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

Eur Neuropsychopharmacol. 2014 Jan;24(1):148-59. doi: 10.1016/j.euroneuro.2013.10.011. Epub 2013 Nov 4.

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.

Keywords: 5-HT depletion; Cognitive impairment; Lu AA21004; Major depressive disorder; Memory; Vortioxetine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 5-Hydroxytryptophan / administration & dosage
  • Animals
  • Carbidopa / administration & dosage
  • Citalopram / therapeutic use*
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Duloxetine Hydrochloride
  • Exploratory Behavior / drug effects
  • Female
  • Hippocampus / drug effects
  • Hippocampus / metabolism
  • Maze Learning / drug effects
  • Memory Disorders / chemically induced
  • Memory Disorders / drug therapy*
  • Memory Disorders / metabolism
  • Memory Disorders / pathology
  • Phenylalanine / analogs & derivatives
  • Phenylalanine / pharmacology
  • Piperazines / therapeutic use*
  • Protein Binding / drug effects
  • Rats
  • Rats, Long-Evans
  • Recognition, Psychology / drug effects
  • Selective Serotonin Reuptake Inhibitors / therapeutic use*
  • Serotonin / deficiency*
  • Sulfides / therapeutic use*
  • Thiophenes / therapeutic use*
  • Vortioxetine

Substances

  • Piperazines
  • Serotonin Uptake Inhibitors
  • Sulfides
  • Thiophenes
  • Citalopram
  • phenylalanine methyl ester
  • Serotonin
  • Vortioxetine
  • Phenylalanine
  • Duloxetine Hydrochloride
  • 5-Hydroxytryptophan
  • Carbidopa