Abstract

This proposal will be a critical appraisal of the quantitative techniques that are available to study dopamine D1 and D2 receptors in schizophrenia and matched control subjects. Over the last 2 years we have been developing Positron Emission Tomography (PET) techniques for studying these receptors in vivo and have recently developed more and more sophisticated models and physics considerations for quantitation of absolute receptor densities. Our preliminary studies with the current state of our quantitative technique have shown striking two to three fold increases of receptor densities in both drug-naive and drug- treated schizophrenic patients as compared to matched controls. However, a detailed and rigorous examination of these models has not been completed and in view of the preliminary results are essential to future study of schisophrenia. A number of the assumptions made in our current models, although reasonable, must be validated in detail. Furthermore, alternative procedures for quantification must also be considered in the light of the resources in our institution. This grant application will examine in detail the analysis methods in all aspects of the quantitative imaging of D2 and D1 receptors with 11C-NMSP and 11C- SCH23390 respectively including the chemical, physical, physiological, mathematical modeling which is available to apply to our schizophrenic populations which are being studied. With the completion of this project we will be in an even stronger position to apply these quantitative methods to further schizophrenia research in areas such as high risk population for schizophrenia and the study of the relationship between therapy and receptor occupancy for better therapeutic monitoring. Our long range goals are thus to validate and improve our quantification of dopamine receptors in living human brain and to apply this to schizophrenic subjects for both absolute densities measures as well as occupancy measures as a function of therapy and clinical course.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH042821-03
Application #
2245555
Study Section
Diagnostic Radiology Study Section (RNM)
Project Start
1987-07-01
Project End
1994-06-30
Budget Start
1989-07-01
Budget End
1994-06-30
Support Year
3
Fiscal Year
1989
Total Cost
Indirect Cost

  Institution

Name
Johns Hopkins University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218

  Publications

Grunder, Gerhard; Carlsson, Arvid; Wong, Dean F (2003) Mechanism of new antipsychotic medications: occupancy is not just antagonism. Arch Gen Psychiatry 60:974-7
Zhou, Yun; Endres, Christopher J; Brasic, James Robert et al. (2003) Linear regression with spatial constraint to generate parametric images of ligand-receptor dynamic PET studies with a simplified reference tissue model. Neuroimage 18:975-89
Yokoi, Fuji; Grunder, Gerhard; Biziere, Kathleen et al. (2002) Dopamine D2 and D3 receptor occupancy in normal humans treated with the antipsychotic drug aripiprazole (OPC 14597): a study using positron emission tomography and [11C]raclopride. Neuropsychopharmacology 27:248-59
Cumming, Paul; Wong, Dean F; Dannals, Robert F et al. (2002) The competition between endogenous dopamine and radioligands for specific binding to dopamine receptors. Ann N Y Acad Sci 965:440-50
Singer, Harvey S; Szymanski, Sally; Giuliano, Joseph et al. (2002) Elevated intrasynaptic dopamine release in Tourette's syndrome measured by PET. Am J Psychiatry 159:1329-36
Wong, Dean F (2002) In vivo imaging of D2 dopamine receptors in schizophrenia: the ups and downs of neuroimaging research. Arch Gen Psychiatry 59:31-4
Gjedde, A; Wong, D F (2001) Quantification of neuroreceptors in living human brain. v. endogenous neurotransmitter inhibition of haloperidol binding in psychosis. J Cereb Blood Flow Metab 21:982-94
Cumming, P; Yokoi, F; Chen, A et al. (1999) Pharmacokinetics of radiotracers in human plasma during positron emission tomography. Synapse 34:124-34
Morris, E D; Chefer, S I; Lane, M A et al. (1999) Loss of D2 receptor binding with age in rhesus monkeys: importance of correction for differences in striatal size. J Cereb Blood Flow Metab 19:218-29
Borbely, K; Brooks, R A; Wong, D F et al. (1999) NMSP binding to dopamine and serotonin receptors in MPTP-induced parkinsonism: relation to dopa therapy. Acta Neurol Scand 100:42-52

Showing the most recent 10 out of 26 publications