title: Chlorpromazine stimulatory effect on iron uptake by rat brain synaptosomes.
abstract: Clinical long-term neuroleptic administration induces extrapyramidal motor side-effects, of which tardive dyskinesia is the most important. Experimentally, dopamine D2 supersensitivity is observed after phenothiazine and butyrophenone treatment. Neuroleptic-induced tardive dyskinesia and D2 modulation have been linked to impaired iron homeostasis in the central nervous system. Increased nonheme iron levels found in the basal ganglia of patients with extrapyramidal symptomology support the connection between iron and neuronal dopaminergic modulation. We now report the effect of chlorpromazine on iron uptake by synaptosomes of rat brain from two different iron donors: [55Fe]citrate and [55Fe]transferrin. Iron uptake from both donors by cortical synaptosomes was stimulated by Ca2+ and enhanced by chlorpromazine in a saturable fashion. Synaptosomes from the striatum also showed increased (60%) iron uptake from [55Fe]citrate in the presence of chlorpromazine. Chlorpromazine stimulated iron uptake by cortical synaptosomes more efficiently than Ca2+, at physiological levels, from both [55Fe]transferrin (50%) and [55Fe]citrate (68%). Calcium potentiated the effect of chloropromazine upon cortical synaptosomal iron uptake from [55Fe]citrate, but had no apparent effect on the uptake from [55Fe]transferrin. Chlorpromazine-stimulated iron uptake from the latter was observed without addition of Ca2+. Moreover, fluorescence measurement of Ca2+ uptake by cortical synaptosomes showed intensified uptake in the presence of 50 microM chlorpromazine (42%). Visible spectral studies of chlorpromazine in the presence of Fe(3+)-citrate and diferric-transferrin did not reveal iron displacement by chlorpromazine from either of the two donors. These data suggest that chlorpromazine may increase iron uptake by neurons, and may be involved in the development of tardive dyskinesia and other extrapyramidal disorders.
authors.affiliation: Instituto De Química, Universidade de Sáo Paulo, Brazil.
authors.forename: M
authors.initials: M
authors.lastname: Demasi
authors.forename: E J
authors.initials: EJ
authors.lastname: Bechara
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D002118:Calcium / Q000494:pharmacology; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D002746:Chlorpromazine / Q000494:pharmacology*; D003342:Corpus Striatum / Q000378:metabolism; D015259:Dopamine Agents / Q000494:pharmacology; D005290:Ferric Compounds / Q000378:metabolism; D007501:Iron / Q000378:metabolism*; D051381:Rats; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism*; D014168:Transferrin / Q000378:metabolism
chemical_list: D014150:Antipsychotic Agents; D015259:Dopamine Agents; D005290:Ferric Compounds; D014168:Transferrin; C025314:ferric citrate; D007501:Iron; D002118:Calcium; D002746:Chlorpromazine