本文選題：可卡因 + 伏隔核　； 參考：《蘇州大學(xué)》2015年博士論文

【摘要】：可卡因是一類成癮性物質(zhì),主要作用于單胺轉(zhuǎn)運(yùn)體,抑制突觸間隙內(nèi)多巴胺的再攝取,從而間接導(dǎo)致突觸間隙內(nèi)多巴胺含量的增加。近年來(lái),糖原合成酶激酶-3β(Glycogen synthase kinase 3β,GSK3β)在可卡因中樞興奮及成癮中的作用受到廣泛關(guān)注。大鼠給予可卡因后導(dǎo)致伏隔核(Nucleus accumbens,Nac)核(Core)中的GSK3β磷酸化降低,并且GSK3β抑制劑能夠緩解可卡因誘發(fā)的神經(jīng)興奮作用以及成癮,但是,其作用的突觸傳導(dǎo)機(jī)制尚不清晰。GSK3β、可卡因、多巴胺與突觸傳導(dǎo)之間的相互關(guān)系仍需進(jìn)一步的實(shí)驗(yàn)研究。本研究利用動(dòng)物行為學(xué)、腦片膜片鉗和胞外電信號(hào)記錄等技術(shù)手段,探索GSK3β在可卡因中樞興奮及成癮中的作用及機(jī)制。我們發(fā)現(xiàn),在整體動(dòng)物中非特異性的GSK3抑制劑氯化鋰(100 mg/kg,i.p.)以及特異性的GSK3β抑制劑SB216763(2.5 mg/kg,i.p.)能夠有效抑制可卡因(20 mg/kg,i.p.)引起的大鼠過(guò)度自發(fā)活動(dòng),而且可卡因抑制了伏隔核(Nac)核區(qū)中等棘突神經(jīng)元(MSN)細(xì)胞放電,氯化鋰及SB216763同樣能夠阻斷可卡因的這一效應(yīng)。在急性分離的腦片中,預(yù)先灌流SB216763(5μM)能夠緩解可卡因(10μM)引起的伏隔核(Nac)核(Core)區(qū)AMPA受體以及NMDA受體介導(dǎo)的EPSC(興奮性突觸后電流)的減弱效應(yīng),而且該效應(yīng)是通過(guò)激活多巴胺D1受體來(lái)實(shí)現(xiàn)的。進(jìn)一步的研究發(fā)現(xiàn),可卡因能夠抑制MSN神經(jīng)元突觸前膜谷氨酸的釋放,但對(duì)靜息電位及膜電阻并無(wú)影響,GSK3β抑制劑SB216763也能夠抑制可卡因在伏隔核的突觸前功能。同時(shí),可卡因能夠激活D2受體,降低MSN細(xì)胞內(nèi)在興奮性(intrinsic),而GSK3β抑制劑不能影響可卡因的這一效應(yīng)。連續(xù)五天給予SD大鼠可卡因(20 mg/kg i.p.),可使AMPA/NMDA比值明顯增加,而GKS3β抑制劑SB216763可以明顯緩解這一效應(yīng),這提示我們GSK3β抑制劑能夠有效干擾可卡因引起的突觸可塑性變化。以上結(jié)果表明,可卡因通過(guò)激活突觸前D1受體,抑制Nac核區(qū)MSN神經(jīng)元的谷氨酸傳導(dǎo),降低其放電頻率,進(jìn)而減少抑制性神經(jīng)遞質(zhì)γ-氨基丁酸(GABA)的投遞,導(dǎo)致其他腦區(qū)的廣泛性興奮,引起可卡因的神經(jīng)興奮作用,長(zhǎng)期的可卡因作用導(dǎo)致突觸重塑,誘發(fā)成癮。GSK3β抑制劑SB216763可以消除多巴胺引起的伏隔核谷氨酸釋放減少,從而阻斷可卡因?qū)ac的抑制效應(yīng),最終抑制可卡因引起的動(dòng)物過(guò)度自發(fā)活動(dòng)。同時(shí),SB216763能夠阻斷可卡因引起的突觸可塑性變化,可能是其抑制可卡因成癮的機(jī)制之一。
[Abstract]:Cocaine is a kind of addictive substance which acts mainly on monoamine transporter and inhibits the reuptake of dopamine in synaptic space which indirectly leads to the increase of dopamine content in synaptic space. In recent years, the role of glycogen synthase kinase 3 尾 -Glycogen synthase kinase 3 尾 -GSK3 尾 in cocaine central excitability and addiction has attracted wide attention. GSK3 尾 phosphorylation in nucleus accumbens nucleus nucleus nucleus was decreased after cocaine administration in rats, and GSK3 尾 inhibitor alleviated the neuroexcitatory effect and addiction induced by cocaine. However, the mechanism of synaptic conduction of cocaine was not clear. GSK3 尾, cocaine. The relationship between dopamine and synaptic conduction needs further experimental study. The purpose of this study was to explore the role and mechanism of GSK3 尾 in cocaine central excitation and addiction by means of animal behavior, brain patch clamp and extracellular electrical signal recording. We found that lithium chloride, a nonspecific GSK3 inhibitor in the whole animal, was 100mg / kg / kg i.p.) And specific GSK3 尾 inhibitor SB216763(2.5 mg / kg i.p. Effective inhibition of cocaine 20 mg / kg i.p.) Moreover, cocaine inhibited the discharges of median spinous neurons in the nucleus accumbens nucleus. Lithium chloride and SB216763 also blocked the effect of cocaine. In acutely isolated brain slices, preperfused SB216763(5 渭 M could attenuate the attenuated effects of AMPA receptors in the nucleus accumbens nucleus of the nucleus accumbens and the excitatory postsynaptic currents mediated by the NMDA receptors in the nucleus accumbens of the nucleus accumbens induced by 10 渭 M cocaine. And this effect is achieved by activating dopamine D 1 receptor. Further studies showed that cocaine could inhibit the release of glutamate from the presynaptic membrane of MSN neurons, but had no effect on the resting potential and membrane resistance. The GSK3 尾 inhibitor SB216763 could also inhibit the presynaptic function of cocaine in nucleus accumbens. At the same time, cocaine can activate D2 receptor and decrease the excitability of intrinsicine in MSN cells, but GSK3 尾 inhibitor can not affect this effect of cocaine. For five consecutive days, the AMPA/NMDA ratio of SD rats was significantly increased by 20 mg/kg i.p.. The GKS3 尾 inhibitor SB216763 could attenuate this effect, which suggested that GSK3 尾 inhibitor could effectively interfere with the synaptic plasticity induced by cocaine. These results suggest that cocaine inhibits glutamate conduction in MSN neurons in the Nac nuclear region by activating presynaptic D1 receptors, reduces its discharge frequency, and thus reduces the delivery of the inhibitory neurotransmitter GABA. It leads to extensive excitement in other brain regions, the neuroexcitatory effect of cocaine, long-term cocaine action leads to synaptic remodeling, and SB216763, an addictive. GSK3 尾 inhibitor, can eliminate the dopamine-induced decrease in glutamate release in nucleus accumbens. The inhibition effect of cocaine on Nac was blocked, and the excessive spontaneous activity induced by cocaine was finally inhibited. At the same time, SB216763 can block the change of synaptic plasticity induced by cocaine, which may be one of the mechanisms of inhibiting cocaine addiction.
【學(xué)位授予單位】：蘇州大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2015
【分類號(hào)】：R96

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