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. 1995 Jan;114(2):315–322. doi: 10.1111/j.1476-5381.1995.tb13229.x

Inhibition by dizocilpine (MK-801) of striatal dopamine release induced by MPTP and MPP+: possible action at the dopamine transporter.

P B Clarke 1, M Reuben 1
PMCID: PMC1510234  PMID: 7881731

Abstract

1. The NMDA-type glutamate receptor antagonist, dizocilpine (MK-801) can protect against neurotoxicity associated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its principal metabolite, the 1-methyl-4-phenylpyridinium ion (MPP+). It has been suggested that these neurotoxic effects may be mediated by release of excitatory amino acids, but possible alternative mechanisms have been little investigated. 2. MPTP and MPP+ (0.1-1000 microM) were tested in superfused rat striatal synaptosomes preloaded with [3H]-dopamine. Both MPTP (10 microM and higher) and MPP+ (1 microM and higher) evoked an immediate and concentration-dependent release of [3H]-dopamine. The maximal effect exceeded that achievable with nicotine. For subsequent experiments, submaximal concentrations of MPTP (50 microM) and MPP+ (10 microM) were tested. 3. MK-801 (0.1-100 microM) inhibited responses to MPTP (50 microM) and MPP+ (10 microM) in a concentration-dependent manner. However, further tests of NMDA-type glutamate receptor involvement proved negative. Responses to MPTP or MPP+ were unaffected by the omission of Mg2+ or Ca2+ and were not reduced by the NMDA receptor antagonists, AP-7 (200 microM) and kynurenic acid (300 microM). In this assay, N-methyl-D-aspartate (even in the absence of Mg2+ and with added glycine and strychnine) did not evoked [3H]-dopamine release. 4. In crude membrane preparations of rat cerebral cortex, MPTP and MPP+ inhibited high-affinity [3H]-nicotine binding to nicotinic cholinoceptors (IC50 1.8 microM and 26 microM, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

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