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

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 (7-30 mg/kg) in Swiss mice submitted to the forced swim test (FST), 30 min (acute) or 7 days (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 (30 min) 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 30 min, but not 7 days later. Intracerebroventricular injection of the TrkB antagonist, K252a (0.05 nmol/μL), or the mTOR inhibitor, rapamycin (1 nmol/μL), 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.

Dietary Supplementation with Fish Oil or Conjugated Linoleic Acid Relieves Depression Markers in Mice by Modulation of the Nrf2 Pathway

“…Beside behavioral signs, activation of inflammatory/oxidative stress pathways, alteration of brain n‐6/n‐3 PUFA ratio, and MUFA/SFA content (e.g., DHA; C22:6 n‐3, Oleic, C18:1; Palmitic, C16:0; stearic acid, C18:0) underlie pathology onset and progression. In addition, several parameters involved in brain functioning (brain‐derived neurotrophic factor, BDNF; Tropomyosin receptor kinase B receptor, TrkB), synaptic transmission, and cholinergic signaling (acetylcholinesterase activity, AChE) have been associated with depression pathogenesis.…”

Rapid anti‐depressant‐like effects of ketamine and other candidates: Molecular and cellular mechanisms

“…Other drugs also produce anti‐depressant effects. Cannabidiol, neuropeptide VGF (non‐acronymic) C‐terminal peptide TLQP‐62 and NV‐5138 increased activity of BDNF‐mTOR signalling in the mPFC to induce rapid anti‐depressant effects 69‐71 . d ‐Methadone is a non‐competitive NMDAR antagonist and could decrease immobility of rats in FST in 24 hours 72 .…”

Cannabidiol modulates phosphorylated rpS6 signalling in a zebrafish model of Tuberous Sclerosis Complex

“…In vitro reduction of cellular viability and proliferation was demonstrated in both tumour cell lines [26][27][28][29][30][31] and primary tumour cells [26], whilst reducing tumour volume [26,28,31] and metastasis in vivo [31][32][33]. Importantly, CBD has been shown to modulate some components of the mTOR pathway [30,31,[34][35][36][37][38], however there is a divergence in the reported effects with evidence from the cancer field supporting a CBD inhibition of mTOR, while epilepsy studies indicate an activation of mTOR. Therefore, in the complex pathology of TSC, the modulation of mTOR signalling via CBD is unclear.…”