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博碩士論文 etd-1022112-133013 詳細資訊
Title page for etd-1022112-133013
論文名稱
Title
蛋白激酶Mζ於古柯鹼引起的藥物成癮中所扮演之角色研究
Role of protein kinase Mζ in cocaine-induced drug addiction
系所名稱
Department
畢業學年期
Year, semester
語文別
Language
學位類別
Degree
頁數
Number of pages
150
研究生
Author
指導教授
Advisor
召集委員
Convenor
口試委員
Advisory Committee
口試日期
Date of Exam
2012-10-18
繳交日期
Date of Submission
2012-10-22
關鍵字
Keywords
制約性地點偏好、長期增益效應、蛋白激酶、成癮、腹側蓋區、古柯鹼
Conditioned-place preference, Long-term potentiation, Protein kinase, Addiction, Ventral tegmental area, Cocaine
統計
Statistics
本論文已被瀏覽 5673 次,被下載 220
The thesis/dissertation has been browsed 5673 times, has been downloaded 220 times.
中文摘要
成癮是一種慢性的腦部疾病,其主要特徵在於經常性或強迫性的重複使用某種物質儘管其隨後會對個體帶來危害。一些中樞神經刺激藥物 (如:古柯鹼或安非他命) 的使用會帶來強大的成癮性,即使經過長時間的禁斷過程仍無法完全戒除。這些非法藥物的施用不僅可能對成人的健康上造成傷害,懷孕母體中的胎兒亦容易遭受其荼毒,臨床證據顯示,懷孕中的媽媽若吸食古柯鹼會增加胎兒早產、體重過輕、頭圍減少與成年後心臟疾病的機率。
研究證實,由腹側蓋區 (ventral tegmental area, VTA)、依核 (nucleus accumbens, NAc) 與前腦皮層 (prefrontal cortex, PFC) 為主軸所構成的邊緣多巴胺系統 (mesolimbic dopamine system) 是負責成癮現象最重要的腦區迴路之一,而其中的VTA更是已知與成癮行為的表現最為相關的位置所在。VTA區域內接受了多個來自不同腦區所投射而來的神經迴路,如:從PFC傳來的麩胺酸神經元 (glutamatergic neuron) 或從NAc傳來的γ-丁氨基酪酸神經元 (GABAergic neuron)。近年來許多文獻證明,古柯鹼這類的藥物會誘導VTA內的多巴胺神經元 (dopaminergic neuron) 產生一種類長期增益效應 (long-term potentiation, LTP─like) 的現象。
長期增益效應機制最早發現於和記憶息息相關的海馬迴區域中,是一種廣泛分佈在中樞神經系統的現象,而記憶的產生過程已被證實與成癮的形成有某種程度上的相似之處。一般來說,長期增益效應大致上可分為兩個階段:誘導期 (induction phase) 與 維持期 (maintenance phase)。誘導期已知需要許多訊息分子的共同參予才能完成,譬如:calcium/calmodulin-dependent protein kinase II (CaMKII)、cyclic AMP (cAMP)、phosphatidylinositol 3-kinases (PI3K) 與protein kinase C (PKC)。然而,至目前為止,僅一種訊息分子─蛋白激酶Mζ (protein kinase Mζ, PKMζ) 被證實在維持期扮演了關鍵性的角色。實驗顯示,PKMζ蛋白質直接從PKCζ基因轉錄轉譯而來,為一種僅表現於腦中且呈現持續活化態 (constitutively active form) 的protein kinase C (PKC),因此,其亦不受鈣離子或diacylglycerol (DAG) 的調控。最新研究指出,若將PKMζ專一性抑制劑─zeta inhibitory peptide (ZIP) 直接打入海馬迴或腦島皮質 (insular cortex) 中可以消除原有的空間與味覺厭惡 (taste aversion) 記憶,再者,因為PKMζ與長期增益效應的相關性,所以利用抑制PKMζ活性來嘗試消除個體的成癮現象似乎是一個值得深入探討的研究。
本篇實驗結果發現,抑制PKMζ可以降低VTA中的多巴胺神經元上因古柯鹼所造成的微興奮性突觸後電流 ( miniature excitatory postsynaptic current, mEPSCs) 或α – amino – 3 – hydroxyl – 5 – methyl – 4 – isoxazolepropionic acid receptor (AMPAR) / N-methyl-D-aspartate receptor (NMDAR) ratio的增加;此外,我們也證實了PKMζ並不參與在spike-timing dependent LTP的過程當中。有趣的是,當抑制了多巴胺神經元內的PKMζ可以逆轉因單次或連續性古柯鹼注射而被排除的spike-timing dependent LTP現象。更進一步的,我們的western blot數據更證實無論單劑或重複古柯鹼給予會造成VTA與NAc中的PKMζ表現量上升,而這種表現量增加現象需多種與LTP相關的訊息分子參與與蛋白質新合成的過程。另外,我們更利用了動物行為模式─制約性地點偏好 (conditioned-place preference, CPP) 實驗來驗證PKMζ於成癮現象中所扮演的角色。我們的結果顯示,消除了VTA內的PKMζ活性可已明顯抑制動物對古柯鹼的成癮情況。
接下來我們探討了古柯鹼對老鼠所造成的運動活性與運動行為致敏化 (locomotor sensitization) 反應。我們實驗發現,出生後21天的青春期前期幼鼠對古柯鹼引發的運動能力表現明顯高於出生後28天與41天的青春期中、後期幼鼠。而當給予高劑量的古柯鹼注射可以使出生後28天的幼鼠運動能力表現達到與21天幼鼠相同,但運動行為致敏化情況則無法維持。此外,我們更加實驗了懷孕中的母鼠接觸古柯鹼後所產下的幼鼠對後續再注射古柯鹼的反應。數據顯示,胎兒時期受到古柯鹼影響的幼鼠,於出生後21天再給予古柯鹼其運動活性與運動行為致敏化和正常組別相比皆會有明顯降低情況。而高劑量的古柯鹼注射並無法使反應增加,反倒是出現抑制作用。最後一部分,我們發現了懷孕時注射古柯鹼的母鼠所生產下的幼鼠於出生後20天時,PFC內的一種鉀─氯離子共同運輸通道 (K+-Cl–co-transporters)─KCC2表現量會顯著下降,這可能與其對後來的古柯鹼反應變差有關。
綜合以上結果,我們的實驗數據證明了PKMζ參與古柯鹼所引起的 (1) mEPSCs增強現象;(2) AMPAR/NMDAR ratio上升情形;(3) 類長期增益效應;(4) 制約性地點偏好行為。除此之外,我們也發現PKMζ與spike-timing dependent LTP兩者之間並無關聯。另一方面,我們更證實無論是單次或連續性古柯鹼注射皆能造成PKMζ的表現量提高。最後,我們的結果指出,胚胎時期受到古柯鹼影響的幼鼠會減少爾後再次接觸時的運動活性反應,且其PFC腦區中的KCC2表現情形會有顯著降低的跡象。
Abstract
Addiction is a chronic disease that characterize as habitual or compulsive involvement in an activity despite it’s bring negative consequences. Some of psystimulants such as cocaine or amphetamine cause a strong reinforcing effects even after prolonged abstinence periods. Such illegal drugs not only hurt on the adult health but also result in fetal physiological damage. For example, that babies born to mothers who abuse with cocaine bring prematurely delivered, low birth weights, smaller head circumferences and increased heart disease in adult offspring.
Mesolimbic dopamine system include nucleus accumbens (NAc) and ventral tegmental area (VTA) are critical regions for the neural adaptations that contribute to addiction. VTA that receives inputs from a large number of brain regions. For example, it receives glutamatergic inputs from prefrontal cortex, or GABAergic inputs from NAc. It has been known that VTA play a major role in the acquisition and expression of learned addictive behaviors. Results from many neuropharmacological studies in animal models indicate that exposure to cocaine or some other drugs of abuse seems to induce long-term potentiation (LTP) ─ like changes of synaptic plasticity among neurons in VTA region.
