Antidepressant and anxiolytic potential of the multimodal antidepressant vortioxetine (Lu AA21004) assessed by behavioural and neurogenesis outcomes in mice

Jean Philippe Guilloux, Indira Mendez-David, Alan Pehrson, Bruno P. Guiard, Christelle Repérant, Sophie Orvoën, Alain M. Gardier, René Hen, Ebert Bjarke, Miller Silke, Sanchez Connie, Denis J. David

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Abstract

Vortioxetine (Lu AA21004) is an investigational novel antidepressant with multimodal activity that functions as a 5-HT 3 , 5-HT 7 and 5-HT 1D receptor antagonist, 5-HT 1B receptor partial agonist, 5-HT 1A receptor agonist and inhibitor of the 5-HT transporter in vitro. Here we explore its anxiolytic and antidepressant potential in adult mice. Vortioxetine was assessed in BalB/cJ@RJ mice using the open-field and forced-swim tests (acute: p.o. 1 h, repeated: daily p.o. 21 days), and in 129S6/SvEvTac mice using the novelty suppressed feeding paradigm (acute: p.o. 1 h, sustained: daily p.o. 14 or 21 days). Fluoxetine and diazepam were controls. Acute and repeated dosing of vortioxetine produced more pronounced anxiolytic- and antidepressant-like activities than fluoxetine. Vortioxetine significantly increased cell proliferation and cell survival and stimulated maturation of immature granule cells in the subgranular zone of the dentate gyrus of the hippocampus after 21 days of treatment. After 14 days, a high dose of vortioxetine increased dendritic length and the number of dendrite intersections, suggesting that vortioxetine accelerates the maturation of immature neurons. Vortioxetine displays an antidepressant and anxiolytic profile following repeated administration associated with increased neurogenesis at several stages. Vortioxetine effects were observed at low levels of 5-HT transporter occupancy, suggesting an alternative mechanism of action to 5-HT reuptake inhibition.

Original languageEnglish
Pages (from-to)147-159
Number of pages13
JournalNeuropharmacology
Volume73
DOIs
StatePublished - 1 Jan 2013

Fingerprint

Anti-Anxiety Agents
Neurogenesis
Antidepressive Agents
Serotonin
Fluoxetine
Receptor, Serotonin, 5-HT1D
Receptor, Serotonin, 5-HT1B
vortioxetine
Serotonin Receptor Agonists
Parahippocampal Gyrus
Receptor, Serotonin, 5-HT1A
Dentate Gyrus
Diazepam
Dendrites
Cell Survival
Cell Proliferation
Neurons

Keywords

  • Antidepressant
  • Anxiolytic
  • Behaviour
  • Mice
  • Multimodal antidepressant
  • Neurogenesis

Cite this

Guilloux, Jean Philippe ; Mendez-David, Indira ; Pehrson, Alan ; Guiard, Bruno P. ; Repérant, Christelle ; Orvoën, Sophie ; Gardier, Alain M. ; Hen, René ; Bjarke, Ebert ; Silke, Miller ; Connie, Sanchez ; David, Denis J. / Antidepressant and anxiolytic potential of the multimodal antidepressant vortioxetine (Lu AA21004) assessed by behavioural and neurogenesis outcomes in mice. In: Neuropharmacology. 2013 ; Vol. 73. pp. 147-159.
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abstract = "Vortioxetine (Lu AA21004) is an investigational novel antidepressant with multimodal activity that functions as a 5-HT 3 , 5-HT 7 and 5-HT 1D receptor antagonist, 5-HT 1B receptor partial agonist, 5-HT 1A receptor agonist and inhibitor of the 5-HT transporter in vitro. Here we explore its anxiolytic and antidepressant potential in adult mice. Vortioxetine was assessed in BalB/cJ@RJ mice using the open-field and forced-swim tests (acute: p.o. 1 h, repeated: daily p.o. 21 days), and in 129S6/SvEvTac mice using the novelty suppressed feeding paradigm (acute: p.o. 1 h, sustained: daily p.o. 14 or 21 days). Fluoxetine and diazepam were controls. Acute and repeated dosing of vortioxetine produced more pronounced anxiolytic- and antidepressant-like activities than fluoxetine. Vortioxetine significantly increased cell proliferation and cell survival and stimulated maturation of immature granule cells in the subgranular zone of the dentate gyrus of the hippocampus after 21 days of treatment. After 14 days, a high dose of vortioxetine increased dendritic length and the number of dendrite intersections, suggesting that vortioxetine accelerates the maturation of immature neurons. Vortioxetine displays an antidepressant and anxiolytic profile following repeated administration associated with increased neurogenesis at several stages. Vortioxetine effects were observed at low levels of 5-HT transporter occupancy, suggesting an alternative mechanism of action to 5-HT reuptake inhibition.",
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Guilloux, JP, Mendez-David, I, Pehrson, A, Guiard, BP, Repérant, C, Orvoën, S, Gardier, AM, Hen, R, Bjarke, E, Silke, M, Connie, S & David, DJ 2013, 'Antidepressant and anxiolytic potential of the multimodal antidepressant vortioxetine (Lu AA21004) assessed by behavioural and neurogenesis outcomes in mice', Neuropharmacology, vol. 73, pp. 147-159. https://doi.org/10.1016/j.neuropharm.2013.05.014

Antidepressant and anxiolytic potential of the multimodal antidepressant vortioxetine (Lu AA21004) assessed by behavioural and neurogenesis outcomes in mice. / Guilloux, Jean Philippe; Mendez-David, Indira; Pehrson, Alan; Guiard, Bruno P.; Repérant, Christelle; Orvoën, Sophie; Gardier, Alain M.; Hen, René; Bjarke, Ebert; Silke, Miller; Connie, Sanchez; David, Denis J.

In: Neuropharmacology, Vol. 73, 01.01.2013, p. 147-159.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Antidepressant and anxiolytic potential of the multimodal antidepressant vortioxetine (Lu AA21004) assessed by behavioural and neurogenesis outcomes in mice

AU - Guilloux, Jean Philippe

AU - Mendez-David, Indira

AU - Pehrson, Alan

AU - Guiard, Bruno P.

AU - Repérant, Christelle

AU - Orvoën, Sophie

AU - Gardier, Alain M.

AU - Hen, René

AU - Bjarke, Ebert

AU - Silke, Miller

AU - Connie, Sanchez

AU - David, Denis J.

PY - 2013/1/1

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