Patients with schizophrenia present a 40% incidence of psychotic reactions following single administration of d-amphetamine (AMPH) at doses that are not psychotogenic in healthy subjects. AMPH being a potent dopamine (DA) releaser, this observation is consistent with the DA hypothesis of schizophrenia. However, the neuronal mechanism underlying this vulnerability is unknown.
The aim of this study is to test the hypothesis that patients with schizophrenia exhibit increased intrasynaptic DA release following AMPH challenge. This hypothesis will be evaluated with single photon emission computerized tomography (SPECT). SPECT scanning will be performed during constant infusion with the D2 radiotracer [123I]IBZM, before and after administration of AMPH (0.3 mg/kg, i.v.). In baboons and in humans, we observed that AMPH reduced the [123I]IBZM equilibrium specific binding. This decreased binding following AMPH reflects a decrease in D2 receptor availability due to increased competition by endogenous DA. In baboons, we observed an excellent correlation between this effect and the AMPH induced extracellular DA release measured with microdialysis. In humans, the reduction in D2 availability correlated well with the subjective activation measured on self rating scales following AMPH. Thus, this paradigm allows measuring, in the same experiment, the baseline D2 binding potential, the reduction in D2 binding potential following AMPH, and the behavioral effects of AMPH. Preliminary data obtained in 8 unmedicated patients with schizophrenia and 8 healthy controls matched for age, sex, ethnic and socioeconomic background suggested increased intrasynaptic DA release after AMPH in schizophrenics compared to controls. This observation points toward dysregulation of the DA neurons in schizophrenia, but should be regarded with caution given the small sample size. Thirty neuroleptic free patients with schizophrenia, fifteen neuroleptic naive patients with schizophrenia and forty-five healthy controls matched for age, gender, ethnic and socioeconomic background will undergo the SPECT experiment with [123I]IBZM and AMPH challenge (0.3 mg/kg). Behavioral response to AMPH will be assessed and compared to the results of the SPECT experiment. This study will test the following hypotheses: 1) AMPH-induced DA release will be increased in the schizophrenic group compared to the control group; 2) in the schizophrenic group, the increase in positive psychotic symptoms following AMPH will be correlated with the magnitude of the DA release. These studies should provide important information regarding the pathophysiology of DA transmission schizophrenia.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH054192-07
Application #
6392125
Study Section
Special Emphasis Panel (ZRG1-BDCN-6 (01))
Program Officer
Meinecke, Douglas L
Project Start
1996-04-01
Project End
2003-03-31
Budget Start
2001-04-01
Budget End
2003-03-31
Support Year
7
Fiscal Year
2001
Total Cost
$312,700
Indirect Cost
Name
New York State Psychiatric Institute
Department
Type
DUNS #
167204994
City
New York
State
NY
Country
United States
Zip Code
10032
Kegeles, Lawrence S; Abi-Dargham, Anissa; Frankle, W Gordon et al. (2010) Increased synaptic dopamine function in associative regions of the striatum in schizophrenia. Arch Gen Psychiatry 67:231-9
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
Zea-Ponce, Yolanda; Kegeles, Lawrence S; Guo, Ningning et al. (2002) Pharmacokinetics and brain distribution in non human primate of R(-)[123I]DOI, A 5HT(2A/2C) serotonin agonist. Nucl Med Biol 29:575-83
Kegeles, Lawrence S; Martinez, Diana; Kochan, Lisa D et al. (2002) NMDA antagonist effects on striatal dopamine release: positron emission tomography studies in humans. Synapse 43:19-29
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
Slifstein, M; Laruelle, M (2001) Models and methods for derivation of in vivo neuroreceptor parameters with PET and SPECT reversible radiotracers. Nucl Med Biol 28:595-608
Laruelle, M; Abi-Dargham, A; van Dyck, C et al. (2000) Dopamine and serotonin transporters in patients with schizophrenia: an imaging study with [(123)I]beta-CIT. Biol Psychiatry 47:371-9
Abi-Dargham, A; Rodenhiser, J; Printz, D et al. (2000) Increased baseline occupancy of D2 receptors by dopamine in schizophrenia. Proc Natl Acad Sci U S A 97:8104-9

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