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 microM partially prevented the dopamine (DA)-depleting effect induced by further incubation with 25 microM MPP+ for 60 min in Mg(2+)-free conditions. Incubation of slices with 15 microM 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 microM. 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.
Venero
J L
JL
Departmento de Bioquimica, Bromatologia y Toxicología, Facultad de Farmacia, Universidad de Sevilla, Spain.
Santiago
M
M
Machado
A
A
Cano
J
J
D015655:1-Methyl-4-phenylpyridinium / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
D018696:Neuroprotective Agents; D016291:Dizocilpine Maleate; D015655:1-Methyl-4-phenylpyridinium; D004298:Dopamine