Authors:
Campos AC, Ortega Z, Palazuelos J, Fogaça MV, Aguiar DC, Díaz-Alonso J, Ortega-Gutiérrez S, Vázquez-Villa H, Moreira FA, Guzmán M, Galve-Roperh I, Guimarães FS.
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.