MPP+-induced increases in extracellular potassium ion activity in rat striatal slices suggest that consequences of MPP+ neurotoxicity are spread beyond dopaminergic terminals.

MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) produces symptoms similar to idiopathic Parkinson's disease in primates. A metabolite of MPTP, MPP+ (1-methyl-4-phenylpyridinium), is actively accumulated by dopaminergic (DA) terminals and selectively destroys nigrostriatal DA neurons. The mechanism of this effect remains unknown but reports that MPP+ inhibits electron transport in isolated mitochondria and increases oxidation of cytochrome b in striatal slices suggest that depression of ATP production is involved. To relate metabolic effects of MPP+ with tissue electrophysiology, extracellular potassium ion activity [K+]o was measured by microelectrodes simultaneous to optical monitoring of reduction/oxidation (redox) activity of cytochrome b during superfusion of MPP+ onto rat striatal and hippocampal slices. MPP+ increased oxidation of cytochrome b and increased [K+]o in slices of striatum. These increases were greater than expected from a selective effect of MPP+ on DA terminals which likely comprise no more than 3% of the total striatal mass. These effects of MPP+ were slowed by a dopamine uptake inhibitor (mazindol) and did not occur in hippocampal slices. These findings indicate that MPP+ influences ion transport as well as metabolic activity and that these actions require the presence of functioning DA terminals. However, the large amplitudes of the MPP+-induced changes suggest that consequences of MPP+-neurotoxicity are not ultimately confined to DA terminals. Two hypothesis are proposed: that energy failure in DA terminals results in leakage of neurotoxic substances or metabolites altering membrane conductance properties of adjacent cells and thereby placing additional demand upon ion transport pumps and mitochondrial oxidative phosphorylation; or that there is secondary uptake of MPP+ leading to mitochondrial inhibition in cells neighboring DA terminals.