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Research ArticleNeuropharmacology

Patterns of Brain Glucose Metabolism Induced by Phosphodiesterase 10A Inhibitors in the Mouse: A Potential Translational Biomarker

Stefanie Dedeurwaerdere, Cindy Wintmolders, Greet Vanhoof and Xavier Langlois
Journal of Pharmacology and Experimental Therapeutics October 2011, 339 (1) 210-217; DOI: https://doi.org/10.1124/jpet.111.182766
Stefanie Dedeurwaerdere
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Cindy Wintmolders
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Greet Vanhoof
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Xavier Langlois
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Abstract

Phosphodiesterase 10A (PDE10A) inhibitors have recently been proposed as a new therapy for schizophrenia. The aim of this study was to enhance our understanding of the role of PDE10A inhibitors and potentially identify a clinically useful mechanistic/functional biomarker by using 2-deoxyglucose (2-DG) autoradiography. PDE10A inhibitors papaverine (10 and 40 mg/kg), 6,7-dimethoxy-4-[(3R)-3-(2-quinoxalinyloxy)-1-pyrrolidinyl]quinazoline (PQ-10), (0.16–10 mg/kg), and 2-[{4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)phenoxy}methyl]quinoline (MP-10) (0.16–40 mg/kg) induced region-specific hypermetabolism in the globus pallidus and lateral habenula of C57BL/6 mice. Studies with MP-10 revealed a dose-dependent relative increase in globus pallidus activation, whereas a bell-shaped curve was observed for the lateral habenula. Although the relative increase in 2-DG uptake in the lateral habenula was also characteristic of the D2 antagonist haloperidol (0.01–0.63 mg/kg), relative 2-DG changes were absent in the globus pallidus. This observation probably is explained by the interaction of PDE10A inhibitors with the D1 direct pathway as suggested by experiments in combination with the D1 agonist (±)-6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide (SKF-82958) (0.16 mg/kg). The absence of an effect of MP-10 (2.5 mg/kg) on relative glucose metabolism in the globus pallidus and lateral habenula of PDE10A knockout mice confirmed the specificity of the signal induced by PDE10A inhibitors. These studies substantiate the regulatory role of PDE10A in the basal ganglia circuit and as such support the potential of PDE10A inhibitors for treating psychiatric disorders. Moreover, we could differentiate PDE10A inhibitors from haloperidol based on specific patterns of hypermetabolism probably caused by its combined action at both direct and indirect dopaminergic pathways. Finally, these specific changes in brain glucose metabolism may act as a translational biomarker for target engagement in future clinical studies.

Footnotes

  • Financial support for the research was provided by Janssen Research and Development (a Division of Janssen Pharmaceutica NV, Beerse, Belgium).

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

    doi:10.1124/jpet.111.182766.

  • ABBREVIATIONS:

    PDE10A
    phosphodiesterase 10A
    2-DG
    2-deoxyglucose
    FDG
    fluorodeoxyglucose
    KO
    knockout
    WT
    wild type
    MED
    minimal effective dose
    PET
    positron emission tomography
    ANOVA
    analysis of variance
    SKF-82958
    (±)-6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide
    PQ-10
    6,7-dimethoxy-4-[(3R)-3-(2-quinoxalinyloxy)-1-pyrrolidinyl]quinazoline
    MP-10
    2-[{4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)phenoxy}methyl]quinoline
    HP-β-CD
    2-hydroxylpropyl-β-cyclodextrin
    GP
    globus pallidus
    hb
    lateral habenula
    CPu
    caudate putamen
    Tha
    thalamic region
    veh
    vehicle.

  • Received April 12, 2011.
  • Accepted July 7, 2011.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 339 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 339, Issue 1
1 Oct 2011
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Research ArticleNeuropharmacology

Phosphodiesterase 10A Inhibitor-Induced Brain Activation

Stefanie Dedeurwaerdere, Cindy Wintmolders, Greet Vanhoof and Xavier Langlois
Journal of Pharmacology and Experimental Therapeutics October 1, 2011, 339 (1) 210-217; DOI: https://doi.org/10.1124/jpet.111.182766

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Research ArticleNeuropharmacology

Phosphodiesterase 10A Inhibitor-Induced Brain Activation

Stefanie Dedeurwaerdere, Cindy Wintmolders, Greet Vanhoof and Xavier Langlois
Journal of Pharmacology and Experimental Therapeutics October 1, 2011, 339 (1) 210-217; DOI: https://doi.org/10.1124/jpet.111.182766
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