11月30日,，國際權(quán)威學(xué)術(shù)期刊《神經(jīng)科學(xué)雜志》上刊登了復(fù)旦大學(xué)醫(yī)學(xué)神經(jīng)生物學(xué)國家重點實驗室主任鄭平教授帶領(lǐng)研究生經(jīng)過3年多的研究成果（Chronic Morphine Treatment Switches the Effect of Dopamine on Excitatory Synaptic Transmission from Inhibition to Excitation in Pyramidal Cells of the Basolateral Amygdala），該研究團(tuán)隊發(fā)現(xiàn)戒斷成癮藥物后所產(chǎn)生的痛苦與激活腦內(nèi)另一個腦區(qū)杏仁核多巴胺系統(tǒng)有關(guān),，提示如果對杏仁核多巴胺系統(tǒng)進(jìn)行干預(yù),，對減少“藥物成癮者”因環(huán)境因素導(dǎo)致的“藥物復(fù)吸”頑癥有重要意義。
這一研究得到了科技部“973”計劃,、國家自然科學(xué)基金委創(chuàng)新群體項目等方面的支持資助,。據(jù)鄭平介紹，藥物成癮是全球普遍存在的公共衛(wèi)生問題,，也是危害嚴(yán)重的社會問題,。實踐證明，藥物成癮者即使“戒毒”后,，也會不顧一切地去尋求藥物,，一是為了享受成癮藥物所帶來的“快感”，二是為了消除戒毒后難以忍受的“痛苦”,。研究證明,，成癮藥物產(chǎn)生的快感和痛苦與環(huán)境中的各種線索相互作用后，會使藥物成癮者產(chǎn)生“關(guān)聯(lián)性記憶”，使他們一遇到“相關(guān)線索”便會激活“相關(guān)記憶”,，產(chǎn)生覓藥,、用藥的沖動，從而導(dǎo)致復(fù)吸行為發(fā)生,。但藥物成癮者的快感和痛苦癥狀是通過何種“神經(jīng)機(jī)制”與環(huán)境中的線索相“偶聯(lián)”的,，一直是科學(xué)家有待解決的難題。
為了尋覓解開這一難題的鑰匙,，鄭平指導(dǎo)他的研究生將嗎啡成癮鼠放在兩個環(huán)境不同的盒子中,，然后在一個盒子中使成癮鼠突然戒斷嗎啡，這時成癮鼠會產(chǎn)生“痛苦”的戒斷癥狀,，并且將這一痛苦與其所處這個盒子的特殊環(huán)境“有機(jī)地”聯(lián)系在一起,；以后將這個鼠再放到這一環(huán)境中，它就會“回想”起當(dāng)初藥物戒斷時的痛苦,，從而迅速“逃離”這一環(huán)境,。但是，如果用藥物干預(yù)的方法,，將成癮鼠杏仁核內(nèi)的多巴胺Ｄ１受體進(jìn)行抑制后,，再將大鼠放入同樣盒子中，它會“忘記”先前所受的痛苦,，且并不“逃離”這個環(huán)境,。
研究人員針對上述現(xiàn)象，深入研究了嗎啡成癮鼠腦內(nèi)杏仁核的變化,，發(fā)現(xiàn)嗎啡使多巴胺對腦內(nèi)“活性分子”谷氨酸的作用由原來的抑制逆轉(zhuǎn)為興奮,，而這種興奮是因為嗎啡“動員”了杏仁核突觸前部位原本“沉默”的多巴胺Ｄ１受體，使其介導(dǎo)的信號傳導(dǎo)通路功能由“低迷”轉(zhuǎn)為“亢進(jìn)”,，從而逆轉(zhuǎn)了杏仁核內(nèi)多巴胺對谷氨酸的作用,。結(jié)果證明，嗎啡成癮鼠腦內(nèi)杏仁核中多巴胺對谷氨酸作用的逆轉(zhuǎn),，可能是將藥物戒斷后的“痛苦”癥狀與周圍環(huán)境線索“偶聯(lián)”的重要神經(jīng)機(jī)制,，如果對這一成癮機(jī)制進(jìn)行干預(yù),，可能成為減少藥物成癮者因環(huán)境因素導(dǎo)致藥物復(fù)吸的新策略,。(生物谷Bioon.com)
doi:10.1523/JNEUROSCI.3806-11.2011
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Chronic Morphine Treatment Switches the Effect of Dopamine on Excitatory Synaptic Transmission from Inhibition to Excitation in Pyramidal Cells of the Basolateral Amygdala
Zicheng Li1,2,*, Wenjie Luan1,*, Yang Chen1,*, Ming Chen1, Yi Dong1, Bin Lai1, Lan Ma1, and Ping Zheng1
Dopaminergic signaling in the basolateral amygdala (BLA) is important for drug-stimulus learning that triggers relapse to drug-seeking behavior. However, little is known about adaptive changes in this signaling pathway upon chronic morphine treatment. In this paper, we observed the influence of chronic morphine treatment on the effect of dopamine (DA) on the excitatory transmission in the pyramidal cells of BLA in slices with the whole-cell patch-clamp method. We also studied its mechanism and significance with pharmacological approaches combined with biochemical and behavioral techniques. The results showed that chronic morphine exposure switched the effect of DA on the excitatory synaptic transmission from inhibition to excitation; the chronic morphine-induced switching action on the effect of DA was due to its influence on D1 receptors; the site of the effect of chronic morphine treatment on D1 receptors was at presynaptic locus; chronic morphine treatment induced a significant increase in the amount of D1 receptor expression in the synaptosomes and synaptosomal membrane fraction from BLA; the enhancement of presynaptic glutamate release by D1 receptor agonist upon chronic morphine treatment was dependent on the activation of cAMP-dependent protein kinase; and the intra-BLA injection of D1 receptor antagonist canceled the conditioned place aversion (CPA) in morphine-dependent rats. In conclusion, chronic morphine treatment switches the effect of DA on the excitatory synaptic transmission from inhibition to excitation by the presynaptic D1 receptor amount increase-mediated glutamate release in the pyramidal cells of BLA and the blockade of D1 receptors in BLA cancels CPA in morphine-dependent rats.
