Isoquinoline derivatives structurally related to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine or 1-methyl-4-phenylpyridinium (MPP+) are potential endogenous neurotoxins causing nigral cell death from Parkinson's disease. We now report the effects of 7 days unilateral supranigral infusion in rats of four isoquinoline derivatives, namely N-n-propylisoquinolinium (N-Pr-IQ+), N-methyl-6,7-dimethoxyisoquinolinium (N-Me-6,7-diOMe-IQ+), 6,7-dimethoxy-1-styryl-3,4-dihydroisoquinoline (6,7-diOMe-1-S-3,4-DHIQ) and 1,2,3,4-tetrahydroisoquinoline (THIQ) compared to MPP+. MPP+ (33 nmol/24h)-infused rats showed a marked reduction in motor activity and displayed ipsilateral postural asymmetry. Administration of apomorphine or (+)-amphetamine to these animals produced robust contralateral and ipsilateral rotations, respectively. In contrast, rats infused with the isoquinoline derivatives (150 nmol/24h) did not show spontaneous or drug-induced motor changes. Infusion of MPP+ decreased the number of tyrosine hydroxylase (TH)-positive cells in the ipsilateral substantia nigra pars compacta (SNc) by approximately 90%. Infusion of N-Me-diOme-IQ+ and THIQ produced approximately 42% and 20% ipsilateral SNc cell loss, respectively, but N-Pr-IQ+ and 6,7-diOMe-1-S-3,4-DHIQ did not alter SNc cell numbers. MPP+ markedly depleted the dopamine (DA, 95%), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) content of the ipsilateral striatum. N-Me-diOMe-IQ+ and THIQ also reduced the DA content of the ipsilateral striatum by approximately 39% and 20% respectively, but N-Pr-IQ+ and 6,7-diOme-1-S-3,4-DHIQ did not deplete striatal DA content. The isoquinoline derivatives slightly reduced (N-Me-diOMe-IQ+ and THIQ) or had no effect (N-Pr-IQ+ and 6,7-diOMe-1-S-3,4-DHIQ) on DOPAC or HVA levels. In conclusion, some isoquinoline derivatives that are substrates for the dopamine re-uptake system and inhibitors of mitochondrial function, are toxic to nigral dopaminergic neurones. Chronic exposure to endogenous or exogenous isoquinoline derivatives might contribute to cell death in Parkinson's disease.