The effects of 1-methyl-4-phenylpyridinium ion (MPP+) on the efflux and metabolism of endogenous dopamine in rat striatal slices

Article abstract of DOI:10.1111/j.2042-7158.1988.tb05321.x

1-Methyl-4-phenylpyridinium ion (MPP⁺) was shown to accumulate concentration-dependently in slices from rat striatum. At 10 μM MPP⁺, the tissue concentration was found to be 118 ± 9 μM following 75 min of incubation. The accumulation of MPP⁺ was reduced in the presence of 10 μM of the selective dopamine uptake inhibitor GBR 12909 (-50%) or by destruction of the dopaminergic terminals by complete hemisection of the forebrain 4 days before the experiments (-75%). Accumulation of MPP⁺ in the catecholamine-poor occipital cortex and cerebellum was only 25% of that obtained in striatum. Reserpine pretreatment of the rats in-vivo did not modify the accumulation of MPP⁺ in the striatal slices. MPP⁺ (1-10 μM) increased the net efflux of dopamine and reduced the efflux of the dopamine metabolite DOPAC from the striatal slices. The effect on dopamine was readily diminished if MPP⁺, after a 15 min incubation, was then omitted from the medium. In contrast, the DOPAC efflux was reduced for 75 min even though MPP⁺ was present in the incubation medium only for the first 15 min. In the presence of the monoamine oxidase inhibitor, pargyline (350 μM), MPP⁺ also produced an increase in dopamine efflux. In normal medium, the presence of the dopamine uptake inhibitor GBR 12909 (10 μM), or the absence of calcium, failed to modify the MPP⁺-induced increase in dopamine efflux. MPP⁺ also increased dopamine efflux from slices from reserpinized rats. In normal medium, MPP⁺ (10 μM) was much more effective than GBR 12909 (10 μM) in increasing dopamine efflux, whereas in the presence of pargyline both drugs were equally effective. It is suggested that, in rat striatal slices, MPP⁺ is selectively accumulated within the dopaminergic nerve terminals by means of a carrier mediated transport, sensitive to GBR 12909. It is concluded that MPP⁺ increases dopamine efflux largely by inhibiting monoamine oxidase and by inhibiting dopamine uptake. These data are discussed in relation to the previously observed action of MPTP on dopamine metabolism in mouse brain in-vivo.