Alterations in function 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 has been limited by the absence of an accurate easily repeatable measure of brain DA activity in man. Plasma levels of the DA metabolite homovanillic acid (HVA) may be such a measure. In animals, plasma levels of HVA (pHVA) accurately reflect changes in the brain DA system. These results have been intially difficult to replicate in a clinical setting. In man, """"""""extraneous"""""""" variables such as diet and activity can substantially alter pHVA. Only by understanding and eliminating the effects of these variables is pHVA likely to be a useful clinical index of brain DA function. Therefore, the focus of this proposal is to develop techniques in man to maximize the degree to which pHVA reflects brain DA function. Three strategies will be utilized. First, """"""""extraneous"""""""" factors that can alter pHAV levels are systematically studied and techniques for controlling their effects are developed. These factors include diet, activity, cigarette smoking, and circadian rhythm. Second, two pharmacologic agents are tested which can produce a direct inhibition of peripheral production of HVA, thereby increasing the degree to which pHVA reflects brain DA activity: debrisoquin and carbidopa. The third strategy is to examine the response of pHVA to pharmacologic """"""""probes"""""""" which produce major changes in brain DA function. Drugs examined are apomorphine, haloperidol, tyrosine and 1-dopa. The results of these studies will form the basis for the rational design and interpretation of studies utilizing pHVA as a measure of brain DA function in neuropsychiatric illness. The ability to repeatedly and accurately measure brain DA function may produce major new insights into the pathophysiology of schizophrenia and the mode of action of neuroleptic drugs.
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