This new application covers the final two years of a currently funded ADAMHA Level I Research Scientist Development Award. A new application is necessary because of a change in the sponsoring institution. The program of research proposed in this application will accomplish several objectives including the acquisition of knowledge relevant to mental health research and the continued development of the scientific expertise of the applicant. Dopamine (DA) has been implicated in the pathophysiology of schizophrenia and other psychotic disorders, although the precise role of DA systems in the production of psychotic symptoms or the negative symptoms of schizophrenia has remained obscure. In addition, the nature of many of these symptoms suggests that they represent abnormalities in information processing within the neocortex. However, relatively little is known about the anatomy of the DA projections to the expanded and highly differentiated neocortex of primates. The proposed studies will answer important methodological questions relevant to the study of the DA projections to primate neocortex, provide a detailed description of the DA projections to monkey prefrontal and parietal cortical regions, and furnish the first analysis of the distribution of DA fibers in human neocortex. These data will provide 1) a foundation for more detailed anatomical and physiological studies aimed at determining the precise cellular targets of the DA afferents to neocortex, 2) an indication of the extent to which studies in monkeys are predictive of the characteristics of the DA projections to human neocortex and 3) a basis for possible future investigations of these DA systems in the brains of patients with schizophrenia or other disorders. The proposed research will also serve as a vehicle for the continued scientific training and development of the applicant. The proposed studies involve continued collaboration with Drs. F. Bloom, J. Morrison and S. Foote at the Scripps Clinic where the applicant has been trained in neuroanatomical techniques over the past 2.5 years. At the University of Pittsburgh, the applicant will have the opportunity to become established as an independent, clinically-oriented neuroscience investigator. This transition will occur under the guidance of senior researchers such as Drs. D. Kupfer, E. Stricker, B. Kaplan and J. Lund. Interactions with these investigators will enhance both the applicant's technical skills and his ability to relate basic neuroscience research to clinical issues.
