| Summary: | 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-versus-food choice procedure during daily 2-hour sessions. In addition to the daily choice sessions, rats were provided extended access to fentanyl during 12-hour self-administration sessions. After 2 weeks of this self-administration regimen, the nucleus accumbens and ventral tegmental area 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-versus-food choice were determined. Results: Before 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with a greater number of differentially expressed genes in the nucleus accumbens and ventral tegmental area of opioid-withdrawn females relative to males.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.
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