This MCSDA application requests support for a career development and associated research plan to study the integrity of GABAergic transmission and its modulation of dopaminergic function in schizophrenia, and to relate these neurochemical indices to measures of psychopathology and cognition. The chemical imaging modalities of magnetic resonance spectroscopy (MRS) and positron emission tomography (PET) permit study in vivo of neurochemistry. The best-established theory of neurochemical disturbance in schizophrenia involves altered dopamine (DA) neurotransmission. Receptor studies to date have focused mainly on the D2 subclass of DA receptors and demonstrated excess dopaminergic function in the striatum. It has been hypothesized that the dopaminergic overactivity at the level of the striatum may be due to a GABAergic deficiency. A growing body of neuropathological evidence points toward abnormalities in frontal cortical gamma- aminobutyric acid (GABA) local circuit neurons. Moreover, the frontal neurochemical imbalances may contribute to the negative symptoms of attentional and working memory deficits. The proposed project involves PET neuroimaging of DA function and MRS measurement of GABA concentration, and studying the relation between these measures and both psychopathology and cognition. The short-term goals of the project include development of MRS methods specific for GABA measurement, and preclinical evaluation and validation of these methods by comparison with PET studies in conjunction with a GABAergic pharmacological challenge. Human studies will begin with a Phase I PET investigation of GABA/DA interactions using the same pharmacological challenge in healthy volunteers. In the final three years of the award period, a clinical study will make use of both the MRS and D2 DA PET receptor approaches to test the hypothesis that the dopaminergic response to a GABAergic challenge is diminished in the striatum in schizophrenia. This research plan is intended to build on the candidate s prior work with D2 receptor investigations of striatal function and its modulation by pharmacological challenges. The career development activities proposed are aimed at building on the candidate s previous fellowship training with neuroreceptor imaging, MRS, and pharmacological challenges to develop the skills needed to execute a program targeting the DA and GABA abnormalities in schizophrenia, their potential interactions, and their potential relation to neurobehavioral measures.
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| 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 |
