title: Vortioxetine, but not escitalopram or duloxetine, reverses memory impairment induced by central 5-HT depletion in rats: evidence for direct 5-HT receptor modulation.
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.
authors.affiliation: Lundbeck Research USA, Inc., 215 College Road, 07652 Paramus, NJ, United States.
authors.forename: Jesper Bornø
authors.initials: JB
authors.lastname: Jensen
authors.affiliation: Lundbeck Research USA, Inc., 215 College Road, 07652 Paramus, NJ, United States.
authors.forename: Kristian Gaarn
authors.initials: KG
authors.lastname: du Jardin
authors.affiliation: Lundbeck Research USA, Inc., 215 College Road, 07652 Paramus, NJ, United States.
authors.forename: Dekun
authors.initials: D
authors.lastname: Song
authors.affiliation: Lundbeck Research USA, Inc., 215 College Road, 07652 Paramus, NJ, United States.
authors.forename: David
authors.initials: D
authors.lastname: Budac
authors.affiliation: Lundbeck Research USA, Inc., 215 College Road, 07652 Paramus, NJ, United States.
authors.forename: Gennady
authors.initials: G
authors.lastname: Smagin
authors.affiliation: Lundbeck Research USA, Inc., 215 College Road, 07652 Paramus, NJ, United States.
authors.forename: Connie
authors.initials: C
authors.lastname: Sanchez
authors.affiliation: Lundbeck Research USA, Inc., 215 College Road, 07652 Paramus, NJ, United States. Electronic address: apeh@lundbeck.com.
authors.forename: Alan Lars
authors.initials: AL
authors.lastname: Pehrson
mesh_terms: D006916:5-Hydroxytryptophan / Q000008:administration & dosage; D000818:Animals; D002230:Carbidopa / Q000008:administration & dosage; D015283:Citalopram / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D000068736:Duloxetine Hydrochloride; D005106:Exploratory Behavior / Q000187:drug effects; D005260:Female; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D018782:Maze Learning / Q000187:drug effects; D008569:Memory Disorders / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000494:pharmacology; D010879:Piperazines / Q000627:therapeutic use*; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D020318:Rats, Long-Evans; D021641:Recognition, Psychology / Q000187:drug effects; D012701:Serotonin / Q000172:deficiency*; D017367:Selective Serotonin Reuptake Inhibitors / Q000627:therapeutic use*; D013440:Sulfides / Q000627:therapeutic use*; D013876:Thiophenes / Q000627:therapeutic use*; D000078784:Vortioxetine
chemical_list: D006916:5-Hydroxytryptophan; D002230:Carbidopa; D015283:Citalopram; D000068736:Duloxetine Hydrochloride; D010649:Phenylalanine; D010879:Piperazines; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors; D013440:Sulfides; D013876:Thiophenes; D000078784:Vortioxetine; C034515:phenylalanine methyl ester
keywords: 5-HT depletion; Cognitive impairment; Lu AA21004; Major depressive disorder; Memory; Vortioxetine