The anxiolytic effect of cannabidiol on chronically stressed mice depends on hippocampal neurogenesis: involvement of the endocannabinoid system
Open accessAbstract
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.
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Repeated administration of CBD prevented the anxiogenic effect of chronic stress by facilitating hippocampal neurogenesis.
“Regarding the hippocampus, although the acute effect of CBD on this structure is still unknown, repeated administration of the drug prevented the anxiogenic effect of chronic stress by facilitating hippocampal neurogenesis (44).”
From Translational investigation of the therapeutic potential of Cannabidiol (CBD): Toward a new age (2018) · cites this paper as [44]
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- Authors
- Campos, A. C., Ortega, Z., Palazuelos, J., Fogaça, M. V., Aguiar, D. C., Díaz-Alonso, J., Ortega-Gutiérrez, S., Vázquez-Villa, H., Moreira, F. A., Guzmán, M., Galve-Roperh, I., & Guimarães, F. S.
- Affiliations
- Universidade de São Paulo (BR)
- Universidad Complutense de Madrid (ES)
- Universidade Federal de Minas Gerais (BR)
- Department of Organic Chemistry, School of Chemistry, Complutense University, Madrid, Spain
- Department of Pharmacology, Biological Sciences Institute, Federal University of Minas Gerais, Belo Horizonte, Brazil
- Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University, Madrid, Spain
- ORCID
- Venue
- International Journal of Neuropsychopharmacology
- Publisher
- Oxford University Press (OUP)
- Published
- 2013-07-01
- Volume
- 16
- Issue
- 6
- Pages
- 1407-1419
- ISSN
- 1461-1457 (ISSN-L)
- 1469-5111
- OpenAlex
- W2136557533
- Cited by
- 313
- References
- 54
- Citations by year
- 2026: 12 · 2025: 21 · 2024: 28 · 2023: 30 · 2022: 33 · 2021: 44 · 2020: 24 · 2019: 26 · 2018: 23 · 2017: 16 · 2016: 19 · 2015: 17 · 2014: 14 · 2013: 5
- FWCI
- 13.46
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The International Journal of Neuropsychopharmacology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Science Foundation
- Comunidad de Madrid (S2010/BMD-2353, S2011-BMD-2336, S-2011/BMD-2308, 950344)
- Fundação de Amparo à Pesquisa do Estado de São Paulo (07/03685-3)
- Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
- Universidad Complutense de Madrid
- Topics
- Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
- Health Sciences › Medicine › Complementary and alternative medicine › Medicinal Plant Extracts Effects
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Keywords
- cannabidiol, anxiolytic effects, hippocampal neurogenesis, chronic unpredictable mild stress, endocannabinoid system, CB1 receptor, CB2 receptor, anandamide, hippocampal progenitor cells, fatty acid amide hydrolase, cell proliferation, anxiety
- MeSH terms
- Rimonabant, Animals, Camphanes, Bromodeoxyuridine, Cannabidiol, Cell Cycle, Cell Line, Transformed, Disease Models, Animal, Feeding Behavior, Glial Fibrillary Acidic Protein, Hippocampus, Mice, Inbred C57BL, Mice, Transgenic, Piperidines, Pyrazoles, Stress, Psychological, Thymidine Kinase, Anti-Anxiety Agents, Maze Learning, Cell Proliferation, Mice, Neurogenesis, Cannabinoid Receptor Antagonists
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