Neurotoxic effect of 4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]-pyridinium (HP+), a major metabolite of haloperidol, in the dopaminergic system in vitro and in vivo

Haloperidol, a neuroleptic drug, causes various neurological side effects including movement disorders, such as Parkinsonism and sometimes irreversible tardive dyskinesia. Haloperidol is metabolized to its pyridinium ion (4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)4-oxobutyl]-pyridinium, HP + ) via the intermediate 1,2,3,6-tetrahydropyridine haloperidol (HTP). We observed that HP + is toxic towards cultured dopamine neuroblastoma cells (SH-SY5Y) in vitro. Its toxicity towards neuroblastoma cells is comparable with the neurotoxin N-methyl-4-phenyl-pyridinium (MPP + ). We found in the present study that HP + at relatively high concentration following intra-nigral administration induces local toxicity and depletion of striatal dopamine. HP + as well as several haloperidol metabolites were also found to be potent catecholamine releasers and uptake blockers. This may cause prolonged elevation of nonsequestered catecholamines at the synaptic gaps, which may become harmful. We observed that dopamine is indeed quite toxic towards neuroblastoma cells. This toxicity can be primarily attributed to free radicals generated via autooxidation of dopamine.