Dynamics of neurotransmitter and extracellular vesicle-derived microRNA landscapes during heroin and methamphetamine withdrawal

Circulating miRNAs in small vesicles known as exosomes within blood have been emerging as a new research hotspot in the field of psychiatric disorders. The aim of this work was to characterize the changes in exosomal microRNA profiles, both short-term and long-term, during substance withdrawal using a cross-sectional study design. Using weighted gene co-expression network analysis, a series of known, conserved, and novel exosomal microRNAs were identified as being associated with withdrawal stage and key neurotransmitters GABA, choline, and serotonin. Bioinformatics analyses established that the differences in the miRNA profile target signaling pathways are associated with developmental and intellectual abnormalities. Notably, a set of dysregulated microRNA signatures including hsa-mia-451a and hsa-mir-21a resulted in an AUC of 0.966 and 0.861, respectively, for predicting patients with substance use disorders. 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. Taken together, these data suggest that the microRNA content of circulating exosomes represent a biomolecular "fingerprint" of the progression of substance withdrawal and may uncover the putative mechanism of how these exosomal microRNAs contribute to central nervous system development and function.