title: Fluoxetine inhibition of glycine receptor activity in rat hippocampal neurons.
abstract: Fluoxetine is a selective serotonin reuptake inhibitor widely used for treating depression. However, fluoxetine treatment may lead to seizures at higher doses, which underlying mechanism remains largely unknown. In this study, we examined the effects of fluoxetine on glycine receptor (GlyR) activity. Using the whole-cell patch-clamp recording method, we found that fluoxetine and its metabolite norfluoxetine inhibited glycine-induced currents in cultured rat hippocampal neurons. This inhibition was dose-dependent, and voltage-independent. Fluoxetine shifted the glycine concentration-response curve to the right without altering the maximal current. Both Lineweaver-Burk and Schild plots suggest competitive inhibition. The amount of fluoxetine inhibition significantly increased when homomeric GlyRs were selectively inhibited with picrotoxin. Moreover, fluoxetine inhibited the current mediated by heteromeric alpha2beta- but not homomeric alpha2-GlyRs transiently expressed in HEK293T cells. These results suggest that fluoxetine is a competitive and subtype-selective GlyR inhibitor, which may explain its capacity to induce seizures.
authors.affiliation: Hefei National Laboratory for Physical Sciences at Microscale and Department of Neurobiology and Biophysics, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China. zyye@mail.ustc.edu.cn
authors.forename: Zeng-You
authors.initials: ZY
authors.lastname: Ye
authors.forename: Yun-Gang
authors.initials: YG
authors.lastname: Lu
authors.forename: Hao
authors.initials: H
authors.lastname: Sun
authors.forename: Xin-Ping
authors.initials: XP
authors.lastname: Cheng
authors.forename: Tian-Le
authors.initials: TL
authors.lastname: Xu
authors.forename: Jiang-Ning
authors.initials: JN
authors.lastname: Zhou
mesh_terms: D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D002491:Central Nervous System Agents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005473:Fluoxetine / Q000031:analogs & derivatives / Q000494:pharmacology*; D005998:Glycine / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D018408:Patch-Clamp Techniques; D010852:Picrotoxin / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018009:Receptors, Glycine / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*
chemical_list: D002491:Central Nervous System Agents; D005473:Fluoxetine; D005998:Glycine; D010852:Picrotoxin; D018009:Receptors, Glycine; D017367:Selective Serotonin Reuptake Inhibitors; C036139:norfluoxetine