LTP was first described in hippocampus, a region that associated with memory formation, and were found widespread events in many mammalian brain sites. In the present time, theories and investigation indicated that memory and addiction might shared the similar neural circuitry and signal pathways. In general, LTP can be separate into two main phases : induction and maintenance phases. Many of molecules participate in induction phase such as calcium/calmodulin-dependent protein kinase II (CaMKII), cyclic AMP (cAMP), phosphatidylinositol 3-kinases (PI3K) and protein kinase C (PKC). However, until now there was only one molecule has been found associated with LTP maintenance—protein kinase Mζ (PKMζ).
PKMζ is a brain specific, constitutively active form of PKC that does not need Ca2+ or diacylglycerol (DAG) for its activation. Molecular evidences showed that PKMζ is translated uniquely by PKMζ mRNA which is generated under the control of an internal promoter in the PKCζ gene. Recently, investigators introduced a PKMζ selective inhibitor—ZIP, to hippocampus or insular cortex both successful to eliminate long-term spatial memory or conditioned taste aversion (CTA) behavior, respectively, on rat. Therefore, exclude PKMζ by specific inhibitors and then result in abolish long-term synaptic potentiation which had already established seem to be a leading candidate for cure addiction.
Here we showed that blocked of PKMζ activity in VTA dopaminergic neuron eliminated mEPSCs or AMPAR/NMDAR ratio increment elicited by cocaine. Otherwise, our results also presented that myristoylatedinhibitory peptide─ZIP had no effect on spike timing-dependent long-term potentiation in rats previously injected with saline but remarkably restored spike timing-dependent long-term potentiation in VTA dopamine neurons in slices prepared from rats that received single or multiple cocaine exposure. Furthermore, our western blot analyses showed that both single and five consecutive cocaine injections induced a significant increase in PKMζ level in VTA or NAc. Moreover, our ex vivo cocaine incubation results indicated that multiple kinases activation or de novo protein synthesis was required for PKMζ increment. The most important, our data provided the first physiological evidence between PKMζ and drug addiction when intracranial administered specific PKMζ inhibitors to VTA reversed cocaine-induced conditioned-place preference (CPP) behavior.
Finally, we investigated the behavioral effect of cocaine-induced locomotor sensitization in an open field apparatus. Our data showed that peri-adolescent (P21) rats exhibited prominently increased in either acute or repeated cocaine-induced locomotor activity than mid-adolescent (P28) and post-adolescent (P41). Interestingly, applied to high dosage cocaine (30 mg/kg) rescued the acute locomotor response in P28 rats but not behavioral sensitization. We further examined the locomotion on rats that were exposed to cocaine in utero after single or multiple cocaine injection. However, cocaine-induced increase in locomotor activity was lower in P21 rats which exposed to cocaine during pregnancy but no significantly difference in P28 rats. Surprisingly, single high dose cocaine treatment caused a marked reduction in locomotor activity on P21 rats prenatally exposed to cocaine. Otherwise, we also provided the first evidences that repeated cocaine injection in pregnant rats induced a significant decreased to KCC2 level in PFC regions prepared from P20 rat.
In conclusion, results from our current studies demonstrate for the first time that persistently active PKMζ is necessary in (1) mEPSC facilitation induced by single cocaine exposure; (2) cocaine-induced enhancement in AMPAR/NMDAR ratio; (3) single or repeated cocaine-induced LTP but not in LTP induced by spike-timing stimulation; and (4) cocaine conditioned place preference in the VTA. In addition, our results also present evidence that the expression of PKMζ is increased by either single or repeated cocaine exposure. Furthermore, our behavioral or Western blotting consequence of cocaine treatment in utero was reflected by the diminishion in the sensitivity of locomotor activity in postnatal rats to cocaine and KCC2 level in PFC regions.
目次 Table of Contents
目錄
目錄..........................................................................................i
圖表目錄..................................................................................v
縮寫檢索表...........................................................................viii
中文摘要.................................................................................ix
英文摘要...............................................................................xiv

