Sex-specific Concordance of Striatal Transcriptional Signatures of Opioid Addiction in Human and Rodent Brains

Background: Opioid use disorder (OUD) has emerged as a severe, ongoing public health emergency. Current treatments for OUD are unsuccessful in lead to lasting abstinence in most users. This underscores the lasting effects of chronic opioid use and emphasizes the need to understand the molecular mechanisms of drug seeking and taking, but also how those alterations persist through acute and protracted withdrawal. Methods: Here, we used RNA sequencing in post-mortem human tissue from males (n=10) and females (n=10) with OUD and age and sex-matched control subjects. We compared molecular alterations associated with human OUD in the nucleus accumbens (NAc) to mouse and rat models of non-volitional (n=3-6 per group per sex) and volitional (n=5-6 per group per sex) exposure to opioids across distinct stages of opioid use and withdrawal (acute and prolonged). Results: We found that the molecular signature in the NAc of females with OUD mirrored effects seen in the NAc of female rodents in a non-volitional paradigm at all stages of exposure. Conversely, males with OUD showed a similar expression profile to rodents with volitional exposure, but only during the acute withdrawal phase. Shared co-expression networks were involved in post-transcriptional modification of RNA and epigenetic modification of chromatin state. Conclusions: Our results provide fundamental insight into the conserved molecular pathways altered by opioids across species, with evidence suggesting that alterations in females with OUD may be driven by drug exposure, while alterations in males with OUD may be driven by volitional intake. Overall design: RNA-sequencing was conducted on prefrontal cortex and nucleus accumbens of Heterogeneous Stock rats and C57BL/6J mice. Both male and female rats and mice were used. Heterogeneous Stock rats underwent oxycodone self-administration, then sacrificed at different times following opioid self-administration. Mice were given either saline solution or morphine solution for oral drinking, then sacrified at different times following opioid drinking. Tissue was collected and gene expression was examined in rats and mice across different times of opioid administration and withdrawal.