Dopamine receptor development has been implicated in the etiology and pathophysiology of schizophrenia. The goal of this research is to characterize the development of dopamine receptor subtypes in human brain and to study potential developmental alterations of dopamine in the brains of subjects with schizophrenia. There has been very little work done in this important area. This study will provide new and important information about dopamine receptor development in human postmortem brain tissue using neurochemical and molecular techniques, and will test the overall hypothesis that dopamine receptor subtypes undergo subtype specific changes in localization and density during development. This characterization of dopamine receptor ontogeny will provide the basis for understanding the role that the development of dopamine receptors, both normal and abnormal, play in the etiology and pathophysiology of schizophrenia. Further, this study will test the hypothesis that there are developmental alterations in dopamine receptor expression in schizophrenia. Dopamine receptor development will be studied two brain regions implicated in schizophrenia, the prefrontal cortex and the striatum, including the nucleus accumbens. Tissue from a variety of ages subjects will be collected from three local sources. Using receptor autoradiography, the age specific changes of Dl and D2 dopamine receptor density and localization will be characterized. In addition, the developmental expression of dopamine receptor subtype mRNA will be characterized using in situ hybridization. Finally these techniques will be used to explore the potential developmental alterations in dopamine receptors in the postmortem brain tissue of adult subjects with schizophrenia. This study will provide important basic information about dopamine receptor development in humans, and may provide evidence that dopamine receptor development is altered in schizophrenia. In addition, it may provide insights into the role of dopamine receptor development in other neurodevelopmental diseases such as Tourette's syndrome, autism, and attention deficit disorder, and may provide the basis for the development of subtype selective drugs useful in the treatment of these diseases.
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