本文選題：嗎啡 + 硫氧還蛋白-1�。� 參考：《昆明理工大學(xué)》2017年碩士論文

【摘要】：嗎啡是一種阿片類藥物,長(zhǎng)期使用導(dǎo)致依賴性和成癮,嗎啡成癮已成為全球關(guān)注的公共衛(wèi)生問(wèn)題之一。中腦腹側(cè)被蓋區(qū)(ventral tegmental area,VTA),伏隔核(nucleus accumbens,NAc),前額葉皮層(prefrontal cortex,PFC),海馬(hippocampus,HiP)是藥物成癮的中樞神經(jīng)系統(tǒng)的重要組成部分。VTA區(qū)多巴胺系統(tǒng)參與獎(jiǎng)賞效應(yīng),NAc接受VTA投射的多巴胺神經(jīng)纖維以及海馬和前額葉皮層傳入的谷氨酸纖維,與復(fù)吸有關(guān),海馬在藥物獎(jiǎng)賞刺激與環(huán)境線索相關(guān)記憶形成中起重要作用。嗎啡成癮后停止給藥則產(chǎn)生戒斷行為,以及獎(jiǎng)賞效應(yīng)的消退,消退不是簡(jiǎn)單的遺忘或擦除原始的記憶,而是新的學(xué)習(xí)記憶形成,而NAc中谷氨酸的突觸可塑性在藥物獎(jiǎng)賞消退中起重要的作用。硫氧還蛋白-1(Thioredoxin-1,Trx-1),是氧化還原調(diào)節(jié)蛋白,對(duì)細(xì)胞組織中氧化還原平衡的調(diào)節(jié)起重要作用,具有保護(hù)和抑制神經(jīng)凋亡的作用。嗎啡作用后可導(dǎo)致硫氧還蛋白-1表達(dá)改變,然而硫氧還蛋白-1是否參與了成癮藥物所致條件性位置偏愛(ài)(conditioned place preference,CPP)的消退還未有報(bào)道。本實(shí)驗(yàn)的目的是確定硫氧還蛋白-1是否通過(guò)調(diào)節(jié)NAc中谷氨酸信號(hào)通路改變嗎啡誘導(dǎo)的CPP消退過(guò)程。我們利用CPP模型以及核團(tuán)定位注射的技術(shù),在嗎啡誘導(dǎo)CPP形成后,在小鼠NAc雙邊注射Trx-1特異性的干擾RNA,構(gòu)建NAc區(qū)Trx-1低表達(dá)小鼠,并比較對(duì)照組、陰性對(duì)照組和低表達(dá)組嗎啡所誘導(dǎo)的小鼠CPP消退過(guò)程的時(shí)間差異。我們的研究結(jié)果表明NAc中Trx-1低表達(dá)減緩了嗎啡所致CPP的消退。我們還檢測(cè)了 NAc、VTA和HiP中相關(guān)蛋白的變化,發(fā)現(xiàn)嗎啡CPP消退誘導(dǎo)NAc、VTA和HiP中α-氨基-3-羥基-5-甲基異惡唑-4-丙酸受體(a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors,AMPAR)的表達(dá)升高,而Trx-1低表達(dá)抑制了嗎啡誘導(dǎo)的AMPAR的升高;嗎啡CPP消退誘導(dǎo)NAc、VTA 和 HiP 中 N-甲基-D 天門冬氨酸(N-methyl-d-aspartate,NMDA)受體的 2B 亞型(NR2B)、突觸后致密物質(zhì) 95(postsynapticdensity-95,PSD95)、磷酸化鈣調(diào)素依賴蛋白激酶 Ⅱ(phosphorylated Calcium/calmodulin-dependent protein kinase Ⅱ,p-CaMKⅡ)、磷酸化細(xì)胞外信號(hào)調(diào)節(jié)蛋白激酶1(phosphorylated extracellular signal-regulated protein kinasel,p-ERKl)及磷酸化 cAMP 反應(yīng)元件結(jié)合蛋白(phosphorylated cAMP response element binding protein,p-CREB)表達(dá)水平的升高,而Trx-1 低表達(dá)進(jìn)一步增加了 NR2B,PSD95,p-CaMKⅡ,p-ERKl,p-CREB的表達(dá)�？偨Y(jié):本研究表明嗎啡誘導(dǎo)的CPP消退與NAc、VTA和HiP谷氨酸信號(hào)通路相關(guān)分子表達(dá)有關(guān)。NAc中Trx-1通過(guò)調(diào)節(jié)谷氨酸信號(hào)通路相關(guān)分子,延緩嗎啡所誘導(dǎo)的CPP消退。該研究可為嗎啡戒斷治療提出供新的思路和作用靶點(diǎn)。
[Abstract]:Morphine is an opioid drug, which leads to dependence and addiction. Morphine addiction has become one of the global public health problems. Ventral tegmental are VTAA in ventral tegmental area, nucleus accumbens in nucleus accumbens, prefrontal cortexa in prefrontal cortex, and hipppocampus in hippocampus are important components of the central nervous system of drug addiction. The dopamine system in VTA region is involved in the reward effect. NAC receives the dopamine neurofibrils projected by VTA. And the afferent glutamate fibers in the hippocampus and the prefrontal cortex, Hippocampus plays an important role in memory formation associated with drug reward stimulation and environmental cues. Withdrawal from morphine addiction results in abstinence and the regression of the reward effect, which is not simply forgetting or erasing the original memory, but the formation of new learning and memory. Synaptic plasticity of glutamate in NAc plays an important role in drug reward regression. Thioredoxin-1, a redox regulatory protein, plays an important role in the regulation of redox balance and protects and inhibits apoptosis. The expression of thioredoxin-1 was changed after morphine treatment. However, it has not been reported whether thioredoxin-1 is involved in the regression of conditioned place preference (CPP) induced by addictive drugs. The aim of this study was to determine whether thioredoxin-1 changes the morphine-induced CPP regression process by regulating the glutamate signaling pathway in NAc. Using CPP model and nucleocapsid injection technique, after morphine induced CPP formation and bilateral injection of Trx-1 specific interference RNAs into mice NAc, we constructed NAc region Trx-1 low expression mice, and compared the control group. The time of CPP regression induced by morphine in negative control group and low expression group was different. Our results suggest that the low expression of Trx-1 in NAc slows the regression of CPP induced by morphine. We also detected the changes of related proteins in HiP and HiP, and found that morphine CPP regression induced the increase of 偽 -amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptorsAMPAR in NAc-3-hydroxy-5-methylisoxazole-4-propionic acid receptorsAMPAR, but the low expression of Trx-1 inhibited the increase of AMPAR induced by morphine. Subtype 2B of N-methyl-D-aspartate NMDA-N-methyl-d-aspartate NMDAR induced by morphine CPP regression, 95 postsynaptic dense substance 95 postsynaptic density-95, phosphorylated calmodulin dependent protein kinase 鈪，

本文編號(hào)：1886057