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.

• 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

In agreement with the neurodevelopmental hypothesis of schizophrenia, prenatal exposure of rats to the antimitotic agent methylazoxymethanol acetate (MAM) at gestational day 17 produced long-lasting behavioral alterations such as social withdrawal and cognitive impairment in the social interaction test and in the novel object recognition test, respectively. At the molecular level, an increased cannabinoid receptor type-1 (CB1) mRNA and protein expression, which might be due to reduction in DNA methylation at the gene promoter in the prefrontal cortex (PFC), coincided with deficits in the social interaction test and in the novel object recognition test in MAM rats. Both the schizophrenia-like phenotype and altered transcriptional regulation of CB1 receptors were reversed by peripubertal treatment (from PND 19 to PND 39) with the non-psychotropic phytocannabinoid cannabidiol (30 mg/kg/day), or, in part, by treatment with the cannabinoid CB1 receptor antagonist/inverse agonist AM251 (0.5 mg/kg/day), but not with haloperidol (0.6 mg/kg/day). These results suggest that early treatment with cannabidiol may prevent both the appearance of schizophrenia-like deficits as well as CB1 alterations in the PFC at adulthood, supporting that peripubertal cannabidiol treatment might be protective against MAM insult.

• MeSH
• endokanabinoidy metabolismus   MeSH
• ethanolaminy metabolismus   MeSH
• glyceridy metabolismus   MeSH
• hipokampus metabolismus   MeSH
• interpersonální vztahy MeSH
• kanabidiol farmakologie   MeSH
• krysa rodu rattus MeSH
• kyseliny arachidonové metabolismus   MeSH
• kyseliny olejové metabolismus   MeSH
• kyseliny palmitové metabolismus   MeSH
• messenger RNA metabolismus   MeSH
• methylazoxymethanolacetát farmakologie   MeSH
• modely nemocí na zvířatech MeSH
• piperidiny farmakologie   MeSH
• pohybová aktivita účinky léků   MeSH
• polynenasycené alkamidy metabolismus   MeSH
• prefrontální mozková kůra metabolismus   MeSH
• puberta MeSH
• pyrazoly farmakologie   MeSH
• receptor kanabinoidní CB1 metabolismus   MeSH
• rozpoznávání (psychologie) účinky léků   MeSH
• schizofrenie chemicky indukované   farmakoterapie   metabolismus   MeSH
• těhotenství MeSH
• zpožděný efekt prenatální expozice farmakoterapie   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Compelling evidence supports the involvement of the endocannabinoid system (ECS) in psychosis vulnerability. We here evaluated the transcriptional regulation of ECS components in human peripheral blood mononuclear cells (PBMCs) obtained from subjects suffering from bipolar disorder, major depressive disorder and schizophrenia, focusing in particular on the effects of DNA methylation. We observed selective alterations of DNA methylation at the promoter of CNR1, the gene coding for the type-1 cannabinoid receptor, in schizophrenic patients (N=25) with no changes in any other disorder. We confirmed the regulation of CNR1 in a well-validated animal model of schizophrenia, induced by prenatal methylazoxymethanol (MAM) acetate exposure (N=7 per group) where we found, in the prefrontal cortex, a significant increase in CNR1 expression and a consistent reduction in DNA methylation at specific CpG sites of gene promoter. Overall, our findings suggest a selective dysregulation of ECS in psychosis, and highlight the evaluation of CNR1 DNA methylation levels in PBMCs as a potential biomarker for schizophrenia.

• MeSH
• bipolární porucha genetika   metabolismus   MeSH
• CpG ostrůvky MeSH
• depresivní porucha unipolární genetika   metabolismus   MeSH
• endokanabinoidy metabolismus   MeSH
• kohortové studie MeSH
• leukocyty mononukleární metabolismus   MeSH
• lidé středního věku MeSH
• lidé MeSH
• methylazoxymethanolacetát MeSH
• metylace DNA * MeSH
• modely nemocí na zvířatech MeSH
• potkani Sprague-Dawley MeSH
• prefrontální mozková kůra metabolismus   MeSH
• promotorové oblasti (genetika) * MeSH
• receptor kanabinoidní CB1 genetika   metabolismus   MeSH
• regulace genové exprese MeSH
• schizofrenie genetika   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH