The sensitivity of nigrostriatal dopamine neurons to MPP+ does not increase with age.
The purpose of this study was to determine if the enhanced striatal dopamine depletion induced by MPTP in older mice is due to increasing sensitivity of older nigrostriatal neurons to MPP+ (1-methyl-4-phenylpyridinium ion). MPP+ (the putative toxic metabolite of MPTP) was administered intracerebroventricularly (i.c.v.) to 6- to 8-week-old and 8- to 10-month-old animals. No significant differences in the dopamine-depleting effects of this compound were observed between the two age groups, suggesting that older nigrostriatal neurons are not more sensitive to MPP+. To be certain that increased sensitivity in older animals was not being masked by (1) increased removal of MPP+ from the CNS compartment or (2) enhanced degradation of MPP+, the fate of i.c.v. administered MPP+ was determined in the two age groups using 3H-labeled MPP+ and gas chromatography/mass spectrometry (GC/MS) analysis. No differences were found in the elimination of radioactivity, all of which could be accounted for as MPP+. We conclude that kinetic factors which alter the concentration of MPP+ at its target site, rather than increased sensitivity of older nigrostriatal neurons to MPP+, account for the age-related effects of systemically administered MPTP.
Irwin
I
I
Institute for Medical Research, San Jose, CA.
Ricaurte
G A
GA
DeLanney
L E
LE
Langston
J W
JW
D015655:1-Methyl-4-phenylpyridinium; D000375:Aging / Q000378:metabolism*; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011726:Pyridinium Compounds / Q000494:pharmacology*; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology
D011726:Pyridinium Compounds; D015655:1-Methyl-4-phenylpyridinium; D004298:Dopamine