Bahi Amine, Dreyer Jean-Luc
Basic Medical Sciences Department, College of Medicine, Ajman University, Ajman, UAE; Center of Medical & Bio-Allied Health Sciences Research, Ajman University, Ajman, UAE.
Division of Biochemistry, Department of Medicine, University of Fribourg, Fribourg, Switzerland.
Physiol Behav. 2025 Oct 1;299:115006. doi: 10.1016/j.physbeh.2025.115006. Epub 2025 Jun 19.
MicroRNAs (miRNAs) are critical regulators of gene expression and have been implicated in the pathophysiology of mood disorders and addiction. Among these, miR-124 is known to modulate synaptic plasticity and neuronal function, yet its specific role in methamphetamine (METH) reward remains poorly understood. This study aimed to investigate the role of miR-124 and its downstream target, brain-derived neurotrophic factor (BDNF), in the nucleus accumbens (NAcc) in mediating METH-induced conditioned place preference (CPP). Using a combination of behavioral assays, RT-PCR, and lentiviral-mediated gene manipulation, we examined the effects of miR-124 gain- and loss-of-function, as well as BDNF overexpression, on METHCPP in male and female rats. METH treatment elicited robust CPP in both sexes, with no significant sex differences. RT-PCR analysis revealed that METH exposure increased miR-124 expression while decreasing BDNF mRNA levels in the NAcc, with a strong negative correlation between the two. miR-124 knockdown reduced METHCPP, increased BDNF expression, and reversed the negative correlation, whereas miR-124 overexpression enhanced CPP, decreased BDNF, and reinforced the correlation. Importantly, BDNF overexpression in the NAcc reduced METHCPP, mimicking the effects of miR-124 knockdown. These findings demonstrate that miR-124 enhances METH reward by suppressing BDNF expression in the NAcc, highlighting a critical miR-124/BDNF regulatory axis in addiction. This study provides novel insights into the molecular mechanisms underlying METH reward and highlights the miR-124/BDNF axis as a pathway that may warrant further investigation in the context of substance use disorders.
微小RNA（miRNA）是基因表达的关键调节因子，与情绪障碍和成瘾的病理生理学有关。其中，已知miR-124可调节突触可塑性和神经元功能，但其在甲基苯丙胺（METH）奖赏中的具体作用仍知之甚少。本研究旨在探讨miR-124及其下游靶点脑源性神经营养因子（BDNF）在伏隔核（NAcc）中介导METH诱导的条件性位置偏爱（CPP）中的作用。我们结合行为学检测、逆转录-聚合酶链反应（RT-PCR）和慢病毒介导的基因操作，研究了miR-124功能增强和缺失以及BDNF过表达对雄性和雌性大鼠METH-CPP的影响。METH处理在两性中均引发了强烈的CPP，且无显著性别差异。RT-PCR分析显示，METH暴露增加了NAcc中miR-124的表达，同时降低了BDNF mRNA水平，二者呈强负相关。敲低miR-124可降低METH-CPP，增加BDNF表达，并逆转负相关，而miR-124过表达则增强了CPP，降低了BDNF，并加强了相关性。重要的是，NAcc中BDNF过表达降低了METH-CPP，模拟了敲低miR-124的效果。这些发现表明，miR-124通过抑制NAcc中BDNF的表达来增强METH奖赏，突出了成瘾中关键的miR-124/BDNF调节轴。本研究为METH奖赏的分子机制提供了新的见解，并强调miR-124/BDNF轴作为一条在物质使用障碍背景下可能值得进一步研究的途径。
