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

Abstract

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 D2/D3 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 = 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 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 [11C]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.

Figures

Figure 1

The effects of amphetamine (0.2 mg/kg) on [11C]raclopride binding in a patient with schizophrenia. Amphetamine was injected at 50 min. (Upper) “Sum” images of five [11C]raclopride PET scans obtained before (Left) and after (Right) amphetamine injection. (Lower) Time-activated curves obtained in the striatum (green) and cerebellum (blue) with a bolus/constant infusion of [11C]raclopride. This patient had a −20.6% reduction in pre- vs. post-[11C]raclopride specific binding (striatum/cerebellum−1).

Figure 2

The effects of amphetamine (0.2 mg/kg) on striatal [11C]raclopride specific binding in normal controls (n = 12) and patients with schizophrenia (n = 11). The data are presented as [11C]raclopride specific binding ratios (striatum/cerebellum−1).

Figure 3

A comparison between amphetamine (0.2 mg/kg)-induced changes in [11C]raclopride specific binding in normal controls (n = 12) and patients with schizophrenia (n = 11). Data are presented as percent change from baseline in striatal binding ratios (striatum/cerebellum − 1).

Figure 4

The relationship between amphetamine (0.2 mg/kg)-induced changes in percent [11C]raclopride specific binding and behavioral effects in schizophrenia patients (n = 11). Behavioral effects were assessed pre- and postamphetamine administration using the total score of BPRS.