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系統識別號 U0026-0812200914092160
論文名稱(中文) 大麻物質CB1受體在恐懼記憶消除作用之角色
論文名稱(英文) The role of cannabinoid CB1 receptors in the extinction of fear memory
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 96
學期 2
出版年 97
研究生(中文) 林惠菁
研究生(英文) Hui-Ching Lin
學號 s5892122
學位類別 博士
語文別 中文
論文頁數 161頁
口試委員 口試委員-黃阿敏
口試委員-郭余民
召集委員-吳豐森
指導教授-簡伯武
口試委員-符文美
口試委員-曾清俊
口試委員-陳慶鏗
中文關鍵字 大麻物質CB1受體  恐懼記憶消除作用 
英文關鍵字 Cannabinoid CB1 receptors  Extinction of fear memory 
學科別分類
中文摘要 創傷後壓力症候群(post-traumatic stress disorder),是指當人們經歷重大創傷事件之後,會因為過度憂慮進而衍生出精神官能症的相關疾病。恐懼記憶消除(Extinction ) 對於病人減緩或改善情緒相關病症非常重要,然而其分子機制,有待進ㄧ步釐清。本研究採用古典恐懼制約動物模式,給予燈光作為制約式刺激(conditioned stimulus[CS]),再配合足部電擊的非制約式刺激(unconditioned stimulus [US]),經過連續配對訓練後,當再次給予制約式刺激(CS)時,動物會產生恐懼驚嚇的生理反應。當一直持續的就只有給予燈光訓練,足部電擊不出現時,動物就會學習到不再害怕,這樣的學習過程稱為恐懼記憶消除作用。

大麻被用來當作改變心智狀態及造成亢奮等非醫療用途已歷史久遠。在內側前額葉皮質注射CB1受體拮抗劑,會阻斷CS-alone 所導致恐懼記憶的消除作用。若給予CB1受體致效劑,則會增進消除恐懼記憶的作用。在內側前額葉皮質投予內生性大麻物質回收抑制劑和抑制内生性大麻代谢的藥物也會降低動物恐懼驚嚇反應。另外, ERK蛋白激酶抑制劑會阻斷CB1受體降低動物恐懼驚嚇反應的表現,也會抑制CB1受體致效劑導致磷酸化ERK蛋白激酶增加的表現。這部分結果顯示,內側前額葉皮質CB1受體的活化進而增加磷酸化ERK蛋白激酶的表現參與在消除恐懼記憶作用機制中。在內側前額葉皮質投予CB1受體致效劑,取杏仁核腦區組織分析現,其並不影響恐懼記憶引起AMPA受體的GluR1次體增加的表現;但GABAA 受體鑲嵌的蛋白Gephyrin、GABAA 受體的γ2次體 和GABAA 受體的2次體的表現增加。這部分結果顯示,大腦內側前額葉皮質大麻CB1受體的活化並降低恐懼記憶的表現,主要是透過加強抑制性GABAergic神經傳遞物質的作用,而影響中樞杏仁核所媒介的恐懼記憶表現。

長期投予CB1受體致效劑WIN產生CB1受體耐受性老鼠,發現其會阻抗經由CS-alone trials 造成動物恐懼記憶降低之作用。CB1受體耐受性的老鼠,對CB1受體致效劑WIN抑制GABAergic神經傳遞物質的作用和磷酸化ERK蛋白激酶的活化皆產生阻抗現象。因此長期投予大麻來治療情緒方面疾病,其療效還是必需評估的。

我們發現將恐懼記憶重新喚起後,在杏仁核二侧注射CB1受體致效劑可以阻斷恐懼記憶再固化(re-consolidation)的過程。CB1受體致效劑阻斷恐懼記憶再固化作用,降低動物恐懼反應,是不會有再復發和自發性回復(spontaneous recovery)之表現。

