Sex differences in adolescent cannabis vapor self-administration mediate enduring effects on behavioral flexibility and prefrontal microglia activation in rats.
Timothy G. Freels, Sara R Westbrook, Hayden R Wright, Jacqulyn R. Kuyat, Erica Zamberletti, Alexandra M Malena, Max W. Melville, Amanda M. Brown, Nicholas C. Glodosky, Darren E Ginder, Courtney M. Klappenbach, Kristen M Delevich, Tiziana Rubino, Ryan J Mclaughlin
bioRxiv : the preprint server for biology January 22, 2023 preprint DOI: 10.1101/2023.01.21.524468 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Observational animal study using a volitional vapor self-administration model |
|---|---|
| Population | Male and female rats; adolescent (35-55 days old) self-administration and adulthood (70-110 days old) testing |
| Intervention | Vaporized Δ9-tetrahydrocannabinol (THC)-dominant cannabis extract (CANTHC) |
| Duration | Adolescent exposure from 35-55 days of age; adulthood testing at 70-110 days of age |
| Measures | Automated attentional set-shifting task, effort-based decision making task, reactive microglia, myelin basic protein expression, dendritic spine density |
| Topics | Cannabis |
| Keywords | Adolescence Behavioral flexibility Microglia Rat Vapor |
| Key findings | Adolescent female rats self-administered vaporized THC-dominant cannabis extract at higher rates than males, and in adulthood female self-administering rats showed greater attentional set-shifting deficits and more reactive medial prefrontal cortex microglia than vehicle rats. Males showed similar set-shifting deficits only when exposed to a non-contingent dosing regimen approximating female intake, suggesting the female-specific deficits are driven by higher self-administration rates rather than a sex difference in cannabis vapor effects per se. |
Abstract
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 Δ9-tetrahydrocannabinol (THC)-dominant cannabis extract (CANTHC) compared to adolescent males. In adulthood (70-110 day old), female, but not male, CANTHC 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 CANTHC vapor dosing regimen that approximated CANTHC self-administration rates in females. No differences were observed in effort-based decision making in either sex. In the mPFC, female (but not male) CANTHC 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 CANTHC self-administration as opposed to a sex difference in the effects of CANTHC vapor per se.
Comparable studies
Other preclinical and animal studies on cannabis, most cited first.
Citations in the library
Cited by 4
- Sex differences in the acute effects of oral THC: a randomized, placebo-controlled, crossover human laboratory study. Psychopharmacology October 1, 2024
- Adolescent THC impacts on mPFC dopamine-mediated cognitive processes in male and female rats. Psychopharmacology February 1, 2025
- Effects of acute THC challenge on behavior and neuroinflammation in HIV-1 Tg26 mice vary based on HIV status, chronic THC history, and sex. Brain, Behavior, and Immunity May 1, 2026
- Age-Related Effects of Cannabis and Cannabinoids on Brain and Behavior. Cannabis and Cannabinoid Research April 2026
Cites 13
- Cannabis use before age 15 and subsequent executive functioning The British Journal of Psychiatry May 31, 2011
- Acute and chronic effects of cannabinoids on effort-related decision-making and reward learning: an evaluation of the cannabis ‘amotivational’ hypotheses Psychopharmacology September 2, 2016
- Pharmacokinetics and central accumulation of delta-9-tetrahydrocannabinol (THC) and its bioactive metabolites are influenced by route of administration and sex in rats. Scientific Reports December 14, 2021
- Long-Term Consequences of Adolescent Exposure to THC-Rich/CBD-Poor and CBD-Rich/THC-Poor Combinations: A Comparison with Pure THC Treatment in Female Rats International Journal of Molecular Sciences August 18, 2021
- Adolescent exposure to Δ9-tetrahydrocannabinol alters the transcriptional trajectory and dendritic architecture of prefrontal pyramidal neurons. Molecular Psychiatry April 2019
and 8 more in the library