INHIBITION BY DIZOCILPINE (MK-801) OF STRIATAL DOPAMINE RELEASE INDUCED BY MPTP AND MPP(+) - POSSIBLE ACTION AT THE DOPAMINE TRANSPORTER

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 mu M) were tested in superfused rat striatal synaptosomes preloaded with [H-3]-dopamine. Both MPTP (10 mu M and higher) and MPP(+) (1 mu M and higher) evoked an immediate and concentration-dependent release of [H-3]-dopamine. The maximal effect exceeded that achievable with nicotine. For subsequent experiments, submaximal concentrations of MPTP (50 mu M) and MPP(+) (10 mu M) were tested. 3 MK-801 (0.1-100 mu M) inhibited responses to MPTP (50 mu M) and MPP(+) (10 mu M) 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 mu M) and kynurenic acid (300 mu M). In this assay, N-methyl-D-aspartate (even in the absence of Mg2+ and with added glycine and strychnine) did not evoke [H-3]-dopamine release. 4 In crude membrane preparations of rat cerebral cortex, MPTP and MPP(+) inhibited high-affinity [H-3]-nicotine binding to nicotinic cholinoceptors (IC50 1.8 mu M and 26 mu M, respectively). 5 [H-3]-dopamine release evoked by nicotine (1 mu M) was blocked by the nicotinic antagonists, mecamylamine and chlorisondamine, and by MK-801 (all at 100 mu M); 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 mu M), the selective dopamine uptake inhibitor, nomifensine, completely blocked [H-3]-dopamine release evoked by amphetamine 0.3 mu M and MPP(+) 10 mu M, attenuated responses to MPTP 50 mu M and did not affect responses to 12 mM K+. MK-801 100 mu M evinced a similar profile but was less effective. 7 MK-801 inhibited [H-3]-dopamine uptake in striatal synaptosomes with an IC50 of 115 mu M. 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.