Effects of a quaternary pyridinium metabolite of haloperidol (HP+) on the viability and catecholamine levels of cultured PC12 cells.
Haloperidol has been found to be metabolized to a pyridinium ion (HP+; 4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]-pyridinium). HP+ is structurally similar to the toxic metabolite of the dopaminergic neurotoxin N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), N-methyl-4-phenylpyridinium (MPP+). HP+ is toxic towards dopaminergic neurons and was proposed to be associated with some of the extrapyramidal side effects of haloperidol. We therefore investigated the neurotoxicity of HP+ towards cultured PC12 cells. At high concentrations, HP+ reduced the viability of PC12 cells as measured by trypan blue exclusion and the MTT method. However, HP+ decreased intracellular dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), and dihydroxyphenylalanine (DOPA) levels at lower concentrations than those required to compromise cell viability. The immunoreactivity of tyrosine hydroxylase was not affected by the treatment with HP+. It was subsequently demonstrated that HP+ can release [3H]DA preloaded in rat striatum slices. Thus, it is proposed that HP+ decreases dopamine content in PC12 cells through actively releasing amines from the cells and (or) blocking the reuptake of the released amines.
Fang
J
J
Department of Psychiatry, University of Alberta, Edmonton, Canada.
Yu
P H
PH
D000818:Animals; D018726:Anti-Dyskinesia Agents / Q000378:metabolism / Q000494:pharmacology*; D002395:Catecholamines / Q000378:metabolism*; D002452:Cell Count / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D006220:Haloperidol / Q000378:metabolism / Q000494:pharmacology*; D016716:PC12 Cells / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D014446:Tyrosine 3-Monooxygenase / Q000187:drug effects / Q000378:metabolism
D018726:Anti-Dyskinesia Agents; D002395:Catecholamines; D014446:Tyrosine 3-Monooxygenase; D006220:Haloperidol