Oxycodone self-administration induces microRNA and gene expression changes in the rat nucleus accumbens

Prescription opioid abuse remains a critical public health concern and is a major risk factor for the development of opioid use disorder (OUD). Thus, there is an urgent need to better understand the neurobiological mechanisms underlying OUD in order to develop therapeutics and address the ongoing opioid epidemic. In this study, we hypothesized that microRNAs regulate gene expression changes following oxycodone self-administration. To test our hypothesis, we utilized a long-access drug self-administration paradigm in rats. Briefly, adult male Sprague-Dawley rats were trained to self-administer oxycodone (0.15mg/kg/infusion) or saline and were sacrificed 24h (withdrawal) following the last self-administration session. Brains were collected and the nucleus accumbens (NAc) was extracted and was processed for small RNA and RNA sequencing. We found that oxycodone self-administration changed the expression of 40 genes and 16 mature microRNAs (miRNAs). Bioinformatic predictions revealed that opioid-regulated genes are predicted targets of differentially regulated miRNAs, suggesting that miRNAs contribute to opioid-mediated transcriptomic changes in the NAc. Furthermore, we validated some of these findings in an independent cohort of male and female rats and across different stages of the addiction cycle. We identified miRNAs that are dynamically regulated during oxycodone withdrawal, as well as others that exhibit sustained regulation across different stages of the addiction cycle. Taken together, our data show that miRNAs may contribute to opioid-regulated gene expression and point to the therapeutic potential of miRNAs for OUD.