Gestational methylazoxymethanol acetate (MAM) treatment produces offspring with adult phenotype relevant to schizophrenia, including positive- and negative-like symptoms, cognitive deficits, dopaminergic dysfunction, structural and functional abnormalities. Here we show that adult rats prenatally treated with MAM at gestational day 17 display significant increase in dopamine D3 receptor (D3) mRNA expression in prefrontal cortex (PFC), hippocampus and nucleus accumbens, accompanied by increased expression of dopamine D2 receptor (D2) mRNA exclusively in the PFC. Furthermore, a significant change in the blood perfusion at the level of the circle of Willis and hippocampus, paralleled by the enlargement of lateral ventricles, was also detected by magnetic resonance imaging (MRI) techniques. Peripubertal treatment with the non-euphoric phytocannabinoid cannabidiol (30 mg/kg) from postnatal day (PND) 19 to PND 39 was able to reverse in MAM exposed rats: i) the up-regulation of the dopamine D3 receptor mRNA (only partially prevented by haloperidol 0.6 mg/kg/day); and ii) the regional blood flow changes in MAM exposed rats. Molecular modelling predicted that cannabidiol could bind preferentially to dopamine D3 receptor, where it may act as a partial agonist according to conformation of ionic-lock, which is highly conserved in GPCRs. In summary, our results demonstrate that the mRNA expression of both dopamine D2 and D3 receptors is altered in the MAM model; however only the transcript levels of D3 are affected by cannabidiol treatment, likely suggesting that this gene might not only contribute to the schizophrenia symptoms but also represent an unexplored target for the antipsychotic activity of cannabidiol.
- MeSH
- antipsychotika farmakologie MeSH
- haloperidol chemie farmakologie MeSH
- kanabidiol chemie farmakologie MeSH
- magnetická rezonanční tomografie MeSH
- methylazoxymethanolacetát toxicita MeSH
- modely nemocí na zvířatech MeSH
- molekulární modely MeSH
- mozek diagnostické zobrazování účinky léků MeSH
- mozkový krevní oběh MeSH
- potkani Sprague-Dawley MeSH
- puberta MeSH
- receptory dopaminu D2 chemie genetika metabolismus MeSH
- receptory dopaminu D3 chemie genetika metabolismus MeSH
- regulace genové exprese MeSH
- schizofrenie chemicky indukované diagnostické zobrazování farmakoterapie genetika MeSH
- simulace molekulární dynamiky MeSH
- těhotenství MeSH
- zpožděný efekt prenatální expozice MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
