In agreement with the neurodevelopmental hypothesis of schizophrenia, prenatal exposure of Sprague-Dawley rats to the antimitotic agent methylazoxymethanol acetate (MAM) at gestational day 17 produces long-lasting behavioral alterations such as social withdrawal and cognitive impairment in adulthood, mimicking a schizophrenia-like phenotype. These abnormalities were preceded at neonatal age both by the delayed appearance of neonatal reflexes, an index of impaired brain maturation, and by higher 2-arachidonoylglycerol (2-AG) brain levels. Schizophrenia-like deficits were reversed by early treatment [from postnatal day (PND) 2 to PND 8] with the CB1 antagonist/inverse agonist AM251 (0.5 mg/kg/day). By contrast, early CB1 blockade affected the behavioral performance of control rats which was paralleled by enhanced 2-AG content in the prefrontal cortex (PFC). These results suggest that prenatal MAM insult leads to premorbid anomalies at neonatal age via altered tone of the endocannabinoid system, which may be considered as an early marker preceding the development of schizophrenia-like alterations in adulthood.

Canada Excellence Research Chair on the Microbiome Endocannabinoidome Axis in Metabolic Health Faculty of Medicine and Faculty of Agricultural and Food Sciences Centre de Recherche de l'Institut de Cardiologie et Pneumologie de l'Université et Institut sur la Nutrition et les Aliments Fonctionnels Centre NUTRISS Université Laval Quebec City QC G1V 4G5 Canada

Central Nervous System Diseases Research Boehringer Ingelheim Pharma GmbH and Co KG 88397 Biberach an der Riss Germany

Department of Biomedical and Biotechnological Sciences Section of Pharmacology School of Medicine University of Catania 95123 Catania Italy

Department of Pharmacology Faculty of Medicine Masaryk University 62500 Brno Czech Republic

Endocannabinoid Research Group Institute of Biomolecular Chemistry Consiglio Nazionale delle Ricerche 80078 Pozzuoli Italy

Faculty of Bioscience and Technology for Food Agriculture and Environment University of Teramo 64100 Teramo Italy

Scientific Core Unit Neuroimaging Max Planck Institute of Psychiatry 80804 Munich Germany

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