【摘要】：甲基苯丙胺俗稱“冰毒”,純品外觀為純白結(jié)晶體,晶瑩剔透,是中樞神經(jīng)系統(tǒng)興奮劑,長期使用會產(chǎn)生藥物依賴,一旦甲基苯丙胺成癮,戒斷是十分不易的,在戒斷期間出現(xiàn)的焦慮、抑郁、精神運動性遲滯等癥狀,嚴重影響患者的生理健康和心理健康等。甲基苯丙胺成癮機制目前尚不明確,關(guān)于甲基苯丙胺成癮機制的研究一直是生物醫(yī)學(xué)的熱點。甲基苯丙胺成癮可引起氧化應(yīng)激,導(dǎo)致機體氧化還原平衡狀態(tài)的失調(diào),從而引起機體損傷。硫氧還蛋白-1 (Thioredoxin-1, Trx-1)是機體內(nèi)廣泛存在的一種小分子量蛋白,也是一種重要的氧化還原調(diào)節(jié)蛋白,對維持機體的氧化還原平衡具有重要的作用,同時還具有促進細胞增殖、調(diào)節(jié)基因轉(zhuǎn)錄因子活性及抗凋亡等作用。Trx的分類可以分為三類,Trx-1、Trx-2以及在精子細胞中的特異的Trx-3,這些不同種類的Trx在細胞內(nèi)作用各不相同。Trx-1是最常見的一類,也是分布最廣泛的。Trx和NADPH以及Trx的還原酶(Thioredoxin reductase, TrxR)共同構(gòu)成了Trx還原系統(tǒng)。抑郁癥發(fā)病機制與單胺類遞質(zhì)、神經(jīng)遞質(zhì)受體、神經(jīng)營養(yǎng)因子、氧化應(yīng)激、細胞因子、NO通路、神經(jīng)變性等有關(guān)。抑郁癥相關(guān)的腦區(qū)有海馬和前額葉皮質(zhì)(prefrontal cortex, PFC)等腦區(qū)。本研究通過構(gòu)建METH所致條件位置偏好(conditioned place preference, CPP)模型,確定METH可以導(dǎo)致成癮行為,通過一周的自然戒斷后,使用經(jīng)典的懸尾實驗方法檢測抑郁行為,比較兩組間“不動狀態(tài)”的時間差異,發(fā)現(xiàn)METH戒斷的小鼠會產(chǎn)生抑郁行為,而Trx-1高表達小鼠能夠抵抗METH戒斷引起的抑郁行為。其次,檢測海馬區(qū)和PFC區(qū)Trx-1、cAMP反應(yīng)元件結(jié)合蛋白(cAMP response element binding protein, CREB)、周期素依賴蛋白激酶(cyclin-dependent kinase 5, CDK5)、單胺氧化酶(monoamine oxidase，，MAO)、5-羥色胺轉(zhuǎn)運體(serotonin transporter,5-HTT)、N-甲基-D-天門冬氨酸(N-methyl-D-aspartate, NMDA)受體的亞基NR2B、谷氨酸受體1(glutamate receptor 1, GluR1)以及鈣調(diào)素依賴性蛋白激酶(Ca2+/calmodulin-dependent protein kinase, CaMKⅡ)等蛋白水平的表達發(fā)現(xiàn)METH引起的小鼠Trx-1、CREB、CDK5蛋白的變化,而Trx-1高表達小鼠能夠抵抗METH引起的這些分子變化,同時METH戒斷引起MAO和ST蛋白水平的升高,引起NR2B、GluR1、p-CaMKⅡ蛋白水平的降低,而Trx-1高表達小鼠對這種變化均有恢復(fù)作用�？偨Y(jié)：Trx-1高表達可以抑制METH戒斷所致的抑郁行為,其作用機理是通過恢復(fù)DA,5-HT,谷氨酸途徑,因此,Trx-1可以作為METH成癮戒斷行為治療的一個新的靶點。
[Abstract]:Methamphetamine, commonly known as "methamphetamine," has a pure white crystal appearance, is crystal clear, is a central nervous system stimulant, long-term use will produce drug dependence, once methamphetamine addiction, withdrawal is very difficult, The symptoms of anxiety, depression and mental retardation during withdrawal seriously affect the patients' physical and mental health. The mechanism of methamphetamine addiction is still unclear, and the research on the mechanism of methamphetamine addiction has been a hot topic in biomedicine. Methamphetamine addiction can lead to oxidative stress, resulting in imbalance of redox balance, which can lead to body damage. Thioredoxin 1 (Thioredoxin-1, Trx-1) is a small molecular weight protein and an important redox regulatory protein, which plays an important role in maintaining redox balance. Trx can be classified into three categories: Trx-1,Trx-2 and specific Trx-3, in sperm cells. Trx-1 is the most common and widely distributed. Trx, NADPH and Trx reductase (Thioredoxin reductase, TrxR) together form the Trx reduction system. The pathogenesis of depression is related to monoamine transmitter, neurotransmitter receptor, neurotrophic factor, oxidative stress, cytokine, NO pathway, neurodegeneration and so on. Depression related brain regions include hippocampus and prefrontal cortex (prefrontal cortex, PFC) and other brain regions. In this study, (conditioned place preference, CPP) model of conditional position preference induced by METH was constructed to determine that METH can lead to addictive behavior. After a week of natural withdrawal, depression behavior was detected by classical tail suspension test. By comparing the time difference of "immobility" between the two groups, it was found that METH abstinent mice had depressive behavior, while Trx-1 high expression mice could resist depressive behavior caused by METH withdrawal. Secondly, cyclin-dependent kinase 5 (CDK5), monoamine oxidase,MAO and (serotonin transporter, Trx-1,cAMP response element binding protein (cAMP response element binding protein, CREB), (CDK5) in hippocampus and PFC region were detected. 5-HTT, N-methyl-D-aspartate (NMDA) receptor subunit NR2B, (glutamate receptor 1 (GluR1) and Ca2 / calmodulin-dependent protein kinase, The expression of CaMK 鈪

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