The discovery that 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes parkinsonism in humans and other primates by selective destruction of substantia nigra dopaminergic neurons has spurred research to define the mechanisms underlying its toxicity. To avoid variables such as tissue distribution, extracerebral metabolism and blood-brain barrier permeability, the authors studied the neurochemical and morphologic effects of direct perinigral infusions of various concentrations of MPTP, its metabolites and analogs in the rat. MPTP, in the highest dose used, 1000 nmol, decreased dopamine and its metabolites in ipsilateral striatum by approximately 75%, whereas 3,3-dimethyl-MPTP (which is oxidized to 1,3,3-trimethyl-4-phenyl-2,3-dihydropyridinium cation but not to a pyridinium species) had no effect. The 2,2 and 3,3-dimethyl analogs of 1-methyl-4-phenyl-2,3-dihydropyridinium cation which also cannot be oxidized to pyridinium species, reduced striatal dopamine, suggesting that these compounds are toxic in their own right. 1-Methyl-4-phenylpyridinium cation (MPP+) and its 4-(4-fluorophenyl) and 4-(2-pyridyl) analogs that have less negative reduction potentials than MPP+, were most potent in decreasing striatal dopamine and metabolites, with MPP+ being 5 to 10 times more effective than its two analogs and approximately 100 times more potent than MPTP and the two dimethyl 1-methyl-4-phenyl-2,3-dihydropyridinium cation analogs. These findings suggest that MPP+ is ultimately responsible for MPTP toxicity but does not act via oxidant stress mechanisms.(ABSTRACT TRUNCATED AT 250 WORDS)