title: Risperidone inhibits voltage-gated sodium channels.
abstract: In contrast to several other antipsychotic drugs, the effects of the atypical antipsychotic risperidone on voltage-gated sodium channels have not been characterized yet, despite its wide clinical use. Here we performed whole-cell voltage-clamp recordings to analyze the effects of risperidone on voltage-dependent sodium currents of N1E-115 mouse neuroblastoma cells carried by either endogenous sodium channels or transfected NaV1.6 channels. Risperidone inhibited both endogenous and NaV1.6-mediated sodium currents at concentrations that are expected around active synaptic release sites owing to its strong accumulation in synaptic vesicles. When determined for pharmacologically isolated NaV1.6, risperidone inhibited peak inward currents with an IC50 of 49 µM. Channel block occurred in a state-dependent fashion with risperidone displaying a fourfold higher affinity for the inactivated state than for the resting state. As a consequence of the low state dependence, risperidone produced only a small, but significant leftward shift of the steady-state inactivation curve and it required concentrations ≥ 30 µM to significantly slow the time course of recovery from inactivation. Risperidone (10 µM) gave rise to a pronounced use-dependent block when sodium currents were elicited by trains of brief voltage pulses at higher frequencies. Our data suggest that, compared to other antipsychotic drugs as well as to local anesthetics and sodium channel-targeting anticonvulsants, risperidone displays an unusual blocking profile where a rather low degree of state dependence is associated with a prominent use-dependent block.
authors: Department of Psychiatry and Psychotherapy, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; Institute of Physiology and Pathophysiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Universitätsstr. 17, 91054 Erlangen, Germany.
authors: Jan M
authors: JM
authors: Brauner
authors: Institute of Physiology and Pathophysiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Universitätsstr. 17, 91054 Erlangen, Germany.
authors: Sabine
authors: S
authors: Hessler
authors: Department of Psychiatry and Psychotherapy, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors: Teja W
authors: TW
authors: Groemer
authors: Institute of Physiology and Pathophysiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Universitätsstr. 17, 91054 Erlangen, Germany.
authors: Christian
authors: C
authors: Alzheimer
authors: Institute of Physiology and Pathophysiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Universitätsstr. 17, 91054 Erlangen, Germany. Electronic address: Tobias.Huth@fau.de.
authors: Tobias
authors: T
authors: Huth
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D062557:NAV1.6 Voltage-Gated Sodium Channel / Q000235:genetics / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D010957:Plasmids; D018967:Risperidone / Q000494:pharmacology*; D014162:Transfection; D061567:Voltage-Gated Sodium Channel Blockers / Q000494:pharmacology*
chemical_list: D014150:Antipsychotic Agents; D062557:NAV1.6 Voltage-Gated Sodium Channel; C491046:Scn8a protein, mouse; D061567:Voltage-Gated Sodium Channel Blockers; D018967:Risperidone
keywords: Antipsychotic drug; Chemical compounds studied in this article:Risperidone (PubChem CID: 5073); Na(V)1.6; Risperidone; Schizophrenia; Sodium channel; Use dependence