Abstract
The toxicity of 4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]pyridinium ion (HPP+), a metabolite of haloperidol, toward dopaminergic neurons was investigated. When HPP+ (~100 µM) was added to primary cultures prepared from rat embryonic mesencephalon for 1 h, the survivability of dopaminergic neurons decreased significantly, and this effect was not inhibited by the dopamine transporter (DAT) inhibitor GBR 12909. In addition, binding characteristics of HPP+ to neuromelanin, which is abundant in dopaminergic neurons, was evaluated using synthetic melanin. A binding analysis using the Scatchard method showed that there are two classes of binding sites: high affinity sites with a dissociation constant Kd1 of 20.2 nM, and low affinity sites with a Kd2 of 4.0 µM. HPP+ was released easily from synthetic melanin using phosphate buffer (pH 7.0), suggesting that this binding is reversible. The results suggest that the toxicity of HPP+ in dopaminergic neurons is due not to DAT-mediated uptake, but to the binding to neuromelanin.
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Kawashima, H., Iida, Y., Kitamura, Y. et al. Binding of 4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]pyridinium ion (HPP+), a metabolite of haloperidol, to synthetic melanin: Implications for the dopaminergic neurotoxicity of HPP+ . neurotox res 6, 535–542 (2004). https://doi.org/10.1007/BF03033449
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DOI: https://doi.org/10.1007/BF03033449