利用電生理紀錄法、生物化學的分析和動物行為模式研究發現,我們發現動物消除恐懼記憶後,會加強抑制性神經傳遞物質的作用,但不改變恐懼記憶導致興奮性神經傳遞物質增加的表現。

綜合以上結果,我們證實了內側前額葉皮質CB1受體的活化以及內側前額葉皮質-中樞杏仁核的神經迴路在消除恐懼記憶作用中扮演非常重要的角色。內側前額葉皮質的CB1受體對於消除恐懼記憶的作用機制是透過抑制GABA神經傳遞物質和增加磷酸化ERK蛋白激酶以增加內側前額葉皮質整體活性,進而影響到中樞杏仁核所媒介的恐懼記憶表現。也發現CB1受體致效劑在中樞杏仁核的作用是會阻斷恐懼記憶的再固化的過程,恐懼反應不會有再復發和自發性回復之表現。最後,我們研究也顯示,確立在杏仁核體恐懼記憶的消除,是透過增強了抑制性神經傳遞物質的作用,並不是影響原有CS-US連結時興奮性神經傳遞物質增加的表現。
英文摘要 People with post-traumatic stress disorder (PTSD) usually experienced traumatic events. PTSD patients may have excessive anxiety that becomes psychiatric disorders. Therefore, extinction of fear memory is very important because it could contribute to therapeutic concepts for the treatment of fear- related disorders. The Classical fear conditioning paradigm is used in our research. In classical fear conditioning, a light stimulus that is initially neutral for the animal, serves as the conditioned stimulus (CS). When this stimulus is temporally paired with a footshock (the unconditioned stimulus [US]), the CS becomes a cue for a conditioned fear response. Extinction is a behavioral paradigm in which the conditioned response gradually disappears if the animals receive the cue only without pairing with a shock.

Cannabinoids have been used as medicines for thousands of years to treat diseases. We showed that infusion of CB1 receptor antagonist into the mPFC blocked CS alone-induced reduction of fear-potentiated startle. Conversely, CB1 agonist facilitated extinction of fear memory. The effect of CB1 agonists was mimicked by the endocannabinoid (eCB) uptake or fatty acid amidehydrolase (FAAH) inhibitors. ERK kinase inhibitor blocked the effect of CB1 agonist on fear-potentiated startle at the same dose that inhibited CB1 agonist-induced ERK phosphorylation. These results suggest that CB1 receptors within the mPFC, acting through phosphorylation of ERK are involved in the extinction of conditioned fear. Furthermore, infusion of CB1 agonists into the mPFC did not affect conditioning induced increase in GluR1 within the amygdala; but the protein levels of gephyrin as well as 2 and 2 subunits of GABAA receptor were increased in the amygdala. These results suggest that CB1 agonist reduced fear memory mainly affect inhibitory GABAergic transmission in the amygdala.

We showed that chronic administration of synthetic cannabinoid agonist WIN produced a functional tolerance to the extinction of conditioned fear. Furthermore, this CB1 receptor tolerance appears to prevent WIN inhibition of GABAergic transmission and activation of ERKs in the mPFC. Thus, it should be cautious that long-term marijunan use will limit their anti-anxiety activity.

We showed that bilateral infusion of CB1 receptor agonists into the amygdala after memory reactivation blocked reconsolidation of fear memory. Concomitant with block of reconsolidation, CB1 agonist-treated animals did not exhibit shock-induced reinstatement or spontaneous recovery of fear.

By using electrophysiological, biochemical and behavioral assessments, we also report that that the extinction does not affect conditioning induced increased excitatory transmission but significantly increases inhibitory tone in the amygdala neurons.

