MK-801 temporarily prevents MPTP-induced acute dopamine depletion and MPP+ elimination in the mouse striatum.
The acute effects of the noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist 5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine [(+)-MK-801] on 1) dopamine depletion caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP); 2) the biodisposition of the MPTP metabolite 1-methyl-4-phenylpyridinium (MPP+) and 3) MPTP-induced ATP loss were investigated in the mouse striatum. Systemic administration of a single dose of MPTP (40 mg/kg s.c.) to C57BL/6 mice rapidly decreased striatal dopamine levels to 30% of control values. A single injection of (+)-MK-801 (1 mg/kg i.p.) 30 min before MPTP treatment completely prevented striatal dopamine depletion at 1.5 and 4 hr. The competitive NMDA antagonist CGS-19755 also completely protected against MPTP-induced acute dopamine depletion at 4 hr in the striatum. The action of (+)-MK-801 was only temporary, however, because at 12 hr, the degree of dopamine depletion was not different between the (+)-MK-801/MPTP-treated animals and mice treated with MPTP alone. Repeated injections of (+)-MK-801 at 4-hr intervals did not provide any additional protective effect. (+)-MK-801 administration before MPTP exposure did not appear to affect the production of MPP+, but it did significantly delay its elimination from the striatum. There was a significant correlation between levels of dopamine and MPP+ both in the presence and in the absence of (+)-MK-801. Finally, MPTP-induced striatal ATP loss was not affected by pretreatment with (+)-MK-801.(ABSTRACT TRUNCATED AT 250 WORDS)
Chan
P
P
Parkinson's Institute, Sunnyvale, California.
Langston
J W
JW
Di Monte
D A
DA
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology*; D015655:1-Methyl-4-phenylpyridinium / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism*; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D004298:Dopamine / Q000172:deficiency / Q000378:metabolism*; D004347:Drug Interactions; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors; D010875:Pipecolic Acids / Q000494:pharmacology; D013997:Time Factors
D010875:Pipecolic Acids; C053672:selfotel; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D000255:Adenosine Triphosphate; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D015655:1-Methyl-4-phenylpyridinium; D004298:Dopamine