title: The anxiolytic effect of cannabidiol on chronically stressed mice depends on hippocampal neurogenesis: involvement of the endocannabinoid system.
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.
authors.affiliation: Department of Pharmacology, School of Medicine of Ribeirão Preto, Centre for Interdisciplinary Research on Applied Neurosciences (NAPNA), University of Sao Paulo, Brazil.
authors.forename: Alline C
authors.initials: AC
authors.lastname: Campos
authors.forename: Zaira
authors.initials: Z
authors.lastname: Ortega
authors.forename: Javier
authors.initials: J
authors.lastname: Palazuelos
authors.forename: Manoela V
authors.initials: MV
authors.lastname: Fogaça
authors.forename: Daniele C
authors.initials: DC
authors.lastname: Aguiar
authors.forename: Javier
authors.initials: J
authors.lastname: Díaz-Alonso
authors.forename: Silvia
authors.initials: S
authors.lastname: Ortega-Gutiérrez
authors.forename: Henar
authors.initials: H
authors.lastname: Vázquez-Villa
authors.forename: Fabricio A
authors.initials: FA
authors.lastname: Moreira
authors.forename: Manuel
authors.initials: M
authors.lastname: Guzmán
authors.forename: Ismael
authors.initials: I
authors.lastname: Galve-Roperh
authors.forename: Francisco S
authors.initials: FS
authors.lastname: Guimarães
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001973:Bromodeoxyuridine / Q000378:metabolism; D001892:Camphanes / Q000494:pharmacology; D002185:Cannabidiol / Q000494:pharmacology / Q000627:therapeutic use*; D063387:Cannabinoid Receptor Antagonists / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D002461:Cell Line, Transformed; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D005247:Feeding Behavior / Q000187:drug effects; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects*; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D055495:Neurogenesis / Q000187:drug effects* / Q000502:physiology; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D000077285:Rimonabant; D013315:Stress, Psychological / Q000188:drug therapy* / Q000473:pathology; D013937:Thymidine Kinase / Q000378:metabolism
chemical_list: D014151:Anti-Anxiety Agents; D001892:Camphanes; D063387:Cannabinoid Receptor Antagonists; D005904:Glial Fibrillary Acidic Protein; D010880:Piperidines; D011720:Pyrazoles; C110630:SR 144528; D002185:Cannabidiol; C103505:AM 251; D013937:Thymidine Kinase; D001973:Bromodeoxyuridine; D000077285:Rimonabant