Cannabidiol Induces Rapid and Sustained Antidepressant-Like Effects Through Increased BDNF Signaling and Synaptogenesis in the Prefrontal Cortex

Author(s)

Sales, Amanda J. ^{[1, 2]} ; Fogaca, Manoela V. ^{[1, 2]} ; Sartim, Ariandra G. ^{[1, 2]} ; Pereira, Vitor S. ^[3] ; Wegener, Gregers ^[3] ; Guimaraes, Francisco S. ^{[4, 1]} ; Joca, Samia R. L. ^{[4, 2, 3]}

Affiliation

^[1] Univ Sao Paulo, Sch Med Ribeirao Preto, Dept Pharmacol, Ribeirao Preto, SP - Brazil

^[2] Univ Sao Paulo, Dept Chem & Phys, Sch Pharmaceut Sci Ribeirao Preto, Ribeirao Preto, SP - Brazil

^[3] Aarhus Univ Hosp, Translat Neuropsychiat Unit, Dept Clin Med, Risskov - Denmark

^[4] Univ Sao Paulo, Ctr Interdisciplinary Res Appl Neurosci NAPNA, Sao Paulo - Brazil

• Document type: Journal article
• Source: Molecular Neurobiology; v. 56, n. 2, p. 1070-1081, FEB 2019.
• Web of Science Citations: 17

Abstract

Currently available antidepressants have a substantial time lag to induce therapeutic response and a relatively low efficacy. The development of drugs that addresses these limitations is critical to improving public health. Cannabidiol (CBD), a non-psychotomimetic component of Cannabis sativa, is a promising compound since it shows large-spectrum therapeutic potential in preclinical models and humans. However, its antidepressant properties have not been completely investigated. Therefore, the aims of this study were to investigate in male rodents (i) whether CBD could induce rapid and sustained antidepressant-like effects after a single administration and (ii) whether such effects could be related to changes in synaptic proteins/function. Results showed that a single dose of CBD dose-dependently induced antidepressant-like effect (7-30mg/kg) in Swiss mice submitted to the forced swim test (FST), 30min (acute) or 7days (sustained) following treatment. Similar effects were observed in the Flinders Sensitive and Flinders Resistant Line (FSL/FRL) rats and the learned helplessness (LH) paradigm using Wistar rats. The acute antidepressant effects (30min) were associated with increased expression of synaptophysin and PSD95 in the medial prefrontal cortex (mPFC) and elevated BDNF levels in both mPFC and hippocampus (HPC). CBD also increased spine density in the mPFC after 30min, but not 7days later. Intracerebroventricular injection of the TrkB antagonist, K252a (0.05nmol/L), or the mTOR inhibitor, rapamycin (1nmol/L), abolished the behavioral effects of CBD. These results indicate that CBD induces fast and sustained antidepressant-like effect in distinct animal models relevant for depression. These effects may be related to rapid changes in synaptic plasticity in the mPFC through activation of the BDNF-TrkB signaling pathway. The data support a promising therapeutic profile for CBD as a new fast-acting antidepressant drug. (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 Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 15/01955-0 - Effect of inhibitors of DNMTs and antidepressants on DNA methylation in candidate genes involved in the neurobiology of depression
• Grantee: Amanda Juliana Sales
• Support Opportunities: Scholarships in Brazil - Doctorate