SCHIZOPHRENIA IS ASSOCIATED WITH ELEVATED AMPHETAMINE-INDUCED SYNAPTIC DOPAMINE CONCENTRATIONS - EVIDENCE FROM A NOVEL POSITRON EMISSION TOMOGRAPHY METHOD

A major line of evidence that supports the hypothesis of dopamine over activity in schizophrenia is the psychomimetic potential of agents suc h as amphetamine that stimulate dopamine outflow, A novel brain imagin g method provides an indirect measure of in vivo synaptic dopamine con centration by quantifying the change in dopamine receptor radiotracer binding produced by agents that alter dopamine release but do not them selves bind to dopamine receptors, The purpose of this investigation i s (i) to determine the sensitivity (i.e., amount of dopamine reflected in radiotracer binding changes) of this method by examining the relat ionship between amphetamine-induced changes in simultaneously derived striatal extracellular dopamine levels with in vivo microdialysis and striatal binding levels with the dopamine D-2/D-3 positron-emission to mography radioligand [C-11]raclopride in nonhuman primates, and (ii) t o test the hypothesis of elevated amphetamine-induced synaptic dopamin e levels in schizophrenia, In the nonhuman primate study (n = 4), doub ling the amphetamine dose produced a doubling in [C-11] raclopride spe cific binding reductions, In addition, the ratio of percent mean dopam ine increase to percent mean striatal binding reduction for amphetamin e (0.2 mg/kg) was 44:1, demonstrating that relatively small binding ch anges reflect large changes in dopamine outflow, In the clinical study , patients with schizophrenia (n = 11) compared with healthy volunteer s (n = 12) had significantly greater amphetamine-related reductions in [C-11]raclopride specific binding (mean +/- SEM): -22.3% (+/- 2.7) vs , -15.5% (+/- 1.8), P = 0.04, respectively, Inferences from the precli nical study suggest that the patients' elevation in synaptic dopamine concentrations was substantially greater than controls, These data pro vide direct evidence for the hypothesis of elevated amphetamine-induce d synaptic dopamine concentrations in schizophrenia.