Schizophrenia is associated with elevated amphetamine-induced synaptic dopamine concentrations: Evidence from a novel positron emission tomography method

Proceedings of the National Academy of Sciences of the United States of America - Tập 94 Số 6 - Trang 2569-2574 - 1997
Alan Breier1, Tung‐Ping Su1, Richard C. Saunders1, Richard E. Carson1, Bhaskar Kolachana1, Andrea de Bartolomeis1, Daniel R. Weinberger1, Neil Weisenfeld1, Anil K. Malhotra1, W.C. Eckelman1, David Pickar1
1Experimental Therapeutics Branch and Clinical Brain Disorders Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892; and Clinical Center Positron-Emission Tomography Department, National Institutes of Health, Bethesda, MD 20892

Tóm tắt

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 outflow. 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 reflected 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 D 2 /D 3 positron-emission tomography radioligand [ 11 C]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 = 4), doubling the amphetamine dose produced a doubling in [ 11 C]raclopride specific binding reductions. In addition, the ratio of percent mean dopamine increase to percent mean striatal binding reduction for amphetamine (0.2 mg/kg) was 44:1, demonstrating that relatively small binding changes reflect large changes in dopamine outflow. In the clinical study, patients with schizophrenia ( n = 11) compared with healthy volunteers ( n = 12) had significantly greater amphetamine-related reductions in [ 11 C]raclopride specific binding (mean ± SEM): −22.3% (±2.7) vs. −15.5% (±1.8), P = 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 amphetamine-induced synaptic dopamine concentrations in schizophrenia.

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Proceedings of the National Academy of Sciences of the United States of America

Tập 94 Số 6

2569-2574

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