The Silvio O. Conte center dopamine dysfunction in Schizophrenia

nyspifacadefaded The Silvio O. Conte Center
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Participate in a brain imaging study

Project 1
Cortical and Subcortical Dopamine Dysregulation in Schizophrenia

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Project 1 of the Center (P1) will test whether the capacity for cortical dopamine (DA) release is altered in patients with schizophrenia and if cortical DA release relates to striatal dopaminergic excess measured in the same patients. While striatal DA excess is a well-established phenotype in schizophrenia, there is little support for DA dysfunction in the cortex, in part because assessment of cortical DA release has not previously been feasible. Now, using the high affinity D2/3 radiotracer [11C]FLB 457 combined with the D-amphetamine challenge, our preliminary data in eleven patients and thirteen demographically matched healthy control volunteers suggests decreased cortical DA in the patients.

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In P1, we will use [18F] DOPA to characterize striatal DA transmission, followed by [11C]FLB 457 before and after D-amphetamine (0.5 mg/kg ingested orally) to assess cortical DA release, in 33 drug naive patients with schizophrenia compared to 33 healthy controls matched for age, gender, ethnicity, smoking, parental socioeconomic status and catechol-0-methyltransferase (COMT) genotype. We postulate that DA will be decreased in dorsolateral prefronal cortex (DLPFC) (SA1), striatal DA will be increased (SA2), and the two measures will be inversely related (SA3). Furthermore, we hypothesize that, as we have observed previously, the associative striatum (AST), in particular the precommissural caudate (preDCA), will be the area of highest DA dysregulation, and that this will be the most predictive indicator of DLPFC DA dysfunction. This will provide the first and most direct examination possible of the capacity for DA release in DLPFC and in other cortical and extra-striatal regions in schizophrenia and its relationship to striatal DA transmission. This knowledge is essential as a first step in the development of treatments for cognitive dysfunction in schizophrenia.

PETFLB

[11C]FLB 457 image from one subject. The sagittal images on the left are an MRI image from the same subject. The PET images (center, right) are the average activity recorded over 90 minutes following injection of [11C]FLB 457, which binds to dopamine D2/D3 receptors. The vertical lines in the MRI show the levels of the coronal image slices (center) and the horizontal lines show the levels of the transverse images (right). The top is in the prefrontal cortex; the bottom is in the striatum. Imaging with [11C]FLB 457 will allow us to examine dopaminergic tone and function in the cortex in schizophrenia, a brain region which has not previously been accessible to in vivo imaging of dopamine D2/D3 receptors with PET.

The researchers involved with project 1 are: PI Anissa Abi-Dargham, Co-PI Jeffrey Lieberman, Co-Investigators Lawrence Kegeles, Mark Slifstein, Balu Easwaramoorthy and Consultant Marc Laruelle.

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