In summary, we provided evidence suggesting that CB1 receptors within the mPFC and mPFC-amygdala circuitry are important to the regulation of fear extinction. Extinction training increased neural activity in the mPFC by decreasing GABAergic inhibition and activating ERKs that may result in the inhibition of amygdala-mediated expression of conditioned fear. Secondly, reactivation-induced amnesia by CB1 agonists within the amygdala is attributable primarily to blockade of re-consolidation Finally, we confirmed that extinction increases inhibitory tone rather than erasing the original excitatory association in the amygdala neurons.
論文目次 目錄(Contents)
中 文 摘 要..............................................1

英 文 摘 要..............................................4

縮 寫 檢 索 表...........................................7

第一章 緒論..............................................9

第二章 研究方法與材料...................................18

2.1實驗動物.............................................19
2.2藥品與試劑來源.......................................19
2.3實驗方法.............................................20

2.3.1 腦立體定位手術(Stereotxic Surgery)..............20
2.3.2 恐懼老鼠動物模式(Classical fear conditioning)...20
2.3.3 組織切片(Histology)...............................24
2.3.4 甩尾試驗分析(Tail Flick Test).....................24
2.3.5 細胞外電生理活性記錄(Extracellular recording) ........................................................25
2.3.6 細胞內電生理活性紀錄(Intracellular recording) ........................................................25
2.3.7 全細胞膜片箝記錄 (Whole cell patch clamp).........27
2.3.8 腦切片之製作 ( Preparation of brain Slice ).......28
2.3.9 全細胞萃取(Whole cell lysate)之製備...............28
2.3.10 突觸神經體之製備(Synaptoneurosome Preparation)...29
2.3.11 細胞膜蛋白標定(Surface biotinylation)............30
2.3.12 西方點墨法(Western blotting analysis)..........30
2.3.13 統計分析(Statistic analysis).....................34

第三章 大麻類物質CB1受體於內側前額葉皮質恐懼記憶之消除作用所扮演的角色 (Essential role for prefrontal cortex CB1 receptors in the extinction of fear memory)..............................35

3.1 緒言................................................36
3.2 實驗結果............................................38
3.2.1內側前額葉皮質注射CB1受體拮抗劑,會阻斷CS alone降低恐懼 ........................................................38
3.2.2內側前額葉皮質注射低劑量CB1受體致效劑,會增進恐懼記憶之 消除作用................................................39
3.2.3內側前額葉皮質投予較高劑量CB1受體致效劑,可以降低動物 恐懼驚嚇反應............................................40
3.2.4在大腦內側前額葉皮質增加內生性大麻類物質表現會降低動物 恐懼驚嚇反應............................................42
3.2.5於內側前額葉皮質投予CB1受體致效劑或CB1受體拮抗劑,不會影響動物的shock reactivity和baseline startle activity.....43
3.2.6大麻類物質降低恐懼記憶是不需條件制約的刺激 (conditioning stimulus).................................43
3.2.7在大腦內側前額葉皮質投予CB1受體致效劑的作用是需要 ERK蛋白激酶的參與.......................................44
3.2.8在大腦內側前額葉皮質區域,CB1受體致效劑會抑制GABAergic神經傳導作用..............................................46

3.3 討論................................................48

第四章 內側前額葉皮質CB1受體活化消除恐懼記憶之作用,對於杏仁核突觸神經傳遞之影響 (Effects of intra-mPFC infusion of CB1 receptor agonists on the synaptic neurotransmission in the amygdala)........62

4.1 緒言..............................................63
4.2 實驗結果..........................................66

4.2.1內側前額葉皮質注射CB1受體致效劑,無法影響恐懼記憶所導致AMPA受體的GluR次體增加的表現.........................66
4.2.2內側前額葉皮質注射投予CB1受體致效劑,Gephyrin的表現增加 .......................................................67
4.3.3內側前額葉皮質注射投予CB1受體致效劑,GABAA 受體γ2次體表現增加.................................................67

4.3 討論...............................................69


第五章 探討長期投予CB1受體致效劑所產生恐懼記憶消除之阻抗現象
(Resistance to the extinction of fear memory after chronic administration of CB1 receptor agonist to the rat).....75

5.1 緒言...............................................76
5.2 實驗結果...........................................78

