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研究生:江耀璋
研究生(外文):Yao-Chang Chiang
論文名稱:大麻CB1受體於甲基安非他命成癮過程中所扮演的角色:離體及活體研究
論文名稱(外文):The roles of cannabinoid CB1 receptors in methamphetamine sensitization: in vitro and in vivo study
指導教授:陳景宗
指導教授(外文):J. C. Chen
學位類別:博士
校院名稱:長庚大學
系所名稱:基礎醫學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2008
畢業學年度:96
論文頁數:113
中文關鍵詞:甲基安非他命大麻第一亞型受體行為致敏化多巴胺第二亞型受體啟動子訊號交互作用
外文關鍵詞:MethamphetamineCannabinoid CB1 receptorBehavioral sensitizationDARPP-32PromoterSignal cross-talk
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內生性大麻系統中,大麻受體可受到內生性大麻配體-極樂醯胺與2-花生四烯甘油所活化。生物體中目前已知存在有兩種大麻受體,分別為第一亞型與第二亞型,其中大麻第一亞型受體在中樞神經系統中大量表現,特別是在邊緣系統的前額葉皮質、海馬迴與依核等區域。大麻第一亞型受體在邊緣系統的表現是乎在於記憶與報償方面扮演重要的角色,而其在基底核與小腦區域的大量表現是乎也暗示著其參與基礎活動能力的調控。

本論文探討大麻第一亞型受體在於甲基安非他命行為致敏化中,活體與離體中所扮演的角色。前人研究發現,拮抗大麻第一亞型受體的活性可以壓制甲基安非他命所引發的自我取食行為,但其詳細機制仍然未知,因此引發我們繼續研究的動機。在我們第一個實驗中發現,長期甲基安非他命處理所引發的行為致敏化可以被局部在依核給予大麻第一亞型受體的拮抗劑 SR147778 所壓制,而此一壓制現象只存在於行為表現期。在行為啟始期時,無論在腹側被蓋區或是依核給予大麻第一亞型受體的拮抗劑,並不會影響甲基安非他命所引發的行為致敏化。而長期給予甲基安非他命在戒斷第七天的依核區域,亦同時觀察到大麻第一亞型受體的結合能力變佳、而表現量趨於減少的現象。其中表現量的部份,我們利用即時定量多聚合鏈反應系統也觀察到,此時大麻第一亞型受體的訊息核醣核酸表現量有顯著的減少。此外,利用依核腦切片實驗,我們發現於依核腦切片急性給予大麻第一亞型致效劑 CP55940,可以在甲基安非他命行為致敏化組中造成環磷酸腺苷隨致效劑劑量的增加而累積的現象,但在生理食鹽水對照組上則無此現象。因此,急性處理大麻受體致效劑於甲基安非他命處理組的依核腦切片,亦可對於下游DARPP-32/T34的磷酸化作用產生劑量效應 (10 nM – 10 μM);但在對照組中,只有高劑量 (10 μM) 的大麻受體致效劑可以誘發DARPP-32/T34的磷酸化。此外在行為致敏化組的依核腦切片上,亦可觀察到基礎的PP-2B的活性改變,同時大麻受體致效劑可以減低PP-2B的表現量。因此在此實驗部分,我們證實了在甲基安非他命行為致敏化的動物,其腦中大麻第一亞型受體與其下游 cyclic AMP/ DARPP-32/T34/PP-2B 訊號均產生顯著的改變。

長期甲基安非他命處理同時改變大麻第一亞型受體在依核區域的蛋白質與訊息核醣核酸的表現量,顯示大麻第一亞型受體在長期甲基安非他命處理後產生向下調控的現象,因此我們進一步想利用 5』RACE 的方式來尋找5』端未轉譯區域並接著尋找啟動子的存在位置。我們利用 5』RACE在大麻第一亞型受體基因上尋找到 375 bp 的5』端未轉譯區域,並得知大白鼠的第一亞型受體訊息核醣核酸,是由兩個由 17 kb的內含子所分開的外顯子所轉錄出來。利用不同的引子配對,我們由5端未轉譯區域上游的 2.4 kb 序列中獲得數個5』端缺損與3』端缺損的多聚合鏈反應產物。依據螢光素酵素呈現反應,在 HEK-293 細胞上,我們觀察到轉錄起始點(+1)上游 -114 到 -130 bp 的序列,對於大麻第一亞型受體基因的調控上扮演一個關鍵的角色,另外在 -1 到 -66 bp 可能存在有正調控元素。而在 PC-12 與 C6 細胞上,我們觀察到最佳的啟動子活性表現區域位於 -1 到 -222 bp 區域,而其核心元素可能位於 -1 到 -66 bp 區域,此外可能在 -223 到 -522 bp 之間存在一個或數個負調控元素。如果利用電腦預測的結果,則推論可能在啟動子區域存在ΔCREB、CRE-BP2、YY1、GATA-1 與Sp1 等核結合位置,有待後期實驗繼續驗證。

