Neurotoxic damage to the nigrostriatal system in rats following intranigral administration of MPDP+ and MPP+.
Unilateral intranigral administration of the oxidative metabolites of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 1-methyl-4-phenyl-dihydropyridine (MPDP+) or 1-methyl-4-phenylpyridine (MPP+) produced dose-dependently a depletion of dopamine in the ipsilateral striatum of rats two weeks following treatment. d-Amphetamine and apomorphine induced circling toward the lesioned side in these unilaterally treated animals. No contralateral circling behavior was observed after challenging with apomorphine. This dopamine lesioning effect of MPP+ was not blocked by pretreatment of animals with a dopamine uptake blocker, GBR 12909. Furthermore, MPP+ increased the 45Ca accumulation into cells at the site of injection and produced "nonspecific" cell membrane and/or cytotoxic damage seen by histological procedures. These results indicate that MPDP+ and MPP+ produced localized cytotoxic damage to nigrostriatal neurons, caused a decrease in striatal dopamine, and disrupted the nigrostriatal system's functioning following intranigral administration to rats. It is postulated that the cationic surfactant properties of MPDP+ and MPP+ might contribute to its neurotoxic effects.
Sun
C J
CJ
Food and Drug Administration, Bethesda, Maryland.
Johannessen
J N
JN
Gessner
W
W
Namura
I
I
Singhaniyom
W
W
Brossi
A
A
Chiueh
C C
CC
D015655:1-Methyl-4-phenylpyridinium; D000662:Amphetamines / Q000494:pharmacology; D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D004298:Dopamine / Q000378:metabolism; D008297:Male; D010879:Piperazines / Q000494:pharmacology; D011726:Pyridinium Compounds / Q000633:toxicity*; D051381:Rats; D011919:Rats, Inbred Strains; D013239:Stereotyped Behavior / Q000187:drug effects*; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology
D000662:Amphetamines; D010879:Piperazines; D011726:Pyridinium Compounds; C043425:vanoxerine; C044755:1-methyl-4-phenyl-2,3-dihydropyridinium; D001058:Apomorphine; D015655:1-Methyl-4-phenylpyridinium; D004298:Dopamine