This proposal is a competing renewal application of an r01 funded by NIMH in April 1993. That project focused on the development of a research strategy using PET to study dopamine (DA) activity and DA modulation in normal control subjectsfor subsequent investigation in schizophrenic patients. These methods were developed to address the hypothesis taht the inabilityof DA to modulate other functionally-linked and etiologically relevant neurotransmitters in cortical and limbic areas underlies symptomatology in schizophrenia. Over the past three years, the following specific aims were accomplished: 1) a paradigm was developed to measure acetylcholine modulatio of DA by measuring the effect of muscarinic cholinergic reeptor blockade on Da receptor availability 2) a paradigm, developed originally to measurethe responsiveness of the DA system, was used in combination with muscarinic cholinergic receptor radiotracer to measure DA modulation of acetylcholine; 3) a paradigm as developed to measure serotonin modulation of DA by measuring the effect of serotonin increase on DA receptor availability; 4) the binding characteristics and test-retest variability of the 5-HT2A radiotracer (18F)-altanserin were measured; 5) a paradigm was developed to measure serotonin responsiveness by measuring the effect of serotonin increase on serotonin receptor availability. This application of PET methodology represents the most direct, nonivasive and quantitative method of measuring neurotransmitter activity in the living human brain. The studies proposed in this application represent one of the initial clinical applications of the PET methodology developed in the first three years of this project and will focus on characterizing serotonin modulation of DA and serotonin responsiveness in unmedicated schizophrenic patients. DA and serotonin represented the logical focus for study based on postmortem date, the role of these systems in mechanism of action of antipsychotic medications and basic neuroanatomic and neurophysioligic data. The results of the proposed studies will determine the direction of future studies of schizophrenic patients earlier in the diseae course and prior to neuroleptic exposure. These studies will serve as a model for future studies to examine DA modulation of other neurotransmitters(such as acetylcholine, norepinephrine and glutamate) and their ability to modulate DA release in vivo. The results of the proposed studies may hve implications for the refinement of pharmacotherpy in schizophrenia and will lead to a better understanding ofhow these systems relate to specific aspects of symptomatology.