The anxiolytic effect of cannabidiol on chronically stressed mice depends on hippocampal neurogenesis: involvement of the endocannabinoid system

Author(s):Show less -

Campos, Alline C. ^[1] ; Ortega, Zaira ^{[2, 3, 4, 5]} ; Palazuelos, Javier ^{[2, 3, 4, 5]} ; Fogaca, Manoela V. ^[1] ; Aguiar, Daniele C. ^[6] ; Diaz-Alonso, Javier ^{[2, 3, 4, 5]} ; Ortega-Gutierrez, Silvia ^[7] ; Vazquez-Villa, Henar ^[7] ; Moreira, Fabricio A. ^[6] ; Guzman, Manuel ^{[2, 3, 4, 5]} ; Galve-Roperh, Ismael ^{[2, 3, 4, 5]} ; Guimaraes, Francisco S.

Affiliation

^[1] Univ Sao Paulo, Ctr Interdisciplinary Res Appl Neurosci NAPNA, Sch Med Ribeirao Preto, Dept Pharmacol, BR-05508 Sao Paulo - Brazil

^[2] Univ Complutense, Sch Biol, Dept Biochem & Mol Biol 1, E-28040 Madrid - Spain

^[3] Ctr Invest Biomed & Red Enfermedades Neurodegener, Madrid - Spain

^[4] IUIN, Madrid - Spain

^[5] IRYCIS, Madrid - Spain

^[6] Univ Fed Minas Gerais, Inst Biol Sci, Dept Pharmacol, Belo Horizonte, MG - Brazil

^[7] Univ Complutense, Sch Chem, Dept Organ Chem, E-28040 Madrid - Spain

• Document type: Journal article
• Source: INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY; v. 16, n. 6, p. 1407-1419, JUL 2013.
• Web of Science Citations: 86

Abstract

Cannabidiol (CBD), the main non-psychotomimetic component of the plant Cannabis sativa, exerts therapeutically promising effects on human mental health such as inhibition of psychosis, anxiety and depression. However, the mechanistic bases of CBD action are unclear. Here we investigate the potential involvement of hippocampal neurogenesis in the anxiolytic effect of CBD in mice subjected to 14 d chronic unpredictable stress (CUS). Repeated administration of CBD (30 mg/kg i.p., 2 h after each daily stressor) increased hippocampal progenitor proliferation and neurogenesis in wild-type mice. Ganciclovir administration to GFAP-thymidine kinase (GFAP-TK) transgenic mice, which express thymidine kinase in adult neural progenitor cells, abrogated CBD-induced hippocampal neurogenesis. CBD administration prevented the anxiogenic effect of CUS in wild type but not in GFAP-TK mice as evidenced in the novelty suppressed feeding test and the elevated plus maze. This anxiolytic effect of CBD involved the participation of the CB1 cannabinoid receptor, as CBD administration increased hippocampal anandamide levels and administration of the CB1-selective antagonist AM251 prevented CBD actions. Studies conducted with hippocampal progenitor cells in culture showed that CBD promotes progenitor proliferation and cell cycle progression and mimics the proliferative effect of CB1 and CB2 cannabinoid receptor activation. Moreover, antagonists of these two receptors or endocannabinoid depletion by fatty acid amide hydrolase overexpression prevented CBD-induced cell proliferation. These findings support that the anxiolytic effect of chronic CBD administration in stressed mice depends on its proneurogenic action in the adult hippocampus by facilitating endocannabinoid-mediated signalling. (AU)

• FAPESP's process: 07/03685-3 - Typical and atypical neurotransmitters in neuropsychiatric disorders
• Grantee: Francisco Silveira Guimaraes
• Support Opportunities: Research Projects - Thematic Grants