The overall goal of this proposal is to develop and apply methods for the tracer kinetic radioassay of dopaminergic systems in the mammalian brain. This approach will combine animal experimentation and human studies with positron emission tomography (PET). The proposed studies will build upon our presently funded work to extend the availability of biochemical probes (e.g., substrate analogs, receptor binding ligands, and enzyme suicide inhibitors) to the study of dopaminergic function in health and disease. Tracer kinetic modeling approaches will be used to determine efficient ways of monitoring brain energy metabolism during behavioral tasks and of enhancing the specificity, delivery and localization of dopamine specific tracers in the central nervous system. A new human PET instrument, that we have developed, will be applied to these studies; it will provide unprecedented spatial resolution and sampling abilities. An animal PET device will be developed (funded from other sources: DOE) and applied in this proposal; it will provide spatial resolution approaching the theoretical limit for PET instruments. Anatomical methods for data analysis will optimize the localization of neurochemical sites in both human and animal brains. Validated biochemical probes of dopaminergic function will be tested during perturbations of dopamine networks in the brain (e.g., electrical stimulation, chemical stimulation, degenerative states (MPTP), lesions, behavioral tasks, and neuropsychiatric disorders). The distribution of dopaminergic sites and their quantitative function both pre- and post-synaptically will be evaluated in normal states, during motor tasks, under the influence of dopamine stimulant drugs, and in patients with spontaneous (depression and obsessive- compulsive disorder) and drug-induced (cocaine and amphetamine addiction) alterations in mood.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH037916-07
Application #
3376406
Study Section
(SRCM)
Project Start
1983-06-01
Project End
1993-05-31
Budget Start
1989-07-01
Budget End
1990-05-31
Support Year
7
Fiscal Year
1989
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Type
Organized Research Units
DUNS #
119132785
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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