Previously we demonstrated that positron emission tomography (PET) can be used to measure changes In the concentrations of synaptic dopamine and acetylcholine. Whether induced directly or indirectly through interactions with other neurotransmitters, these studies support the use of PET for investigating the functional responsiveness ofa specific neurotransmitter to a pharmacologic challenge. In an extension of these findings to the human brain, PET studies designed to measure the responsiveness of striatal dopamine release to central cholinergic blockade were conducted in normal male volunteers using high-resolution PET and Neurotransmitter receptor studies using functional imaging techniques including positron emission tomography (PET) and single photon emission computed tomography initially examined single neurotransmitter systems in human and primate brains. For example, the first application of these techniques to neuropsychiatric disease addressed one important component of the dopamine hypothesis of schizophrenia (1, 2). However, the results were controversial and have been the subject of continued debate with respect to differences in methodology and subject characteristics (3, 4). Therefore, the need to further study mechanisms that regulate synaptic dopamine activity is supported not only by the evidence that schizophrenic patients may or may not show significant changes in dopamine receptor number (Bmax) from normal controls but by the fact that the degree of striatal D2 receptor occupancy is not indicative of response to neuroleptic treatment (5, 6). As a result, a series of PET studies using a multiple mechanistic approach, including an examination of the interactions that have been shown to exist between acetylcholine and dopamine, have demonstrated that the binding of labeled N-methylspiroperidol (NMSP) (7) and raclopride, radiotracers used in these early studies, is sensitive to changes in synaptic dopamine concentrations (8-12). Both raclopride and NMSP are used as PET imaging agents for postsynaptic dopamine D2 receptors.PET's sensitivity for detecting alterations in labeled raclopride or NMSP binding has been demonstrated by pharmacologic agents that selectively increase or decrease synaptic dopamine concentrations by neurochemically different mechanisms (8, 9). These findings suggest that this experimental approach is well suited for studies designed to investigate disease states that begin with or result from a loss in the ability to adequately regulate synaptic dopamine release. Furthermore, the potential for this experimental approach clearly extends beyond the ability to measure changes in a single neurotransmitter system after a specific pharmacologic challenge. As it is well known that neurotransmitter systems do not work in isolation, we have extended these studies to include an examination ofthe utility ofPET for noninvasively assessing neurotransmitter interactions in the human brain.Neurotransmitter interactions have been demonstrated anatomically, physiologically, and beha...