10月4日,， 《神經科學雜志》（The Journal of Neuroscience）發(fā)表了中科院上海藥物研究所劉景根研究組題為“細胞外信號調節(jié)激酶信號通路介導的表觀遺傳機制調控腦源性神經營養(yǎng)因子轉錄參與嗎啡條件性戒斷負性情緒的消退學習”的研究論文,。該論文報道了腹內側前額皮層（vmPFC）表觀遺傳機制參與急性嗎啡條件性戒斷大鼠的消退學習過程,。該工作是有藥物所博士生王維勝等人在劉景根教授的指導下完成,。
阿片類藥物濫用過程伴隨的線索阻擾成癮者的戒斷,，容易引起患者的復吸和覓藥,；減少藥物線索的誘發(fā)作用成為治療藥物成癮的關鍵,。消退訓練是有效減少藥物線索誘發(fā)作用的一種行為方法,。
研究工作發(fā)現大鼠腹內側前額皮層（vmPFC）部位內表觀遺傳機制調控的腦源性神經營養(yǎng)因子（BDNF）表達參與嗎啡負性情緒消退學習,。消退訓練促進BDNF外顯子Ⅰ啟動子部位與cAMP反應元件結合蛋白（CREB）及組蛋白H3乙酰化結合增加,；并且BDNF轉錄與表達顯著性升高,。研究進一步發(fā)現組蛋白去乙酰化酶（HDAC）抑制劑曲古霉素A(Trichostatin A)促進表觀遺傳調節(jié)的BDNF基因轉錄,，而細胞外信號調節(jié)激酶（ERK）抑制劑U0126的作用卻相反,。同時，U0126和TrkB受體抑制劑K252a或BDNF清除劑TrkB-FC可以阻斷BDNF信號通路抑制消退行為發(fā)生,。在vmPFC部位給予NMDA受體部分激動劑D-環(huán)絲氨酸（D-cycloserine）可促進嗎啡條件性戒斷的消退行為以及消退訓練引起的ERK和CREB激活,；給予NMDA受體抑制劑AP5卻顯著抑制消退行為以及ERK和CREB的激活。這些結果表明NMDA受體介導ERK/CREB信號通路激活,，促進組蛋白乙?；{控的BDNF基因轉錄參與嗎啡條件戒斷引起負性情緒消退學習。
該項工作首次闡明了表觀遺傳機制參與嗎啡戒斷負性情緒消退學習,，解釋了調控表觀遺傳機制的上游信號通路,，為深入解釋成癮消退行為提供新的可能，為成癮治療研究提供了新的思路,。
該工作得到科技部 “973”項目和國家自然科學基金重點項目的資助,。（生物谷Bioon.com）
doi: 10.1523/JNEUROSCI.1991-12.2012
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Extinction of Aversive Memories Associated with Morphine Withdrawal Requires ERK-Mediated Epigenetic Regulation of Brain-Derived Neurotrophic Factor Transcription in the Rat Ventromedial Prefrontal Cortex.
Wang WS, Kang S, Liu WT, Li M, Liu Y, Yu C, Chen J, Chi ZQ, He L, Liu JG.
Recent evidence suggests that histone deacetylase (HDAC) inhibitors facilitate extinction of rewarding memory of drug taking. However, little is known about the role of chromatin modification in the extinction of aversive memory of drug withdrawal. In this study, we used conditioned place aversion (CPA), a highly sensitive model for measuring aversive memory of drug withdrawal, to investigate the role of epigenetic regulation of brain-derived neurotrophic factor (BDNF) gene expression in extinction of aversive memory. We found that CPA extinction training induced an increase in recruiting cAMP response element-binding protein (CREB) to and acetylation of histone H3 at the promoters of BDNF exon I transcript and increased BDNF mRNA and protein expression in the ventromedial prefrontal cortex (vmPFC) of acute morphine-dependent rats and that such epigenetic regulation of BDNF gene transcription could be facilitated or diminished by intra-vmPFC infusion of HDAC inhibitor trichostatin A or extracellular signal-regulated kinase (ERK) inhibitor U0126 (1,4-diamino-2,3-dicyano-1,4-bis(methylthio)butadiene) before extinction training. Correspondingly, disruption of the epigenetic regulation of BDNF gene transcription with U0126 or suppression of BDNF signaling with Trk receptor antagonist K252a or BDNF scavenger tyrosine kinase receptor B (TrkB)-Fc blocked extinction of CPA behavior. We also found that extinction training-induced activation of ERK and CREB and extinction of CPA behavior could be potentiated or suppressed by intra-vmPFC infusion of d-cycloserine, a NMDA receptor partial agonist or aminophosphonopentanoic acid, a NMDA receptor antagonist. We conclude that extinction of aversive memory of morphine withdrawal requires epigenetic regulation of BDNF gene transcription in the vmPFC through activation of the ERK-CREB signaling pathway perhaps in a NMDA receptor-dependent manner.
