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Crosstalk between the transcriptional regulation of dopamine D2 and cannabinoid CB1 receptors in schizophrenia: Analyses in patients and in perinatal Δ9-tetrahydrocannabinol-exposed rats
M. Di Bartolomeo, T. Stark, OM. Maurel, FA. Iannotti, M. Kuchar, J. Ruda-Kucerova, F. Piscitelli, S. Laudani, V. Pekarik, S. Salomone, B. Arosio, R. Mechoulam, M. Maccarrone, F. Drago, CT. Wotjak, V. Di Marzo, M. Vismara, B. Dell'Osso, C....
Jazyk angličtina Země Nizozemsko
Typ dokumentu časopisecké články, práce podpořená grantem
- MeSH
- chování zvířat účinky léků MeSH
- lidé MeSH
- maternofetální výměna látek MeSH
- messenger RNA metabolismus MeSH
- metylace DNA účinky léků MeSH
- potkani Sprague-Dawley MeSH
- prefrontální mozková kůra účinky léků metabolismus MeSH
- receptor kanabinoidní CB1 genetika MeSH
- receptory dopaminu D2 genetika MeSH
- regulace genové exprese účinky léků MeSH
- schizofrenie genetika MeSH
- těhotenství MeSH
- tetrahydrokanabinol farmakologie MeSH
- zpožděný efekt prenatální expozice * MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
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.
Boehringer Ingelheim Pharma GmbH and KO KG Germany
Department of Biomedical and Clinical Sciences 'Luigi Sacco' University of Milan Milan Italy
Department of Biotechnological and Applied Clinical Sciences University of L'Aquila L'Aquila Italy
Department of Clinical Neuroscience Karolinska Institutet Stockholm Sweden
Department of Clinical Sciences and Community Health University of Milan Milan Italy
Department of Mental Health ASST Fatebenefratelli Sacco Milan Italy
Department of Pharmacology Faculty of Medicine Masaryk University Brno Czech Republic
Department of Physiology Faculty of Medicine Masaryk University Brno Czech Republic
Department of Psychiatry and Behavioral Sciences Stanford University California USA
European Center for Brain Research IRCCS Santa Lucia Foundation Rome Italy
Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico Milan Italy
Institute for Drug Research Faculty of Medicine Hebrew University of Jerusalem Jerusalem Israel
Citace poskytuje Crossref.org
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- $a Di Bartolomeo, Martina $u Faculty of Bioscience and Technology for Food, Agriculture and Environment, University of Teramo, Teramo, Italy
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- $a 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.
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