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
