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. ? ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA019670-02
Application #
7221305
Study Section
Special Emphasis Panel (ZRG1-BDCN-N (02))
Program Officer
Grant, Steven J
Project Start
2006-04-10
Project End
2009-12-31
Budget Start
2007-01-01
Budget End
2007-12-31
Support Year
2
Fiscal Year
2007
Total Cost
$335,086
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Smith, Christopher T; Dang, Linh C; Burgess, Leah L et al. (2018) Lack of consistent sex differences in D-amphetamine-induced dopamine release measured with [18F]fallypride PET. Psychopharmacology (Berl) :
Smith, C T; Dang, L C; Buckholtz, J W et al. (2017) The impact of common dopamine D2 receptor gene polymorphisms on D2/3 receptor availability: C957T as a key determinant in putamen and ventral striatum. Transl Psychiatry 7:e1091
Smith, Christopher T; Dang, Linh C; Cowan, Ronald L et al. (2016) Variability in paralimbic dopamine signaling correlates with subjective responses to d-amphetamine. Neuropharmacology 108:394-402
Dang, Linh C; Samanez-Larkin, Gregory R; Young, Jacob S et al. (2016) Caudate asymmetry is related to attentional impulsivity and an objective measure of ADHD-like attentional problems in healthy adults. Brain Struct Funct 221:277-86
Smith, Christopher T; Weafer, Jessica; Cowan, Ronald L et al. (2016) Individual differences in timing of peak positive subjective responses to d-amphetamine: Relationship to pharmacokinetics and physiology. J Psychopharmacol 30:330-43
Treadway, Michael T; Zald, David H (2013) Parsing Anhedonia: Translational Models of Reward-Processing Deficits in Psychopathology. Curr Dir Psychol Sci 22:244-249
Samanez-Larkin, Gregory R; Buckholtz, Joshua W; Cowan, Ronald L et al. (2013) A thalamocorticostriatal dopamine network for psychostimulant-enhanced human cognitive flexibility. Biol Psychiatry 74:99-105
Treadway, Michael T; Buckholtz, Joshua W; Cowan, Ronald L et al. (2012) Dopaminergic mechanisms of individual differences in human effort-based decision-making. J Neurosci 32:6170-6
Woodward, Neil D; Cowan, Ronald L; Park, Sohee et al. (2011) Correlation of individual differences in schizotypal personality traits with amphetamine-induced dopamine release in striatal and extrastriatal brain regions. Am J Psychiatry 168:418-26
Treadway, Michael T; Zald, David H (2011) Reconsidering anhedonia in depression: lessons from translational neuroscience. Neurosci Biobehav Rev 35:537-55

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