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

Gaurav Bedse, Nolan D. Hartley, Emily Neale, Andrew D. Gaulden, Toni A. Patrick, Philip J. Kingsley, Md Jashim Uddin, Niels Plath, Lawrence J. Marnett, Sachin Patel*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

62 Scopus citations

Abstract

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 Δ9-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.

Original languageEnglish (US)
Pages (from-to)488-499
Number of pages12
JournalBiological psychiatry
Volume82
Issue number7
DOIs
StatePublished - Oct 1 2017
Externally publishedYes

Keywords

  • 2-Arachidonoylglycerol
  • Amygdala
  • Anxiety
  • JZL184
  • MAGL inhibition
  • Stress

ASJC Scopus subject areas

  • Biological Psychiatry

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