Vortioxetine dose-dependently reverses 5-HT depletion-induced deficits in spatial working and object recognition memory

A potential role for 5-HT1A receptor agonism and 5-HT3 receptor antagonism

Kristian Gaarn du Jardin, Jesper Bornø Jensen, Connie Sanchez, Alan Pehrson

Research output: Contribution to journalArticleResearchpeer-review

84 Citations (Scopus)

Abstract

We previously reported that the investigational multimodal antidepressant, vortioxetine, reversed 5-HT depletion-induced memory deficits while escitalopram and duloxetine did not. The present report studied the effects of vortioxetine and the potential impact of its 5-HT1A receptor agonist and 5-HT3 receptor antagonist properties on 5-HT depletion-induced memory deficits. Recognition and spatial working memory were assessed in the object recognition (OR) and Y-maze spontaneous alternation (SA) tests, respectively. 5-HT depletion was induced in female Long-Evans rats using 4-cholro-DL-phenylalanine methyl ester HCl (PCPA) and receptor occupancies were determined by ex vivo autoradiography. Rats were acutely dosed with vortioxetine, ondansetron (5-HT3 receptor antagonist) or flesinoxan (5-HT1A receptor agonist). The effects of chronic vortioxetine administration on 5-HT depletion-induced memory deficits were also assessed. 5-HT depletion reliably impaired memory performance in both the tests. Vortioxetine reversed PCPA-induced memory deficits dose-dependently with a minimal effective dose (MED) ≤0.1mg/kg (~80% 5-HT3 receptor occupancy; OR) and ≤3.0mg/kg (5-HT1A, 5-HT1B, 5-HT3 receptor occupancy: ~15%, 60%, 95%) in SA. Ondansetron exhibited a MED ≤3.0μg/kg (~25% 5-HT3 receptor occupancy; OR), but was inactive in the SA test. Flesinoxan had a MED ≤1.0mg/kg (~25% 5-HT1A receptor occupancy; SA); only 1.0mg/kg ameliorated deficits in the NOR. Chronic p.o. vortioxetine administration significantly improved memory performance in OR and occupied 95%, 66%, and 9.5% of 5-HT3, 5-HT1B, and 5-HT1A receptors, respectively. Vortioxetine's effects on SA performance may involve 5-HT1A receptor agonism, but not 5-HT3 receptor antagonism, whereas the effects on OR performance may involve 5-HT3 receptor antagonism and 5-HT1A receptor agonism.

Original languageEnglish
Pages (from-to)160-171
Number of pages12
JournalEuropean Neuropsychopharmacology
Volume24
Issue number1
DOIs
StatePublished - 1 Jan 2014

Fingerprint

Receptors, Serotonin, 5-HT3
Receptor, Serotonin, 5-HT1A
Serotonin
Memory Disorders
Serotonin 5-HT1 Receptor Agonists
Serotonin 5-HT3 Receptor Antagonists
Ondansetron
Long Evans Rats
Citalopram
vortioxetine
Recognition (Psychology)
Autoradiography
Short-Term Memory
Antidepressive Agents

Keywords

  • 5-HT depletion
  • 5-HT receptor
  • 5-HT receptor
  • Cognitive dysfunction
  • Major depressive disorder
  • Vortioxetine

