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Psychopharmacology (Berl). 2018 Sep 24. doi: 10.1007/s00213-018-5020-7. [Epub ahead of print]

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

Author information

1
Department of Anatomy and Neurobiology, University of California, 3101 Gillespie NRF, Irvine, CA, 92697-4625, USA.
2
Department of Molecular & Cellular Biology, The University of Arizona, Tucson, AZ, USA.
3
Department of Anatomy, Physiology, and Genetics, Uniformed Service University of the Health Sciences, Bethesda, MD, USA.
4
Center for the Study of Traumatic Stress, Department of Psychiatry, Uniformed Service University of the Health Sciences, Bethesda, MD, USA.
5
Department of Anatomy and Neurobiology, University of California, 3101 Gillespie NRF, Irvine, CA, 92697-4625, USA. piomelli@uci.edu.
6
Department of Pharmacology, University of California, Irvine, CA, 92697, USA. piomelli@uci.edu.
7
Department of Biological Chemistry, University of California, Irvine, CA, 92697, USA. piomelli@uci.edu.

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.

KEYWORDS:

Anandamide; CB1 receptors; Endocannabinoid; Oleoylethanolamide; Palmitoylethanolamide; Peroxisome proliferator-activated receptor-α; Post-traumatic stress disorder

PMID:
30251159
DOI:
10.1007/s00213-018-5020-7

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