Protein thiol oxidation by haloperidol results in inhibition of mitochondrial complex I in brain regions: comparison with atypical antipsychotics

Usage of 'typical' but not 'atypical' antipsychotic drugs is associated wit h severe side effects involving extrapyramidal tract (EPT). Single dose of haloperidol caused selective inhibition of complex I in frontal cortex, str iatum and midbrain (41 and 26%, respectively) which was abolished by pretre atment of mice with thiol antioxidants, alpha -lipoic acid and glutathione isopropyl ester: and reversed, in vitro, by disulfide reductant, dithiothre itol. Prolonged administration of haloperidol to mice resulted in complex I loss in frontal cortex, hippocampus, striatum and midbrain, while chronic dosing with clozapine affected only hippocampus and frontal cortex. Risperi done caused complex I loss in frontal cortex, hippocampus and striatum but not in midbrain from which extrapyramidal tract emanates. Inhibition of the electron transport chain component, complex I by haloperidol is mediated t hrough oxidation of essential thiol groups to disulfides, in vivo. Further, loss of complex I in extrapyramidal brain regions by anti-psychotics corre lated with their known propensity to generate side-effects involving extra- pyramidal tract. (C) 2001 Elsevier Science Ltd. All rights reserved.