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.

Department of Biomedical and Biotechnological Sciences Section of Pharmacology University of Catania Catania Italy

Department of Biomedical and Biotechnological Sciences Section of Pharmacology University of Catania Catania Italy; National Institute of Mental Health Klecany Czech Republic

Department of Biomedical and Clinical Sciences 'Luigi Sacco' University of Milan Milan Italy; Department of Mental Health ASST Fatebenefratelli Sacco Milan Italy

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

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

Department of Clinical Sciences and Community Health University of Milan Milan Italy; Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico Milan Italy

Department of Pharmacology Faculty of Medicine Masaryk University Brno Czech Republic

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

Department of Physiology Faculty of Medicine Masaryk University Brno Czech Republic

Faculty of Bioscience and Technology for Food Agriculture and Environment University of Teramo Teramo Italy

Faculty of Bioscience and Technology for Food Agriculture and Environment University of Teramo Teramo Italy; Department of Clinical Neuroscience Karolinska Institutet Stockholm Sweden

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

Institute for Drug Research Faculty of Medicine Hebrew University of Jerusalem Jerusalem Israel

Institute of Biomolecular Chemistry Consiglio Nazionale delle Ricerche Endocannabinoid Research Group Naples Italy

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 between Université Laval and Institute of Biomolecular Chemistry CNR Pozzuoli Italy

Neuronal Plasticity Research Group Department of Stress Neurobiology and Neurogenetics Max Planck Institute of Psychiatry Munich Germany; Boehringer Ingelheim Pharma GmbH and KO KG Germany

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

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