Background and aim
Post-traumatic stress disorder (PTSD), a chronic debilitating condition that affects nearly 5–10% of American adults, is treated with a handful of FDA-approved drugs that provide at best symptomatic relief and exert multiple side effects. Preclinical and clinical evidence shows that inhibitors of the enzyme fatty acid amide hydrolase (FAAH), which deactivates the endocannabinoid anandamide, exhibit anxiolytic-like properties in animal models. In the present study, we investigated the effects of two novel brain-permeable FAAH inhibitors – the compounds ARN14633 and ARN14280 – in a rat model of predator stress-induced long-term anxiety used to study PTSD.
We exposed male Sprague–Dawley rats to 2,5-dihydro-2,4,5-trimethylthiazoline (TMT), a volatile constituent of fox feces, and assessed anxiety-like behaviors in the elevated plus maze (EPM) test seven days later. We measured FAAH activity using a radiometric assay and brain levels of FAAH substrates by liquid chromatography/tandem mass spectrometry.
Rats challenged with TMT developed persistent (≥ 7 days) anxiety-like symptoms in the EPM test. Intraperitoneal administration of ARN14633 or ARN14280 1 h before testing suppressed TMT-induced anxiety-like behaviors with median effective doses (ED50) of 0.23 and 0.33 mg/kg, respectively. The effects were negatively correlated (ARN14663: R2 = 0.455; ARN14280: R2 = 0.655) with the inhibition of brain FAAH activity and were accompanied by increases in brain FAAH substrate levels.
The results support the hypothesis that FAAH-regulated lipid signaling serves important regulatory functions in the response to stress and confirm that FAAH inhibitors may be useful for the management of PTSD.
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Kayla Chang and Cecilia Thien Dang assisted during behavioral experiments.
This work was supported by a contract from Endosane Pharmaceuticals GmbH (to DP). The company was not involved in the study's design, execution, or data analysis.
D.P. is an inventor in patent applications, owned by the Regents of the University of California, which protect the composition and use of ARN14663, ARN14280, and other FAAH inhibitors.
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Fotio, Y., Mabou Tagne, A., Jung, KM. et al. Fatty acid amide hydrolase inhibition alleviates anxiety-like symptoms in a rat model used to study post-traumatic stress disorder. Psychopharmacology (2023). https://doi.org/10.1007/s00213-023-06358-y