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

Elena Dale, Morten Grunnet, Alan Pehrson, Kristen Frederiksen, Peter H. Larsen, Jacob Nielsen, Tine B. Stensbøl, Bjarke Ebert, Haolan Yin, Dunguo Lu, Huiquing Liu, Thomas N. Jensen, Charles R. Yang, Connie Sanchez

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

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
Pages (from-to)1-11
Number of pages11
JournalBrain Research
Volume1689
DOIs
StatePublished - 15 Jun 2018

Fingerprint

Pyramidal Cells
Serotonin Receptors
Interneurons
Antidepressive Agents
Hippocampus
Ondansetron
Serotonin
Hippocampal CA1 Region
Oocytes
Guinea Pigs
vortioxetine
In Vitro Techniques
Receptor, Serotonin, 5-HT1B
Receptor, Serotonin, 5-HT1A
HEK293 Cells
Xenopus
Neuroblastoma
Constriction
Synaptic Transmission
In Situ Hybridization

Keywords

  • Antidepressant
  • Interneurons
  • Pyramidal cells
  • Serotonin receptors

Cite this

Dale, Elena ; Grunnet, Morten ; Pehrson, Alan ; Frederiksen, Kristen ; Larsen, Peter H. ; Nielsen, Jacob ; Stensbøl, Tine B. ; Ebert, Bjarke ; Yin, Haolan ; Lu, Dunguo ; Liu, Huiquing ; Jensen, Thomas N. ; Yang, Charles R. ; Sanchez, Connie. / 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. In: Brain Research. 2018 ; Vol. 1689. pp. 1-11.
@article{e1d9c2b8fbcc43bc89a8d437039e12c9,
title = "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",
abstract = "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.",
keywords = "Antidepressant, Interneurons, Pyramidal cells, Serotonin receptors",
author = "Elena Dale and Morten Grunnet and Alan Pehrson and Kristen Frederiksen and Larsen, {Peter H.} and Jacob Nielsen and Stensb{\o}l, {Tine B.} and Bjarke Ebert and Haolan Yin and Dunguo Lu and Huiquing Liu and Jensen, {Thomas N.} and Yang, {Charles R.} and Connie Sanchez",
year = "2018",
month = "6",
day = "15",
doi = "10.1016/j.brainres.2017.12.025",
language = "English",
volume = "1689",
pages = "1--11",
journal = "Brain Research",
issn = "0006-8993",
publisher = "Elsevier",

}

Dale, E, Grunnet, M, Pehrson, A, Frederiksen, K, Larsen, PH, Nielsen, J, Stensbøl, TB, Ebert, B, Yin, H, Lu, D, Liu, H, Jensen, TN, Yang, CR & Sanchez, C 2018, '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', Brain Research, vol. 1689, pp. 1-11. https://doi.org/10.1016/j.brainres.2017.12.025

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. / Dale, Elena; Grunnet, Morten; Pehrson, Alan; Frederiksen, Kristen; Larsen, Peter H.; Nielsen, Jacob; Stensbøl, Tine B.; Ebert, Bjarke; Yin, Haolan; Lu, Dunguo; Liu, Huiquing; Jensen, Thomas N.; Yang, Charles R.; Sanchez, Connie.

In: Brain Research, Vol. 1689, 15.06.2018, p. 1-11.

Research output: Contribution to journalArticle

TY - JOUR

T1 - The multimodal antidepressant vortioxetine may facilitate pyramidal cell firing by inhibition of 5-HT 3 receptor expressing interneurons

T2 - An in vitro study in rat hippocampus slices

AU - Dale, Elena

AU - Grunnet, Morten

AU - Pehrson, Alan

AU - Frederiksen, Kristen

AU - Larsen, Peter H.

AU - Nielsen, Jacob

AU - Stensbøl, Tine B.

AU - Ebert, Bjarke

AU - Yin, Haolan

AU - Lu, Dunguo

AU - Liu, Huiquing

AU - Jensen, Thomas N.

AU - Yang, Charles R.

AU - Sanchez, Connie

PY - 2018/6/15

Y1 - 2018/6/15

N2 - 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.

AB - 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.

KW - Antidepressant

KW - Interneurons

KW - Pyramidal cells

KW - Serotonin receptors

UR - http://www.scopus.com/inward/record.url?scp=85044603623&partnerID=8YFLogxK

U2 - 10.1016/j.brainres.2017.12.025

DO - 10.1016/j.brainres.2017.12.025

M3 - Article

C2 - 29274875

AN - SCOPUS:85044603623

VL - 1689

SP - 1

EP - 11

JO - Brain Research

JF - Brain Research

SN - 0006-8993

ER -