Effects of 1-Methyl-4-Phenyl-1,2,5,6-Tetrahydropyridine and Related Compounds on the Uptake of [3H]3,4-Dihydroxyphenylethylamine and [3H]5-Hydroxytryptamine in Neostriatal Synaptosomal Preparations |
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Authors: | Richard E Heikkila Stephen K Youngster Lawrence Manzino Felicitas S Cabbat Roger C Duvoisin |
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Institution: | Department of Neurology, University of Medicine and Dentistry of New Jersey-Rutgers Medical School, Piscataway, New Jersey, U.S.A. |
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Abstract: | 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 3H]3,4-dihydroxyphenylethylamine-(3H]DA), 3H]5-hydroxytryptamine (3H]5-HT), and 3H]gamma-aminobutyric acid ( 3H]GABA) in mouse neostriatal synaptosomal preparations. MPTP was a very potent inhibitor of 3H]5-HT uptake (IC50 value 0.14 microM), a moderate inhibitor of 3H]DA uptake (IC50 value 2.6 microM), and a very weak inhibitor of 3H]GABA uptake (no significant inhibition observed at 10 microM MPTP). In other experiments, MPTP caused some release of previously accumulated 3H]DA and 3H]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 3H]DA uptake (IC50 value 0.45 microM) and of 3H]5-HT uptake (IC50 value 0.78 microM) but MPP+ was a very weak inhibitor of 3H]GABA uptake. These data may have relevance to the neurotoxic actions of MPTP. |
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Keywords: | 1-Methyl-4-phenyl-1 2 5 6-tetrahydropyridine [3H]3 4-Dihydroxyphenylethylamine 1 - Methyl - 4 - phenyl-pyridinium iodide |
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