title: Differential interaction with the serotonin system by S-ketamine, vortioxetine, and fluoxetine in a genetic rat model of depression.
abstract: The mechanisms mediating ketamine's antidepressant effect have only been partly resolved. Recent preclinical reports implicate serotonin (5-hydroxytryptamine; 5-HT) in the antidepressant-like action of ketamine. Vortioxetine is a multimodal-acting antidepressant that is hypothesized to exert its therapeutic activity through 5-HT reuptake inhibition and modulation of several 5-HT receptors.
  
  
  
  The objective of this study was to evaluate the therapeutic-like profiles of S-ketamine, vortioxetine, and the serotonin reuptake inhibitor fluoxetine in response to manipulation of 5-HT tone.
  
  
  
  Flinders Sensitive Line (FSL) rats, a genetic model of depression, were depleted of 5-HT by repeated administration of 4-chloro-DL-phenylalanine methyl ester HCl (pCPA). Using pCPA-pretreated and control FSL rats, we investigated the acute and sustained effects of S-ketamine (15 mg/kg), fluoxetine (10 mg/kg), or vortioxetine (10 mg/kg) on recognition memory and depression-like behavior in the object recognition task (ORT) and forced swim test (FST), respectively.
  
  
  
  The behavioral phenotype of FSL rats was unaffected by 5-HT depletion. Vortioxetine, but not fluoxetine or S-ketamine, acutely ameliorated the memory deficits of FSL rats in the ORT irrespective of 5-HT tone. No sustained effects were observed in the ORT. In the FST, all three drugs demonstrated acute antidepressant-like activity but only S-ketamine had sustained effects. Unlike vortioxetine, the antidepressant-like responses of fluoxetine and S-ketamine were abolished by 5-HT depletion.
  
  
  
  These observations suggest that the acute and sustained antidepressant-like effects of S-ketamine depend on endogenous stimulation of 5-HT receptors. In contrast, the acute therapeutic-like effects of vortioxetine on memory and depression-like behavior may be mediated by direct activity at 5-HT receptors.
authors.affiliation: Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Skovagervej 2, 8240, Risskov, Denmark. du_jardin@clin.au.dk.
authors.forename: Kristian Gaarn
authors.initials: KG
authors.lastname: du Jardin
authors.affiliation: Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Skovagervej 2, 8240, Risskov, Denmark.
authors.forename: Nico
authors.initials: N
authors.lastname: Liebenberg
authors.affiliation: Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Skovagervej 2, 8240, Risskov, Denmark.
authors.forename: Heidi Kaastrup
authors.initials: HK
authors.lastname: Müller
authors.affiliation: Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Skovagervej 2, 8240, Risskov, Denmark.
authors.forename: Betina
authors.initials: B
authors.lastname: Elfving
authors.affiliation: Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Skovagervej 2, 8240, Risskov, Denmark.|Lundbeck US LLC, 215 College Rd, Paramus, NJ, 07652, USA.
authors.forename: Connie
authors.initials: C
authors.lastname: Sanchez
authors.affiliation: Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Skovagervej 2, 8240, Risskov, Denmark.|School of Pharmacy (Pharmacology), North-West University, 11 Hoffman St, Potchefstroom, 2531, South Africa.
authors.forename: Gregers
authors.initials: G
authors.lastname: Wegener
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000627:therapeutic use*; D000928:Antidepressive Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D003866:Depressive Disorder / Q000188:drug therapy*; D004195:Disease Models, Animal; D005473:Fluoxetine / Q000494:pharmacology*; D007649:Ketamine / Q000494:pharmacology*; D008124:Locomotion / Q000187:drug effects; D008297:Male; D008569:Memory Disorders / Q000188:drug therapy; D010879:Piperazines / Q000494:pharmacology*; D051381:Rats; D021641:Recognition, Psychology / Q000187:drug effects; D017367:Selective Serotonin Reuptake Inhibitors / Q000627:therapeutic use*; D013440:Sulfides / Q000494:pharmacology*; D013550:Swimming; D000078784:Vortioxetine
chemical_list: D014151:Anti-Anxiety Agents; D000928:Antidepressive Agents; D005473:Fluoxetine; D007649:Ketamine; D010879:Piperazines; D017367:Selective Serotonin Reuptake Inhibitors; D013440:Sulfides; D000078784:Vortioxetine
keywords: Antidepressants; Fluoxetine; Forced swim test; Ketamine; Object recognition; Serotonin; Vortioxetine