Cannabidiol Attenuates Sensorimotor Gating Disruption and Molecular Changes Induced by Chronic Antagonism of NMDA receptors in Mice

Author(s)

Gomes, Felipe V. ^{[1, 2]} ; Issy, Ana Carolina ^{[3, 2]} ; Ferreira, Frederico R. ^[4] ; Viveros, Maria-Paz ^[5] ; del Bel, Elaine A. ^{[3, 2]} ; Guimaraes, Francisco S. ^{[1, 2]}

Affiliation

^[1] Univ Sao Paulo, Med Sch Ribeirao Preto, Dept Pharmacol, BR-14049900 Ribeirao Preto, SP - Brazil

^[2] Univ Sao Paulo, Ctr Interdisciplinary Res Appl Neurosci, BR-14049900 Ribeirao Preto, SP - Brazil

^[3] Univ Sao Paulo, Fac Odontol Ribeirao Preto, Dept Physiol, BR-14049900 Ribeirao Preto, SP - Brazil

^[4] Fundacao Oswaldo Cruz, Inst Oswaldo Cruz, Rio De Janeiro - Brazil

^[5] Univ Complutense Madrid, Fac Biol, Dept Physiol Anim Physiol 2, E-28040 Madrid - Spain

• Document type: Journal article
• Source: INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY; v. 18, n. 5 MAR 2015.
• Web of Science Citations: 23

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 1 mg/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 60 mg/kg) would attenuate the PPI impairment induced by chronic treatment with MK-801 (1 mg/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/Delta FosB 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 1 mg/kg for 28 days impaired PPI responses. Chronic treatment with CBD (30 and 60 mg/kg) attenuated PPI impairment. MK-801 treatment increased FosB/Delta FosB 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. (AU)

• FAPESP's process: 10/17343-0 - Evaluation of CBD effects on the molecular and behavioral changes induced by repeated treatment with MK-801
• Grantee: Felipe Villela Gomes
• Support Opportunities: Scholarships in Brazil - Doctorate