Cortical neuroinflammation contributes to long-term cognitive dysfunctions following adolescent delta-9-tetrahydrocannabinol treatment in female rats.
Erica Zamberletti, Marina Gabaglio, Pamela Prini, Tiziana Rubino, Daniela Parolaro
European Neuropsychopharmacology December 2015 DOI: 10.1016/j.euroneuro.2015.09.021 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical experimental study in rats Peer reviewed |
|---|---|
| Population | Female rats |
| Interventions | delta-9-tetrahydrocannabinol (THC) ibudilast |
| Duration | THC administered during adolescence (PND 35-45); outcomes assessed in adulthood |
| Topics | Cannabis |
| Keywords | Adolescence Cognition Neuroinflammation Prefrontal cortex Rats |
| Key findings | Adolescent THC administration in female rats produced a persistent neuroinflammatory state in the adult prefrontal cortex, with increased TNF-alpha, iNOS, and COX-2 and decreased IL-10, plus CB1 down-regulation on neurons and CB2 up-regulation on microglia. Blocking microglia with ibudilast attenuated short-term memory impairments and the inflammatory changes, but not depressive-like behaviors, suggesting microglial activation contributes causally to THC-induced cognitive deficits. |
Abstract
Over 180 million people consume cannabis globally. Cannabis use peaks during adolescence with a trend for continued consumption by adults. Notably, several studies have shown that long-term and heavy cannabis use during adolescence can impair brain maturation and predispose to neurodevelopmental disorders, although the neurobiological mechanisms underlying this association remain largely unknown. In this study, we evaluated whether, in female rats, chronic administration of increasing doses of the psychotropic plant-derived cannabis constituent, delta-9-tetrahydrocannabinol (THC), during adolescence (PND 35-45) could affect microglia function in the long-term. Furthermore, we explored a possible contribution of microglia to the development of THC-induced alterations in mood and cognition in adult female rats. Present data indicate that adolescent THC administration induces a persistent neuroinflammatory state specifically localized within the adult prefrontal cortex (PFC), characterized by increased expression of the pro-inflammatory markers, TNF-α, iNOS and COX-2, and reduction of the anti-inflammatory cytokine, IL-10. This neuroinflammatory phenotype is associated with down-regulation of CB1 receptor on neuronal cells and up-regulation of CB2 on microglia cells, conversely. Interestingly, blocking microglia activation with ibudilast during THC treatment significantly attenuates short-term memory impairments in adulthood, simultaneously preventing the increases in TNF-α, iNOS, COX-2 levels as well as the up-regulation of CB2 receptors on microglia cells. In contrast, THC-induced depressive-like behaviors were unaffected by ibudilast treatment. Our findings demonstrate that adolescent THC administration is associated with persistent neuroinflammation within the PFC and provide evidence for a causal association between microglial activation and the development long-term cognitive deficits induced by adolescent THC treatment.
Comparable studies
Other preclinical and animal studies on cannabis, most cited first.
Citations in the library
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- Chronic adolescent exposure to cannabis in mice leads to sex-biased changes in gene expression networks across brain regions Neuropsychopharmacology August 22, 2022
- 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
- Chronic THC exposure modulates behavioral outcomes and endocannabinoid signaling in HIV-1 Tg26 mice in a sex-dependent manner. Brain Research Bulletin August 1, 2026
- Adolescent female rats are resistant to the affective and cognitive impacts of Δ9-tetrahydrocannabinol exposure despite long-lasting molecular and neuronal disturbances in the hippocampal-hypothalamic network. Psychopharmacology November 1, 2025
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- Chronic URB597 treatment at adulthood reverted most depressive-like symptoms induced by adolescent exposure to THC in female rats. Neuropharmacology 2011
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