Differential interaction with the serotonin system by S-ketamine, vortioxetine, and fluoxetine in a genetic rat model of depression

• Published in: Psychopharmacology Vol. 233; no. 14; pp. 2813 - 2825
• Main Authors: du Jardin, Kristian Gaarn, Liebenberg, Nico, Müller, Heidi Kaastrup, Elfving, Betina, Sanchez, Connie, Wegener, Gregers
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.07.2016; Springer; Springer Nature B.V
• Subjects: Animal research models; Animals; Anti-Anxiety Agents - therapeutic use; Antidepressants; Antidepressive Agents - pharmacology; Behavior, Animal - drug effects; Biomedical and Life Sciences; Biomedicine; Comparative analysis; Depression (Mood disorder); Depressive Disorder - drug therapy; Disease Models, Animal; Dosage and administration; Drug therapy; Fluoxetine; Fluoxetine - pharmacology; Ketamine; Ketamine - pharmacology; Locomotion - drug effects; Male; Memory Disorders - drug therapy; Mental depression; Neurosciences; Original Investigation; Patient outcomes; Pharmacology/Toxicology; Piperazines - pharmacology; Psychiatry; Rats; Recognition (Psychology) - drug effects; Serotonin; Serotonin Uptake Inhibitors - therapeutic use; Sulfides - pharmacology; Swimming; Vortioxetine; Ketamine; Forced swim test; Serotonin; Fluoxetine; Antidepressants; Object recognition; Vortioxetine
• ISSN: 0033-3158; 1432-2072
• DOI: 10.1007/s00213-016-4327-5

Rationale 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. Objectives 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. Method 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. Results 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. Conclusions 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.