Lentiviral-mediated modulation of miR-124 regulates methamphetamine reward through BDNF suppression in the nucleus accumbens of male and female rats

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 METH[sbnd]CPP 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 METH[sbnd]CPP, 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 METH[sbnd]CPP, 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.