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Fatty acid amide hydrolase inhibition alleviates anxiety-like symptoms in a rat model used to study post-traumatic stress disorder

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Abstract

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.

Methods

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.

Results

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.

Conclusions

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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Data availability

Data will be made available upon reasonable request.

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Acknowledgements

Kayla Chang and Cecilia Thien Dang assisted during behavioral experiments.

Funding

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.

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Authors and Affiliations

  1. Department of Anatomy and Neurobiology, University of California, Irvine, CA, 92697, USA

    Yannick Fotio, Alex Mabou Tagne, Kwang-Mook Jung & Daniele Piomelli

  2. Department of Biological Chemistry, University of California, Irvine, CA, 92697, USA

    Daniele Piomelli

  3. Department of Pharmaceutical Sciences, University of California, Irvine, CA, 92697-4625, USA

    Daniele Piomelli

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  1. Yannick Fotio
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  2. Alex Mabou Tagne
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  4. Daniele Piomelli
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Contributions

This study was ideated and designed by DP. The experiments were conducted by YF, AMT, and K-MJ. YF performed statistical analyses. YF wrote and DP edited the manuscript. All the authors reviewed and approved it.

Corresponding author

Correspondence to Daniele Piomelli.

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Competing interest

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

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