本文關鍵詞：硫氧還蛋白-1抵抗甲基苯丙胺所致條件性位置偏好的作用及其分子機制　出處：《昆明理工大學》2015年碩士論文　論文類型：學位論文

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【摘要】：藥物成癮(Drug addiction)是一種慢性、復發(fā)性腦病。主要特征為不顧后果的強迫性覓藥和用藥,以及行為控制障礙等行為改變。進入21世紀以來,以苯丙胺類興奮劑(amphetamine type stimulants,ATS)為代表的新型毒品成為全球范圍內廣泛,以及危害較嚴重的毒品,其中甲基苯丙胺(methamphetamine, METH)是典型代表。METH純品為純白色結晶體,俗稱“冰毒”。起效快、作用時間長久,長期使用會導致神經元異常地代償性適應,導致耐受、依賴、敏化以及復吸等癥狀,但其成癮的機制尚不完全清楚。METH是中樞神經系統(tǒng)興奮劑,直接影響神經系統(tǒng),長期使用導致精神依賴。中腦邊緣多巴胺系統(tǒng)(mesolimbic dopamine system, MLDS)是公認的成癮藥物產生獎賞效應的腦區(qū),主要涉及中腦腹側被蓋區(qū)(Ventral Tegmental Area, VTA),還有其投射區(qū)伏隔核(nucleus accumbens, NAc)、前額葉皮層(prefrontal cortex, PFC)等腦區(qū),它是多數(shù)成癮藥物強迫覓藥和復吸的重要神經環(huán)路,因此,VTA-NAc-PFC可能是成癮藥物引起獎賞效應的最后公共通路。MLDS的神經元胞體主要位于VTA, VTA是多巴胺神經元集中的腦區(qū),成癮藥物作用于VTA引起DA水平升高。釋放多巴胺(dopamine, DA)的部位除了神經末梢之外還有胞體和樹突,因此,NAc的DA水平升高也起到了重要作用,釋放DA可以從作用于臨近的受體。METH通過作用多巴胺D1受體介導的腺苷酸環(huán)化酶(adenylate cyclase, AC)及其下游環(huán)磷酸腺苷(Cyclic Adenosine monophosphate, cAMP)通路與多巴胺D2受體介導的磷酸肌醇3激酶(phosphatidyl inositol 3 kinase, PI3K)/Akt/糖原合成激酶-3β (Glycogen synthase kinase-3β, GSK-3β),引起的神經元結構和功能適應性改變。此外,cAMP反應元件結合蛋白(cAMP response element binding protein, CREB) ΔFosB蛋白和細胞周期依賴蛋白激酶5(Cyclin-depdent kinase 5, Cdk5)與藥物產生的獎賞效應相關。甲基苯丙胺成癮還可導致氧化應激以及氧化還原平衡狀態(tài)的失調。硫氧還蛋白-1(Thioredoxin-1, Trx-1)是體內重要的抗氧化蛋白,廣泛存在于原核和真核生物中,其分子量約為12KDa。除了抗氧化的作用外還有具有多種生物學功能：促進細胞增殖、調節(jié)基因轉錄及抗凋亡等作用。Trx-1與硫氧還蛋白-1還原酶(Thioredoxin-1 reductase, Trx-1R)、煙酰胺腺嘌呤二核苷磷酸(Nicotinamide adenine dinucleotide phosphate, NADPH)共同組成硫氧還蛋白-1系統(tǒng)來維持機體內氧化還原平衡。我們的前期研究發(fā)現(xiàn)：硫氧還蛋白-1誘導物預處理的小鼠對METH成癮有一定的抵抗作用。為了進一步驗證Trx-1在METH成癮中的作用,通過構建METH所致條件位置偏好(conditioned place preference, CPP)模型,比較Trx-1高表達轉基因小鼠和野生型小鼠的位置偏好改變的差異,檢測VTA、NAc、PFC和海馬(Hippocampus, HP)四大腦區(qū)中與METH成癮相關蛋白Trx-1、CREB、 ΔFosB以及CDK5蛋白水平。結果：本課題證實了Trx-1高表達對METH所致小鼠CPP有一定的抵抗作用,它能夠緩解METH慢性作用誘導的條件性位置偏愛形成以及運動增強。從分子水平上,Trx-1高表達轉基因小鼠能夠恢復VTA區(qū)和NAc區(qū)Trx-1的顯著下調以,抑制p-CREB、AFosB及CDK5的顯著上調。總結：Trx-1在METH所致的CPP發(fā)揮一定的抵抗作用,因此進一步研究METH與Trx-1的相關性,可能為METH成癮的治療提供新的理論依據(jù)。
[Abstract]:Drug addiction (Drug addiction) is a chronic, relapsing encephalopathy. The main features of reckless compulsive drug seeking and drug use, change the behavior and control problems. Since twenty-first Century, the ATS (amphetamine type stimulants, ATS) is a new generation of drugs table become a worldwide widely. And the serious harm of drugs, including methamphetamine (methamphetamine, METH) is a typical representative of pure.METH for pure white crystal, commonly known as "ice". The rapid onset of action for a long time, long-term use can lead to abnormal neuronal compensatory adaptation, leading to tolerance, dependence, sensitization and relapse and other symptoms, but the mechanism addiction is not completely clear that.METH is a central nervous system stimulant, directly affects the nervous system, leading to long-term use of psychological dependence. The mesolimbic dopamine system (mesolimbic dopamine system, MLD S) is a brain region recognized addictive drugs produce reward effect, mainly involving the ventral tegmental area (Ventral Tegmental, Area, VTA), and the projection area of the nucleus accumbens (nucleus accumbens, NAc (prefrontal cortex), prefrontal cortex, PFC) and other brain regions, it is an important neural circuit, a plurality of