We propose to develop and apply emission tomography (PET) as an analytical biochemical assay technique to study normal human cerebral function and affective disorders. The objectives are: 1.) Chemistry/Biochemistry. Rapid synthetic techniques will be developed and/or improved for preparation of (F-18)-fluoro and (C-11) deoxyglucose for measurement of glucose metabolism, C-11 and N-13 labeled amino acids for measurement of protein synthesis rates and F-18 ligands for receptor assays (principally spiroperidol but also development of high specific activity F-18 labeling techniques to be applied to other ligands). Tissue biochemical assay and autoradiographic studies in rats and monkeys will be used to structure and define kinetic models and select among different tracers for protein synthesis and receptor assay measurements. 2.) Tomography. The NeuroECAT will be upgraded to provide unprecedented level of spatial resolution, image quality and quantification necessary to measure the detailed neuroanatomical components of cerebral function required by this proposal. 3.) Tracer kinetic modeling. Operational equations for measuring cerebral blood flow, protein synthesis, oxygen metabolism and receptor assays will be developed and validated. 4.) Normal Subjects. Studies will be performed to validate methods, and to determine norms and variations in local glucose and oxygen metabolism, blood flow and protein synthesis rates. Studies will be carried out to determine metabolic and blood flow responses to specific sensory stimulations to activate visual, auditory, linguistic and cognitive functions and the use of these stimulation-response tasks as provocative tests for affective disorder patients. 5.) Patients. Local glucose metabolism will be measured in patients with bipolar and unipolar affective disorders to determine if there are measurable local biochemical alterations, to establish the neuroanatomical distribution and magnitude of the functional changes and to objectively evaluate the metabolic consequences of drugs administered diagnostically (Ritalin - unipolar, depressed and also normal volunteers as controls) and therapeutically (Lithium - bipolar). Success in basic studies of F-18 spiroperidol will allow studies in these patients to examine the dopamine hypothesis of manic/depressive disorders.
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