Vortioxetine, but not escitalopram or duloxetine, reverses memory impairment induced by central 5-HT depletion in rats: Evidence for direct 5-HT receptor modulation

Jesper Bornø Jensen, Kristian Gaarn du Jardin, Dekun Song, David Budac, Gennady Smagin, Connie Sanchez, Alan Pehrson

Research output: Contribution to journalArticle

64 Citations (Scopus)

Abstract

Depressed patients suffer from cognitive dysfunction, including memory deficits. Acute serotonin (5-HT) depletion impairs memory and mood in vulnerable patients. The investigational multimodal acting antidepressant vortioxetine is a 5-HT3, 5-HT7 and 5-HT1D receptor antagonist, 5-HT1B receptor partial agonist, 5-HT1A receptor agonist and 5-HT transporter (SERT) inhibitor that enhances memory in normal rats in novel object recognition (NOR) and conditioned fear (Mørk et al., 2013). We hypothesized that vortioxetine's 5-HT receptor mechanisms are involved in its memory effects, and therefore investigated these effects in 5-HT depleted rats. Four injections of the irreversible tryptophan hydroxylase inhibitor 4-chloro-dl-phenylalanine methyl ester hydrochloride (PCPA, 86mg/kg, s.c.) induced 5-HT depletion, as measured in hippocampal homogenate and microdialysate. The effects of acute challenge with vortioxetine or the 5-HT releaser fenfluramine on extracellular 5-HT were measured in PCPA-treated and control rats. PCPA's effects on NOR and spontaneous alternation (SA) performance were assessed along with the effects of acute treatment with 5-hydroxy-l-tryptophan (5-HTP), vortioxetine, the selective 5-HT reuptake inhibitor escitalopram, or the 5-HT norepinephrine reuptake inhibitor duloxetine. SERT occupancies were estimated by ex vivo autoradiography. PCPA depleted central 5-HT by >90% in tissue and microdialysate, and impaired NOR and SA performance. Restoring central 5-HT with 5-HTP reversed these deficits. At similar SERT occupancies (>90%) vortioxetine, but not escitalopram or duloxetine, restored memory performance. Acute fenfluramine significantly increased extracellular 5-HT in control and PCPA-treated rats, while vortioxetine did so only in control rats. Thus, vortioxetine restores 5-HT depletion impaired memory performance in rats through one or more of its receptor activities.

Original languageEnglish
Pages (from-to)148-159
Number of pages12
JournalEuropean Neuropsychopharmacology
Volume24
Issue number1
DOIs
StatePublished - 1 Jan 2014

Fingerprint

Citalopram
Serotonin Receptors
Serotonin
Fenfluramine
5-Hydroxytryptophan
vortioxetine
Duloxetine Hydrochloride
Receptor, Serotonin, 5-HT1D
Serotonin 5-HT1 Receptor Antagonists
Receptor, Serotonin, 5-HT1B
Serotonin 5-HT1 Receptor Agonists
Tryptophan Hydroxylase
Receptor, Serotonin, 5-HT1A
Memory Disorders
Autoradiography
Antidepressive Agents
Fear
Norepinephrine

Keywords

  • 5-HT depletion
  • Cognitive impairment
  • Lu AA21004
  • Major depressive disorder
  • Memory
  • Vortioxetine

Cite this

Jensen, Jesper Bornø ; du Jardin, Kristian Gaarn ; Song, Dekun ; Budac, David ; Smagin, Gennady ; Sanchez, Connie ; Pehrson, Alan. / Vortioxetine, but not escitalopram or duloxetine, reverses memory impairment induced by central 5-HT depletion in rats : Evidence for direct 5-HT receptor modulation. In: European Neuropsychopharmacology. 2014 ; Vol. 24, No. 1. pp. 148-159.
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abstract = "Depressed patients suffer from cognitive dysfunction, including memory deficits. Acute serotonin (5-HT) depletion impairs memory and mood in vulnerable patients. The investigational multimodal acting antidepressant vortioxetine is a 5-HT3, 5-HT7 and 5-HT1D receptor antagonist, 5-HT1B receptor partial agonist, 5-HT1A receptor agonist and 5-HT transporter (SERT) inhibitor that enhances memory in normal rats in novel object recognition (NOR) and conditioned fear (M{\o}rk et al., 2013). We hypothesized that vortioxetine's 5-HT receptor mechanisms are involved in its memory effects, and therefore investigated these effects in 5-HT depleted rats. Four injections of the irreversible tryptophan hydroxylase inhibitor 4-chloro-dl-phenylalanine methyl ester hydrochloride (PCPA, 86mg/kg, s.c.) induced 5-HT depletion, as measured in hippocampal homogenate and microdialysate. The effects of acute challenge with vortioxetine or the 5-HT releaser fenfluramine on extracellular 5-HT were measured in PCPA-treated and control rats. PCPA's effects on NOR and spontaneous alternation (SA) performance were assessed along with the effects of acute treatment with 5-hydroxy-l-tryptophan (5-HTP), vortioxetine, the selective 5-HT reuptake inhibitor escitalopram, or the 5-HT norepinephrine reuptake inhibitor duloxetine. SERT occupancies were estimated by ex vivo autoradiography. PCPA depleted central 5-HT by >90{\%} in tissue and microdialysate, and impaired NOR and SA performance. Restoring central 5-HT with 5-HTP reversed these deficits. At similar SERT occupancies (>90{\%}) vortioxetine, but not escitalopram or duloxetine, restored memory performance. Acute fenfluramine significantly increased extracellular 5-HT in control and PCPA-treated rats, while vortioxetine did so only in control rats. Thus, vortioxetine restores 5-HT depletion impaired memory performance in rats through one or more of its receptor activities.",
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Vortioxetine, but not escitalopram or duloxetine, reverses memory impairment induced by central 5-HT depletion in rats : Evidence for direct 5-HT receptor modulation. / Jensen, Jesper Bornø; du Jardin, Kristian Gaarn; Song, Dekun; Budac, David; Smagin, Gennady; Sanchez, Connie; Pehrson, Alan.

In: European Neuropsychopharmacology, Vol. 24, No. 1, 01.01.2014, p. 148-159.

Research output: Contribution to journalArticle

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AU - Jensen, Jesper Bornø

AU - du Jardin, Kristian Gaarn

AU - Song, Dekun

AU - Budac, David

AU - Smagin, Gennady

AU - Sanchez, Connie

AU - Pehrson, Alan

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