The anxiolytic effects of cannabidiol in chronically stressed mice are mediated by the endocannabinoid system: Role of neurogenesis and dendritic remodeling

Author(s)

Fogaca, Manoela V. ^{[1, 2, 3]} ; Campos, Alline C. ^{[1, 2]} ; Coelho, Ludmila D. ^{[1, 2]} ; Duman, Ronald S. ^[3] ; Guimaraes, Francisco S. ^{[1, 2]}

Affiliation

^[1] Univ Sao Paulo, Ctr Interdisciplinary Res Appl Neurosci NAPNA, Ribeirao Preto, SP - Brazil

^[2] Univ Sao Paulo, Med Sch Ribeirao Preto, Dept Pharmacol, FMRP, Bandeirantes Ave 3900, BR-14049900 Ribeirao Preto, SP - Brazil

^[3] Yale Univ, Sch Med, Dept Psychiat, 34 Pk St, New Haven, CT 06520 - USA

• Document type: Journal article
• Source: Neuropharmacology; v. 135, p. 22-33, JUN 2018.
• Web of Science Citations: 22

Abstract

Repeated injections of cannabidiol (CBD), the major non-psychotomimetic compound present in the Cannabis sativa plant, attenuate the anxiogenic effects induced by Chronic Unpredictable Stress (CUS). The specific mechanisms remain to be fully understood but seem to involve adult hippocampal neurogenesis and recruitment of endocannabinoids. Here we investigated for the first time if the behavioral and pro-neurogenic effects of CBD administered concomitant the CUS procedure (14 days) are mediated by CB1, CB2 or 5HT(1A) receptors, as well as CBD effects on dendritic remodeling and on intracellular/synaptic signaling (fatty acid amide hydrolase - FAAH, Akt, GSK3 beta and the synaptic proteins Synapsin la/b, mGluR1 and PSD95). After 14 days, CBD injections (30 mg/kg) induced anxiolytic responses in stressed animals in the elevated plus-maze and novelty suppressed feeding tests, that were blocked by pretreatment with a CB1 (AM251, 0.3 mg/kg) or CB2 (AM630, 0.3 mg/kg), but not by a 5HT(1A) (WAY100635, 0.05 mg/kg) receptor antagonist. Golgi staining and immunofluorescence revealed that these effects were associated with an increase in hippocampal neurogenesis and spine density in the dentate gyrus of the hippocampus. AM251 and AM630 abolished the effects of CBD on spines density. However, AM630 was more effective in attenuating the pro-neurogenic effects of CBD. CBD decreased FAAH and increased p-GSK3 beta expression in stressed animals, which was also attenuated by AM630. These results indicate that CBD prevents the behavioral effects caused by CUS probably due to a facilitation of endocannabinoid neurotransmission and consequent CB1/CB2 receptors activation, which could recruit intracellular/synaptic proteins involved in neurogenesis and dendritic remodeling. (C) 2018 Elsevier Ltd. All rights reserved. (AU)

• FAPESP's process: 12/17626-7 - Cellular and molecular mechanisms involved in the role of atypical neurotransmitters in neuropsychiatric disorders
• Grantee: Francisco Silveira Guimaraes
• Support type: Research Projects - Thematic Grants
• FAPESP's process: 12/09300-4 - Bed nucleus of the stria terminalis noradrenergic system modulates contextual fear conditionig: possible interaction with CRF and glutamatergic and nitrergic neurotransmission
• Grantee: Leonardo Resstel Barbosa Moraes
• Support type: Regular Research Grants