title: Decreased glial reactivity could be involved in the antipsychotic-like effect of cannabidiol.
abstract: NMDA receptor hypofunction could be involved, in addition to the positive, also to the negative symptoms and cognitive deficits found in schizophrenia patients. An increasing number of data has linked schizophrenia with neuroinflammatory conditions and glial cells, such as microglia and astrocytes, have been related to the pathogenesis of schizophrenia. Cannabidiol (CBD), a major non-psychotomimetic constituent of Cannabis sativa with anti-inflammatory and neuroprotective properties induces antipsychotic-like effects. The present study evaluated if repeated treatment with CBD (30 and 60 mg/kg) would attenuate the behavioral and glial changes observed in an animal model of schizophrenia based on the NMDA receptor hypofunction (chronic administration of MK-801, an NMDA receptor antagonist, for 28 days). The behavioral alterations were evaluated in the social interaction and novel object recognition (NOR) tests. These tests have been widely used to study changes related to negative symptoms and cognitive deficits of schizophrenia, respectively. We also evaluated changes in NeuN (a neuronal marker), Iba-1 (a microglia marker) and GFAP (an astrocyte marker) expression in the medial prefrontal cortex (mPFC), dorsal striatum, nucleus accumbens core and shell, and dorsal hippocampus by immunohistochemistry. CBD effects were compared to those induced by the atypical antipsychotic clozapine. Repeated MK-801 administration impaired performance in the social interaction and NOR tests. It also increased the number of GFAP-positive astrocytes in the mPFC and the percentage of Iba-1-positive microglia cells with a reactive phenotype in the mPFC and dorsal hippocampus without changing the number of Iba-1-positive cells. No change in the number of NeuN-positive cells was observed. Both the behavioral disruptions and the changes in expression of glial markers induced by MK-801 treatment were attenuated by repeated treatment with CBD or clozapine. These data reinforces the proposal that CBD may induce antipsychotic-like effects. Although the possible mechanism of action of these effects is still unknown, it may involve CBD anti-inflammatory and neuroprotective properties. Furthermore, our data support the view that inhibition of microglial activation may improve schizophrenia symptoms.
authors: Department of Pharmacology, Medical School of Ribeirão Preto, University of São Paulo, Brazil; Center for Interdisciplinary Research on Applied Neurosciences (NAPNA), University of São Paulo, Brazil. Electronic address: gomesfv@usp.br.
authors: Felipe V
authors: FV
authors: Gomes
authors: Department of Physiology, Faculty of Medicine, Complutense University of Madrid, Spain.
authors: Ricardo
authors: R
authors: Llorente
authors: Center for Interdisciplinary Research on Applied Neurosciences (NAPNA), University of São Paulo, Brazil; Department of Physiology, Faculty of Odontology of Ribeirão Preto, University of São Paulo, Brazil.
authors: Elaine A
authors: EA
authors: Del Bel
authors: Department of Physiology (Animal Physiology II), Faculty of Biology, Complutense University of Madrid, Spain.
authors: Maria-Paz
authors: MP
authors: Viveros
authors: Department of Physiology, Faculty of Medicine, Complutense University of Madrid, Spain.
authors: Meritxell
authors: M
authors: López-Gallardo
authors: Department of Pharmacology, Medical School of Ribeirão Preto, University of São Paulo, Brazil; Center for Interdisciplinary Research on Applied Neurosciences (NAPNA), University of São Paulo, Brazil. Electronic address: fsguimar@fmrp.usp.br.
authors: Francisco S
authors: FS
authors: Guimarães
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000627:therapeutic use*; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002185:Cannabidiol / Q000627:therapeutic use*; D003024:Clozapine / Q000627:therapeutic use; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000633:toxicity; D005106:Exploratory Behavior / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008840:Microfilament Proteins / Q000378:metabolism; D009457:Neuroglia / Q000187:drug effects* / Q000378:metabolism; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D011618:Psychotic Disorders / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology*; D021641:Recognition, Psychology / Q000187:drug effects
chemical_list: C491049:Aif1 protein, mouse; D014150:Antipsychotic Agents; D002135:Calcium-Binding Proteins; D018691:Excitatory Amino Acid Antagonists; D005904:Glial Fibrillary Acidic Protein; D008840:Microfilament Proteins; D002185:Cannabidiol; D016291:Dizocilpine Maleate; D010751:Phosphopyruvate Hydratase; D003024:Clozapine
keywords: Astrocytes; Cannabinoid; Clozapine; MK-801; Microglia; NMDA receptor; NeuN; Psychosis