Fondazione Santa Lucia Clinical and Research Center - IRCCS
Published November 28, 2020 | Version v1
Journal article Restricted

Crosstalk between the transcriptional regulation of dopamine D2 and cannabinoid CB1 receptors in schizophrenia: Analyses in patients and in perinatal Δ9-tetrahydrocannabinol-exposed rats

Authors/Creators

  • 1. Faculty of Bioscience and Technology for Food, Agriculture and Environment, University of Teramo, Teramo, Italy.
  • 2. Department of Pharmacology, Faculty of Medicine, Masaryk University, Brno, Czech Republic; Neuronal Plasticity Research Group, Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany.
  • 3. Neuronal Plasticity Research Group, Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany; Department of Biomedical and Biotechnological Sciences, Section of Pharmacology, University of Catania, Catania, Italy.
  • 4. Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Endocannabinoid Research Group, Naples, Italy.
  • 5. Forensic Laboratory of Biologically Active Substances, Department of Chemistry of Natural Compounds, University of Chemistry and Technology Prague, Prague, Czech Republic; National Institute of Mental Health, Klecany, Czech Republic.
  • 6. Department of Pharmacology, Faculty of Medicine, Masaryk University, Brno, Czech Republic
  • 7. Department of Biomedical and Biotechnological Sciences, Section of Pharmacology, University of Catania, Catania, Italy.
  • 8. Department of Physiology, Faculty of Medicine, Masaryk University, Brno, Czech Republic.
  • 9. Department of Biomedical and Biotechnological Sciences, Section of Pharmacology, University of Catania, Catania, Italy
  • 10. Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy; Fondazione Ca' Granda, IRCCS, Ospedale Maggiore Policlinico, Milan, Italy.
  • 11. Institute for Drug Research, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel.
  • 12. Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy; European Center for Brain Research, IRCCS Santa Lucia Foundation, Rome, Italy
  • 13. Neuronal Plasticity Research Group, Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany; Boehringer Ingelheim Pharma GmbH & KO KG, Germany.
  • 14. Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Endocannabinoid Research Group, Naples, Italy; Canada Excellence Research Chair on the Microbiome-Endocannabinoidome Axis in Metabolic, Health, Université Laval, Quebec City, Canada; Joint International Unit on Chemical and Biomolecular Research on the Microbiome and its Impact on Metabolic Health and Nutrition (UMI-MicroMeNu), between Université Laval and Institute of Biomolecular Chemistry, CNR, Pozzuoli, Italy.
  • 15. Department of Biomedical and Clinical Sciences 'Luigi Sacco', University of Milan, Milan, Italy; Department of Mental Health, ASST Fatebenefratelli-Sacco, Milan, Italy.
  • 16. Department of Biomedical and Clinical Sciences 'Luigi Sacco', University of Milan, Milan, Italy; Department of Mental Health, ASST Fatebenefratelli-Sacco, Milan, Italy; "Aldo Ravelli" Research Center for Neurotechnology and Experimental Brain Therapeutics, Department of Health Sciences, University of Milan Medical School, Milan, Italy; Department of Psychiatry and Behavioral Sciences, Stanford University, California, USA.
  • 17. Faculty of Bioscience and Technology for Food, Agriculture and Environment, University of Teramo, Teramo, Italy; Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
  • 18. Department of Biomedical and Biotechnological Sciences, Section of Pharmacology, University of Catania, Catania, Italy; National Institute of Mental Health, Klecany, Czech Republic.

Description

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.

Files

Restricted

The record is publicly accessible, but files are restricted to users with access.

Additional details

Related works

Is cited by
Journal article: 10.1016/j.phrs.2020.105357 (DOI)