MK-801 partially protects against the acute MPP(+) depleting effect on dopamine levels in rat striatal slices

We tested the ability of the non-competitive N-methyl-D-aspartate (NMDA) antagonist, dizocilpine (MK-801), to promote protection against the acute effect of 1-methyl-4-phenylpyridinium ion (MPP(+)) in rat striatal slices. Pretreatment with MK-801 at concentrations higher than 15 mu M partially prevented the dopamine(DA)-depleting effect induced by further incubation with 25 mu M MPP(+) for 60 min in Mg2+-free conditions. Incubation of slices with 15 mu M MK-801 without MPP(+) only affected the levels of 3-methoxytyramine (3-MT). The ratio of 3-MT to 3,4-dihydroxyphenylacetic acid (DOPAC), a proposed index of DA reuptake inhibition, increased + 68% of control levels, clearly suggesting an inhibitory effect of MK-801 on the high affinity DA transport system. To test this possibility, we performed a dose-response study of MK-801 on the high-affinity DA transport system in rat striatal synaptosomes. MK-801 induced a dose-dependent inhibition of DA uptake, with an IC50 of 57.0 mu M. We present evidence that the protective effect rendered by MK-801 against the acute DA-depleting effect induced by MPP(+) is not associated to NMDA receptor function, but rather to an inhibition of the high affinity DA uptake system. Copyright (C) 1996 Elsevier Science Ltd.