Modulation of amphetamine-induced dopamine release by group II metabotropic glutamate receptor agonist LY354740 in non-human primates studied with positron emission tomography

Abstract

Pharmacological evidence suggests that schizophrenia is associated with increased stimulation of dopamine (DA) D2 receptors. Recently, several groups have demonstrated that amphetamine-induced DA release is increased in schizophrenia, providing direct evidence for dysregulation of DA systems in this condition. In healthy volunteers, pretreatment with the noncompetitive N-methyl-D-aspartate (NMDA) antagonist ketamine increases amphetamine-induced DA release to levels similar to those observed in patients with schizophrenia. Therefore, the dysregulation of DA function observed in schizophrenia might be secondary to NMDA hypofunction. In this study, the regulation of this response by glutamate (GLU) transmission was further characterized by using a metabotropic glutamate (mGlu) receptor group II agonist to inhibit GLU transmission. The amphetamine- (0.5 mg/kg intravenously (i.v.)) induced decrease in [11C]raclopride equilibrium-specific binding (V3″) was measured under control conditions and following pretreatment with the mGlu2/3 receptor agonist LY354740 (20 mg/kg i.v.) in four baboons. Amphetamine reduced [11C]raclopride V3″ by 28 ± 7% under control conditions. Following LY354740 pretreatment, amphetamine-induced reduction in [11C]raclopride V3″ was significantly enhanced (35 ± 7%, p = 0.002). The enhancement of the amphetamine-induced reduction in [11C]raclopride V3″ by LY354740 was not a simple additive effect, as LY354740 alone did not reduce [11C]raclopride V3″. In conclusion, the results of this study further document the involvement of GLU transmission in regulating the effect of amphetamine-induced DA release, and provide additional support to the hypothesis that the dysregulation of DA function revealed by the amphetamine challenge in schizophrenia might stem from a deficit in GLU transmission. © 2006 Nature Publishing Group All rights reserved.