in male mice. However, this enhancing effect was not synergistic with that of rimonabant. In order to examine the possible interaction between sex hormone and CB1 receptors, we used female ovariectomized (OVX) mice and found that rimonabant facilitated cocaine CPP memory in these mice. We also found that estrogen per se enhanced cocaine CPP memory in the OVX mice. However, combination of rimonabant with estrogen impaired the same memory. Furthermore, blockade of mGluR5 had no effect on cocaine memory in the OVX mice. We then used three different behavioral procedures (the extinction, the retrieval-extinction, and the extinction-retrieval procedures) to impair cocaine-associated memory. The results indicated that there was no significant difference of the memory-impairing effect on cocaine CPP among three behavioral procedures. However, we found that the effects of the behavioral procedures depended on the dosage of cocaine used in the CPP paradigm. The behavioral procedures had a long-lasting suppression on a high-dose cocaine-induced CPP, while their suppressing effect only transiently lasted on a low-dose cocaine-induced CPP. In conclusion, the CB1 receptors modulate cocaine-associated memory via corticosterone increase and mGluR5 signaling in male mice. In addition, estrogen interferes with the effect of CB1 receptors on cocaine-associated memory in female mice. Hence, there is a sex difference in the modulatory effect of CB1 receptors in cocaine-associated memory. Finally, the efficacy of different retrieval-extinction manipulations and memory reconsolidation theory awaits further investigation.
論文目次 口試合格證明
摘要...I
Abstract...III
Acknowledgements...V
Contents...VI
List of figures...VIII
List of tables...IX
1. Introduction...1
1.1 Cocaine addiction is hard to cure...1
1.2 Cannabinoids modulate cocaine-associated memory and play different roles in male and female...1
1.3 The mechanisms of CB1-mediated modulation of cocaine-associated memory...4
1.4 Involvement of mGluR5 in CB1-mediated modulation of cocaine-associated memory...5
1.5 Estrogen plays an important role in rimonabant’s modulatory effect of cocaine-associated memory in female mice...6
1.6 A novel behavioral procedure to treat cocaine addiction...8
2. A sex difference in the facilitating effect of rimonabant on cocaine-induced CPP and possible mechanisms involved...11
2.1 Materials and Methods...11
2.2 Results...20
2.3 Discussion...27
3. The effect of different retrieval-extinction procedures on cocaine-induced conditioned place preference...34
3.1 Materials and Methods...34
3.2 Results...40
3.3 Discussion...46
4. References...51
5. Figures and Legends...58
6. Tables...78
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