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.

CEITEC Central European Institute of Technology Masaryk University Brno Czech Republic

Department of Biomedical and Biotechnological Sciences Section of Pharmacology School of Medicine University of Catania Catania Italy

Department of Experimental Medicine and Surgery Tor Vergata University of Rome Rome Italy

Department of Medicine Campus Bio Medico University of Rome Rome Italy

Department of Pharmacology Faculty of Medicine Masaryk University Brno Czech Republic

Department of Physiology Faculty of Medicine Masaryk University Brno Czech Republic

Department of Stress Neurobiology and Neurogenetics Max Planck Institute of Psychiatry Munich Germany

European Center for Brain Research IRCCS Santa Lucia Foundation Rome Italy

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

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 Scientific Instruments Czech Academy of Sciences Brno Czech Republic

National Institute of Mental Health Klecany Czech Republic

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$a Peripubertal cannabidiol treatment rescues behavioral and neurochemical abnormalities in the MAM model of schizophrenia / $c T. Stark, J. Ruda-Kucerova, FA. Iannotti, C. D'Addario, R. Di Marco, V. Pekarik, E. Drazanova, F. Piscitelli, M. Bari, Z. Babinska, G. Giurdanella, M. Di Bartolomeo, S. Salomone, A. Sulcova, M. Maccarrone, CT. Wotjak, Z. Starcuk, F. Drago, R. Mechoulam, V. Di Marzo, V. Micale,

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$a 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.

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