EFFECTS OF HALOPERIDOL METABOLITES ON NEUROTRANSMITTER UPTAKE AND RELEASE - POSSIBLE ROLE IN NEUROTOXICITY AND TARDIVE-DYSKINESIA

This research explored the effects of haloperidol (HP) metabolites on biogenic amine uptake and release, and compared them to those of MPTP and its toxic metabolite, MPP+. In synaptosome preparations from mouse striatum and cortex, the HP metabolites haloperidol pyridinium (HPP+) , reduced haloperidol pyridinium (RHPP+), and haloperidol tetrahydropy ridine (HPTP) inhibited the presynaptic uptake of dopamine and seroton in, with greater affinity for the serotonin transporter. HPP+ was the most potent inhibitor of dopamine uptake, and HPTP of serotonin uptake , both with IC50 values in the low micromolar range. RHPP+ was less ac tive than the other metabolites, but was more active than the parent c ompound, HP. Inhibition of uptake was reversed when free drug was remo ved by centrifugation and then resuspension of the synaptosomes in fre sh buffer, suggesting that inhibition of uptake was due to interaction with the transporters and was not due to irreversible cytotoxicity. H PP+ showed noncompetitive inhibition of both serotonin and dopamine up take, suggesting that it has a relatively slow dissociation rate for i ts interaction with the transporter proteins. In experiments on amine release, HPP+ and HPTP were four-fold less potent than MPP+ for releas ing preloaded dopamine from striatal synaptosomes, and only MPP+-depen dent release was antagonized by the uptake blocker, mazindol. In contr ast, RHPP+ displayed little ability to release either amine neurotrans mitter. HPTP was about two-fold more potent than MPP+ for releasing se rotonin from cortical synaptosomes, whereas HPP+ was less active than MPP+. The specific serotonin transport blocker fluoxetine was only abl e to antagonize release induced by MPP+. These results suggest that HP metabolites bind to the transporters for dopamine and serotonin, but are not transporter substrates. In contrast to their potent effects on amine release, HPP+ and HPTP were unable to release preloaded GABA fr om cortical synaptosomes. The implications of these results concerning a possible role of HP metabolites in the development of tardive dyski nesia are discussed. (C) 1998 Elsevier Science B.V.