The non-competitive NMDA-receptor antagonist MK-801 prevents the massive release of glutamate and aspartate from rat striatum induced by 1-methyl-4-phenylpyridinium (MPP +)

Abstract

The concentrations of dopamine (DA) and of the excitatory amino acids (EAAs) glutamate (Glu) and aspartate (Asp) were measured in dialysates from the striatum of awake rats in order to study the link between the release of DA and of EAAs induced by the infusion of 1-methyl-4-phenylpyridinium ion (MPP +). DA and EAAs were detected simultaneously by HPLC-EC. The infusion of MPP + at the concentration of 1 mM elevated DA levels in the perfusates, but did not affect EAA release. However, MPP + at 10 mM maximally stimulated Glu and Asp release to 230- and 68-fold of baseline, respectively. In this condition, pretreatment with the N- methyl- d-aspartate (NMDA) receptor antagonist MK-801 (5 mg/kg, i.p.), prevented the MPP +-induced EAA release. In contrast, MK-801 had no effect on DA release induced either by 1 or 10 mM MPP +. These results suggest that MPP +-induced DA and EAA release are independently regulated processes. In addition, the finding that MK-801 inhibits MPP +-induced EAA release suggests that EAAs may act on NMDA receptors to stimulate their own release through a positive-feedback mechanism.