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Neuropharmacology. 2018 Nov 26;146:212-221. doi: 10.1016/j.neuropharm.2018.11.035. [Epub ahead of print]

Peripubertal cannabidiol treatment rescues behavioral and neurochemical abnormalities in the MAM model of schizophrenia.

Author information

1
Department of Pharmacology, Faculty of Medicine, Masaryk University, Brno, Czech Republic.
2
Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Endocannabinoid Research Group, Naples, Italy.
3
Faculty of Bioscience and Technology for Food, Agriculture and Environment, University of Teramo, Teramo, Italy.
4
Department of Biomedical and Biotechnological Sciences, Section of Pharmacology, School of Medicine, University of Catania, Catania, Italy.
5
Department of Physiology, Faculty of Medicine, Masaryk University, Brno, Czech Republic.
6
Department of Pharmacology, Faculty of Medicine, Masaryk University, Brno, Czech Republic; Institute of Scientific Instruments, Czech Academy of Sciences, Brno, Czech Republic.
7
Department of Experimental Medicine and Surgery, Tor Vergata University of Rome, Rome, Italy.
8
CEITEC - Central European Institute of Technology, Masaryk University, Brno, Czech Republic.
9
Department of Medicine, Campus Bio-Medico University of Rome, Rome, Italy; European Center for Brain Research/IRCCS Santa Lucia Foundation, Rome, Italy.
10
Department of Stress Neurobiology & Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany.
11
Institute of Scientific Instruments, Czech Academy of Sciences, Brno, Czech Republic.
12
Institute for Drug Research, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel.
13
Department of Biomedical and Biotechnological Sciences, Section of Pharmacology, School of Medicine, University of Catania, Catania, Italy; CEITEC - Central European Institute of Technology, Masaryk University, Brno, Czech Republic; National Institute of Mental Health, Klecany, Czech Republic. Electronic address: vincenzomicale@inwind.it.

Abstract

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.

KEYWORDS:

Cannabidiol; Cannabinoid CB1 receptor; MAM model; Schizophrenia

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