EFFECTS OF A QUATERNARY PYRIDINIUM METABOLITE OF HALOPERIDOL (HP+) ONTHE 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 n eurotoxin N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), N-methy l-4-phenylpyridinium (MPP+). HP+ is toxic towards dopaminergic neurons and was proposed to be associated with some of the extrapyramidal sid e effects of haloperidol. We therefore investigated the neurotoxicity of HP+ towards cultured PC12 cells. At high concentrations, HP+ reduce d 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 (DOP A) levels at lower concentrations than those required to compromise ce ll viability. The immunoreactivity of tyrosine hydroxylase was not aff ected by the treatment with HP+. It was subsequently demonstrated that HP+ can release [H-3]DA preloaded in rat striatum slices. Thus, it is proposed that HP+ decreases dopamine content in PC12 cells through ac tively releasing amines from the cells and (or) blocking the reuptake of the released amines.