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

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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 μm) were tested in superfused rat striatal synaptosomes preloaded with [3H]-dopamine. Both MPTP (10 μm and higher) and MPP+ (1 μm 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 μm) and MPP+ (10 μm) were tested. 3 MK-801 (0.1–100 μm) inhibited responses to MPTP (50 μm) and MPP+ (10 μm) 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 μm) and kynurenic acid (300 μm). In this assay, N-methyl-d-aspartate (even in the absence of Mg2+ and with added glycine and strychnine) did not evoke [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 μm and 26 μm, respectively). 5 [3H]-dopamine release evoked by nicotine (1 μm) was blocked by the nicotinic antagonists, mecamylamine and chlorisondamine, and by MK-801 (all at 100 μm); K+-evoked release was not affected. Release evoked by MPTP and MPP+ was significantly attenuated by MK-801 but not by mecamylamine or chlorisondamine. 6 At a high concentration (10 μm), the selective dopamine uptake inhibitor, nomifensine, completely blocked [3H]-dopamine release evoked by amphetamine 0.3 μm and MPP+ 10 μm, attenuated responses to MPTP 50 μm and did not affect responses to 12 mm K+. MK-801 100 μm evinced a similar profile but was less effective. 7 MK-801 inhibited [3H]-dopamine uptake in striatal synaptosomes with an IC50 of 115 μm. 8 It is concluded that high concentrations of MK-801 inhibit the acute dopamine release evoked by MPTP and MPP+ in synaptosomes. This antagonism may occur, at least in part, through inhibition of the cell membrane dopamine transporter. MPTP and MPP+ also appear to interact with brain nicotinic cholinoceptors but the functional consequences of this interaction are not yet clear.

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