Functional Redundancy Between Canonical Endocannabinoid Signaling Systems in the Modulation of Anxiety.

Bedse G, Hartley ND, Neale E, Gaulden AD, Patrick TA, Kingsley PJ, Uddin MJ, Plath N, Marnett LJ, Patel S
Biol Psychiatry. 2017 82 (7): 488-499

PMID: 28438413 · PMCID: PMC5585044 · DOI:10.1016/j.biopsych.2017.03.002

BACKGROUND - Increasing the available repertoire of effective treatments for mood and anxiety disorders represents a critical unmet need. Pharmacological augmentation of endogenous cannabinoid (eCB) signaling has been suggested to represent a novel approach to the treatment of anxiety disorders; however, the functional interactions between two canonical eCB pathways mediated via anandamide (N-arachidonylethanolamine [AEA]) and 2-arachidonoylglycerol (2-AG) in the regulation of anxiety are not well understood.

METHODS - We utilized pharmacological augmentation and depletion combined with behavioral and electrophysiological approaches to probe the role of 2-AG signaling in the modulation of stress-induced anxiety and the functional redundancy between AEA and 2-AG signaling in the modulation of anxiety-like behaviors in mice.

RESULTS - Selective 2-AG augmentation reduced anxiety in the light/dark box assay and prevented stress-induced increases in anxiety associated with limbic AEA deficiency. In contrast, acute 2-AG depletion increased anxiety-like behaviors, which was normalized by selective pharmacological augmentation of AEA signaling and via direct cannabinoid receptor 1 stimulation with Δ-tetrahydrocannabinol. Electrophysiological studies revealed 2-AG modulation of amygdala glutamatergic transmission as a key synaptic correlate of the anxiolytic effects of 2-AG augmentation.

CONCLUSIONS - Although AEA and 2-AG likely subserve distinct physiological roles, a pharmacological and functional redundancy between these canonical eCB signaling pathways exists in the modulation of anxiety-like behaviors. These data support development of eCB-based treatment approaches for mood and anxiety disorders and suggest a potentially wider therapeutic overlap between AEA and 2-AG augmentation approaches than was previously appreciated.

Copyright © 2017 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

MeSH Terms (22)

Adaptation, Ocular Animals Anti-Anxiety Agents Anxiety Arachidonic Acids Benzodioxoles Brain Cannabinoid Receptor Agonists Cyclohexanols Disease Models, Animal Dronabinol Endocannabinoids Excitatory Postsynaptic Potentials Glycerides Heterocyclic Compounds, 1-Ring Locomotion Male Mice Mice, Inbred ICR Piperidines Pyridines Signal Transduction

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