Neurochemical and toxic effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and 1-methyl-4-phenylpyridine to rat serotonin neurons in dissociated cell cultures.
Dissociated cell cultures from the pontine area of embryonic rat brain were used to study the sensitivity of serotonin (5-hydroxy-tryptamine (5-HT)) neurons to the neurotoxins 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 1-methyl-4-phenylpyridine (MPP+). Treatment with MPTP (up to 100 microM) for 7 days did not cause degeneration of 5-HT neurons. A 50% inhibition of [3H]5-HT uptake caused by 100 microM MPTP was a direct effect on the 5-HT uptake carrier, reversed by washing for 7 days. Incubation of cultures with MPTP increased the intraneuronal levels of 5-HT and reduced the levels of 5-hydroxyindoleacetic acid, suggesting a reduction in 5-HT metabolism. MPTP reduced monoamine oxidase activity in the cultures, which probably led to the reduction in 5-HT metabolism. Exposure to MPP+ (0.5-10 microM) for 4 to 7 days decreased [3H]5-HT uptake and induced loss of neurons stained with antibodies against 5-HT. Comparison between 5-HT and dopamine (DA) neurons indicated a differential sensitivity to MPP+ toxicity with DA neurons being more susceptible. Analysis of the competition of MPP+ with the natural substrates for uptake sites of 5-HT and DA neurons demonstrated higher affinity of MPP+ for DA compared to 5-HT neurons. The lower affinity of MPP+ for 5-HT neurons could be responsible for the accumulation of lower MPP+ levels observed in pontine cultures and explain the resistance of 5-HT neurons to this toxin.
Friedman
L K
LK
Department of Neurology, Mount Sinai School of Medicine, New York, New York.
Mytilineou
C
C
D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity*; D000818:Animals; D002478:Cells, Cultured; D020267:MPTP Poisoning; D008636:Mesencephalon / Q000196:embryology / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D012701:Serotonin / Q000378:metabolism* / Q000493:pharmacokinetics; D014316:Tritium
D014316:Tritium; D012701:Serotonin; D015655:1-Methyl-4-phenylpyridinium