Connie Sánchez

The multimodal antidepressant vortioxetine may facilitate pyramidal cell firing by inhibition of 5-HT 3 receptor expressing interneurons: An in vitro study in rat hippocampus slices

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

  • Elena Dale, H. Lundbeck A/S
  • ,
  • Morten Grunnet, H. Lundbeck A/S
  • ,
  • Alan L. Pehrson, H. Lundbeck A/S
  • ,
  • Kristen Frederiksen, H. Lundbeck A/S
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  • Peter H. Larsen, H. Lundbeck A/S
  • ,
  • Jacob Nielsen, H. Lundbeck A/S
  • ,
  • Tine B. Stensbøl, H. Lundbeck A/S
  • ,
  • Bjarke Ebert, H. Lundbeck A/S
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  • Haolan Yin, ChemPartner Co. Ltd.
  • ,
  • Dunguo Lu, ChemPartner Co. Ltd.
  • ,
  • Huiquing Liu, ChemPartner Co. Ltd.
  • ,
  • Thomas N. Jensen, H. Lundbeck A/S
  • ,
  • Charles R. Yang, ChemPartner Co. Ltd.
  • ,
  • Connie Sanchez

The multimodal antidepressant vortioxetine is thought to mediate its pharmacological effects via 5-HT 1A receptor agonism, 5-HT 1B receptor partial agonism, 5-HT 1D , 5-HT 3 , 5-HT 7 receptor antagonism and 5-HT transporter inhibition. Here we studied vortioxetine's functional effects across species (canine, mouse, rat, guinea pig and human) in cellular assays with heterologous expression of 5-HT 3A receptors (in Xenopus oocytes and HEK-293 cells) and in mouse neuroblastoma N1E-115 cells with endogenous expression of 5-HT 3A receptors. Furthermore, we studied the effects of vortioxetine on activity of CA1 Stratum Radiatum interneurons in rat hippocampus slices using current- and voltage-clamping methods. The patched neurons were subsequently filled with biocytin for confirmation of 5-HT 3 receptor mRNA expression by in situ hybridization. Whereas, both vortioxetine and the 5-HT 3 receptor antagonist ondansetron potently antagonized 5-HT-induced currents in the cellular assays, vortioxetine had a slower off-rate than ondansetron in oocytes expressing 5-HT 3A receptors. Furthermore, vortioxetine's but not ondansetron's 5-HT 3 receptor antagonistic potency varied considerably across species. Vortioxetine had the highest potency at rat and the lowest potency at guinea pig 5-HT 3A receptors. Finally, in 5-HT 3 receptor-expressing GABAergic interneurons from the CA1 stratum radiatum, vortioxetine and ondansetron blocked depolarizations induced by superfusion of either 5-HT or the 5-HT 3 receptor agonist mCPBG. Taken together, these data add to a growing literature supporting the idea that vortioxetine may inhibit GABAergic neurotransmission in some brain regions via a 5-HT 3 receptor antagonism-dependent mechanism and thereby disinhibit pyramidal neurons and enhance glutamatergic signaling.

Original languageEnglish
JournalBrain Research
Volume1689
Pages (from-to)1-11
Number of pages11
ISSN0006-8993
DOIs
Publication statusPublished - 15 Jun 2018

    Research areas

  • Antidepressant, Interneurons, Pyramidal cells, Serotonin receptors

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