Introduction: Cannabis is the most used illicit drug in the United States. With many states passing legislation to permit its recreational use, there is concern that cannabis use among adolescents could increase dramatically in the coming years. Historically, it has been difficult to model real-world cannabis use to investigate the causal relationship between cannabis use in adolescence and behavioral and neurobiological effects in adulthood. Materials and Methods: We used a response-contingent vapor administration model to investigate long-term effects of cannabis use during adolescence on the medial prefrontal cortex (mPFC) and mPFC-dependent behaviors in male and female rats. Results: Adolescent (35- to 55-day-old) female rats had significantly higher rates of responding for vaporized Δ⁹-tetrahydrocannabinol (THC)-dominant cannabis extract (CAN_THC) compared with adolescent males. In adulthood (70-110 days old), female, but not male, CAN_THC rats also took more trials to reach criterion and made more regressive errors in an automated attentional set-shifting task compared with vehicle rats, thereby indicating sex differences in behavioral flexibility impairments. Notably, sex-treatment interactions were not observed when rats of each sex were exposed to a noncontingent CAN_THC vapor dosing regimen that approximated CAN_THC vapor deliveries earned by females. No differences were observed in effort-based decision making in either sex. In the mPFC, female (but not male) CAN_THC rats displayed more reactive microglia with no changes in myelin basic protein expression or dendritic spine density. Conclusion: Altogether, these data reveal important sex differences in rates of responding for CAN_THC vapor in adolescence that may confer enduring alterations to mPFC structure and function and suggest that there may be subtle differences in the effects of response-contingent versus noncontingent cannabis exposure that should be systematically examined in future studies.

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