Oxidation of dopamine by monoamine oxidase results in the endogenous metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL). The toxicity of DOPAL for dopaminergic neurons was investigated using rat neostriatal synaptosomes, PC-12 cells and cultures of fetal rat dissociated mesencephalon. The Na(+)-dependent uptake of [3H]DOPAL in synaptosomes was inhibited by mazindol. DOPAL selectively inhibited dopamine uptake but not [14C]GABA uptake, induced membrane damage and liberation of dopamine into the medium. Incubation of PC-12 cells with 6.5 microM of DOPAL for 24 h caused degeneration of the neuritic process, and the number of viable cells were reduced by 25% of control. There were practically no surviving cells after 24 h of incubation with 33 microM of DOPAL. After 8 h of treatment with 33 microM of DOPAL, dopamine and 3,4-dihydroxyphenylacetic acid content in the cells were reduced by 38% and 53% of control. DOPAL-induced cell damage released lactic acid dehydrogenase into the incubation media. This toxic effect of DOPAL was time- and concentration-dependent. In mesencephalic cultures, after exposure to 33 microM of DOPAL, the surviving TH+ cells showed rounded cell body, and fibre network was highly reduced. These results indicate DOPAL is a neurotoxin and may be involved in the degeneration of dopaminergic neurons.