Cite this

@article{2baba56ca0c2419bad138db178df655b,
title = "Vortioxetine dose-dependently reverses 5-HT depletion-induced deficits in spatial working and object recognition memory: A potential role for 5-HT1A receptor agonism and 5-HT3 receptor antagonism",
abstract = "We previously reported that the investigational multimodal antidepressant, vortioxetine, reversed 5-HT depletion-induced memory deficits while escitalopram and duloxetine did not. The present report studied the effects of vortioxetine and the potential impact of its 5-HT1A receptor agonist and 5-HT3 receptor antagonist properties on 5-HT depletion-induced memory deficits. Recognition and spatial working memory were assessed in the object recognition (OR) and Y-maze spontaneous alternation (SA) tests, respectively. 5-HT depletion was induced in female Long-Evans rats using 4-cholro-DL-phenylalanine methyl ester HCl (PCPA) and receptor occupancies were determined by ex vivo autoradiography. Rats were acutely dosed with vortioxetine, ondansetron (5-HT3 receptor antagonist) or flesinoxan (5-HT1A receptor agonist). The effects of chronic vortioxetine administration on 5-HT depletion-induced memory deficits were also assessed. 5-HT depletion reliably impaired memory performance in both the tests. Vortioxetine reversed PCPA-induced memory deficits dose-dependently with a minimal effective dose (MED) ≤0.1mg/kg (~80{\%} 5-HT3 receptor occupancy; OR) and ≤3.0mg/kg (5-HT1A, 5-HT1B, 5-HT3 receptor occupancy: ~15{\%}, 60{\%}, 95{\%}) in SA. Ondansetron exhibited a MED ≤3.0μg/kg (~25{\%} 5-HT3 receptor occupancy; OR), but was inactive in the SA test. Flesinoxan had a MED ≤1.0mg/kg (~25{\%} 5-HT1A receptor occupancy; SA); only 1.0mg/kg ameliorated deficits in the NOR. Chronic p.o. vortioxetine administration significantly improved memory performance in OR and occupied 95{\%}, 66{\%}, and 9.5{\%} of 5-HT3, 5-HT1B, and 5-HT1A receptors, respectively. Vortioxetine's effects on SA performance may involve 5-HT1A receptor agonism, but not 5-HT3 receptor antagonism, whereas the effects on OR performance may involve 5-HT3 receptor antagonism and 5-HT1A receptor agonism.",
keywords = "5-HT depletion, 5-HT receptor, 5-HT receptor, Cognitive dysfunction, Major depressive disorder, Vortioxetine",
author = "{du Jardin}, {Kristian Gaarn} and Jensen, {Jesper Born{\o}} and Connie Sanchez and Alan Pehrson",
year = "2014",
month = "1",
day = "1",
doi = "10.1016/j.euroneuro.2013.07.001",
language = "English",
volume = "24",
pages = "160--171",
journal = "European Neuropsychopharmacology",
issn = "0924-977X",
publisher = "Elsevier",
number = "1",

}

Vortioxetine dose-dependently reverses 5-HT depletion-induced deficits in spatial working and object recognition memory : A potential role for 5-HT1A receptor agonism and 5-HT3 receptor antagonism. / du Jardin, Kristian Gaarn; Jensen, Jesper Bornø; Sanchez, Connie; Pehrson, Alan.

In: European Neuropsychopharmacology, Vol. 24, No. 1, 01.01.2014, p. 160-171.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Vortioxetine dose-dependently reverses 5-HT depletion-induced deficits in spatial working and object recognition memory