addiction drug compulsive drug seeking and relapse. Therefore, VTA-NAc-PFC may be caused by drug addiction pericaryon last public reward pathway of.MLDS is mainly located in VTA, VTA is the brain dopamine neurons on the effect of drug addiction in VTA caused by elevated levels of DA. The release of dopamine (dopamine, DA) of the site in addition to nerve endings and the somata and dendrites, therefore, increased NAc levels of DA also played an important role in adenosine monophosphate release from DA can act on adjacent receptor.METH by dopamine D1 receptor mediated (adenylate, cyclase, AC) And the downstream of cyclic adenosine monophosphate (Cyclic Adenosine, monophosphate, cAMP) pathway and dopamine D2 receptor mediated phosphoinositide 3 kinase (phosphatidyl inositol 3 kinase, PI3K) /Akt/ glycogen synthase kinase -3 beta (Glycogen beta synthase kinase-3, GSK-3), change the structure and function of adaptive neurons caused. In addition, cAMP response element binding protein (cAMP response element binding protein, CREB) protein and cell cycle of FosB dependent protein kinase 5 (Cyclin-depdent kinase 5, Cdk5) and the related drug reward effect. Methamphetamine addiction can lead to disorders of oxidative stress and redox equilibrium. Thioredoxin -1 (Thioredoxin-1, Trx-1) is important in vivo the antioxidant proteins, exist widely in prokaryotic and eukaryotic organisms, its molecular weight is about 12KDa. in addition to the antioxidant effect and has a variety of biological functions Can promote cell proliferation, regulating gene transcription and apoptosis of.Trx-1 and thioredoxin reductase -1 (Thioredoxin-1 reductase Trx-1R), nicotinamide adenine nucleoside phosphate (Nicotinamide two adenine dinucleotide phosphate, NADPH) composed of thioredoxin -1 system to maintain redox balance. Our previous study found that: mouse thioredoxin -1 inducer pretreatment has certain role of resistance. In order to further verify the role of METH addiction Trx-1 in METH addiction, by constructing the METH induced conditioned place preference (conditioned place, preference, CPP) model, Trx-1 high expression, location preference of transgenic mice and wild-type mice change the detection of VTA, NAc, PFC and hippocampus (Hippocampus, HP) Trx-1, and METH protein in brain region four addiction CREB, Delta FosB and CDK5 protein levels. Results: This paper confirms the high expression of Trx-1 have a certain role in the resistance of mice induced by METH CPP, it can alleviate the conditioned place preference induced by chronic treatment with METH formation and enhancement. From the molecular level and high expression of Trx-1 in transgenic mice can restore VTA and NAc region of Trx-1 to inhibit p-CREB, significantly reduced, significantly increased the AFosB and CDK5. Conclusion: Trx-1 plays a certain role in the resistance induced by METH in CPP, the correlation the further study for METH and Trx-1, provide a new theoretical basis for possible treatment for METH addiction.

【學位授予單位】：昆明理工大學
【學位級別】：碩士
【學位授予年份】：2015
【分類號】：R749.64

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相關期刊論文 前1條

1 楊黎華;;多巴胺系統(tǒng)在甲基苯丙胺成癮中的作用[J];大理學院學報;2014年10期

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本文編號：1406542