Department of Neuroscience and Addiction Studies, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran.
Department of Physiology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
Behav Brain Res. 2021 Sep 24;414:113477. doi: 10.1016/j.bbr.2021.113477. Epub 2021 Jul 22.
Recently, epigenetic mechanisms are considered as the new potential targets for addiction treatment. This research was designed to explore the effect of histone acetylation on ΔFosB gene expression in morphine-induced conditioned place preference (CPP) in male rats. CPP was induced via morphine injection (5 mg/kg) for three consecutive days. Animals received low-dose theophylline (LDT) or Suberoylanilide Hydroxamic acid (SAHA), as an histone deacetylase (HDAC) activator or inhibitor, respectively, and a combination of both in subsequent extinction days. Following extinction, a priming dose of morphine (1 mg/kg) was administered to induce reinstatement. H4 acetylation and ΔFosB expression in the nucleus accumbens (NAc) and medial prefrontal cortex (mPFC) were assessed on the last day of extinction and the following CPP reinstatement. Our results demonstrated that daily administration of SAHA (25 mg/kg; i.p.), facilitated morphine-extinction and decreased CPP score in reinstatement of place preference. Conversely, injections of LDT (20 mg/kg; i.p.) prolonged extinction in animals. Co-administration of LDT and SAHA on extinction days counterbalanced each other, such that maintenance and reinstatement were no different than the control group. The gene expression of ΔFosB was increased by SAHA in NAc and mPFC compared to the control group. Administration of SAHA during extinction days, also altered histone acetylation in the NAc and mPFC on the last day of extinction, but not on reinstatement day. Collectively, administration of SAHA facilitated extinction and reduced reinstatement of morphine-induced CPP in rats. This study confirms the essential role of epigenetic mechanisms, specifically histone acetylation, in regulating drug-induced plasticity and seeking behaviors.
最近，表观遗传机制被认为是成瘾治疗的新潜在靶点。本研究旨在探讨组蛋白乙酰化对吗啡诱导条件性位置偏爱（CPP）中 ΔFosB 基因表达的影响。通过连续 3 天给雄性大鼠注射吗啡（5mg/kg）诱导 CPP。动物在随后的消退日接受低剂量茶碱（LDT）或 Suberoylanilide Hydroxamic acid（SAHA），分别作为组蛋白去乙酰化酶（HDAC）激活剂或抑制剂，以及两者的组合。在消退后，给予吗啡（1mg/kg）引发重新激发。在消退的最后一天和随后的 CPP 重新激发时，评估伏隔核（NAc）和前额叶皮质（mPFC）中的 H4 乙酰化和 ΔFosB 表达。结果表明，每天给予 SAHA（25mg/kg；腹腔注射）促进了吗啡消退，并降低了重新激发位置偏好的 CPP 评分。相反，LDT（20mg/kg；腹腔注射）的注射延长了动物的消退。在消退日共同给予 LDT 和 SAHA 相互抵消，维持和重新激发与对照组没有不同。与对照组相比，SAHA 增加了 NAc 和 mPFC 中 ΔFosB 的基因表达。在消退日给予 SAHA 还改变了 NAc 和 mPFC 中最后一天的组蛋白乙酰化，但在重新激发日没有改变。总的来说，SAHA 的给药促进了吗啡诱导的 CPP 在大鼠中的消退并减少了重新激发。这项研究证实了表观遗传机制，特别是组蛋白乙酰化，在调节药物诱导的可塑性和寻求行为方面的重要作用。