第一章 緒論............................................................................1
1.1 藥物濫用...........................................................................3
1.2 成癮...................................................................................3
1.3 報償迴路與成癮...............................................................4
1.4 成癮與記憶.......................................................................5
1.5 長期增益效應...................................................................6
1.6 ..Protein Kinase Mζ........................................................7
1.7 ..AMPA接受器與PKMζ....................................................9
1.8..成癮行為之消除...........................................................10
1.9 研究目的........................................................................11

第二章 實驗設計與研究方法..............................................19
2.1 實驗動物........................................................................21
2.2 主要藥品試劑來源........................................................21
2.3 腦組織切片的備製........................................................21
2.4 電氣生理學紀錄法........................................................22
2.4.1 .VTA位置鑑定與多巴胺神經元特性識別.................22
2.4.2 全細胞嵌定記錄法.....................................................24
2.4.3 長期增益效應誘導.....................................................25
2.5 地點偏好性行為實驗的測定 (Conditioned Place Preference, CPP) ...............................................................26
2.6 運動活性測量 (Locomotor activity)............................28
2.7 西方點墨法....................................................................29
2.7.1 蛋白質萃取.................................................................29
2.7.2 蛋白質的定量.............................................................30
2.7.3 硫酸十二酯鈉-聚丙烯醯胺凝膠電泳........................30
2.7.4 蛋白質電泳轉印.........................................................31
2.7.5 免疫染色.....................................................................31
2.8 實驗數據分析及統計....................................................32

