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.
authors.affiliation: Lundbeck Research USA, Inc., 215 College Road, 07652 Paramus, NJ, United States. Electronic address: apeh@lundbeck.com.
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: Jesper Bornø
authors.initials: JB
authors.lastname: Jensen
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.
authors.forename: Alan L
authors.initials: AL
authors.lastname: Pehrson
mesh_terms: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000493:pharmacokinetics; D000818:Animals; D001549:Benzamides / Q000493:pharmacokinetics; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D007191:Indazoles / Q000493:pharmacokinetics; D018782:Maze Learning / Q000187:drug effects; D008569:Memory Disorders / Q000139:chemically induced / Q000188:drug therapy*; D008570:Memory, Short-Term / Q000187:drug effects*; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000494:pharmacology; D010879:Piperazines / Q000627:therapeutic use*; D011485:Protein Binding / Q000187:drug effects; D011725:Pyridines / Q000493:pharmacokinetics; D051381:Rats; D020318:Rats, Long-Evans; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism; D044406:Receptors, Serotonin, 5-HT3 / Q000378:metabolism; D021641:Recognition, Psychology / Q000187:drug effects*; D058825:Serotonin 5-HT1 Receptor Agonists / Q000627:therapeutic use*; D058831:Serotonin 5-HT3 Receptor Antagonists / Q000627:therapeutic use*; D013440:Sulfides / Q000627:therapeutic use*; D013997:Time Factors; D014316:Tritium / Q000493:pharmacokinetics; D014326:Tropanes / Q000493:pharmacokinetics; D000078784:Vortioxetine
chemical_list: D001549:Benzamides; D007191:Indazoles; C107225:N-(4-methoxy-3-(4-methylpiperazin-1-yl)phenyl)-3-methyl-4-(4-pyridyl)benzamide; D010879:Piperazines; D011725:Pyridines; D044406:Receptors, Serotonin, 5-HT3; D058825:Serotonin 5-HT1 Receptor Agonists; D058831:Serotonin 5-HT3 Receptor Antagonists; D013440:Sulfides; D014326:Tropanes; D014316:Tritium; D044282:Receptor, Serotonin, 5-HT1A; C061531:LY 278584; C034515:phenylalanine methyl ester; D000078784:Vortioxetine; D010649:Phenylalanine; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin
keywords: 5-HT depletion; 5-HT(1A) receptor; 5-HT(3) receptor; Cognitive dysfunction; Major depressive disorder; Vortioxetine