Despite decades of research in the field of substance withdrawal, molecular biomarkers and related mechanistic study have generally been lacking. In addition to known neurotransmitters, circulating miRNAs are found in small vesicles known as exosomes within blood that have diagnostic potential and are known to contribute to psychiatric disorders. The aim of this work was to characterize the changes in neurotransmitter and exosomal miRNA profiles during heroin and methamphetamine withdrawal using a cross-sectional study design, and to determine their associations to psychiatric comorbidities in a large group of patients with substance use disorders (SUDs). Using weighted gene co-expression network analysis, a series of known, conserved, and novel exosomal miRNAs were identified as being associated with the severity of anxiety and depression, as well as the concentrations of neurotransmitters GABA, choline, and serotonin. Bioinformatics analyses established that the differences in the miRNA profile target signaling pathways are significantly associated with developmental and intellectual abnormalities. Notably, a set of dysregulated miRNA signatures including hsa-mia-451a and hsa-mir-21a resulted in an AUC of 0.966 and 0.861, respectively, for predicting the patients with SUDs. Furthermore, hsa-miR-744a-5p was positively correlated with serotonin, and its important role in maintaining neuronal development and function was revealed using an in vitro human induced pluripotent stem cells derived neuronal model. Our results suggest that the miRNA content of circulating exosomes represent a biomolecular “fingerprint” of the progression of substance withdrawal and may uncover the putative mechanism of how these exosomal miRNAs contribute to psychiatric symptoms.

尽管在物质戒断领域进行了数十年的研究，但普遍缺乏分子生物标志物和相关的机制研究。除了已知的神经递质外，循环 miRNA 还存在于血液中称为外泌体的小囊泡中，这些囊泡具有诊断潜力并且已知会导致精神疾病。这项工作的目的是使用横断面研究设计来描述海洛因和甲基苯丙胺戒断期间神经递质和外泌体 miRNA 谱的变化，并确定它们与一大群物质使用障碍 (SUD) 患者的精神合并症的关联。 . 使用加权基因共表达网络分析，一系列已知的、保守的和新的外泌体 miRNA 被确定为与焦虑和抑郁的严重程度相关，以及神经递质 GABA、胆碱和血清素的浓度。生物信息学分析确定 miRNA 谱靶信号通路的差异与发育和智力异常显着相关。值得注意的是，一组失调的 miRNA 特征包括 hsa-mia-451a 和 hsa-mir-21a 分别导致用于预测 SUD 患者的 AUC 为 0.966 和 0.861。此外，hsa-miR-744a-5p 与血清素呈正相关，并且使用体外人诱导的多能干细胞衍生的神经元模型揭示了其在维持神经元发育和功能中的重要作用。