Effects of haloperidol and its pyridinium metabolite on plasma membrane permeability and fluidity in the rat brain.
The use of antipsychotic drugs is limited by their tendency to produce extrapyramidal movement disorders such as tardive dyskinesia and parkinsonism. In previous reports it was speculated that extrapyramidal side effects associated with the butyrophenone neuroleptic agent haloperidol (HP) could be caused in part by the neurotoxic effect of its pyridinium metabolite (HPP(+)). Although both HPP(+) and HP have been shown to induce neurotoxic effects such as loss of cell membrane integrity, no information exists about the difference in the neurotoxic potency, especially in the potency to induce plasma membrane damage, between these two agents. In the present study, we compared the potency of the interaction of HPP(+) and HP with the plasma membrane integrity in the rat brain. Membrane permeabilization (assessed as [(18)F]2-fluoro-2-deoxy-d-glucose-6-phosphate release from brain slices) and fluidization (assessed as the reduction in the plasma membrane anisotropy of 1,6-diphenyl 1,3,5-hexatriene) were induced by HPP(+) loading (at >or=100 microM and >or=10 microM, respectively), while comparable changes were induced only at a higher concentration of HP (=1 mM). These results suggest that HPP(+) has a higher potency to induce plasma membrane damage than HP, and these actions of HPP(+) may partly underlie the pathogenesis of HP-induced extrapyramidal side effects.
Murata
Tetsuhito
T
Department of Neuropsychiatry, University of Fukui, Fukui 910-1193, Japan. tmurata@fmsrsa.fukui-med.ac.jp
Maruoka
Nobuyuki
N
Omata
Naoto
N
Takashima
Yasuhiro
Y
Igarashi
Kazuo
K
Kasuya
Fumiyo
F
Fujibayashi
Yasuhisa
Y
Wada
Yuji
Y
D000818:Animals; D016880:Anisotropy; D001345:Autoradiography; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000502:physiology / Q000648:ultrastructure; D001931:Brain Mapping; D002462:Cell Membrane / Q000187:drug effects*; D002463:Cell Membrane Permeability / Q000187:drug effects*; D019788:Fluorodeoxyglucose F18 / Q000493:pharmacokinetics; D006220:Haloperidol / Q000494:pharmacology*; D066298:In Vitro Techniques; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D011726:Pyridinium Compounds / Q000494:pharmacology*; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D018709:Statistics, Nonparametric; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D013997:Time Factors
D011726:Pyridinium Compounds; D019275:Radiopharmaceuticals; D017392:Thiobarbituric Acid Reactive Substances; D019788:Fluorodeoxyglucose F18; D007770:L-Lactate Dehydrogenase; D006220:Haloperidol