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Evaluation of fatty acid amide hydrolase inhibition in murine models of emotionality

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Abstract

Rationale

Manipulations of the endocannabinoid/fatty acid amide hydrolase (FAAH) signaling systems result in conflicting and paradoxical effects in rodent models of emotional reactivity.

Objectives

In the present study, we tested the hypothesis that the inhibition of FAAH would elicit significant effects in murine models used to screen anxiolytic and antidepressant drugs.

Materials and methods

FAAH (−/−) mice and wild-type mice treated with FAAH inhibitors (URB597 and OL-135) were evaluated in standard behavioral screening models for antidepressant (i.e., tail suspension and forced-swim tests) and anxiolytic (i.e., elevated plus maze) agents. The doses of URB597 and OL-135 selected were based on their ability to augment the pharmacological effects (i.e., analgesia, catalepsy, and hypothermia) of exogenously administered anandamide.

Results

FAAH (−/−) mice, anandamide-injected FAAH (−/−) mice, or wild-type mice injected with FAAH inhibitors or anandamide failed to exhibit significant effects in standard tests of emotional reactivity, although the antidepressant desipramine and the anxiolytic agent midazolam were active in the appropriate assays. FAAH- (−/−) and URB597-treated mice finally displayed significant effects in the tail suspension test when substantial methodological changes were made (i.e., altered ambient light and increased sample sizes).

Conclusions

Although FAAH suppression can elicit significant effects under some instances in which consequential procedural modifications are made, the present results indicate that the pharmacological inhibition or genetic deletion of FAAH is ineffective in standard mouse models of emotional reactivity. It remains to be established whether the effects of FAAH inhibition in these modified tasks are predictive of their efficacy in treating emotional disorders.

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Acknowledgment

The authors thank Dr. Lisa Gold for her constructive comments on an earlier version of this manuscript, as well as Dr. Marco Bortolato, Dr. Cecilia Hillard, Dr. Sachin Patel, and Dr. Danielle Piomelli for their professionalism and cooperation. This work was supported by the National Institute on Drug Abuse (DA15197, DA017259, DA015683, and DA005274) and Pfizer.

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Authors and Affiliations

  1. Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA, 23298-0613, USA

    Pattipati S. Naidu, Stephen A. Varvel, Billy R. Martin & Aron H. Lichtman

  2. Pfizer Global Research and Development, Molecular Pharmacology, 2800 Plymouth Road, Ann Arbor, MI, 48105, USA

    Kyunghye Ahn

  3. The Skaggs Institute for Chemical Biology and Departments of Cell Biology and Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Rd, La Jolla, CA, 92037, USA

    Benjamin F. Cravatt

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  1. Pattipati S. Naidu
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  2. Stephen A. Varvel
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  6. Aron H. Lichtman
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Correspondence to Aron H. Lichtman.

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Naidu, P.S., Varvel, S.A., Ahn, K. et al. Evaluation of fatty acid amide hydrolase inhibition in murine models of emotionality. Psychopharmacology 192, 61–70 (2007). https://doi.org/10.1007/s00213-006-0689-4

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  • DOI: https://doi.org/10.1007/s00213-006-0689-4

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