Vortioxetine treatment reverses subchronic PCP treatment-induced cognitive impairments

A potential role for serotonin receptor-mediated regulation of GABA neurotransmission

Alan Pehrson, Christian S. Pedersen, Kirstine Sloth Tølbøl, Connie Sanchez

Research output: Contribution to journalArticleResearchpeer-review

3 Citations (Scopus)

Abstract

Major depressive disorder (MDD) is associated with cognitive impairments that may contribute to poor functional outcomes. Clinical data suggests that the multimodal antidepressant vortioxetine attenuates some cognitive impairments in MDD patients, but the mechanistic basis for these improvements is unclear. One theory suggests that vortioxetine improves cognition by suppressing γ-amino butyric acid (GABA)ergic neurotransmission, thereby increasing glutamatergic activation. Vortioxetine's effects on cognition, GABA and glutamate neurotransmission have been supported in separate experiments, but no empirical work has directly connected vortioxetine's cognitive effects to those on GABA and glutamate neurotransmission. In this paper, we attempt to bridge this gap by evaluating vortioxetine's effects in the subchronic PCP (subPCP) model, which induces impaired cognitive function and altered GABA and glutamate neurotransmission. We demonstrate that acute or subchronic vortioxetine treatment attenuated subPCP-induced deficits in attentional set shifting (AST) performance, and that the selective 5-HT3 receptor antagonist ondansetron or the 5-HT reuptake inhibitor escitalopram could mimic this effect. Furthermore, acute vortioxetine treatment reversed subPCP-induced object recognition (OR) deficits in rats, while subchronic vortioxetine reversed subPCP-induced Object Recognition and object placement impairments in mice. Finally, subPCP treatment reduced GABAB receptor expression in a manner that was insensitive to vortioxetine treatment, and subchronic vortioxetine treatment alone, but not in combination with subPCP, significantly increased GABA's affinity for the GABAA receptor. These data suggest that vortioxetine reverses cognitive impairments in a model associated with altered GABA and glutamate neurotransmission, further supporting the hypothesis that vortioxetine's GABAergic and glutamatergic effects are relevant for cognitive function.

Original languageEnglish
Article number162
JournalFrontiers in Pharmacology
Volume9
Issue numberMAR
DOIs
StatePublished - 6 Mar 2018

Fingerprint

Serotonin Receptors
Synaptic Transmission
gamma-Aminobutyric Acid
Cognition
Glutamic Acid
Therapeutics
Major Depressive Disorder
Cognitive Dysfunction
vortioxetine
GABA Agents
Serotonin 5-HT3 Receptor Antagonists
Receptors, Serotonin, 5-HT3
Ondansetron
Citalopram
Butyric Acid
GABA-A Receptors
Antidepressive Agents
Serotonin

Keywords

  • Attentional set-shifting test
  • GABA
  • Novel object placement
  • Novel object recognition
  • Serotonin
  • Subchronic PCP
  • Vortioxetine

Cite this

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title = "Vortioxetine treatment reverses subchronic PCP treatment-induced cognitive impairments: A potential role for serotonin receptor-mediated regulation of GABA neurotransmission",
abstract = "Major depressive disorder (MDD) is associated with cognitive impairments that may contribute to poor functional outcomes. Clinical data suggests that the multimodal antidepressant vortioxetine attenuates some cognitive impairments in MDD patients, but the mechanistic basis for these improvements is unclear. One theory suggests that vortioxetine improves cognition by suppressing γ-amino butyric acid (GABA)ergic neurotransmission, thereby increasing glutamatergic activation. Vortioxetine's effects on cognition, GABA and glutamate neurotransmission have been supported in separate experiments, but no empirical work has directly connected vortioxetine's cognitive effects to those on GABA and glutamate neurotransmission. In this paper, we attempt to bridge this gap by evaluating vortioxetine's effects in the subchronic PCP (subPCP) model, which induces impaired cognitive function and altered GABA and glutamate neurotransmission. We demonstrate that acute or subchronic vortioxetine treatment attenuated subPCP-induced deficits in attentional set shifting (AST) performance, and that the selective 5-HT3 receptor antagonist ondansetron or the 5-HT reuptake inhibitor escitalopram could mimic this effect. Furthermore, acute vortioxetine treatment reversed subPCP-induced object recognition (OR) deficits in rats, while subchronic vortioxetine reversed subPCP-induced Object Recognition and object placement impairments in mice. Finally, subPCP treatment reduced GABAB receptor expression in a manner that was insensitive to vortioxetine treatment, and subchronic vortioxetine treatment alone, but not in combination with subPCP, significantly increased GABA's affinity for the GABAA receptor. These data suggest that vortioxetine reverses cognitive impairments in a model associated with altered GABA and glutamate neurotransmission, further supporting the hypothesis that vortioxetine's GABAergic and glutamatergic effects are relevant for cognitive function.",
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Vortioxetine treatment reverses subchronic PCP treatment-induced cognitive impairments : A potential role for serotonin receptor-mediated regulation of GABA neurotransmission. / Pehrson, Alan; Pedersen, Christian S.; Tølbøl, Kirstine Sloth; Sanchez, Connie.

In: Frontiers in Pharmacology, Vol. 9, No. MAR, 162, 06.03.2018.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Vortioxetine treatment reverses subchronic PCP treatment-induced cognitive impairments

T2 - A potential role for serotonin receptor-mediated regulation of GABA neurotransmission

AU - Pehrson, Alan

AU - Pedersen, Christian S.

AU - Tølbøl, Kirstine Sloth

AU - Sanchez, Connie

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AB - Major depressive disorder (MDD) is associated with cognitive impairments that may contribute to poor functional outcomes. Clinical data suggests that the multimodal antidepressant vortioxetine attenuates some cognitive impairments in MDD patients, but the mechanistic basis for these improvements is unclear. One theory suggests that vortioxetine improves cognition by suppressing γ-amino butyric acid (GABA)ergic neurotransmission, thereby increasing glutamatergic activation. Vortioxetine's effects on cognition, GABA and glutamate neurotransmission have been supported in separate experiments, but no empirical work has directly connected vortioxetine's cognitive effects to those on GABA and glutamate neurotransmission. In this paper, we attempt to bridge this gap by evaluating vortioxetine's effects in the subchronic PCP (subPCP) model, which induces impaired cognitive function and altered GABA and glutamate neurotransmission. We demonstrate that acute or subchronic vortioxetine treatment attenuated subPCP-induced deficits in attentional set shifting (AST) performance, and that the selective 5-HT3 receptor antagonist ondansetron or the 5-HT reuptake inhibitor escitalopram could mimic this effect. Furthermore, acute vortioxetine treatment reversed subPCP-induced object recognition (OR) deficits in rats, while subchronic vortioxetine reversed subPCP-induced Object Recognition and object placement impairments in mice. Finally, subPCP treatment reduced GABAB receptor expression in a manner that was insensitive to vortioxetine treatment, and subchronic vortioxetine treatment alone, but not in combination with subPCP, significantly increased GABA's affinity for the GABAA receptor. These data suggest that vortioxetine reverses cognitive impairments in a model associated with altered GABA and glutamate neurotransmission, further supporting the hypothesis that vortioxetine's GABAergic and glutamatergic effects are relevant for cognitive function.

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