依據前人的活體與離體研究指出,多巴胺第二亞型受體與大麻第一亞型受體,會同時表現在依核區域並可能形成異種二聚體。刺激大麻第一亞型受體或是多巴胺第二亞型受體,可以分別抑制或活化下游環磷酸腺苷與 ERK 1/2 訊號。而在我們實驗中發現長期處理甲基安非他命後會改變依核區域的大麻第一亞型受體對於下游磷酸腺苷相關訊號路徑的調控,顯示這個部分可能有多巴胺受體與大麻受體的交互作用參與其中。為了瞭解在大麻第一亞型受體與多巴胺第二亞型之間,是否可能存在 ERK 1/2 訊號的交互作用,我們利用紋狀體初級細胞培養實驗去探討這個課題。從結果中顯示,活化多巴胺第二亞型受體與大麻第一亞型受體分別可以增加對 ERK 1/2 的磷酸化作用,而同時刺激這兩種受體則會顯露出趨近於加成的作用。另一方面,前處理百日咳毒素可以完全抑制多巴胺第二亞型受體、大麻第一亞型受體或同時刺激此兩種受體所引發的 ERK 1/2 磷酸化,顯示這兩種受體活化 ERK 1/2 是透過 Gαi/o 路徑。前處理多巴胺第二亞型受體拮抗劑可以抑制大麻第一亞型受體所引發的 ERK 1/2 磷酸化,顯示兩者之間可能具有異種二聚體的存在。整體而言,透過這些活體與離體的實驗,我們證實大麻第一亞型受體可以透過基因調控,或是與多巴胺第二亞型受體的交互作用來參與藥物成癮的過程。總體實驗證實,大麻第一亞型受體確實參與甲基安非他命的行為致敏化作用;這受體可能經由若干核訊息來達到其基因表現的增加,並可能和依核區內的多巴胺第二亞型受體交互作用,造成個體成癮的現象。
The endocannabinoids (eCBs), N-arachidonoylethanlamine (anandamine) and 2-arachidonoylglycerol (2-AG) belong to a family of endogenous lipids that could activate cannabinoid receptors. eCBs are released from cell in a stimulus-dependent manner by cleavage of membrane lipid precursors. Two cannabinoid receptors, CB1 and CB2 receptors have been identified so far. The CB1 receptors express most abundantly in the CNS, especially in the limbic forebrain area, such as cerebral cortex, hippocampus, and nucleus accumbens. The higher density of the cannabinoid receptors in the basal ganglia and cerebellum may correlate with its marked effects on spontaneous motor activity. Higher expression of cannabinoid receptors in limbic system may play an important role for memory and rewarding.

It is known that blockade of the cannabinoid CB1 receptor could suppress methamphetamine self-administration; however, the cellular mechanism remains unclear. In the first study, we intended to investigate the significance of brain CB1 receptors on the development of behavioral sensitization to methamphetamine. Male Sprague-Dawley rats treated with chronic methamphetamine (4 mg/kg, i.p.) for either 7 or 14 days developed behavioral sensitization to methamphetamine, evaluated by drug challenge (1 mg/kg) at withdrawal day 7. A progressive decrease in numbers of CB1 receptor (both Bmax and mRNA) but increase in binding affinity (Kd) was noticed during withdrawal days 3 to 7. Microinjection of CB1 antagonist SR 147778 into the nucleus accumbens at withdrawal day 7 significantly suppressed the behavioral sensitization to methamphetamine. In accumbal brain slices preparation, acute incubation with CB1 agonist CP 55940 dose-dependently enhanced cyclic AMP accumulation in sensitized rats; no change was noticed in control groups. Consequently, treatment of CP 55940 induced a dose-dependent (10 nM – 10 μM) phosphorylation on down-stream DARPP-32/Thr34 in sensitized rats, whiles only 10 μM CP 55940 was able to enhance the phosphoDARPP-32/T34 in control groups. Alternatively, both basal activity of PP-2B and CP 55940-induced changes in the amount of PP-2B in the nucleus accumbens were decreased in sensitized rats, but not in controls.

