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 [18F]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 ≥ 100 μM and ≥ 10 μM, 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.