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.

Department of Biomedical and Biotechnological Sciences University of Catania Catania Italy

Department of Biomedical and Biotechnological Sciences University of Catania Catania Italy; National Institute of Mental Health Klecany Czech Republic

Department of Pharmacology Faculty of Medicine Masaryk University Brno Czech Republic

Department of Pharmacology Faculty of Medicine Masaryk University Brno Czech Republic; Institute of Scientific Instruments of the Czech Academy of Sciences Brno Czech Republic

Department of Pharmacology Faculty of Medicine Masaryk University Brno Czech Republic; RG Neuronal Plasticity Max Planck Institute of Psychiatry Munich Germany

Department of Physiology Faculty of Medicine Masaryk University Brno Czech Republic

Faculty of Bioscience and Technology for Food Agriculture and Environment University of Teramo Teramo Italy

ICCI International Cannabis and Cannabinoid Institute Praha Czech Republic

Institute for Drug Research Faculty of Medicine Hebrew University of Jerusalem Jerusalem Israel

Institute of Biomolecular Chemistry Consiglio Nazionale delle Ricerche Endocannabinoid Research Group Naples Italy

Institute of Biomolecular Chemistry Consiglio Nazionale delle Ricerche Endocannabinoid Research Group Naples Italy; Canada Excellence Research Chair on the Microbiome Endocannabinoidome Axis in Metabolic Health Université Laval Quebec City Canada; Joint International Unit on Chemical and Biomolecular Research on the Microbiome and its Impact on Metabolic Health and Nutrition Université Laval and Institute of Biomolecular Chemistry CNR Pozzuoli Italy

Institute of Scientific Instruments of the Czech Academy of Sciences Brno Czech Republic

International Research Centre Biotechnologies of the 3rd Millennium ITMO University St Petersburg Russian Federation; Laboratory of Neuroendocrinology 1 P Pavlov Institute of Physiology RASci St Petersburg Russian Federation; Lobachevsky State University of Nizhny Novgorod Institute of Biology and Biomedicine Nizhny Novgorod Russian Federation

RG Neuronal Plasticity Max Planck Institute of Psychiatry Munich Germany; Boehringer Ingelheim Pharma GmbH and KO KG Germany

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