CHLORPROMAZINE STIMULATORY EFFECT ON IRON UPTAKE BY RAT-BRAIN SYNAPTOSOMES

Clinical long-term neuroleptic administration induces extrapyramidal m otor side-effects, of which tardive dyskinesia is the most important. Experimentally, dopamine D-2 supersensitivity is observed after phenot hiazine and butyrophenone treatment. Neuroleptic-induced tardive dyski nesia and D-2 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 suppor t the connection between iron and neuronal dopaminergic modulation. We now report the effect of chlorpromazine on iron uptake by synaptosome s of rat brain from two different iron donors: [Fe-55]citrate and [Fe- 55]transferrin. Iron uptake from both donors by cortical synaptosomes was stimulated by Ca2+ and enhanced by chlorpromazine in a saturable f ashion. Synaptosomes from the striatum also showed increased (60%) iro n uptake from [Fe-55]citrate in the presence of chlorpromazine. Chlorp romazine stimulated iron uptake by cortical synaptosomes more efficien tly than Ca2+, at physiological levels, from both [Fe-55]transferrin ( 50%) and [Fe-55]citrate (68%). Calcium potentiated the effect of chlor promazine upon cortical synaptosomal iron uptake from [Fe-55]citrate, but had no apparent effect on the uptake from [Fe-55]transferrin. Chlo rpromazine-stimulated iron uptake from the latter was observed without addition of Ca2+. Moreover, fluorescence measurement of Ca2+ uptake b y cortical synaptosomes showed intensified uptake in the presence of 5 0 mu M chlorpromazine (42%). Visible spectral studies of chlorpromazin e in the presence of Fe3+-citrate and diferric-transferrin did not rev eal iron displacement by chlorpromazine from either of the two donors. These data suggest that chlorpromazine may increase iron uptake by ne urons, and may be involved in the development of tardive dyskinesia an d other extrapyramidal disorders.