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 (NMD A) antagonist, dizocilpine (MK-801), to promote protection against the acute effect of 1-methyl-4-phenylpyridinium ion (MPP(+)) in rat stria tal 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 conditi ons. Incubation of slices with 15 mu M MK-801 without MPP(+) only affe cted the levels of 3-methoxytyramine (3-MT). The ratio of 3-MT to 3,4- dihydroxyphenylacetic acid (DOPAC), a proposed index of DA reuptake in hibition, increased + 68% of control levels, clearly suggesting an inh ibitory 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. M K-801 induced a dose-dependent inhibition of DA uptake, with an IC50 o f 57.0 mu M. We present evidence that the protective effect rendered b y MK-801 against the acute DA-depleting effect induced by MPP(+) is no t associated to NMDA receptor function, but rather to an inhibition of the high affinity DA uptake system. Copyright (C) 1996 Elsevier Scien ce Ltd.