杏仁核和腹内侧前额皮层染色质组蛋白乙酰化修饰在吗啡戒断引起的负性情感消退学习中的作用研究

阿片类药物戒断引起的负性情感记忆是吸毒者强迫性用药和戒断后复吸的重要原因。利用条件位置厌恶这一经典研究成瘾药物负性情感的动物模型，我们最近发现消退训练能够显著的降低吗啡负性情感。腹内侧前额皮层（vmPFC）注射NMDA受体部分激动剂和组蛋白去乙酰化酶抑制剂能够促进消退学习，而注射ERK激活抑制剂则弱消退学习。我们还发现消退训练增加vmPFC染色质组蛋白乙酰化水平和引起BDNF和Arc蛋白表达。这些初步结果表明吗啡负性情感记忆消退学习涉及到表观遗传机制。我们将深入研究vmPFC染色质组蛋白乙酰化修饰与BDNF和Arc蛋白表达的关系；研究ERK信号通路激活对染色质表观遗传修饰的调控作用; 研究BDNF和Arc蛋白表达在吗啡负性情感消退学习记忆中的作用；研究基底外侧杏仁核和vmPFC在消退学习记忆中的功能联系及神经环路。研究阿片负性情感消退学习记忆机制对治疗阿片成瘾和预防复吸有重要意义。

Aversive memories associated with drug withdrawal may contribute to persistent drug seeking. Understanding the molecular mechanisms underlying the extinction of aversive memories associated with drug withdrawal could lead to pharmacological approaches for enhancing extinction memory, which might facilitate the treatment of drug addiction. Our preliminary data showed that extinction training attenuated the expression of conditioned place aversion (CPA). Intra-vmPFC injections of the NMDA receptor partial agonist D-cycloserine and the histone deacetylase inhibitor TSA promoted CPA extinction. In contrast, intra-vmPFC injection of U0126 inhibits inhibited CPA extinction. Our preliminary data also demonstrated that extinction training induced induce histone H3 and H4 acetylations and increased BDNF and Arc expression. These initial data suggest that extinction of morphine withdrawal-induced conditioned place aversion is associated with chromatin modifications. Therefore, we will further study: 1) whether increases in histon acetylation in the vmPFC contributes to enhancement of BDNF and Arc protein expression; 2) what role ERK signaling plays in regulation of chromatin modification following extinction training; 3) whether enhancement of BDNF and Arc protein expression in the vmPFC is involved in the extinction of CPA; and 4) what interplay occurs among vmMPFC, amygdala and hippocampus during extinction training. This study will give insight in the mechanisms underlying the extinction of CPA, and thus facilitate the treatment of drug addiction.