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.

Cannabidiol as a Potential Treatment for Anxiety Disorders

“…In a subchronic study, CBD administered daily 1 h after predator stress (a proposed model of PTSD) reduced the long-lasting anxiogenic effects of chronic predator stress, partially via 5-HT 1A R activation [77]. In a chronic study, systemic CBD prevented increased anxiety produced by chronic unpredictable stress, in addition to increasing hippocampal AEA; these anxiolytic effects depended upon CB 1 R activation and hippocampal neurogenesis, as demonstrated by genetic ablation techniques [81]. Prior stress also appears to modulate CBD's anxiogenic effects: microinjection of CBD into the prelimbic cortex of unstressed animals was anxiogenic in the EPM but following restraint stress was found to be anxiolytic [87].…”

Adult Neurogenesis and Mental Illness

“…Cannabinoid effects on anxietylike behavior in rodents have recently been described (Braida et al, 2007;Jiang et al, 2005;Patel and Hillard, 2006). Cannabinoids and cannabinoid receptor agonists increase the proliferation of new neurons in the adult dentate gyrus (Avraham et al, 2014;Campos et al, 2013;Jiang et al, 2005) and increase new granule cell survival (Wolf et al, 2010). However, the rapid time course of cannabinoid effects on behavior, and dissociations between behavioral and neurogenic effects of different cannabinoids (Wolf et al, 2010), argue against the anxiolytic effects of cannabinoids being mediated by adult neurogenesis.…”

“…Cannabinoids, however, have anxiolytic-like effects in elevated plus maze and the NSF test that are blocked by ablation of new neurons (Campos et al, 2013;Jiang et al, 2005). Adult neurogenesis is required for the anxiolytic-like effects of cannabinoids in a chronic stress model of anxiety as well as under baseline conditions (Campos et al, 2013).…”

From Phytocannabinoids to Cannabinoid Receptors and Endocannabinoids: Pleiotropic Physiological and Pathological Roles Through Complex Pharmacology

“…CBD can increase also the levels of the other endocannabinoid, 2-arachidonoylglycerol (2-AG), as seen in the mouse periaqueductal grey (519), or colorectal cancer cells (24). Accordingly, some CBD effects are blocked by CB1 or CB2 receptor inverse agonists (79,113,115,124,183,464,519,715), or are absent in CB1 receptor knockout mice (922).…”