Isoquinoline derivatives structurally related to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine or 1-methyl-4-phenylpyridinium (MPP+) are inhibitors of mitochondrial function and substrates for the dopamine re-uptake system, but their neuronal toxicity is unclear. In this study, the effects of exposing PC12 cells to four isoquinoline derivatives (isoquinoline, N-methylisoquinolinium, 6,7-methylenedioxyisoquinoline and 1,2,3,4-tetrahydroisoquinoline) and MPP+ (100-1000 microM) were examined. All compounds exhibited concentration-dependent toxicity as determined by lactate dehydrogenase release, but none of the isoquinoline derivatives were more toxic than MPP+. Cytotoxicity of these compounds appears to be directly correlated with their substrate affinity for the dopamine reuptake system, but not mitochondrial inhibition. Thus, the low toxicity of isoquinoline derivatives towards PC12 cells suggests that high concentrations of or prolonged exposure to these compounds may be necessary to cause the neurodegenerative changes related to Parkinson's disease.