10月4日, 《神经科学杂志》(The Journal of Neuroscience)发表了中科院上海药物研究所刘景根研究组题为“细胞外信号调节激酶信号通路介导的表观遗传机制调控脑源性神经营养因子转录参与吗啡条件性戒断负性情绪的消退学习”的研究论文。该论文报道了腹内侧前额皮层(vmPFC)表观遗传机制参与急性吗啡条件性戒断大鼠的消退学习过程。该工作是有药物所博士生王维胜等人在刘景根教授的指导下完成。
阿片类药物滥用过程伴随的线索阻扰成瘾者的戒断,容易引起患者的复吸和觅药;减少药物线索的诱发作用成为治疗药物成瘾的关键。消退训练是有效减少药物线索诱发作用的一种行为方法。
研究工作发现大鼠腹内侧前额皮层(vmPFC)部位内表观遗传机制调控的脑源性神经营养因子(BDNF)表达参与吗啡负性情绪消退学习。消退训练促进BDNF外显子Ⅰ启动子部位与cAMP反应元件结合蛋白(CREB)及组蛋白H3乙酰化结合增加;并且BDNF转录与表达显著性升高。研究进一步发现组蛋白去乙酰化酶(HDAC)抑制剂曲古霉素A(Trichostatin A)促进表观遗传调节的BDNF基因转录,而细胞外信号调节激酶(ERK)抑制剂U0126的作用却相反。同时,U0126和TrkB受体抑制剂K252a或BDNF清除剂TrkB-FC可以阻断BDNF信号通路抑制消退行为发生。在vmPFC部位给予NMDA受体部分激动剂D-环丝氨酸(D-cycloserine)可促进吗啡条件性戒断的消退行为以及消退训练引起的ERK和CREB激活;给予NMDA受体抑制剂AP5却显著抑制消退行为以及ERK和CREB的激活。这些结果表明NMDA受体介导ERK/CREB信号通路激活,促进组蛋白乙酰化所调控的BDNF基因转录参与吗啡条件戒断引起负性情绪消退学习。
该项工作首次阐明了表观遗传机制参与吗啡戒断负性情绪消退学习,解释了调控表观遗传机制的上游信号通路,为深入解释成瘾消退行为提供新的可能,为成瘾治疗研究提供了新的思路。
该工作得到科技部 “973”项目和国家自然科学基金重点项目的资助。(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.