Relationship between Dose, Drug Levels, and D2 Receptor Occupancy for the Atypical Antipsychotics Risperidone and Paliperidone
- 3 January 2012
- journal article
- research article
- Published by American Society for Pharmacology & Experimental Therapeutics (ASPET) in The Journal of pharmacology and experimental therapeutics
- Vol. 341 (1), 81-89
- https://doi.org/10.1124/jpet.111.189076
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.Keywords
This publication has 60 references indexed in Scilit:
- Antipsychotic Occupancy of Dopamine Receptors in SchizophreniaCNS Neuroscience & Therapeutics, 2010
- Dopamine D2 Receptor Levels in Striatum, Thalamus, Substantia Nigra, Limbic Regions, and Cortex in Schizophrenic SubjectsBiological Psychiatry, 2009
- Striatal and Extrastriatal D2/D3-Receptor-Binding Properties of ZiprasidoneJournal of Clinical Psychopharmacology, 2008
- No regional difference in dopamine D2 receptor occupancy by the second-generation antipsychotic drug risperidone in humans: a positron emission tomography studyInternational Journal of Neuropsychopharmacology, 2008
- Reward Processing in Schizophrenia: A Deficit in the Representation of ValueSchizophrenia Bulletin, 2008
- Occupancy of Striatal and Extrastriatal Dopamine D2/D3 Receptors by Olanzapine and HaloperidolNeuropsychopharmacology, 2005
- Increased volume of the nucleus accumbens in schizophreniaJournal of Neural Transmission, 2001
- PET Mapping of Extrastriatal D2-like Dopamine Receptors in the Human Brain Using an Anatomic Standardization Technique and [11C]FLB 457NeuroImage, 1999
- The Basal Ganglia and Adaptive Motor ControlScience, 1994
- The effect of haloperidol on D2 dopamine receptor subtype mRNA levels in the brainFEBS Letters, 1994