College of Forensic Medicine, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, 710061, China; Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA, 19129, USA.
Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA, 19129, USA.
Neuropharmacology. 2018 Oct;141:113-125. doi: 10.1016/j.neuropharm.2018.08.030. Epub 2018 Aug 27.
Epigenetic remodeling contributes to synaptic plasticity via modification of gene expression, which underlies cocaine-induced long-term memory. A prevailing hypothesis in drug addiction is that drugs of abuse rejuvenate developmental machinery to render reward circuitry highly plastic and thus engender drug memories to be highly stable. Identification and reversal of these pathological pathways are therefore critical for cocaine abuse treatment. Previous studies revealed an interesting finding in which the mRNA of histone lysine demethylase, KDM6B, is upregulated in the medial prefrontal cortex (mPFC) during early cocaine withdrawal. However, whether and how it contributes to drug-seeking behavior remain unknown. Here we used a conditioned place preference paradigm to investigate the potential role of KDM6B in drug-associated memory. We found that KDM6B protein levels selectively increased in the mPFC during cocaine withdrawal. Notably, systemic injection of KDM6B inhibitor, GSK-J4, disrupted both reconsolidation of cocaine-conditioned memory and cocaine-primed reinstatement, suggesting dual effects of KDM6B in cocaine reward memory. In addition, we found that NMDAR expression and function were both enhanced during early cocaine withdrawal in mPFC. Injection of GSK-J4 selectively reversed this cocaine-induced increase of NR2A expression and synaptic function, suggesting that mal-adaptation of cocaine-induced synaptic plasticity in mPFC largely underlies KDM6B-mediated cocaine-associated memory. Altogether, these data suggest that KDM6B plays an essential role in cocaine-associated memory, which mainly acts through enhancing cocaine-induced synaptic plasticity in the mPFC. Our findings revealed a novel role of KDM6B in cocaine-associated memory and inhibition of KDM6B is a potential strategy to alleviate drug-seeking behavior.
表观遗传重塑通过修饰基因表达促进突触可塑性，这是可卡因诱导长期记忆的基础。在药物成瘾中，一个流行的假设是，滥用药物会恢复发育机制，使奖励回路具有高度可塑性，从而使药物记忆具有高度稳定性。因此，识别和逆转这些病理途径对于可卡因滥用治疗至关重要。先前的研究揭示了一个有趣的发现，即在可卡因戒断早期，组蛋白赖氨酸去甲基酶 KDM6B 的 mRNA 在中前额叶皮层（mPFC）中上调。然而，它是否以及如何有助于觅药行为尚不清楚。在这里，我们使用条件性位置偏好范式来研究 KDM6B 在药物相关记忆中的潜在作用。我们发现，KDM6B 蛋白水平在可卡因戒断期间选择性地增加了 mPFC。值得注意的是，系统注射 KDM6B 抑制剂 GSK-J4 破坏了可卡因条件记忆的再巩固和可卡因引发的复燃，表明 KDM6B 在可卡因奖赏记忆中具有双重作用。此外，我们发现，在 mPFC 中，NMDAR 表达和功能在可卡因戒断早期都增强了。GSK-J4 的注射选择性地逆转了这种可卡因诱导的 NR2A 表达和突触功能的增加，表明 mPFC 中可卡因诱导的突触可塑性的适应性不良在很大程度上是由 KDM6B 介导的可卡因相关记忆所导致的。总之，这些数据表明 KDM6B 在可卡因相关记忆中发挥着重要作用，主要通过增强 mPFC 中可卡因诱导的突触可塑性来发挥作用。我们的研究结果揭示了 KDM6B 在可卡因相关记忆中的新作用，抑制 KDM6B 可能是减轻觅药行为的一种潜在策略。
