1. ¹Department of Psychiatry, Columbia University, New York, NY, USA
2. ²Department of Radiology, Columbia University, New York, NY, USA

Correspondence: Dr BNM van Berckel, Department of Nuclear Medicine & PET research, VU University Medical Center, De Boelelaan 1117, Amsterdam 1007 MB, The Netherlands. Tel: ++31204444214; Fax: ++31204444329; E-mail: B.Berckel@VUmc.nl

Received 20 January 2005; Revised 20 July 2005; Accepted 5 August 2005; Published online 21 September 2005.

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 287% under control conditions. Following LY354740 pretreatment, amphetamine-induced reduction in [¹¹C]raclopride V₃" was significantly enhanced (357%, 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.