title: Cannabidiol attenuates sensorimotor gating disruption and molecular changes induced by chronic antagonism of NMDA receptors in mice.
abstract: BACKGROUND
  Preclinical and clinical data suggest that cannabidiol (CBD), a major non-psychotomimetic compound from Cannabis sativa, induces antipsychotic-like effects. However, the antipsychotic properties of repeated CBD treatment have been poorly investigated. Behavioral changes induced by repeated treatment with glutamate N-methyl-D-aspartate receptor (NMDAR) antagonists have been proposed as an animal model of schizophrenia-like signs. In the present study, we evaluated if repeated treatment with CBD would attenuate the behavioral and molecular modifications induced by chronic administration of one of these antagonists, MK-801.
  
  
  METHODS
  Male C57BL/6J mice received daily i.p. injections of MK-801 (0.1, 0.5, or 1mg/kg) for 14, 21, or 28 days. Twenty-four hours after the last injection, animals were submitted to the prepulse inhibition (PPI) test. After that, we investigated if repeated treatment with CBD (15, 30, and 60mg/kg) would attenuate the PPI impairment induced by chronic treatment with MK-801 (1mg/kg; 28 days). CBD treatment began on the 6th day after the start of MK-801 administration and continued until the end of the treatment. Immediately after the PPI, the mice brains were removed and processed to evaluate the molecular changes. We measured changes in FosB/ΔFosB and parvalbumin (PV) expression, a marker of neuronal activity and a calcium-binding protein expressed in a subclass of GABAergic interneurons, respectively. Changes in mRNA expression of the NMDAR GluN1 subunit gene (GRN1) were also evaluated. CBD effects were compared to those induced by the atypical antipsychotic clozapine.
  
  
  RESULTS
  MK-801 administration at the dose of 1mg/kg for 28 days impaired PPI responses. Chronic treatment with CBD (30 and 60mg/kg) attenuated PPI impairment. MK-801 treatment increased FosB/ΔFosB expression and decreased PV expression in the medial prefrontal cortex. A decreased mRNA level of GRN1 in the hippocampus was also observed. All the molecular changes were attenuated by CBD. CBD by itself did not induce any effect. Moreover, CBD effects were similar to those induced by repeated clozapine treatment.
  
  
  CONCLUSIONS
  These results indicate that repeated treatment with CBD, similar to clozapine, reverses the psychotomimetic-like effects and attenuates molecular changes observed after chronic administration of an NMDAR antagonist. These data support the view that CBD may have antipsychotic properties.
authors.affiliation: Department of Pharmacology, Medical School of Ribeirão Preto, University of São Paulo, Brazil (Gomes and Guimarães); Department of Physiology, Faculty of Odontology of Ribeirão Preto, University of São Paulo, Brazil (Issy and Del Bel); Center for Interdisciplinary Research on Applied Neurosciences, University of São Paulo, Brazil (Gomes, Issy, Del Bel, and Guimarães); Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil (Ferreira); Department of Physiology (Animal Physiology II), Faculty of Biology, Complutense University of Madrid, Spain (Viveros). gomesfv@usp.br.
authors.forename: Felipe V
authors.initials: FV
authors.lastname: Gomes
authors.affiliation: Department of Pharmacology, Medical School of Ribeirão Preto, University of São Paulo, Brazil (Gomes and Guimarães); Department of Physiology, Faculty of Odontology of Ribeirão Preto, University of São Paulo, Brazil (Issy and Del Bel); Center for Interdisciplinary Research on Applied Neurosciences, University of São Paulo, Brazil (Gomes, Issy, Del Bel, and Guimarães); Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil (Ferreira); Department of Physiology (Animal Physiology II), Faculty of Biology, Complutense University of Madrid, Spain (Viveros).
authors.forename: Ana Carolina
authors.initials: AC
authors.lastname: Issy
authors.affiliation: Department of Pharmacology, Medical School of Ribeirão Preto, University of São Paulo, Brazil (Gomes and Guimarães); Department of Physiology, Faculty of Odontology of Ribeirão Preto, University of São Paulo, Brazil (Issy and Del Bel); Center for Interdisciplinary Research on Applied Neurosciences, University of São Paulo, Brazil (Gomes, Issy, Del Bel, and Guimarães); Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil (Ferreira); Department of Physiology (Animal Physiology II), Faculty of Biology, Complutense University of Madrid, Spain (Viveros).
authors.forename: Frederico R
authors.initials: FR
authors.lastname: Ferreira
authors.affiliation: Department of Pharmacology, Medical School of Ribeirão Preto, University of São Paulo, Brazil (Gomes and Guimarães); Department of Physiology, Faculty of Odontology of Ribeirão Preto, University of São Paulo, Brazil (Issy and Del Bel); Center for Interdisciplinary Research on Applied Neurosciences, University of São Paulo, Brazil (Gomes, Issy, Del Bel, and Guimarães); Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil (Ferreira); Department of Physiology (Animal Physiology II), Faculty of Biology, Complutense University of Madrid, Spain (Viveros).
authors.forename: Maria-Paz
authors.initials: MP
authors.lastname: Viveros
authors.affiliation: Department of Pharmacology, Medical School of Ribeirão Preto, University of São Paulo, Brazil (Gomes and Guimarães); Department of Physiology, Faculty of Odontology of Ribeirão Preto, University of São Paulo, Brazil (Issy and Del Bel); Center for Interdisciplinary Research on Applied Neurosciences, University of São Paulo, Brazil (Gomes, Issy, Del Bel, and Guimarães); Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil (Ferreira); Department of Physiology (Animal Physiology II), Faculty of Biology, Complutense University of Madrid, Spain (Viveros).
authors.forename: Elaine A
authors.initials: EA
authors.lastname: Del Bel
authors.affiliation: Department of Pharmacology, Medical School of Ribeirão Preto, University of São Paulo, Brazil (Gomes and Guimarães); Department of Physiology, Faculty of Odontology of Ribeirão Preto, University of São Paulo, Brazil (Issy and Del Bel); Center for Interdisciplinary Research on Applied Neurosciences, University of São Paulo, Brazil (Gomes, Issy, Del Bel, and Guimarães); Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil (Ferreira); Department of Physiology (Animal Physiology II), Faculty of Biology, Complutense University of Madrid, Spain (Viveros).
authors.forename: Francisco S
authors.initials: FS
authors.lastname: Guimarães
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002185:Cannabidiol / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D059330:GABAergic Neurons / Q000187:drug effects / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000235:genetics; D010320:Parvalbumins / Q000378:metabolism*; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D065808:Prepulse Inhibition / Q000187:drug effects*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism*; D012333:RNA, Messenger / Q000187:drug effects; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000235:genetics; D012559:Schizophrenia / Q000139:chemically induced / Q000378:metabolism; D055139:Sensory Gating / Q000187:drug effects*; D016896:Treatment Outcome
chemical_list: C483819:Fosb protein, mouse; C121673:Gprin1 protein, mouse; D009419:Nerve Tissue Proteins; D010320:Parvalbumins; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D016194:Receptors, N-Methyl-D-Aspartate; D002185:Cannabidiol; D016291:Dizocilpine Maleate
keywords: NMDA receptor hypofunction; antipsychotic; cannabidiol; cannabinoid; clozapine; schizophrenia