硫氧还蛋白-1抵抗甲基苯丙胺所致条件性位置偏好的作用及其分子机制

发布时间：2018-01-10 19:27

本文关键词：硫氧还蛋白-1抵抗甲基苯丙胺所致条件性位置偏好的作用及其分子机制　出处：《昆明理工大学》2015年硕士论文　论文类型：学位论文

【摘要】：药物成瘾(Drug addiction)是一种慢性、复发性脑病。主要特征为不顾后果的强迫性觅药和用药,以及行为控制障碍等行为改变。进入21世纪以来,以苯丙胺类兴奋剂(amphetamine type stimulants,ATS)为代表的新型毒品成为全球范围内广泛,以及危害较严重的毒品,其中甲基苯丙胺(methamphetamine, METH)是典型代表。METH纯品为纯白色结晶体,俗称“冰毒”。起效快、作用时间长久,长期使用会导致神经元异常地代偿性适应,导致耐受、依赖、敏化以及复吸等症状,但其成瘾的机制尚不完全清楚。METH是中枢神经系统兴奋剂,直接影响神经系统,长期使用导致精神依赖。中脑边缘多巴胺系统(mesolimbic dopamine system, MLDS)是公认的成瘾药物产生奖赏效应的脑区,主要涉及中脑腹侧被盖区(Ventral Tegmental Area, VTA),还有其投射区伏隔核(nucleus accumbens, NAc)、前额叶皮层(prefrontal cortex, PFC)等脑区,它是多数成瘾药物强迫觅药和复吸的重要神经环路,因此,VTA-NAc-PFC可能是成瘾药物引起奖赏效应的最后公共通路。MLDS的神经元胞体主要位于VTA, VTA是多巴胺神经元集中的脑区,成瘾药物作用于VTA引起DA水平升高。释放多巴胺(dopamine, DA)的部位除了神经末梢之外还有胞体和树突,因此,NAc的DA水平升高也起到了重要作用,释放DA可以从作用于临近的受体。METH通过作用多巴胺D1受体介导的腺苷酸环化酶(adenylate cyclase, AC)及其下游环磷酸腺苷(Cyclic Adenosine monophosphate, cAMP)通路与多巴胺D2受体介导的磷酸肌醇3激酶(phosphatidyl inositol 3 kinase, PI3K)/Akt/糖原合成激酶-3β (Glycogen synthase kinase-3β, GSK-3β),引起的神经元结构和功能适应性改变。此外,cAMP反应元件结合蛋白(cAMP response element binding protein, CREB) ΔFosB蛋白和细胞周期依赖蛋白激酶5(Cyclin-depdent kinase 5, Cdk5)与药物产生的奖赏效应相关。甲基苯丙胺成瘾还可导致氧化应激以及氧化还原平衡状态的失调。硫氧还蛋白-1(Thioredoxin-1, Trx-1)是体内重要的抗氧化蛋白,广泛存在于原核和真核生物中,其分子量约为12KDa。除了抗氧化的作用外还有具有多种生物学功能：促进细胞增殖、调节基因转录及抗凋亡等作用。Trx-1与硫氧还蛋白-1还原酶(Thioredoxin-1 reductase, Trx-1R)、烟酰胺腺嘌呤二核苷磷酸(Nicotinamide adenine dinucleotide phosphate, NADPH)共同组成硫氧还蛋白-1系统来维持机体内氧化还原平衡。我们的前期研究发现：硫氧还蛋白-1诱导物预处理的小鼠对METH成瘾有一定的抵抗作用。为了进一步验证Trx-1在METH成瘾中的作用,通过构建METH所致条件位置偏好(conditioned place preference, CPP)模型,比较Trx-1高表达转基因小鼠和野生型小鼠的位置偏好改变的差异,检测VTA、NAc、PFC和海马(Hippocampus, HP)四大脑区中与METH成瘾相关蛋白Trx-1、CREB、 ΔFosB以及CDK5蛋白水平。结果：本课题证实了Trx-1高表达对METH所致小鼠CPP有一定的抵抗作用,它能够缓解METH慢性作用诱导的条件性位置偏爱形成以及运动增强。从分子水平上,Trx-1高表达转基因小鼠能够恢复VTA区和NAc区Trx-1的显著下调以,抑制p-CREB、AFosB及CDK5的显著上调。总结：Trx-1在METH所致的CPP发挥一定的抵抗作用,因此进一步研究METH与Trx-1的相关性,可能为METH成瘾的治疗提供新的理论依据。
[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.

【学位授予单位】：昆明理工大学
【学位级别】：硕士
【学位授予年份】：2015
【分类号】：R749.64

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