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Effects of fatty acid amide hydrolase inhibitor URB597 in a rat model of trauma-induced long-term anxiety

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Abstract

Rationale

The endocannabinoid neurotransmitter, anandamide, has been implicated in the central modulation of stress responses. Previous animal experiments have shown that inhibitors of the anandamide-degrading enzyme, fatty acid amide hydrolase (FAAH), enhance the ability to cope with acute and chronic stress.

Objectives

Here, we investigated the effects of the globally active FAAH inhibitor URB597 in a rat model of predator stress-induced long-term anxiety.

Results

Rats exposed to 2,5-dihydro-2,4,5-trimethylthiazoline (TMT), a chemical constituent of fox feces, developed a persistent anxiety-like state, which was assessed 7 days after exposure using the elevated plus maze (EPM) test. Systemic administration of URB597 [0.03–0.1-0.3 mg/kg, intraperitoneal (ip)] 2 h before testing suppressed TMT-induced behaviors with a median effective dose (IC50) of 0.075 mg/kg. This effect was strongly correlated with inhibition of brain FAAH activity (r2 = 1.0) and was accompanied by increased brain levels of three FAAH substrates: the endocannabinoid anandamide and the endogenous peroxisome proliferator-activated receptor-α (PPAR-α) agonists, oleoylethanolamide (OEA), and palmitoylethanolamide (PEA). The anxiolytic-like effects of URB597 were blocked by co-administration of the CB1 receptor antagonist rimonabant (1 mg/kg, ip), but not of the PPAR-α antagonist GW6471 (1 mg/kg, ip). Finally, when administered 18 h after TMT exposure (i.e., 6 days before the EPM test), URB597 (0.3 mg/kg, ip) prevented the consolidation of anxiety-like behavior in a CB1-dependent manner.

Conclusions

The results support the hypothesis that anandamide-mediated signaling at CB1 receptors serves an important regulatory function in the stress response, and confirm that FAAH inhibition may offer a potential therapeutic strategy for post-traumatic stress disorder.

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Abbreviations

FAAH:

Fatty acid amide hydrolase

TMT:

2,5-Dihydro-2,4,5-trimethylthiazoline

EPM:

Elevated plus maze

OEA:

Oleoylethanolamide

PEA:

Palmitoylethanolamide

PPAR-α:

Peroxisome proliferator-activated receptor-α

PTSD:

Post-traumatic stress disorder

PEG-400:

Polyethylene glycol

BCA:

Bicinchoninic acid

LC/MS:

Liquid chromatography/mass spectrometry

ESI:

Electrospray ionization

ANOVA:

Analysis of variance

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Funding

This work was supported in part by a contract from the Department of Defense through the Jackson Foundation (grant number HU0001-15-2-0067).

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Author notes

  1. James Lim

    Present address: Department of Molecular & Cellular Biology, The University of Arizona, Tucson, AZ, USA

Authors and Affiliations

  1. Department of Anatomy and Neurobiology, University of California, 3101 Gillespie NRF, Irvine, CA, 92697-4625, USA

    Andalib Danandeh, Valentina Vozella, James Lim, Fariba Oveisi, Gina L. Ramirez & Daniele Piomelli

  2. Department of Anatomy, Physiology, and Genetics, Uniformed Service University of the Health Sciences, Bethesda, MD, USA

    David Mears

  3. Center for the Study of Traumatic Stress, Department of Psychiatry, Uniformed Service University of the Health Sciences, Bethesda, MD, USA

    David Mears & Gary Wynn

  4. Department of Pharmacology, University of California, Irvine, CA, 92697, USA

    Daniele Piomelli

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

    Daniele Piomelli

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  1. Andalib Danandeh
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Correspondence to Daniele Piomelli.

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Conflicts of interest

DP is an inventor in patents and patent application owned or filed by the University of California, which protects composition and uses of chemicals described in the present report. Other authors have no conflict of interest to disclose.

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The opinions and assertions expressed herein are those of the authors and do not necessarily reflect the official policy or position of the Uniformed Services University or the Department of Defense.

Ethical approval

All experimental procedures were approved by the Institutional Animal Care and Use Committee at University of California Irvine and carried out in strict accordance with the National Institutes of Health guidelines for care and use of experimental animals.

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Danandeh, A., Vozella, V., Lim, J. et al. Effects of fatty acid amide hydrolase inhibitor URB597 in a rat model of trauma-induced long-term anxiety. Psychopharmacology 235, 3211–3221 (2018). https://doi.org/10.1007/s00213-018-5020-7

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  • DOI: https://doi.org/10.1007/s00213-018-5020-7

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