Effect of MPTP and its pyridinium metabolites on monoamine uptake and on central catecholamine neurons in mice.

The effect of MPTP and its pyridinium metabolites MPDP+ and MPP+ on the in vitro [3H]monoamine uptake in synaptosomal preparations from mouse striatum and cerebral cortex was investigated. All compounds inhibited [3H]monoamine uptake in a dose-dependent manner in both regions analysed. MPP+ had the highest affinity to dopamine and noradrenaline uptake sites, while MPTP had the highest affinity to serotonin uptake sites. The results indicate that the affinity of MPP+ to different monoamine uptake sites appears to be better correlated to MPTP neurotoxicity as expressed in vivo than MPTP and MPDP+. Intracerebral injection of MPP+ into substantia nigra produced an almost complete disappearance of dopamine in striatum and noradrenaline in cerebral cortex, while injection of MPTP or MPDP+ had no or only moderate catecholamine-depleting effects. The MPP+-induced catecholamine depletion could be partially reversed by pretreatment with the catecholamine uptake blocker nomifensine. Histological analysis disclosed that MPP+ was a potent generally cytotoxic agent, while MPDP+ less and MPTP least so. The present results are compatible with the view that an interaction with the catecholamine uptake mechanism, probably through an uptake and accumulation of extraneuronally formed MPP+, is most likely the explanation for neuron-specific neurotoxic action on catecholamine neurons following MPTP administration.