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

Background: Recent brain imaging studies have indicated that schizophrenia is associated with increased amphetamine-induced dopamine release in the st riatum. It has long been hypothesized that dysregulation of subcortical dop amine systems in schizophrenia might result from a failure of the prefronta l cortex (PFC) to adequately control subcortical dopaminergic neurons is re gulated, in part, by glutamatergic projections from the PFC acting via glut amatergic N-methyl- D-aspartate (NMDA) receptors. The goal of this study wa s to test the hypothesis that a pharmacologically induced disruption of NMD A transmission leads to an increase in amphetamine-induced dopamine release in humans. Methods: In eight healthy volunteers, we compared striatal amphetamine-indu ced (0.25 mg/kg) dopamine release under control conditions and under sustai ned disruption of NMDA transmission induced by infusion of the noncompetiti ve NMDA antagonist ketamine (0.2 mg/kg intravenous bolus followed by 0.4 mg /kg/hour intravenous infusion for 4 hours). Amphetamine-induced dopamine re lease was determined with single photon emission computed tomography, as th e reduction in the binding potential (BP) of the radiolabeled D-2 receptor antagonist [I-123]IBZM. Results: Ketamine significantly enhanced the amphetamine-induced decrease i n [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 b y ketamine (greater than two-fold) was comparable in magnitude to the exagg erated response seen in patients with schizophrenia. These data are consist ent with the hypothesis that the alteration of dopamine release revealed by amphetamine challenge in schizophrenia results from a disruption of glutam atergic neuronal systems regulating dopaminergic cell activity. (C) 2000 So ciety of Biological Psychiatry.