Modulation of amphetamine-induced striatal dopamine release by ketamine in humans: Implications for schizophrenia

Background: Recent brain imaging studies have indicated that schizophrenia is associated with increased amphetamine-induced dopamine release in the striatum. It has long been hypothesized that dysregulation of subcortical dopamine systems in schizophrenia might result from a failure of the prefrontal cortex (PFC) to adequately control subcortical dopaminergic neurons is regulated, in part, by glutamatergic projections from the PFC acting via glutamatergic N-methyl- D-aspartate (NMDA) receptors. The goal of this study was to test the hypothesis that a pharmacologically induced disruption of NMDA transmission leads to an increase in amphetamine-induced dopamine release in humans. Methods: In eight healthy volunteers, we compared striatal amphetamine-induced (0.25 mg/kg) dopamine release under control conditions and under sustained disruption of NMDA transmission induced by infusion of the noncompetitive NMDA antagonist ketamine (0.2 mg/kg intravenous bolus followed by 0.4 mg/kg/hour intravenous infusion for 4 hours). Amphetamine-induced dopamine release was determined with single photon emission computed tomography, as the reduction in the binding potential (BP) of the radiolabeled D-2 receptor antagonist [I-123]IBZM. Results: Ketamine significantly enhanced the amphetamine-induced decrease in [I-123]IBZM BP, from -5.5% +/- 3.5% under control conditions to -12.8% +/- 8.8% under ketamine pretreatment (repeated-measures analysis of variance, p = .023). Conclusions: The increase in amphetamine-induced dopamine release induced by ketamine (greater than two-fold) was comparable in magnitude to the exaggerated response seen in patients with schizophrenia. These data are consistent with the hypothesis that the alteration of dopamine release revealed by amphetamine challenge in schizophrenia results from a disruption of glutamatergic neuronal systems regulating dopaminergic cell activity. (C) 2000 Society of Biological Psychiatry.