The broad objective of the project is to clarify the role of D1-like dopamine receptors in the pathophysiology of schizophrenia.
The specific aim i s to further develop and apply PET scan procedures for quantitative radioligand studies on D1-like dopamine receptors in all areas of the human living brain. This methodology will be applied to replicate and further develop the investigator's preliminary finding of reduced D1 dopamine receptor binding in brain regions of drug-naive schizophrenic patients. For the PET scanning procedure the new high affinity and relatively selective D1 dopamine receptor antagonist (11C)NNC 112 will be used. The investigators's preliminary results have demonstrated that this ligand has a higher ratio of specific to nonspecific binding and other advantages as compared to the investigator's previously developed radioligand (11C)SCH 23390. This allows the quantification of D1-densities in a number of limbic and neocortical regions besides the basal ganglia in living healthy and schizophrenic subjects. The second specific aim is to systematically combine the PET approach with human postmortem brain studies. Whole hemispheres from control and schizophrenic subjects will be cryosectioned in extenso to provide up to 1 500 hemisphere sections from each brain. These consecutive sections will allow the development of comprehensive detailed quantitative maps of D1 dopamine receptor binding in all regions of the human brain using (3H) NNC 112. This postmortem material will also be processed in parallel to explore the quantitative distribution of the gene messages for D1 and D5 dopamine receptors and related proteins throughout the human brain by in situ hybridization histochemistry. The PET scan experiments will be performed using the investigator's new 3D acquisition Siemens ECAT HR 47 PET camera system allowing the resolution of structures in the living human brain down to the order of about 3-4 mm. For the postmortem studies autoradiographic image information will be retrieved by a high resolution video camera system allowing the quantification and visualization of D1 dopamine receptor characteristics in all areas of brain of human subjects down to a resolution of about 50 microns. The complete sets of image data from PET and postmortem analyses will be stored and processed by means of fast high capacity computer media (Silicon Graphics) for the construction of the first rapidly accessible quantitative 3D information banks concerning D1-like dopamine receptor characteristics throughout the brain of individual healthy and schizophrenic human subjects.
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