The rapid recovery of 5-HT cell firing induced by the antidepressant vortioxetine involves 5-HT3 receptor antagonism

Cécile Bétry, Alan L. Pehrson, Adeline Etiévant, Bjarke Ebert, Connie Sánchez, Nasser Haddjeri

Research output: Contribution to journalArticle

46 Citations (Scopus)

Abstract

The therapeutic effect of current antidepressant drugs appears after several weeks of treatment and a significant number of patients do not respond to treatment. Here, we report the effects of the multi-modal antidepressant vortioxetine (Lu AA21004), a 5-HT3 and 5-HT7 receptor antagonist, 5-HT1B receptor partial agonist, 5-HT1A receptor agonist and 5-HT transporter (SERT) inhibitor, on rat 5-HT neurotransmission. Using in vivo electrophysiological recordings in the dorsal raphe nucleus of anaesthetized rats, we assessed the acute and subchronic effects of vortioxetine and/or the selective 5-HT3 receptor agonist, SR57227 or the selective 5-HT1A receptor agonist flesinoxan, on 5-HT neuronal firing activity. Using ex-vivo autoradiography, we correlated SERT occupancy and presumed 5-HT firing activity. The selective serotonin reuptake inhibitor, fluoxetine, was used as comparator. Importantly, the recovery of 5-HT neuronal firing was achieved after 1 d with vortioxetine and 14 d with fluoxetine. SR57227 delayed this recovery. In contrast, vortioxetine failed to alter the reducing action of 3 d treatment of flesinoxan. Acute dosing of vortioxetine inhibited neuronal firing activity more potently than fluoxetine. SR57227 prevented the suppressant effect of vortioxetine, but not of fluoxetine. In contrast, flesinoxan failed to modify the suppressant effect of vortioxetine acutely administered. Differently to fluoxetine, vortioxetine suppressed neuronal firing without saturating occupancy at the SERT. Vortioxetine produced a markedly faster recovery of 5-HT neuronal firing than fluoxetine. This is at least partly due to 5-HT3 receptor antagonism of vortioxetine in association with its reduced SERT occupancy.

Original languageEnglish
Pages (from-to)1115-1127
Number of pages13
JournalInternational Journal of Neuropsychopharmacology
Volume16
Issue number5
DOIs
StatePublished - 1 Jun 2013

Fingerprint

Receptors, Serotonin, 5-HT3
Antidepressive Agents
Serotonin
Fluoxetine
Serotonin 5-HT1 Receptor Agonists
Receptor, Serotonin, 5-HT1A
vortioxetine
Serotonin 5-HT3 Receptor Agonists
Receptor, Serotonin, 5-HT1B
Serotonin Uptake Inhibitors
Therapeutic Uses
Autoradiography
Synaptic Transmission
Therapeutics

Keywords

  • 5-HT receptors
  • 5-HTA receptors
  • Antidepressant
  • SERT occupancy
  • dorsal raphe nucleus

Cite this

Bétry, Cécile ; Pehrson, Alan L. ; Etiévant, Adeline ; Ebert, Bjarke ; Sánchez, Connie ; Haddjeri, Nasser. / The rapid recovery of 5-HT cell firing induced by the antidepressant vortioxetine involves 5-HT3 receptor antagonism. In: International Journal of Neuropsychopharmacology. 2013 ; Vol. 16, No. 5. pp. 1115-1127.
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The rapid recovery of 5-HT cell firing induced by the antidepressant vortioxetine involves 5-HT3 receptor antagonism. / Bétry, Cécile; Pehrson, Alan L.; Etiévant, Adeline; Ebert, Bjarke; Sánchez, Connie; Haddjeri, Nasser.

In: International Journal of Neuropsychopharmacology, Vol. 16, No. 5, 01.06.2013, p. 1115-1127.

Research output: Contribution to journalArticle

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