The candidate's research career is directed toward developing original brain imaging methods to better characterize neurochemical alterations associated with schizophrenia, the clinical correlates of these alterations, and their relevance to treatment strategies. The candidate's previous research experience included postmortem analysis of neurochemical markers in schizophrenic brains (Clinical Brain Disorders Branch at NIMH) and neuroreceptor imaging using single photon computerized tomography (SPECT) (Department of Psychiatry, Yale University). The candidate has developed original methods for in vivo neuroreceptors quantification and evaluation of neurotransmitter release with SPECT. These developments allowed measuring dopamine (DA) synaptic transmission in the living human brain. Using this technique, the candidate and his collaborators demonstrated a dysregulation of DA transmission in the striatum of patients with schizophrenia, a finding which has been independently replicated and may constitute an important step in the elucidation of the pathophysiology of schizophrenia. The long-term goals of the candidate are to integrate multiple neurochemical imaging modalities to expand beyond static measures of neurochemicals toward testing models involving neuronal networks dysfunction implicated in schizophrenia. To achieve this objective, the candidate will continue to use SPECT neuroreceptor imaging, and will develop expertise in two brain neurochemical imaging modalities that are new to him, positron emission tomography (PET), and magnetic resonance spectroscopy (MRS). Columbia University provides a unique environment to achieve this purpose. The research plan proposes to integrate these imaging modalities to test the overall hypothesis that, in schizophrenia, a failure of development of the cortical connectivity results in dysregulation of DA subcortical systems. Functional mapping of nigrostriatal, mesolimbic and mesocortical DA synaptic activities will be achieved by combining imaging with several new radiotracers and pharmacological challenges. Correlation between scan and clinical data will be assessed, to test the hypotheses that mesolimbic hyperactivity at the D2 and D3 receptors is associated with positive symptoms, and that mesocortical hypoactivity at the D1 receptors is associated with negative symptoms. The possible role of glutamatergic transmission in these dysregulations will also be assessed. Ultimately, better understanding of these dysregulations and their role in symptomatology will lead to improved treatment strategies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Scientist Development Award - Research (K02)
Project #
5K02MH001603-02
Application #
2889946
Study Section
Clinical Neuroscience and Biological Psychopathology Review Committee (CNBP)
Program Officer
Meinecke, Douglas L
Project Start
1998-07-15
Project End
2003-06-30
Budget Start
1999-09-15
Budget End
2000-06-30
Support Year
2
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Psychiatry
Type
Schools of Medicine
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; 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
Frankle, W Gordon; Slifstein, Mark; Gunn, Roger N et al. (2006) Estimation of serotonin transporter parameters with 11C-DASB in healthy humans: reproducibility and comparison of methods. J Nucl Med 47:815-26
van Berckel, Bart N M; Kegeles, Lawrence S; Waterhouse, Rikki et al. (2006) Modulation of amphetamine-induced dopamine release by group II metabotropic glutamate receptor agonist LY354740 in non-human primates studied with positron emission tomography. Neuropsychopharmacology 31:967-77
Slifstein, Mark; Hwang, Dah-Ren; Martinez, Diana et al. (2006) Biodistribution and radiation dosimetry of the dopamine D2 ligand 11C-raclopride determined from human whole-body PET. J Nucl Med 47:313-9
Frankle, W Gordon; Lombardo, Ilise; New, Antonia S et al. (2005) Brain serotonin transporter distribution in subjects with impulsive aggressivity: a positron emission study with [11C]McN 5652. Am J Psychiatry 162:915-23
Laruelle, Marc; Frankle, W Gordon; Narendran, Rajesh et al. (2005) Mechanism of action of antipsychotic drugs: from dopamine D(2) receptor antagonism to glutamate NMDA facilitation. Clin Ther 27 Suppl A:S16-24
Talbot, Peter S; Frankle, W Gordon; Hwang, Dah-Ren et al. (2005) Effects of reduced endogenous 5-HT on the in vivo binding of the serotonin transporter radioligand 11C-DASB in healthy humans. Synapse 55:164-75
Abi-Dargham, Anissa; Laruelle, Marc (2005) Mechanisms of action of second generation antipsychotic drugs in schizophrenia: insights from brain imaging studies. Eur Psychiatry 20:15-27
Narendran, Rajesh; Hwang, Dah-Ren; Slifstein, Mark et al. (2005) Measurement of the proportion of D2 receptors configured in state of high affinity for agonists in vivo: a positron emission tomography study using [11C]N-propyl-norapomorphine and [11C]raclopride in baboons. J Pharmacol Exp Ther 315:80-90

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