Adolescent THC exposure in female rats leads to cognitive deficits through a mechanism involving chromatin modifications in the prefrontal cortex.
Pamela Prini, Franceso Rusconi, Erica Zamberletti, Marina Gabaglio, Federica Penna, Mauro Fasano, Elena Battaglioli, Daniela Parolaro, Tiziana Rubino
Journal of Psychiatry and Neuroscience March 2018 DOI: 10.1503/jpn.170082 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical animal study Peer reviewed |
|---|---|
| Population | Female rats exposed to THC during adolescence or adulthood |
| Interventions | Δ9-tetrahydrocannabinol (THC) chaetocin |
| Topics | Cannabis |
| Key points | Adolescent, but not adult, THC exposure in female rats produced broader and stronger changes in histone modifications (mainly H3K9me3) and plasticity-related gene expression in the prefrontal cortex. THC raised Suv39H1 levels, which the authors propose explains the increased H3K9me3. Blocking H3K9me3 with chaetocin prevented THC-induced cognitive deficits, suggesting this pathway contributes to those deficits. |
Abstract
Increasing cannabis consumption among adolescents, studies that link its early use with mental illnesses, and the political debate on cannabis legalization together call for an urgent need to study molecular underpinnings of adolescent brain vulnerability. The emerging role of epigenetic mechanisms in psychiatric diseases led us to hypothesize that epigenetic alterations could play a role in causes and subsequent development of the depressive/psychotic-like phenotype induced by adolescent, but not adult, Δ9-tetrahydrocannabinol (THC) exposure in female rats. We performed a time-course analysis of histone modifications, chromatin remodelling enzymes and gene expression in the prefrontal cortex of female rats after adolescent and adult THC exposure. We also administered a specific epigenetic drug (chaetocin) with THC to investigate its impact on THC-induced behavioural alterations. Adolescent THC exposure induced alterations of selective histone modifications (mainly H3K9me3), impacting the expression of genes closely associated with synaptic plasticity. Changes in both histone modifications and gene expression were more widespread and intense after adolescent treatment, suggesting specific adolescent susceptibility. Adolescent THC exposure significantly increased Suv39H1 levels, which could account for the enhanced H3K9me3. Pharmacological blockade of H3K9me3 during adolescent THC treatment prevented THC-induced cognitive deficits, suggesting the relevant role played by H3K9me3 in THC-induced effects. Only female rats were investigated, and the expression studies were limited to a specific subset of genes. Through a mechanism involving SUV39H1, THC modifies histone modifications and, thereby, expression of plasticity genes. This pathway appears to be relevant for the development of cognitive deficits.
Comparable studies
Other preclinical and animal studies on cannabis, most cited first.
Citations in the library
Cited by 6
- Effects of Chronic Exposure to Low-Dose delta-9-Tetrahydrocannabinol in Adolescence and Adulthood on Serotonin/Norepinephrine Neurotransmission and Emotional Behavior The International Journal of Neuropsychopharmacology July 23, 2020
- 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
- Consensus paper of the WFSBP task force on cannabis, cannabinoids and psychosis The World Journal of Biological Psychiatry March 22, 2022
- Dos(e)Age: Role of Dose and Age in the Long-Term Effect of Cannabinoids on Cognition Molecules February 1, 2022
- Frequent Δ9- tetrahydrocannabinol exposure during adolescence impairs sociability in adult mice exposed to an aversive painful stimulus. European Neuropsychopharmacology December 2021
and 1 more in the library
Cites 11
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- Alterations of prefrontal cortex GABAergic transmission in the complex psychotic-like phenotype induced by adolescent delta-9-tetrahydrocannabinol exposure in rats. Neurobiology of Disease March 1, 2014
and 6 more in the library