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Effects of 1‐Methyl‐4‐Phenyl‐1,2,5,6‐Tetrahydropyridine and Related Compounds on the Uptake of [ 3 H]3,4‐Dihydroxyphenylethylamine and [ 3 H]5‐Hydroxytryptamine in Neostriatal Synaptosomal Preparations
Author(s) -
Heikkila Richard E.,
Youngster Stephen K.,
Manzino Lawrence,
Cabbat Felicitas S.,
Duvoisin Roger C.
Publication year - 1985
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.1471-4159.1985.tb07146.x
Subject(s) - mptp , chemistry , dopaminergic , ic50 , neurotoxin , pharmacology , stereochemistry , biochemistry , dopamine , in vitro , biology , endocrinology
1‐Methyl‐4‐phenyl‐1,2,5,6‐tetrahydropyridine (MPTP) is known to cause a destruction of the dopaminergic nigrostriatal pathway in certain animal species including mice. MPTP and some structurally related analogs were tested in vitro for their capacity to inhibit the uptake of [ 3 H]3,4‐dihydroxyphenylethylamine‐([ 3 H]DA), [ 3 H]5‐hydroxytryptamine ([ 3 H]5‐HT), and [ 3 H]γ‐aminobutyric acid ([ 3 H]GABA) in mouse neostriatal synaptosomal preparations. MPTP was a very potent inhibitor of [ 3 H]5‐HT uptake (IC 50 value 0.14 μ M ), a moderate inhibitor of [ 3 H]DA uptake (IC 50 value 2.6 μ M ), and a very weak inhibitor of [ 3 H]GABA uptake (no significant inhibition observed at 10 μ M MPTP). In other experiments, MPTP caused some release of previously accumulated [ 3 H]DA and [ 3 H]5‐HT, but in each case MPTP was considerably better as an uptake inhibitor than as a releasing agent. The 4‐electron oxidation product of MPTP, i.e., 1‐methyl‐4‐phenyl‐pyridinium iodide (MPP + ), was a very potent inhibitor of [ 3 H]DA uptake (IC 50 value 0.45 μ M ) and of [ 3 H]5‐HT uptake (IC 50 value 0.78 μ M ) but MPP + was a very weak inhibitor of [ 3 H]GABA uptake. These data may have relevance to the neurotoxic actions of MPTP.