第三章 .探討VTA中Protein kinase Mζ於古柯鹼所造成的AMPA接受器訊號增強之角色.............................................39
3.1 緒論................................................................................41
3.1.1 .Glutamatergic system在VTA多巴胺神經細胞上扮演之角色...............................................................................41
3.1.2 .Glutamate receptor、古柯鹼與PKMζ之相關性...42
3.1.3 研究目的.....................................................................44
3.2 實驗結果........................................................................45
3.2.1 .Dopaminergic neuron特性鑑定............................45
3.2.2 抑制PKMζ能降低古柯鹼所誘導的微興奮性突觸後電流 (mEPSCs) 之頻率與振幅增強現象.............................45
3.2.3 阻斷PKMζ能消除古柯鹼增加AMPAR/NMDAR ratio的現象...................................................................................46
3.2.4 .PKMζ參與古柯鹼所引起的GluR2-lacking AMPAR運送過程...............................................................................47
3.3 討論................................................................................49

第四章 .探討PKMζ在spike-timing dependent plasticity和古柯鹼誘發之LTP扮演的角色與其調控機制或生理意義 ...............................................................................................60
4.1 緒論................................................................................62
4.1.1 Spike-timing dependent plasticity機制.................62
4.1.2 Spike-timing dependent plasticity與古柯鹼所誘導的LTP-like之關聯性............................................................63
4.1.3 PKMζ的調控...............................................................63
4.1.4 PKMζ相關之生理功能...............................................65
4.1.5研究原理及目的..........................................................66
4.2 實驗結果........................................................................67
4.2.1 PKMζ與古柯鹼所誘發的LTP現象有關...................67
4.2.2古柯鹼能增加PKMζ的表現量....................................68
4.2.3阻斷PKMζ的表現能消除古柯鹼引發的行為成癮現象 ...............................................................................................69
4.3 討論................................................................................71

第五章 懷孕母鼠施用古柯鹼後影響其新生小鼠運動能力之分析...................................................................................87
5.1 緒論................................................................................89
5.1.1 藥物濫用對懷孕之影響.............................................89
5.1.2 古柯鹼影響胎兒dopamine system........................90
5.1.3 懷孕時期暴露古柯鹼對GABAergic neuron神經迴路的影響...................................................................................91
5.1.4 研究原理及目的.........................................................93
5.2 實驗結果........................................................................94
5.2.1 年齡較輕的正常小鼠對古柯鹼反應較佳.................94
5.2.2 懷孕時期給予古柯鹼注射的母鼠其所產之小鼠對古柯鹼反應較差.......................................................................94
5.2.3 連續給予懷孕母鼠注射古柯鹼會減緩其所產之幼鼠PFC腦區中的KCC2發育....................................................95
5.3 討論................................................................................97
5.3.1 青春期早期對古柯鹼的locomotor反應最佳...........97
5.3.2 懷孕過程受到古柯鹼施打的母鼠其所產下之小鼠會降低對古柯鹼的反應...........................................................99
5.2.3 懷孕時期接觸古柯鹼會干擾PFC區域KCC2的正常表現.....................................................................................101

第六章 結論........................................................................114

參考文獻.............................................................................120
Publications......................................................................136

