Schizophrenia is associated with elevated amphetamine-induced synaptic dopamine concentrations: Evidence from a novel positron emission tomography method (racloprideybrain imagingystriatumyin vivo microdialysisypsychostimulants)

A major line of evidence that supports the hypothesis of dopamine overactivity in schizophrenia is the psychomimetic potential of agents such as amphetamine that stimulate dopamine outf low. A novel brain imaging method provides an indirect measure of in vivo synaptic dopamine concentration by quantifying the change in dopamine receptor radiotracer binding produced by agents that alter dopamine release but do not themselves bind to dopamine receptors. The purpose of this investigation is (i) to determine the sensitivity (i.e., amount of dopamine ref lected in radiotracer binding changes) of this method by examining the relationship between amphetamine-induced changes in simultaneously derived striatal extracellular dopamine levels with in vivo microdialysis and striatal binding levels with the dopamine D2yD3 positron-emission tomography radioligand [11C]raclopride in nonhuman primates, and (ii) to test the hypothesis of elevated amphetamine-induced synaptic dopamine levels in schizophrenia. In the nonhuman primate study (n 5 4), doubling the amphetamine dose produced a doubling in [11C]raclopride specific binding reductions. In addition, the ratio of percent mean dopamine increase to percent mean striatal binding reduction for amphetamine (0.2 mgykg) was 44:1, demonstrating that relatively small binding changes ref lect large changes in dopamine outf low. In the clinical study, patients with schizophrenia (n 5 11) compared with healthy volunteers (n 5 12) had significantly greater amphetamine-related reductions in [11C]raclopride specific binding (mean 6 SEM): 222.3% (62.7) vs. 215.5% (61.8), P 5 0.04, respectively. Inferences from the preclinical study suggest that the patients’ elevation in synaptic dopamine concentrations was substantially greater than controls. These data provide direct evidence for the hypothesis of elevated amphetamineinduced synaptic dopamine concentrations in schizophrenia. Dopamine overactivity has been the predominant pathophysiologic hypothesis of schizophrenia for the past two decades (1–3). A major line of evidence used to support dopamine’s involvement in schizophrenia is the psychotomimetic effects of agents that stimulate dopamine outflow, such as the psychostimulant amphetamine. Psychostimulants can produce a paranoid psychosis in healthy individuals (4) and cause symptomatic worsening in approximately one-third of patients with schizophrenia (5). These data support the hypothesis that at least a subgroup of schizophrenia is associated with increased synaptic dopamine concentrations. This hypothesis, however, could not be directly tested because, prior to the introduction of the experimental paradigm described here (6, 7), there has been no method to quantify in vivo synaptic dopamine levels in clinical populations. A relatively new application of in vivo brain imaging provides an estimate of changes in synaptic dopamine concentrations. This approach determines the change in striatal radiotracer binding levels following administration of pharmacologic agents that affect dopamine outflow but do not themselves bind to dopamine receptors (6, 7). The change in striatal radiotracer binding levels is attributable to changes in synaptic dopamine that competes with the radiotracer for receptor binding. In a recently published report using the D2 ligand 123I-IBZM (iodobenzamide) and single photon emission tomography (SPECT), Laruelle et al. (8) found that schizophrenic patients compared with controls had significantly greater reductions in amphetamine-induced striatal radiotracer binding ratios, which supports enhanced dopamine outflow. Although this method has undergone extensive validation (6, 7, 9–12), there has yet to be a direct comparison between simultaneous changes in extracellular dopamine levels and changes in radiotracer binding levels in mammalian brain. These data would provide an important measure of sensitivity (i.e., amount of dopamine reflected in radiotracer binding changes), which would allow inferences about the magnitude of dopamine responses in clinical populations. In this paper, we report results from two experiments. The first examined the relationship between changes in extracellular striatal dopamine and striatal dopamine receptor radiotracer binding in nonhuman primates. The effects of two doses of amphetamine (0.2 and 0.4 mgykg) on extracellular striatal dopamine levels derived with in vivo microdialysis and striatal dopamine receptor radiotracer binding levels determined with positron-emission tomography (PET) were assessed simultaneously. Our brain imaging approach involved a constant infusion of the PET radiotracer [11C]raclopride (13, 14) until tracer equilibrium was reached. [11C]raclopride has high selectivity and low affinity for dopamine D2yD3 receptors and avidly competes with synaptic dopamine for receptor occupancy (15–19). Then, amphetamine was administered which increases synaptic dopamine which in turn displaces [11C]raclopride striatal binding. In the second experiment, we employed this brain imaging method to test the hypothesis that schizophrenic patients, in comparison to healthy controls, have greater amphetamine-induced striatal synaptic dopamine concentrations. Data from the first experiment were used to draw inferences about the magnitude of dopamine response differences between controls and patients. The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked ‘‘advertisement’’ in accordance with 18 U.S.C. §1734 solely to indicate this fact. 0027-8424y97y942569-6$0.00y0 PNAS is available online at http:yywww.pnas.org. Abbreviations: SPECT, single photon emission tomography; PET, positron-emission tomography; BPRS, Brief Psychiatric Rating Scale; CSF, cerebrospinal f luid; 123I-IBZM, iodobenzamide. †To whom reprint requests should be addressed. e-mail: [email protected].