Elsevier

IBRO Neuroscience Reports

Volume 11, December 2021, Pages 88-102
IBRO Neuroscience Reports

Cannabidiol and the corticoraphe circuit in post-traumatic stress disorder

https://doi.org/10.1016/j.ibneur.2021.08.001 Get rights and content
Under a Creative Commons license
open access

Highlights

  • CBD reduces PTSD symptoms via the DRN and corticoraphe circuit.

  • Acute effects of CBD reduce DRN-amygdala excitatory signaling to lessen the activity disparity between amygdala and mPFC.

  • Chronic CBD officially resolves mPFC hypoactivity by facilitating 5-HT release from DRN to mPFC.

  • CBD-facilitated endocannabinoid signaling stabilizes DRN activity and restores mPFC inhibitory control.

  • Chronically administered CBD acts via the corticoraphe circuit to favor fear extinction over fear memory reconsolidation.

Abstract

Post-Traumatic Stress Disorder (PTSD), characterized by re-experiencing, avoidance, negative affect, and impaired memory processing, may develop after traumatic events. PTSD is complicated by impaired plasticity and medial prefrontal cortex (mPFC) activity, hyperactivity of the amygdala, and impaired fear extinction. Cannabidiol (CBD) is a promising candidate for treatment due to its multimodal action that enhances plasticity and calms hyperexcitability. CBD’s mechanism in the mPFC of PTSD patients has been explored extensively, but literature on the mechanism in the dorsal raphe nucleus (DRN) is lacking. Following the PRISMA guidelines, we examined current literature regarding CBD in PTSD and overlapping symptomologies to propose a mechanism by which CBD treats PTSD via corticoraphe circuit. Acute CBD inhibits excess 5-HT release from DRN to amygdala and releases anandamide (AEA) onto amygdala inputs. By first reducing amygdala and DRN hyperactivity, CBD begins to ameliorate activity disparity between mPFC and amygdala. Chronic CBD recruits the mPFC, creating harmonious corticoraphe signaling. DRN releases enough 5-HT to ameliorate mPFC hypoactivity, while the mPFC continuously excites DRN 5-HT neurons via glutamate. Meanwhile, AEA regulates corticoraphe activity to stabilize signaling. AEA prevents DRN GABAergic interneurons from inhibiting 5-HT release so the DRN can assist the mPFC in overcoming its hypoactivity. DRN-mediated restoration of mPFC activity underlies CBD’s mechanism on fear extinction and learning of stress coping.

Abbreviations

2-AG
2-arachidonoylglycerol
5-HT
Serotonin
5-HT1AR
5-HT Receptor Type 1A
5-HT2AR
5-HT Receptor Type 2 A
AEA
Anandamide
CB1R
Cannabinoid Receptor Type 1
CB2R
Cannabinoid Receptor Type 2
CBD
Cannabidiol
COVID-19
SARS-CoV-2
DRN
Dorsal Raphe Nucleus
ERK1/2
Extracellular Signal-Related Kinases Type 1 or Type 2
FAAH
Fatty Acid Amide Hydrolase
fMRI
Functional Magnetic Resonance Imaging
GABA
Gamma-Aminobutyric Acid
GPCRs
G-Protein Coupled Receptors
mPFC
Medial Prefrontal Cortex
NMDAR
N-Methyl-D-aspartate Receptors
PET
Positron Emission Tomography
PFC
Prefrontal Cortex
PTSD
Post-Traumatic Stress Disorder
SSRI
Selective Serotonin Reuptake Inhibitor
SSNRI
Selective Norepinephrine Reuptake Inhibitor
TRPV1
Transient Receptor Potential Vanilloid 1 Channels

Keywords

Cannabidiol
PTSD
Traumatic Stress
Serotonin
PFC, DRN and Raphe

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