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Research ArticleBehavioral Pharmacology

Fatty Acid Amide Hydrolase (FAAH) Inhibition Reduces l-3,4-Dihydroxyphenylalanine-Induced Hyperactivity in the 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-Lesioned Non-Human Primate Model of Parkinson's Disease

Tom H. Johnston, Philippe Huot, Susan H. Fox, James D. Wakefield, Kristine A. Sykes, Wilmin P. Bartolini, G. Todd Milne, James P. Pearson and Jonathan M. Brotchie
Journal of Pharmacology and Experimental Therapeutics February 2011, 336 (2) 423-430; DOI: https://doi.org/10.1124/jpet.110.169532
Tom H. Johnston
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Philippe Huot
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Susan H. Fox
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James D. Wakefield
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Kristine A. Sykes
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Wilmin P. Bartolini
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G. Todd Milne
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James P. Pearson
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Jonathan M. Brotchie
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Abstract

Dopaminergic therapies remain the most efficacious symptomatic treatments for Parkinson's disease (PD) but are associated with motor complications, including dyskinesia, and nonmotor complications, such as psychosis, impulse control disorders (ICD), and dopamine dysregulation syndrome (DDS). Nondopaminergic neurotransmitter systems, including the endocannabinoid system, are probably critical to the development of these complications. The role of fatty acid amide hydrolase (FAAH) in mediating l-3,4-dihydroxyphenylalanine (l-DOPA)-induced behaviors was explored in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned marmoset model of PD. Pharmacodynamic and locomotor effects of the selective FAAH inhibitor [3-(3-carbamoylphenyl)phenyl] N-cyclohexylcarbamate (URB597) were assessed via bioanalytical (liquid chromatography-tandem mass spectrometry) and behavioral observation approaches. URB597 (3, 10, 30, or 60 mg/kg p.o.) increased plasma levels of the FAAH substrates N-arachidonoyl ethanolamide (anandamide), N-oleoyl ethanolamide, and N-palmitoyl ethanolamide by 10.3 ± 0.3-, 7.8 ± 0.2-, and 1.8 ± 0.1-fold (mean of URB597 groups ± S.E.M.), respectively, compared with vehicle (all p < 0.001) 4 h after administration. Treatment with l-DOPA (20 mg/kg s.c.) alleviated parkinsonism but elicited dyskinesia, psychosis-like-behaviors and hyperactivity, a potential correlate of ICD and DDS. During the 2 to 4 h after l-DOPA, corresponding to 4 to 6 h after URB597 administration, URB597 reduced total l-DOPA-induced activity and the magnitude of hyperactivity by 32 and 52%, respectively, to levels equivalent to those seen in normal animals. Treatment with URB597 (10 mg/kg p.o.) did not modify the antiparkinsonian actions of l-DOPA or l-DOPA-induced dyskinesia and psychosis. URB597 did not alter plasma l-DOPA levels and was without behavioral effects when administered alone. Inhibition of FAAH may represent a novel approach to reducing l-DOPA-induced side effects, such as ICD and DDS, while maintaining the antiparkinsonian benefits of l-DOPA treatment.

Footnotes

  • This work was supported by Ironwood Pharmaceuticals, Inc. and Atuka Ltd.

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    doi:10.1124/jpet.110.169532.

  • ↵Embedded Image The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    PD
    Parkinson's disease
    ICD
    impulse control disorders
    DDS
    dopamine dysregulation syndrome
    l-DOPA
    l-3,4-dihydroxyphenylalanine
    FAA
    fatty acid amide
    FAAH
    FAA hydrolase
    MPTP
    1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
    AEA
    N-arachidonoyl-ethanolamide
    OEA
    N-oleoyl ethanolamide
    PEA
    N-palmitoyl ethanolamide
    URB597
    [3-(3-carbamoylphenyl)phenyl] N-cyclohexylcarbamate
    RM-ANOVA
    repeated-measures analysis of variance
    TRPV1
    vanilloid receptor type 1
    IQR
    interquartile range
    FS
    Friedman statistic.

  • Received April 23, 2010.
  • Accepted October 20, 2010.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 384 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 384, Issue 2
1 Feb 2023
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Fatty Acid Amide Hydrolase (FAAH) Inhibition Reduces l-3,4-Dihydroxyphenylalanine-Induced Hyperactivity in the 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-Lesioned Non-Human Primate Model of Parkinson's Disease
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Research ArticleBehavioral Pharmacology

Fatty Acid Amide Hydrolase (FAAH) Inhibition Reduces l-3,4-Dihydroxyphenylalanine-Induced Hyperactivity in the 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-Lesioned Non-Human Primate Model of Parkinson's Disease

Tom H. Johnston, Philippe Huot, Susan H. Fox, James D. Wakefield, Kristine A. Sykes, Wilmin P. Bartolini, G. Todd Milne, James P. Pearson and Jonathan M. Brotchie
Journal of Pharmacology and Experimental Therapeutics February 1, 2011, 336 (2) 423-430; DOI: https://doi.org/10.1124/jpet.110.169532

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Research ArticleBehavioral Pharmacology

Fatty Acid Amide Hydrolase (FAAH) Inhibition Reduces l-3,4-Dihydroxyphenylalanine-Induced Hyperactivity in the 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-Lesioned Non-Human Primate Model of Parkinson's Disease

Tom H. Johnston, Philippe Huot, Susan H. Fox, James D. Wakefield, Kristine A. Sykes, Wilmin P. Bartolini, G. Todd Milne, James P. Pearson and Jonathan M. Brotchie
Journal of Pharmacology and Experimental Therapeutics February 1, 2011, 336 (2) 423-430; DOI: https://doi.org/10.1124/jpet.110.169532
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