Effect of haloperidol and its metabolites on dopamine and noradrenaline uptake in rat brain slices.

The effects of haloperidol and its metabolites on dopamine (DA) and noradrenaline (NA) uptake were investigated. Both direct uptake of [3H]DA and [3H]NA into the rat striatal and hippocampus slices and binding of a specific DA uptake inhibitor [3H]GBR-12935 were employed in the present study. Haloperidol pyridinium (HP+), haloperidol 1,2,3,6-tetrahydropyridine (HTP), 4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine (CPTP) and reduced haloperidol (RHAL) are potent inhibitors of DA uptake. HTP N-oxide (HTPNO) exhibits a relatively weak effect on DA uptake. Other metabolites of haloperidol, i.e. 4-(4-chlorophenyl)-4-hydroxypyridine (CPHP) and haloperidol N-oxide (HNO), as well as haloperidol itself possess negligible inhibitory effect on DA uptake. HP+ has been shown to be an amine releaser. It is possible that HP+ may induce amphetamine-like neurotoxicity. The effects of the metabolites of haloperidol on [3H]NA uptake are similar to those on [3H]DA uptake. HP+ appears to be different from MPP+, which is a more potent [3H]NA uptake blocker than on [3H]DA uptake. Although haloperidol exhibits no DA uptake inhibitory effect, it has a high affinity for the [3H]GBR-12935 binding site. The possible pharmacological implications such inhibitory effects on amine uptake are discussed.