Neurochemical investigations in vitro with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in preparations of rat brain

Abstract

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in concentrations ranging from 10−8 M to 10−6 M induced a decrease, and at 10−5 M an increase of both basal and electrically evoked tritium outflow from [3H]dopamine-pre-labeled rat striatal slices. These effects of MPTP were almost abolished in the presence of nomifensine. Chromatographic separation of the released tritium compounds revealed that the decrease of tritium outflow was mostly due to a decrease in the outflow of the dopamine metabolite [3H]3,4-dihydroxyphenylacetic acid (DOPAC) and the increase of tritium outflow due to a massive release of [3H]dopamine. MPTP inhibited oxidative deamination of [3H]dopamine non-competitively in a crude mitochondrial preparation of rat brain, with an apparent Ki value of 4.5 μM. No relevant effect of MPTP on adenylate cyclase activity in homogenates and on basal and electrically evoked tritium outflow from [3H]choline-prelabeled slices of rat striatum could be detected. In contrast, MPTP facilitated both basal and electrically evoked tritium outflow from [3H]noradrenaline-prelabeled rat cerebral occipital cortex slices. Furthermore, MPTP counteracted the inhibitory effect of clonidine on evoked tritium outflow from rat cerebral occipital cortex slices. Moreover, in the presence of cocaine, the effect on basal, but not that on electrically evoked tritium outflow was attenuated. These results are compatible with the view that MPTP has no affinity to dopamine receptors but is preferentially taken up into dopaminergic nerve terminals by the nomifensine-sensitive uptake system where it reaches a concentration sufficient to inhibit intraneuronal monoamine oxidase (MAO). In contrast, the facilitatory effect of MPTP on evoked tritium outflow from [3H]noradrenaline prelabeled rat cerebral occipital cortex slices appears to result from antagonistic effects at presynaptic α-adrenoceptors. The observation that MPTP at lower concentrations (10−8 to 10−7 M) inhibits basal tritium outflow from rat cerebral occipital cortex slices suggests that this compound inhibits also intraneuronal deamination of noradrenaline by MAO in noradrenergic nerve terminals.