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Attenuation by dopamine uptake blockers of the inhibitory effects of 1- methyl-4-phenyl-1,2,3,6-tetrahydropyridine and some of its analogs on NADH-linked metabolism in mouse neostriatal slices

S Ofori, RE Heikkila and WJ Nicklas

Department of Neurology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway.

In previous studies it was shown that the pyridinium species formed by the monoamine-oxidase-catalyzed conversion of 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP) and 1-methyl-4-(2'methylphenyl)-1,2,3,6- tetrahydropyridine (2'Me-MPTP) inhibited mitochondrial electron transport at Complex I. In addition, these substances, when incubated with mouse neostriatal slices, caused an increased lactate accumulation. However, it was not clear whether this inhibition could occur within dopamine nerve terminals. In the present study we investigated if dopamine uptake blockers, shown previously to protect against tetrahydropyridine-induced dopaminergic neurotoxicity, would attenuate MPTP- and 2'Me-MPTP-promoted lactate formation in neostriatal slices. 2'Me-MPTP-induced lactate accumulation in neostriatal slices from mice or rats with a lesion of the nigrostriatal pathway was also studied. The dopamine uptake blocker, Win 35,428 [8- azabicyclo[3.2.1]octane-2-carboxylic acid, 3-(4-fluorophenyl)-8-methyl- , methylester [1R-(exo, exol)]), attenuated the increased lactate formation caused by MPTP and 2'Me-MPTP. At low concentrations of 2'Me- MPTP (5 microM), the increased lactate production was inhibited completely by Win 35,428. These latter data suggest that at low concentrations of 2'Me-MPTP, the increased lactate accumulation was associated primarily with dopaminergic nerve terminals. Two other dopamine uptake inhibitors, McN 5908 [trans-4-(1,2,3,5,6,10b- hexahydropyrrolo[2,1-alpha]isoquinolin+ ++-6-yl) benzenamine hydrobromide methanolate (4:4:1)] and mazindol [5-(4-chlorophenyl)-2,5- dihydro-3H-imidazo- [2,1-alpha]isoindol-5-ol], also attenuated tetrahydropyridine-induced lactate formation. At concentrations selective for their respective uptake systems, norepinephrine- and serotonin-uptake inhibitors did not attenuate 2'Me-MPTP-induced lactate accumulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Volume 251, Issue 1, pp. 258-266, 10/01/1989
Copyright © 1989 by American Society for Pharmacology and Experimental Therapeutics






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