T2 - A potential role for 5-HT1A receptor agonism and 5-HT3 receptor antagonism

AU - du Jardin, Kristian Gaarn

AU - Jensen, Jesper Bornø

AU - Sanchez, Connie

AU - Pehrson, Alan

PY - 2014/1/1

Y1 - 2014/1/1

N2 - We previously reported that the investigational multimodal antidepressant, vortioxetine, reversed 5-HT depletion-induced memory deficits while escitalopram and duloxetine did not. The present report studied the effects of vortioxetine and the potential impact of its 5-HT1A receptor agonist and 5-HT3 receptor antagonist properties on 5-HT depletion-induced memory deficits. Recognition and spatial working memory were assessed in the object recognition (OR) and Y-maze spontaneous alternation (SA) tests, respectively. 5-HT depletion was induced in female Long-Evans rats using 4-cholro-DL-phenylalanine methyl ester HCl (PCPA) and receptor occupancies were determined by ex vivo autoradiography. Rats were acutely dosed with vortioxetine, ondansetron (5-HT3 receptor antagonist) or flesinoxan (5-HT1A receptor agonist). The effects of chronic vortioxetine administration on 5-HT depletion-induced memory deficits were also assessed. 5-HT depletion reliably impaired memory performance in both the tests. Vortioxetine reversed PCPA-induced memory deficits dose-dependently with a minimal effective dose (MED) ≤0.1mg/kg (~80% 5-HT3 receptor occupancy; OR) and ≤3.0mg/kg (5-HT1A, 5-HT1B, 5-HT3 receptor occupancy: ~15%, 60%, 95%) in SA. Ondansetron exhibited a MED ≤3.0μg/kg (~25% 5-HT3 receptor occupancy; OR), but was inactive in the SA test. Flesinoxan had a MED ≤1.0mg/kg (~25% 5-HT1A receptor occupancy; SA); only 1.0mg/kg ameliorated deficits in the NOR. Chronic p.o. vortioxetine administration significantly improved memory performance in OR and occupied 95%, 66%, and 9.5% of 5-HT3, 5-HT1B, and 5-HT1A receptors, respectively. Vortioxetine's effects on SA performance may involve 5-HT1A receptor agonism, but not 5-HT3 receptor antagonism, whereas the effects on OR performance may involve 5-HT3 receptor antagonism and 5-HT1A receptor agonism.

AB - We previously reported that the investigational multimodal antidepressant, vortioxetine, reversed 5-HT depletion-induced memory deficits while escitalopram and duloxetine did not. The present report studied the effects of vortioxetine and the potential impact of its 5-HT1A receptor agonist and 5-HT3 receptor antagonist properties on 5-HT depletion-induced memory deficits. Recognition and spatial working memory were assessed in the object recognition (OR) and Y-maze spontaneous alternation (SA) tests, respectively. 5-HT depletion was induced in female Long-Evans rats using 4-cholro-DL-phenylalanine methyl ester HCl (PCPA) and receptor occupancies were determined by ex vivo autoradiography. Rats were acutely dosed with vortioxetine, ondansetron (5-HT3 receptor antagonist) or flesinoxan (5-HT1A receptor agonist). The effects of chronic vortioxetine administration on 5-HT depletion-induced memory deficits were also assessed. 5-HT depletion reliably impaired memory performance in both the tests. Vortioxetine reversed PCPA-induced memory deficits dose-dependently with a minimal effective dose (MED) ≤0.1mg/kg (~80% 5-HT3 receptor occupancy; OR) and ≤3.0mg/kg (5-HT1A, 5-HT1B, 5-HT3 receptor occupancy: ~15%, 60%, 95%) in SA. Ondansetron exhibited a MED ≤3.0μg/kg (~25% 5-HT3 receptor occupancy; OR), but was inactive in the SA test. Flesinoxan had a MED ≤1.0mg/kg (~25% 5-HT1A receptor occupancy; SA); only 1.0mg/kg ameliorated deficits in the NOR. Chronic p.o. vortioxetine administration significantly improved memory performance in OR and occupied 95%, 66%, and 9.5% of 5-HT3, 5-HT1B, and 5-HT1A receptors, respectively. Vortioxetine's effects on SA performance may involve 5-HT1A receptor agonism, but not 5-HT3 receptor antagonism, whereas the effects on OR performance may involve 5-HT3 receptor antagonism and 5-HT1A receptor agonism.

KW - 5-HT depletion

KW - 5-HT receptor

KW - 5-HT receptor

KW - Cognitive dysfunction

KW - Major depressive disorder

KW - Vortioxetine

UR - http://www.scopus.com/inward/record.url?scp=84892475914&partnerID=8YFLogxK

U2 - 10.1016/j.euroneuro.2013.07.001

DO - 10.1016/j.euroneuro.2013.07.001

M3 - Article

VL - 24

SP - 160

EP - 171

JO - European Neuropsychopharmacology

JF - European Neuropsychopharmacology

SN - 0924-977X

IS - 1

ER -