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

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 neurogene...

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Published in:	Neuropharmacology Vol. 135; pp. 22 - 33
Main Authors:	Fogaça, Manoela V., Campos, Alline C., Coelho, Ludmila D., Duman, Ronald S., Guimarães, Francisco S.
Format:	Journal Article
Language:	English
Published:	England Elsevier Ltd 01-06-2018
Subjects:	Amidohydrolases - metabolism Animals Anti-Anxiety Agents - pharmacology Anxiety Behavior, Animal - drug effects Cannabidiol Cannabidiol - pharmacology CB1 receptor CB2 receptor Dendritic spines Disks Large Homolog 4 Protein Glycogen Synthase Kinase 3 beta - metabolism Hippocampus - cytology Indoles - pharmacology Male Mice Neurogenesis Neurogenesis - drug effects Neuronal Plasticity - drug effects Piperazines Piperidines - pharmacology Proto-Oncogene Proteins c-akt Pyrazoles - pharmacology Pyridines Receptor, Cannabinoid, CB1 - antagonists & inhibitors Receptor, Cannabinoid, CB2 - antagonists & inhibitors Receptors, Metabotropic Glutamate - metabolism Serotonin 5-HT1 Receptor Antagonists - pharmacology Stress, Psychological - metabolism Stress, Psychological - prevention & control Synapsins - metabolism CB2 receptor Dendritic spines Cannabidiol Anxiety CB1 receptor Neurogenesis
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Summary:	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 5HT1A receptors, as well as CBD effects on dendritic remodeling and on intracellular/synaptic signaling (fatty acid amide hydrolase - FAAH, Akt, GSK3β and the synaptic proteins Synapsin Ia/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 pre-treatment with a CB1 (AM251, 0.3 mg/kg) or CB2 (AM630, 0.3 mg/kg), but not by a 5HT1A (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-GSK3β 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. •CBD prevents the anxiogenic effect induced by CUS through CB1/CB2 receptors.•CBD prevents the decrease in neurogenesis induced by CUS through CB2 receptors.•CBD increases p-GSK3β in CUS animals through CB2 receptors.•CBD decreases FAAH and increases synaptic proteins expression in CUS animals.•CBD prevents the decrease in dendritic remodeling induced by CUS through CB1/CB2 receptors.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0028-3908 1873-7064
DOI:	10.1016/j.neuropharm.2018.03.001