The International Journal of Neuropsychopharmacology

Research Article

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

Alline C. Camposa1, Zaira Ortegaa2a3, Javier Palazuelosa2a3, Manoela V. Fogaçaa1, Daniele C. Aguiara4, Javier Díaz-Alonsoa2a3, Silvia Ortega-Gutiérreza5, Henar Vázquez-Villaa5, Fabricio A. Moreiraa4, Manuel Guzmána2a3, Ismael Galve-Roperha2a3 c1 and Francisco S. Guimarãesa1

a1 Department of Pharmacology, School of Medicine of Ribeirão Preto, Centre for Interdisciplinary Research on Applied Neurosciences (NAPNA), University of Sao Paulo, Brazil

a2 Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University, Madrid, Spain

a3 Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Universitario de Investigación en Neuroquímica (IUIN) and Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain

a4 Department of Pharmacology, Biological Sciences Institute, Federal University of Minas Gerais, Belo Horizonte, Brazil

a5 Department of Organic Chemistry, School of Chemistry, Complutense University, Madrid, Spain


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.

(Received April 16 2012)

(Reviewed June 30 2012)

(Revised November 15 2012)

(Accepted November 18 2012)

(Online publication January 09 2013)

Key words

  • Anxiety;
  • endocannabinoid system;
  • hippocampal neural progenitor;
  • neurogenesis;
  • stress


c1 Address for correspondence: Dr I. Galve-Roperh, Department of Biochemistry and Molecular Biology, School of Biology, Universidad Complutense, c/Jose Antonio Novais 2, 28040 Madrid, Spain. Tel.: +34 913 944668 Fax: +34 913 944672 Email: