GSE173959
Opioid withdrawal produces sex-specific effects on fentanyl-vs.-food choice and mesolimbic transcription
Background: Opioid withdrawal is a key driver of opioid addiction and an obstacle to  recovery. However, withdrawal effects on opioid reinforcement and mesolimbic  neuroadaptation are understudied and the role of sex is largely unknown.  Methods: Male (n=13) and female (n=12) rats responded under a fentanyl-vs.-food  “choice” procedure during daily 2h sessions. In addition to the daily choice sessions,  rats were provided extended access to fentanyl during 12h self-administration  sessions. After two weeks of this selfadministration  regimen, the nucleus accumbens (NAc) and ventral tegmental area  (VTA) of a subset of rats were subjected to RNA sequencing. In the remaining rats, a  third week of this self-administration regimen was conducted, during which methadone  effects on fentanyl-vs.-food choice were determined.  Results: Prior to opioid dependence, male and female rats similarly allocated  responding between fentanyl and food. Abstinence from extended fentanyl access  elicited similar increases in somatic withdrawal signs in both sexes. Despite similar  withdrawal signs and extended access fentanyl intake, opioid withdrawal was  accompanied by a maladaptive increase in fentanyl  choice in males, but not females. Behavioral sex differences corresponded with a  greater number of differentially expressed genes in the NAc and VTA of opioidwithdrawn  females relative to males. Methadone blocked withdrawal-associated  increases in fentanyl choice in males, but failed to further decrease fentanyl choice in  females.  Conclusions: These results provide foundational evidence of sex-specific  neuroadaptations to opioid withdrawal, which may be relevant to the female-specific  resilience to withdrawal-associated increases in opioid choice and aid in the  identification of novel therapeutic targets. Overall design: Bulk RNA sequencing from microdissected rat nucleus accumbens and ventral tegmental area brain areas, drug treated group DEGs generated relative to saline treated controls.