Alterations in functions of the brain dopamine (DA) system have been implicated in the pathophysiology of schizophrenia and in the therapeutic action of neuroleptic drugs. Detailed understanding of these changes in brain DA function have been limited by the absence of an accurate and easily repeatable measure of brain DA activity in man. Plasma levels of the main DA metabolite, homovanillic acid (HVA) may be such a measure. In animals, pHVA accurately reflects changes in the brain DA functions. Reflections of brain DA activity by pHVA measurements in human subjects requires the elimination of confounding variables affecting these measurements. The previous grant application developed methods for controlling these variables and identified abnormal pHVA concentrations in schizophrenic patients. The present grant application propose to identify additional confounding factors affecting pHVA measurements in man, improve the methodology of controlling these factors, and apply this information to the study of schizophrenia and other neuropsychiatric disorders. The effect of age, weight, seasonality, and previous pharmacological treatment on pHV will be examined in human subjects. An improvement in the control of confounding variables will consist of developing a pharmacological method to suppress peripheral HVA production. This method will be based on pretreatment with the MAO inhibitor debrisoquin. Using the optimal method for reflecting brain DA activity, pHVA will be measured in remitted, exacerbated, and treatment resistant schizophrenic patients. The ability to perform serial evaluations of dopaminergic activity may help elucidate the role of this neurotransmitter in schizophrenics.
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