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

Abstract

Background

Opioid use disorder (OUD) has emerged as a severe, ongoing public health emergency. Current treatments for OUD are unsuccessful in leading 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 and how those alterations persist through acute and protracted withdrawal.

Methods

Here, we used RNA sequencing in postmortem 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 nonvolitional (n = 4–5 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 nonvolitional paradigm at all stages of exposure. Conversely, males with OUD showed an expression profile similar to that of rodents with volitional exposure but only during the acute withdrawal phase. Shared coexpression networks were involved in posttranscriptional 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.