圖表目錄
Figure 1.1 Regulation of gene expression by drugs of abuse...................................................................................12
Figure 1.2 Mesolimbic dopamine system circuitry ...............................................................................................13
Figure 1.3 Simplified schematic of the early and late phases of long-term potentiation....................................14
Figure 1.4 PKMζ is a brain-specific form of PKCζ........15
Figure 1.5 PKMζ formation in LTP...................................16
Figure 1.6 Regulation of AMPA receptors during synaptic plasticity...............................................................17
Figure 1.7 Mechanism of synaptic potentiation by PKMζ in LTP maintenance..........................................................18

Figure 2.1 Infrared differential interference contrast (IR-DIC) images of ventral tegmental area.........................33
Figure 2.2 Schematic drawing of the optical set-up used for infrared-guided electrophysiological recording in brain slices.....................................................................34
Figure 2.3 Whole-cell patch clamp protocol in brain slice......................................................................................35
Figure 2.4 Conditioned-place preference protocol ...............................................................................................36
Figure 2.5 Injection sites in rats......................................37
Figure 2.6 Locomotor activity apparatus........................38

Figure 3.1 Electrophysiological properties of dopamine neurons................................................................................51
Figure 3.2 Protein kinase Mζ is involved in cocaine-induced miniature excitatory postsynaptic current (mEPSC) potentiation .......................................................52
Figure 3.3 Cocaine exposure had no effect on paired-pulse modulation..........................................................................53
Figure 3.4 Myristoylatedinhibitory peptide (ZIP) disrupts single cocaine-induced increase in AMPA receptor (AMPAR)/N-methyl-D-aspartate receptor (NMDAR) ratio ...............................................................................................54
Figure 3.5 Myristoylated ζ inhibitory peptide (ZIP) disrupts repeated cocaine exposure-induced increase in AMPAR/NMDAR ratio.....................................................56
Figure 3.6 Single cocaine exposure triggers the insertion of glutamate receptor 2-lacking AMPA receptors on ventral tegmental area neurons..............58

Figure 4.1 Synaptic modification induced by repetitively paired pre- and postsynaptic spikes in layer 2/3 of visual cortical slices from the rat.....................................75
Figure 4.2 Spike-timing protocol for LTP induction ...............................................................................................76
Figure 4.3 Myristoylated inhibitory peptide (ZIP) restores spike-timing dependent long-term potentiation (LTP) in ventral tegmental area slices from rats exposed to cocaine the previous day.....................77
Figure 4.4. Myristoylated inhibitory peptide (ZIP) restores spike timing-dependent long-term potentiation in ventral tegmental area slices from rat that received multiple cocaine exposure.......................79
Figure 4.5 Single or repeated cocaine exposure resulted in upregulation of protein kinase Mζ (PKMζ) expression in the ventral tegmental area......................81
Figure 4.6 Cocaine but not saline is associated with increased PKMζ protein levels in nucleus accumbens ...............................................................................................82
Figure 4.7 Effect of cocaine exposure on the PKMζ expression in brain slice..................................................83
Figure 4.8 Summary of various pharmacological inhibitors on cocaine incubation-induced PKMζ expression...........................................................................84
Figure 4.9 Protein kinase Mζ inhibition abolishes cocaine conditioned place preference (CPP)...............85

Figure 5.1 Cocaine in the brain.....................................103
Figure 5.2 Early expression of NKCC1 and late expression of KCC2 determines developmental changes in [Cl-]i...............................................................104
Figure 5.3 Different developmental stages of a rat .............................................................................................105
Figure 5.4 Locomotor sensitization induced by repeated cocaine injected in vivo in different developmental stages of rats........................................106
Figure 5.5 Effect of high dosage cocaine exposure on locomotor activity in postnatal day 28 rats..................107
Figure 5.6 Prenatal cocaine exposure decreased the sensitivity of the locomotor activity to cocaine in postnatal rats....................................................................108
Figure 5.7 Locomotor activity showed no significantly difference between control and rats exposure to cocaine in utero at postnatal 28 day............................110
Figure 5.8 Effect of high dose cocaine injection on locomotor activity in rats exposure to cocaine in utero .............................................................................................111
Figure 5.9 Prenatal cocaine exposure reduced the KCC2 expression in the PFC........................................112
Figure 5.10 Repeated cocaine exposure in utero had no effect on KCC2 expression in the NAc...................113
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