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Research ArticleNeuropharmacology

Relationship between Dose, Drug Levels, and D2 Receptor Occupancy for the Atypical Antipsychotics Risperidone and Paliperidone

E. C. Muly, J. R. Votaw, J. Ritchie and L. L. Howell
Journal of Pharmacology and Experimental Therapeutics April 2012, 341 (1) 81-89; DOI: https://doi.org/10.1124/jpet.111.189076
E. C. Muly
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J. R. Votaw
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J. Ritchie
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L. L. Howell
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Abstract

Blockade of D2 family dopamine receptors (D2Rs) is a fundamental property of antipsychotics, and the degree of striatal D2R occupancy has been related to antipsychotic and motor effects of these drugs. Recent studies suggest the D2R occupancy of antipsychotics may differ in extrastriatal regions compared with the dorsal striatum. We studied this issue in macaque monkeys by using a within-subjects design. [18F]fallypride positron emission tomography scans were obtained on four different doses of risperidone and paliperidone (the 9-OH metabolite of risperidone) and compared with multiple off-drug scans in each animal. The half-life of the two drugs in these monkeys was determined to be between 3 and 4 h, and drug was administered by a constant infusion through an intragastric catheter. The D2R occupancy of antipsychotic was determined in the caudate, putamen, ventral striatum, and four prefrontal and temporal cortical regions and was related to serum and cerebrospinal fluid drug levels. Repeated 2-week treatment with risperidone or paliperidone did not produce lasting changes in D2R binding potential in any region examined. As expected, D2R binding potential was highest in the caudate and putamen and was approximately one-third that level in the ventral striatum and 2% of that level in the cortical regions. We found dose-dependent D2R occupancy for both risperidone and paliperidone in both basal ganglia and cortical regions of interest. We could not find evidence of regional variation in D2R occupancy of either drug. Comparison of D2R occupancy and serum drug levels supports a target of 40 to 80 ng/ml active drug for these two atypical antipsychotics.

Footnotes

  • This work was supported by an Investigator Initiated Study Award from Ortho-McNeil Janssen Scientific Affairs, LLC; a Merit Award from the Office of Research and Development, Department of Veterans Affairs (to E.C.M.); the National Institutes of Health National Institute on Drug Abuse [Grant K02 DA0000517] (to L.L.H.); and the National Institutes of Health National Center for Research Resources [Grant P51-RR000165] (to Yerkes National Primate Research Center).

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

    http://dx.doi.org/10.1124/jpet.111.189076.

  • ABBREVIATIONS:

    D2R
    D2 family dopamine receptor
    ANOVA
    analysis of variance
    BP
    binding potential
    CSF
    cerebrospinal fluid
    DVR
    distribution volume ratio
    MRI
    magnetic resonance imaging
    PAL
    paliperidone
    PET
    positron emission tomography
    PFC
    prefrontal cortex
    dlPFC
    dorsolateral PFC
    oPFC
    orbital PFC
    mPFC
    medial PFC
    RIS
    risperidone
    ROI
    region of interest
    TCtx
    temporal cortex.

  • Received October 19, 2011.
  • Accepted December 28, 2011.
  • U.S. Government work not protected by U.S. copyright
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Journal of Pharmacology and Experimental Therapeutics: 341 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 341, Issue 1
1 Apr 2012
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Research ArticleNeuropharmacology

Striatal and Extrastriatal D2R Occupancy of Antipsychotics

E. C. Muly, J. R. Votaw, J. Ritchie and L. L. Howell
Journal of Pharmacology and Experimental Therapeutics April 1, 2012, 341 (1) 81-89; DOI: https://doi.org/10.1124/jpet.111.189076

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Research ArticleNeuropharmacology

Striatal and Extrastriatal D2R Occupancy of Antipsychotics

E. C. Muly, J. R. Votaw, J. Ritchie and L. L. Howell
Journal of Pharmacology and Experimental Therapeutics April 1, 2012, 341 (1) 81-89; DOI: https://doi.org/10.1124/jpet.111.189076
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