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Prevention of the Nigrostriatal Toxicity of 1‐Methyl‐4‐Phenyl‐1,2,3,6‐Tetrahydropyridine by Inhibitors of 3,4‐Dihydroxyphenylethylamine Transport
Author(s) -
Mayer Roberta A.,
Kindt M. Victoria,
Heikkila Richard E.
Publication year - 1986
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.1986.tb00722.x
Subject(s) - nomifensine , mptp , chemistry , mazindol , in vivo , pharmacology , dopaminergic , dopamine , toxicity , endocrinology , biology , microbiology and biotechnology , organic chemistry
The 3,4‐dihydroxyphenylethylamine (DA, dopamine) uptake inhibitors GBR 13,069, amfonelic acid, WIN‐35,065‐2, WIN‐35,428, nomifensine, mazindol, cocaine, M c N‐5908, M c N‐5847, and M c N‐5292 were effective in preventing [ 3 H]DA and [ 3 H]l‐methyl‐4‐phenylpyridinium (MPP + ) uptake in rat and mouse neostriatal tissue slices. These DA uptake inhibitors also were effective in attenuating the MPP + ‐induced release of [ 3 H]DA in vitro. 1‐Methyl‐4‐phenyl‐l,2,3,6‐tetrahydropyridine (MPTP) administration to mice (6 ± 25 mg/kg i.p.) resulted in a large (70–80%) decrement in neostriatal DA. WIN‐35,428 (5 mg/kg), GBR 13,069 (10 mg/kg), M c N‐5292 (5 mg/kg), M c N‐5908 (2 mg/ kg), and amfonelic acid (2 mg/kg), when administered intraperitoneally 30 min prior to each MPTP injection, fully protected against MPTP‐induced neostriatal damage. Other DA uptake inhibitors showed partial protection in vivo at the doses selected. Desmethylimipramine did not prevent [ 3 H]MPP + uptake or MPP + ‐induced release of [ 3 H]DA in vitro, and did not protect against MPTP neurotoxicity in vivo. These results support the hypothesis put forth previously by others that the active uptake of MPP + by dopaminergic neurons is necessary for toxicity.