The candidate research career is directed toward developing original brain imaging methods to characterize neurochemical alterations associated with schizophrenia and the clinical correlates of these alterations. The candidate 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) and positron emission tomography (PET, Columbia University). Current research effort is directed toward characterization of dopamine (DA) function abnormalities in the prefrontal cortex (PFC) and its relationship to cognitive processes in schizophrenia. The long-term goal of the candidate is to become an independent leader in the field of PET imaging. The candidate will continue to use PET neuroreceptor imaging of the D1 receptors to test the overall hypothesis that, in schizophrenia, a deficit in PFC DA function is implicated in the working memory limitations presented by these patients. D1 receptors are the most abundant DA receptors in the PFC. Preliminary data show that schizophrenia is associated with a selective increase in dorso-lateral PFC (DLPFC) [11C]NNC 112 binding, a specific D1 receptor radiotracer, and that this increased binding is associated with poor performance at the n back test. This increased binding might reflect an upregulation of D1 receptors secondary to a deficiency in DA tone. The candidate plans to extend these findings in a larger cohort. Measurement of D1 receptor binding potential with PET and [11C]NNC 112, will be obtained in untreated patients with schizophrenia well characterized in terms of cognitive function (specific aim 1), and repeated in a group of drug naive patients who will undergo risperidone treatment (specific aim 2) to assess the effects of antipsychotic treatment on D 1 receptors in relationship to changes in cognition. The candidate also proposes to develop a new D1 receptor radioligand vulnerable to fluctuations in synaptic DA (specific aim 3). Such a radiotracer would allow direct testing of the hypothesis that schizophrenia is associated with a deficit in DA function in the DLPFC. Finally specific aim 4 focuses on the study of the impact of cellular localization of D 1 receptors on the binding of D 1 radioligands. This investigation will provide additional information on the factors affecting the in vivo binding of dopaminergic PET radiotracers, and will help understand results of PET neuroreceptor studies in patients with schizophrenia.
|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|
|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|
|Laruelle, Marc; Kegeles, Lawrence S; Abi-Dargham, Anissa (2003) Glutamate, dopamine, and schizophrenia: from pathophysiology to treatment. Ann N Y Acad Sci 1003:138-58|