Chronic METH treatment decreased the expression of CB1R in the NAc at both protein and mRNA levels on withdrawal day 7. The decrease of CB1R mRNA indicates CB1R gene could be regulated by chronic treatment with METH- and dopamine-dependent addictive drug. We used 5』RACE approaches to isolate complete 5』UTR. The results of 5』RACE explored a 375 bp of 5』untranslated region of CB1 gene, also revealed that rat CB1R mRNA is encoded by two exons separated by a 17-kb intron. Using different primer pairs, we were able to obtain several 5』-deletion sequences and 3』-deletion sequences from PCR products. According to results from luciferase reporter assay conducted in HEK293 cells, we identified -114 to -130 bp of upstream of transcription start site (+1) could play a critical role for CB1R gene regulation, and a positive regulatory element existed at -1 to -66 bp. On the other hand, expressed in PC-12 and C6 cells, the best promoter activity located on -1 to -222, and the core promoter element might lie within -1 to -66, and with one or more negative regulatory elements lied within -223 to -522. Computer-assisted databank prediction suggests that there are ΔCREB, CRE-BP2, YY1, GATA-1 and Sp1 sites in the promoter region, which showed the possible transcription factors binding site of dopamine regulation in CB1R promoter.

Chronic METH treatment would change CB1R-mediated down-stream cAMP/PKA/DARP32/T34/PP2B signals in nucleus accumbal slices, which indicated that there exists a possible interaction with dopamine system and CB1R. Based on previous in vivo and in vitro studies, dopamine D2R and CB1R are co-localized in the nucleus accumbens and possible to form a heterodimer. Stimulatoin of either CB1R or D2R was evidenced to inhibit or evoke down-stream adenylyl clyclase and ERK1/2 signals, respectively. To investigate the possible signal crosstalk between CB1R and D2R, we used striatal primary culture to characterize if CB1R and dopamine D2R signaling would interact on ERK pathway. The results showed that chronic METH treatment would change the sensitivity of CB1R agonist CP55940-induced cAMP accumulation and ERK 1/2 activity. In primary striatal cultures, there are interactions between CB1 receptor and D2 receptor in regulation of ERK 1/2 signal. Activation of either CB1R or D2R in primary striatal cultures resulted an increase in ERK 1/2 phosphorylation. Co-stimulation of CB1R and D2R appeared to evoke a synergistic effect on phosphor-ERK1/2 signal. On the other hand, pertussis toxin pretreatment totally blocked the CB1R-, D2R- or CB1R/D2R-induced ERK 1/2 phosphorylation, indicates both receptors activated via the Gαi/o pathway. Pre-treatment with D2R antagonist could inhibit the CB1R-induced ERK 1/2 phosphorylation, suggests a possible heterodimer form of CB1R and D2R. Overall, through these in vivo and in vitro studies, we demonstrate that CB1R participates the progress of drug addiction through either its gene regulation or signaling interaction with dopamine D2 receptor. In the present studies, we conclude the involvement of endocannabinoid system, especially the CB1R, in drug addiction through a dopamine-dependent modulation, from behavioral to subcellular signals.
指導教授推薦書………………………………………………………….
口試委員審定書………………………………………………………….
國家圖書館授權書……………………………………………………..iii
長庚大學博碩士論文著作授權書…………………………………..…iv
誌謝…………………….……………………………………….……….v
中文摘要…………………………….…………………………………..vi
英文摘要…………………………….…………………………….……..x
目錄…………………………….………………………..……………..xiv
Chapter I. Background and Specific Aims………………………………1
1. Effects of Methamphetamine……………………………………..1
2. The endocannabinoid system……………………………………..3
3. Interactions of dopaminergic, Glutamatergic, GABAergic projections and endocannabinoid system in mesolimbocortical pathways………………….………………………………………..6
4. The cannabinoid CB1 receptors and drug rewarding……………...8
5. Specific Aims…………….………………………………………10
Chapter II. The Role of the Cannabinoid Type 1 Receptor and Down-stream cAMP/ DARPP-32 Signal in the Nucleus Accumbens of Methamphetamine-Sensitized Rats………………………………12
1. Background……………….……………………………………...12
2. Materials and Methods…….……………………………………..14
3. Results…….…………………………………………………..…21
4. Discussion….……………………………………………………26
5. Tables and Figures………………………………………………33
Chapter III. Cloning and characterization of rat cannabinoid CB1 receptor promoter………………………...……………………………….…..45
1. Background……………….……………………………………...45
2. Materials and Methods…….……………………………………..47
3. Results…….………………………………………………….…..50
4. Discussion….………………………………………………….…52
5. Tables and Figures…………………………………………….…56
Chapter IV. Signaling cross-talk between cannabinoid CB1 receptor and dopamine D2 receptor. …….…………………………………….….64
1. Background……………….………………………………….…..64
2. Materials and Methods…….……………………………………..66
3. Results…….……………………………………………….…..…68
4. Discussion….……………………………………………….……69
5. Figures………………………………………………………....…74
Chapter V. Conclusion…………………………….………………….…79
References……………………………………………………………….83
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