The general aim of this proposal is to study with brain imaging the neurochemical mechanisms underlying sensitization to psychostimulants in humans. Cocaine produces its reinforcing effects by blockade of the dopamine (DA) transporter, leading to an increase in DA synaptic concentration. In rodents, repeated exposure to psychostimulants such as amphetamine or cocaine results in a enhanced behavioral response to subsequent exposures, a phenomenon referred to as sensitization. Behavioral sensitization to psychostimulants has also been described in humans and is believed to play a role in addiction. Enhanced stimulant-induced DA release is the neurobiological mechanism underlying behavioral sensitization to stimulants in rodents. Until recently, the relevance of this observation to humans could not be assessed. We recently developed a noninvasive method using SPECT and the radiotracer [l23I]IBZM to measure amphetamine-induced DA release in humans.
In specific aim #1, we propose to measure amphetamine-induced DA release with SPECT and [l23I]IBZM in 24 cocaine abusers after 3 weeks of abstinence and 24 healthy control subjects, never previously exposed to psychostimulants, matched for age, gender, race and socioeconomic status. The hypothesis is that enhanced DA release will be observed in abstinent cocaine abusers. The DA transporter gene (DAT1 ) presents a variable number of tandem repeat (VNTR) in the 3' untranslated region of the gene. In humans, allele frequency for 9 and 10 repeats are about 30% and 70%, respectively. Cocaine-induced paranoia, a well characterized manifestation of sensitization in humans, is associated with the 9 repeat allele at this locus. We previously showed with SPECT and [l23I]IBZM that psychostimulant-induced psychotic reaction was associated with increased DA release. In addition, preliminary data suggest that amphetamine-induced DA release is increased in carriers of the 9 allele. Thus, the presence of the 9 allele might represent a risk factor for sensitization to psychostimulants.
In specific aim 2, we propose to compare amphetamine-induced DA release in 18 """"""""9-9"""""""" and 18 """"""""10-10"""""""" homozygote subjects, never previously exposed to psychostimulants, to test the hypothesis that this genetic marker is associated with increased vulnerability to the effects of psychostimulants.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA010219-02
Application #
2683847
Study Section
Human Development Research Subcommittee (NIDA)
Program Officer
Mcnamara-Spitznas, Cecilia M
Project Start
1997-05-10
Project End
2000-03-31
Budget Start
1998-04-01
Budget End
1999-03-31
Support Year
2
Fiscal Year
1998
Total Cost
Indirect Cost
Name
New York State Psychiatric Institute
Department
Type
DUNS #
167204994
City
New York
State
NY
Country
United States
Zip Code
10032
Martinez, Diana; Narendran, Rajesh; Foltin, Richard W et al. (2007) Amphetamine-induced dopamine release: markedly blunted in cocaine dependence and predictive of the choice to self-administer cocaine. Am J Psychiatry 164:622-9
Martinez, Diana; Broft, Allegra; Foltin, Richard W et al. (2004) Cocaine dependence and d2 receptor availability in the functional subdivisions of the striatum: relationship with cocaine-seeking behavior. Neuropsychopharmacology 29:1190-202
Martinez, Diana; Slifstein, Mark; Broft, Allegra et al. (2003) Imaging human mesolimbic dopamine transmission with positron emission tomography. Part II: amphetamine-induced dopamine release in the functional subdivisions of the striatum. J Cereb Blood Flow Metab 23:285-300
Abi-Dargham, Anissa; Kegeles, Lawrence S; Martinez, Diana et al. (2003) Dopamine mediation of positive reinforcing effects of amphetamine in stimulant naive healthy volunteers: results from a large cohort. Eur Neuropsychopharmacol 13:459-68
Mawlawi, O; Martinez, D; Slifstein, M et al. (2001) Imaging human mesolimbic dopamine transmission with positron emission tomography: I. Accuracy and precision of D(2) receptor parameter measurements in ventral striatum. J Cereb Blood Flow Metab 21:1034-57
Martinez, D; Gelernter, J; Abi-Dargham, A et al. (2001) The variable number of tandem repeats polymorphism of the dopamine transporter gene is not associated with significant change in dopamine transporter phenotype in humans. Neuropsychopharmacology 24:553-60
Kegeles, L S; Zea-Ponce, Y; Abi-Dargham, A et al. (1999) Stability of [123I]IBZM SPECT measurement of amphetamine-induced striatal dopamine release in humans. Synapse 31:302-8
Zea-Ponce, Y; Laruelle, M (1999) Protein precipitation: an expedient procedure for the routine analysis of the plasma metabolites of [123I]IBZM. Nucl Med Biol 26:811-4