Dopaminergic neurotransmission in cortex, limbic regions and thalamus is believed to be centrally involved in the pathophysiology of schizophrenia, psychostimulant drug abuse, and attention deficit disorder. While there are PET and SPECT methods for evaluating striatal dopamine (DA) release and baseline extracellular DA levels in man, at present there are no well validated methods for studying DA release and baseline extracellular DA levels in extrastriatal regions in man. [18F] fallypride is an extremely potent and selective dopamine D2 radioligand, i.e., a KD of 31 pM for the dopamine D2 receptor, which can be used do delineate and quantitate striatal, thalamic, limbic and cortical dopamine D2 receptors in man. Studies in primates demonstrate that [18F] fallypride is sensitive to levels of d-amphetamine released dopamine in both striatum and extrastriatal regions. We propose to perform [18F] fallypride PET studies in 12 normal subjects (ages 18-40, 6M, 6F) prior to and following d-amphetamine administration (0.43mg/kg orally) to study d-amphetamine induced dopamine release in extrastriatal regions. This dose of real d-amphetamine produces decrements in striatal [11C] raclopride binding potentials similar to those seen with a 0.2-0.3 mg/kg IV dose of d-amphetamine with similar variability, but with fewer and less severe side effects. We propose to perform additional [18F] fallypride PET studies in 12 normal subjects (ages 18-40, 6M, 6F) prior to and following a 36-hour course of 56.6 mg/kg alphamethylparatyrosine/24 hours (6 grams over 36 hours for a 70 kg subject) to estimate baseline extracellular dopamine levels in extrastriatal regions. The development of methods for estimating DA release and baseline extracellular DA levels in extrastriatal regions will allow important new research studies in a number of psychiatric and neurological disorders which may allow design and evaluation of new therapeutic interventions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21MH068757-01
Application #
6678142
Study Section
Special Emphasis Panel (ZRG1-BDCN-2 (02))
Program Officer
Brady, Linda S
Project Start
2003-09-10
Project End
2006-07-31
Budget Start
2003-09-10
Budget End
2004-07-31
Support Year
1
Fiscal Year
2003
Total Cost
$169,875
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Woodward, Neil D; Zald, David H; Ding, Zhaohua et al. (2009) Cerebral morphology and dopamine D2/D3 receptor distribution in humans: a combined [18F]fallypride and voxel-based morphometry study. Neuroimage 46:31-8
Kessler, Robert M; Woodward, Neil D; Riccardi, Patrizia et al. (2009) Dopamine D2 receptor levels in striatum, thalamus, substantia nigra, limbic regions, and cortex in schizophrenic subjects. Biol Psychiatry 65:1024-31