5.2.1長時間投予WIN造成CB1受體耐受性之大鼠,對於大麻物質降低熱痛覺之作用產生耐受性...................................78
5.2.2長時間給予WIN造成CB1受體耐受性之大鼠,對恐懼記憶消除具有阻抗作用...............................................79
5.2.3長時間投予造成CB1受體耐受性之大鼠,對於恐懼記憶消除產生阻抗現象,是可回復的...................................80
5.2.4長時間投予造成CB1受體耐受性之大鼠,對經由內側前額葉皮質注射低劑量CB1受體致效劑所增進恐懼記憶消除作用之現象,會產生阻抗作用.................................................80
5.2.5長時間投予WIN造成CB1受體耐受性之大鼠,對經由內側前額葉皮質投予 CB1受體致效劑所降低的恐懼驚嚇反應產生阻抗作用...81
5.2.6長時間投予WIN造成CB1受體耐受性之大鼠,對經由內側前額葉皮質投予CB1受體致效劑所降低的恐懼驚嚇反應產生阻抗現象,是可回復的.....................................................82
5.2.7長時間投予WIN而造成CB1受體耐受性之大鼠,對於CB1受體致效劑活化ERK蛋白激酶的表現,產生阻抗作用..................82
5.2.8長時間投予WIN造成CB1受體耐受性之大鼠,對於CB1受體致效劑抑制GABAergic神經傳導作用,產生阻抗現象................83
5.2.9長期投予WIN造成CB1受體耐受性之大鼠,CB1受體表現減少 .......................................................84
5.3 討論...............................................86

第六章 大麻類物質CB1受體致效劑在中樞杏仁核抑制恐懼記憶再固化的過程(Effects of intra-amygdala infusion of CB1 receptor agonists on the re-consolidation of fear-potentiated startle) .......................................................99

6.1 緒言...............................................100
6.2 實驗結果...........................................102

6.2.1在training前,在中樞杏仁核注射CB1受體致效劑,會干擾恐懼記憶的獲得過程.........................................102
6.2.2 CB1受體致效劑的處理並不會傷害中樞杏仁核神經元....102
6.2.3在training後和testing前,在中樞杏仁核注射CB1受體致效劑,不會干擾恐懼記憶的固化及恐懼記憶的表現過程.............103
6.2.4在testing後經由中樞杏仁核注射CB1受體致效劑,會干擾恐懼記憶的再固化過程.........................................103
6.2.5中樞杏仁核注射CB1受體致效劑干擾恐懼記憶的表現,要在恐懼記憶重新被喚起後給予,才會有效果.......................104
6.2.6中樞杏仁核CB1受體致效劑阻斷恐懼記憶的再固化過程,恐懼 反應不會有再復發和自發性回復的表現.....................105
6.2.7中樞杏仁核注射CB1受體致效劑不會影響動物的shock reactivity和baseline startle activity..................106
6.2.8中樞杏仁核投予CB1受體致效劑,會降低恐懼訓練後AMPA受體的GluR1次體增加的表現....................................107
6.3 討論...............................................108

第七章 恐懼記憶之消除作用是一種新的抑制性學習,還是一種遺忘的機制(Is extinction a new inhibitory learning or the unlearning)............................................122

7.1 緒言..............................................123
7.2 實驗結果..........................................124

7.2.1經由恐懼配對訓練後,動物恐懼驚嚇反應表現增加......124
7.2.2經由恐懼配對訓練後,興奮性神經傳遞物質增加........124
7.2.3經由恐懼配對訓練後,抑制性神經傳遞物質減少........126
7.2.4動物進行extinction trials訓練後,動物恐懼驚嚇反應降低 .......................................................127
7.2.5動物消除恐懼記憶後,對於興奮性神經傳遞物質之影響..127
7.2.6動物消除恐懼記憶後,對於抑制性神經傳遞物質之影響..127

7.3 討論...............................................129

第八章 結論............................................137

參 考 文 獻............................................146

著 作..................................................156

圖 表 索 引............................................158
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