NEUROLEPTIC DRUG-STIMULATED IRON UPTAKE BY SYNAPTOSOME PREPARATIONS OF RAT CEREBRAL-CORTEX

Neuroleptic-induced tardive dyskinesia has been linked to impaired iro n homeostasis in the central nervous system attributed to increased ir on levels. A chlorpromazine stimulatory effect upon iron uptake from F e-55-citrate and Fe-55-transferrin by cortical synaptosome preparation s of rats was recently demonstrated. The present work extends this stu dy to other neuroleptic drugs such as thioridazine? haloperidol, cloza pine and fluphenazine. Like chlorpromazine, thioridazine showed a stim ulatory effect upon iron uptake from both iron donors whereas fluphena zine highly increased uptake from Fe-55-citrate but not from 55Fe-tran sferrin. Haloperidol and clozapine had no effect. Stimulation of iron uptake by neuroleptics is probably related to their property of calmod ulin antagonism, since calmidazolium also stimulated synaptosomal iron uptake from both donors. Calmidazolium-stimulated uptake from Fe-55-c itrate was approx. 5-fold when compared to control samples while uptak e from Fe-55-transferrin was 250% higher. The results are in agreement with the iron uptake magnitude observed with the different drugs for the two iron donors used and the reported K-i values of neuroleptic dr ugs for calmodulin antagonism evaluated by the inhibition of 3',5'-mon ophosphate phosphodiesterase activity. Moreover, vanadate, an inhibito r of protein phosphorylation and KCl-promoted membrane depolarization, greatly inhibited iron uptake from Fe-55-citrate by both chlorpromazi ne-treated and untreated synaptosome preparations. (C) 1998 Elsevier S cience B.V. All rights reserved.