Crosstalk between the transcriptional regulation of dopamine D2 and cannabinoid CB1 receptors in schizophrenia: Analyses in patients and in perinatal Δ9-tetrahydrocannabinol-exposed rats.
Martina di Bartolomeo, Tibor Stark, Oriana Maria Maurel, Fabio Arturo Iannotti, Martin Kuchař, Jana Ruda-Kucerova, Fabiana Piscitelli, Samuele Laudani, Vladimir Pekarik, Salvatore Salomone, Beatrice Arosio, Raphael Mechoulam, Mauro Maccarrone, Filippo Drago, Carsten T. Wotjak, Vincenzo Di Marzo, Matteo Vismara, Bernardo Dell'Osso, Claudio D'Addario, Vincenzo Micale
Pharmacological Research February 2021 DOI: 10.1016/j.phrs.2020.105357 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical animal study with human cohort component Peer reviewed |
|---|---|
| Population | Male rats perinatally exposed to THC, plus a cohort of subjects with schizophrenia |
| Interventions | THC Cannabidiol |
| Topics | Cannabis CBD |
| Keywords | Cannabinoid cb1 receptor Dna methylation Dopamine d2 receptor Epigenetics Schizophrenia |
| Key findings | Perinatal THC exposure in male rats produced adult prefrontal cortex increases in Cnr1 and Drd2 mRNA, reduced Drd2 DNA methylation, social withdrawal, and cognitive impairment, all reversed by peripubertal cannabidiol. Neonatal delays in reflexes, higher Drd2 mRNA, and lower 2-AG persisted to adulthood. DRD2 methylation changes also appeared in people with schizophrenia, suggesting dopamine-cannabinoid dysregulation may contribute to schizophrenia spectrum disorders. |
Abstract
Perinatal exposure to Δ9-tetrahydrocannabinol (THC) affects brain development and might increase the incidence of psychopathology later in life, which seems to be related to a dysregulation of endocannabinoid and/or dopaminergic systems. We here evaluated the transcriptional regulation of the genes encoding for the cannabinoid CB1 receptor (Cnr1) and the dopamine D2 receptor (Drd2) in perinatal THC-(pTHC) exposed male rats, focusing on the role of DNA methylation analyzed by pyrosequencing. Simultaneously, the molecular and behavioral abnormalities at two different time points (i.e., neonatal age and adulthood) and the potential preventive effect of peripubertal treatment with cannabidiol, a non-euphoric component of Cannabis, were assessed. The DRD2 methylation was also evaluated in a cohort of subjects with schizophrenia. We observed an increase in both Cnr1 and Drd2 mRNA levels selectively in the prefrontal cortex of adult pTHC-exposed rats with a consistent reduction in DNA methylation at the Drd2 regulatory region, paralleled by social withdrawal and cognitive impairment which were reversed by cannabidiol treatment. These adult abnormalities were preceded at neonatal age by delayed appearance of neonatal reflexes, higher Drd2 mRNA and lower 2-arachidonoylglycerol (2-AG) brain levels, which persisted till adulthood. Alterations of the epigenetic mark for DRD2 were also found in subjects with schizophrenia. Overall, reported data add further evidence to the dopamine-cannabinoid interaction in terms of DRD2 and CNR1 dysregulation which could be implicated in the pathogenesis of schizophrenia spectrum disorders, suggesting that cannabidiol treatment may normalize pTHC-induced psychopathology by modulating the altered dopaminergic activity.
Comparable studies
Other preclinical and animal studies on cannabis, most cited first.
Citations in the library
Cited by 9
- The Effects of Peripubertal THC Exposure in Neurodevelopmental Rat Models of Psychopathology International Journal of Molecular Sciences February 15, 2023
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- A Comparison of Acute Neurocognitive and Psychotomimetic Effects of a Synthetic Cannabinoid and Natural Cannabis at Psychotropic Dose Equivalence Frontiers in Psychiatry May 19, 2022
- Prenatal THC exposure and binge-like alcohol drinking in early adolescence: From sex-specific drinking vulnerability to abnormal endocannabinoid-dopamine nexus in the nucleus accumbens. Journal of Psychopharmacology February 27, 2026
- Unraveling Cannabidiol's Dual Modulatory Role in Schizophrenia: Network Pharmacology and In Vivo Validation of Neuroinflammatory and Behavioral Modulation Molecular Neurobiology December 10, 2025
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