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Effects of fatty acid amide hydrolase (FAAH) inhibitors on working memory in rats

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Abstract

Rationale

Manipulations of the endocannabinoid system could potentially produce therapeutic effects with minimal risk of adverse cannabis-like side effects. Inhibitors of fatty acid amide hydrolase (FAAH) increase endogenous levels of the cannabinoid-receptor agonist, anandamide, and show promise for treating a wide range of disorders. However, their effects on learning and memory have not been fully characterized.

Objectives

We determined the effects of five structurally different FAAH inhibitors in an animal model of working memory known to be sensitive to impairment by delta-9 tetrahydrocannabinol (THC).

Methods

A delayed nonmatching-to-position procedure was used in rats. Illuminated nosepoke holes were used to provide sample cues (left versus right) and record responses (correct versus incorrect) after delays ranging from 0 to 28 s. Various test drugs were given acutely up to two times per week before daily sessions.

Results

One FAAH inhibitor, AM3506 (3 mg/kg), decreased accuracy in the memory task. Four other FAAH inhibitors (URB597, URB694, PF-04457845, and ARN14633) and a monoacylglycerol lipase inhibitor (JZL184, which blocks the degradation of the endocannabinoid 2-arachidonoylglycerol) had no effect. Testing of AM3506 in combination with antagonists for receptors known to be affected by anandamide and other fatty acid amides indicated that the impairment induced by AM3506 was mediated by cannabinoid CB1 receptors, and not by alpha-type peroxisome proliferator-activated receptors (PPAR-alpha) or vanilloid transient receptor potential cation channels (TRPV1).

Conclusions

FAAH inhibitors differ with respect to their potential for memory impairment, abuse liability, and probably other cannabis-like effects, and they should be evaluated individually for specific therapeutic and adverse effects.

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Acknowledgments

This research was supported by the Intramural Research Program of the NIH, National Institute on Drug Abuse (LVP, EBT, SRG, ZJ), by grant 5 DP1 DA031387 (DP) and by grants DA031020, DA09158, and DA3801 (AM).

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Authors and Affiliations

  1. Preclinical Pharmacology Section, Behavioral Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, 21224, USA

    Leigh V. Panlilio, Eric B. Thorndike, Steven R. Goldberg & Zuzana Justinova

  2. Center for Drug Discovery and Department of Pharmaceutical Sciences, Northeastern University, Boston, MA, USA

    Spyros P. Nikas

  3. MAKScientific, LLC, Boston, MA, USA

    Shakiru O. Alapafuja

  4. The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA, USA

    Benjamin F. Cravatt

  5. Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA, 92037, USA

    Benjamin F. Cravatt

  6. Drug Discovery and Development, Istituto Italiano di Tecnologia, Genoa, Italy

    Tiziano Bandiera & Daniele Piomelli

  7. Center for Drug Discovery, Department of Pharmaceutical Sciences and Chemistry and Chemical Biology, Northeastern University, Boston, MA, USA

    Alexandros Makriyannis

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

    Daniele Piomelli

Authors
  1. Leigh V. Panlilio
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  2. Eric B. Thorndike
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  3. Spyros P. Nikas
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  4. Shakiru O. Alapafuja
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  5. Tiziano Bandiera
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  6. Benjamin F. Cravatt
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  7. Alexandros Makriyannis
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  8. Daniele Piomelli
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  9. Steven R. Goldberg
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  10. Zuzana Justinova
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Corresponding author

Correspondence to Leigh V. Panlilio.

Ethics declarations

The facilities were fully accredited by the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC), and all experiments were conducted in accordance with the guidelines of the Animal Care and Use Committee of the National Institute on Drug Abuse Intramural Research Program and the Guidelines for the Care and Use of Mammals in Neuroscience and Behavioral Research.

Conflict of interest

DP and TB are inventors in patent applications filed by the University of California and the Fondazione Istituto Italiano di Tecnologia, which protect composition and use of chemicals described in the present study. All other authors declare that there is no actual or potential conflict of interest related to this manuscript.

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Panlilio, L.V., Thorndike, E.B., Nikas, S.P. et al. Effects of fatty acid amide hydrolase (FAAH) inhibitors on working memory in rats. Psychopharmacology 233, 1879–1888 (2016). https://doi.org/10.1007/s00213-015-4140-6

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  • DOI: https://doi.org/10.1007/s00213-015-4140-6

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