Individual Differences in Extrastriatal DA Release

Project Details


Both personality and genetic factors are reliably associated with vulnerability for developing psychostimulant
drug abuse. Some of this vulnerability is likely expressed as individual differences in the cognitive and
subjective response to psychostimulants. PET and SPECT imaging studies of striatal dopamine (DA)
binding indicate the presence of significant individual differences in the amount of DA released by
psychostimulants. these differences in DA release are associated with the subjective effects of these
agents. Studies also suggest that baseline variables, such as basal D2/D3 binding in the striatum, and
novelty/sensation seeking personality traits may predict responsiveness to psychostimulants. Unfortunately,
this literature has been limited to measurement of striatal DA functioning due to difficulties imaging
extrastriatal DA with most available DA receptor ligands. However, substantial evidence indicates that
extrastriatal regions are also involved in processes related to drug abuse. We propose to examine the
relationship between extrastriatal DA functions, personality and responsiveness to oral amphetamine (d-
AMPH) using [18F]Fallypride in 54 healthy human subjects. [18F]Fallypride is a high affinity D2/D3 ligand that
labels both striatal and extrastriatal receptors and is sensitive to endogenous DA levels allowing it to index
the amount of endogenous DA released by psychostimulants. Preliminary data using [18F]Fallypride PET in
healthy subjects indicate that d-AMPH produces significant DA release in the striatum. The amount of DA
released in both the striatum and extrastriatal regions was associated with objective psychomotor
improvements on d-AMPH. However, significant associations between DA release and subjective effects of
d-AMPH localized to extrastriatal regions, especially portions of the cingulate. Consistent with animal
models, the data indicate that individuals high on sensation seeking have lower basal D2/D3 binding levels in
both the striatum and midbrain DA producing regions (likely reflecting reduced autoreceptor density). The
present proposal aims to confirm and extend these findings in a large sample of subjects. We additionally
aim to test hypothesis that the catechol-o-methyltransferase val158met polymorphism effects DA release.
This will be assessed by specifically recruiting equal numbers of met/met, val/met and val/val subjects. We
will additionally provide an initial exploration of whether several additional candidate genes that are related to
risk for drug abuse have a measurable effect on either baseline D2/D3 binding and/or DA release. Finally,
in order to better understand the regional regulation of DA, we will examine the inter-relations between DA
functioning in the midbrain, striatum, thalamus and cortex. Taken together, the study will provide unique
information on how individual differences in the organization of the human DA system are associated with
personality, genetics and the subjective and cognitive effects of psychostimulants.
Effective start/end date4/10/0612/31/10


  • National Institute on Drug Abuse: $335,086.00
  • National Institute on Drug Abuse: $343,688.00
  • National Institute on Drug Abuse: $328,653.00
  • National Institute on Drug Abuse: $328,653.00


  • Psychiatry and Mental health
  • Radiology Nuclear Medicine and imaging


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