College of Forensic Medicine, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, 710061, China.
The Key Laboratory of Health Ministry for Forensic Medicine, Xi'an Jiaotong University, Shaanxi, 710061, China.
Addict Biol. 2021 Jan;26(1):e12881. doi: 10.1111/adb.12881. Epub 2020 Feb 14.
Methamphetamine (METH) -induced behavioral sensitization depends on long-term neuroplasticity in the mesolimbic dopamine system, especially in the nucleus accumbens (NAc). miR-128, a brain enriched miRNA, was found to have abilities in regulating neuronal excitability and formation of fear-extinction memory. Here, we aim to identify the role of miR-128 on METH-induced locomotor sensitization of male mice. We identified a significant increase of miR-128 in the NAc of mice upon repeated-intermittent METH exposure but not acute METH administration. Microinjection of adeno-associated virus (AAV)-miR-128 over-expression and inhibition constructs into the NAc of mice resulted in enhanced METH-induced locomotor sensitization and attenuated effects of METH respectively. Isobaric tags for relative and absolute quantification (iTRAQ) technology and ingenuity pathway analysis (IPA) were carried out to uncover the potential molecular mechanisms underlying miR-128-regulated METH sensitization. Differentially expressed proteins, including 25 potential targets for miR-128 were annotated in regulatory pathways that modulate dendritic spines, synaptic transmission and neuritogenesis. Of which, Arf6, Cpeb3 and Nlgn1, were found to be participating in miR-128-regulated METH sensitization. Consistently, METH-induced abnormal changes of Arf6, Cpeb3 and Nlgn1 in the NAc of mice were also detected by qPCR and validated by western blot analysis. Thus, miR-128 may contribute to METH sensitization through controlling neuroplasticity. Our study suggested miR-128 was an important regulator of METH- induced sensitization and also provided the potential molecular networks of miR-128 in regulating METH-induced sensitization.
甲基苯丙胺（METH）诱导的行为敏化依赖于中脑边缘多巴胺系统的长期神经可塑性，尤其是在伏隔核（NAc）中。miR-128 是一种富含大脑的 miRNA，被发现具有调节神经元兴奋性和形成恐惧消退记忆的能力。在这里，我们旨在确定 miR-128 在雄性小鼠 METH 诱导的运动敏化中的作用。我们发现，在反复间歇性 METH 暴露后，小鼠 NAc 中的 miR-128 显著增加，但急性 METH 给药则没有。将腺相关病毒（AAV）-miR-128 过表达和抑制构建体微注射到小鼠的 NAc 中，导致 METH 诱导的运动敏化增强和 METH 作用减弱。采用同位素标记相对和绝对定量（iTRAQ）技术和 ingenuity 通路分析（IPA），揭示了 miR-128 调节 METH 敏化的潜在分子机制。差异表达蛋白，包括 miR-128 的 25 个潜在靶标，被注释在调节树突棘、突触传递和神经发生的调节途径中。其中，Arf6、Cpeb3 和 Nlgn1 被发现参与了 miR-128 调节的 METH 敏化。一致地，通过 qPCR 检测到 METH 在小鼠 NAc 中诱导的 Arf6、Cpeb3 和 Nlgn1 的异常变化，并通过 Western blot 分析进行了验证。因此，miR-128 可能通过控制神经可塑性来促进 METH 敏化。我们的研究表明，miR-128 是 METH 诱导敏化的重要调节剂，并为 miR-128 调节 METH 诱导敏化的潜在分子网络提供了证据。
