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Altered dopamine D3 receptor gene expression in MAM model of schizophrenia is reversed by peripubertal cannabidiol treatment
T. Stark, M. Di Bartolomeo, R. Di Marco, E. Drazanova, CBM. Platania, FA. Iannotti, J. Ruda-Kucerova, C. D'Addario, L. Kratka, V. Pekarik, F. Piscitelli, Z. Babinska, J. Fedotova, G. Giurdanella, S. Salomone, A. Sulcova, C. Bucolo, CT. Wotjak, Z....
Language English Country Great Britain
Document type Journal Article, Research Support, Non-U.S. Gov't
- MeSH
- Antipsychotic Agents pharmacology MeSH
- Haloperidol chemistry pharmacology MeSH
- Cannabidiol chemistry pharmacology MeSH
- Magnetic Resonance Imaging MeSH
- Methylazoxymethanol Acetate toxicity MeSH
- Disease Models, Animal MeSH
- Models, Molecular MeSH
- Brain diagnostic imaging drug effects MeSH
- Cerebrovascular Circulation MeSH
- Rats, Sprague-Dawley MeSH
- Puberty MeSH
- Receptors, Dopamine D2 chemistry genetics metabolism MeSH
- Receptors, Dopamine D3 chemistry genetics metabolism MeSH
- Gene Expression Regulation MeSH
- Schizophrenia chemically induced diagnostic imaging drug therapy genetics MeSH
- Molecular Dynamics Simulation MeSH
- Pregnancy MeSH
- Prenatal Exposure Delayed Effects MeSH
- Animals MeSH
- Check Tag
- Male MeSH
- Pregnancy MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
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.
Boehringer Ingelheim Pharma GmbH and KO KG Germany
Department of Biomedical and Biotechnological Sciences University of Catania Catania Italy
Department of Pharmacology Faculty of Medicine Masaryk University Brno Czech Republic
Department of Physiology Faculty of Medicine Masaryk University Brno Czech Republic
ICCI International Cannabis and Cannabinoid Institute Praha Czech Republic
Institute for Drug Research Faculty of Medicine Hebrew University of Jerusalem Jerusalem Israel
Institute of Scientific Instruments of the Czech Academy of Sciences Brno Czech Republic
National Institute of Mental Health Klecany Czech Republic
RG Neuronal Plasticity Max Planck Institute of Psychiatry Munich Germany
References provided by Crossref.org
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