Sex differences in adolescent cannabis vapor self-administration mediate enduring effects on behavioral flexibility and prefrontal microglia activation in rats

• Published in: bioRxiv
• Main Authors: Freels, Timothy G, Westbrook, Sara R, Wright, Hayden R, Kuyat, Jacqulyn R, Zamberletti, Erica, Malena, Alexandra M, Melville, Max W, Brown, Amanda M, Glodosky, Nicholas C, Ginder, Darren E, Klappenbach, Courtney M, Delevich, Kristen M, Rubino, Tiziana, McLaughlin, Ryan J
• Format: Journal Article Paper
• Language: English
• Published: United States Cold Spring Harbor Laboratory Press 22.01.2023
• Subjects: Adolescents; Cannabis; Child development; Decision making; Dendritic spines; Females; Gender differences; Long-term effects; Males; Marijuana; Microglia; Myelin; Myelin basic protein; Prefrontal cortex; Self-administration; Sex differences; Structure-function relationships; Tetrahydrocannabinol; Vapors; adolescence; cannabis; behavioral flexibility; rat; vapor; microglia
• ISSN: 2692-8205; 2692-8205
• DOI: 10.1101/2023.01.21.524468

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. To this end, we used a novel volitional 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. Adolescent (35-55 day old) female rats had significantly higher rates of responding for vaporized Δ -tetrahydrocannabinol (THC)-dominant cannabis extract (CAN ) compared to adolescent males. In adulthood (70-110 day old), female, but not male, CAN rats also took more trials to reach criterion and made more regressive errors in an automated attentional set-shifting task compared to vehicle rats. Similar set-shifting deficits were observed in males when they were exposed to a non-contingent CAN vapor dosing regimen that approximated CAN self-administration rates in females. No differences were observed in effort-based decision making in either sex. In the mPFC, female (but not male) CAN rats displayed more reactive microglia with no significant changes in myelin basic protein expression or dendritic spine density. Together, these data reveal important sex differences in rates of cannabis vapor self-administration in adolescence that confer enduring alterations to mPFC structure and function. Importantly, female-specific deficits in behavioral flexibility appear to be driven by elevated rates of CAN self-administration as opposed to a sex difference in the effects of CAN vapor .