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

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Abstract

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.

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Acknowledgments

This study was supported by H. Lundbeck A/S and the AU-IDEAS initiative (eMOOD). The funders had no role in study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.

We gratefully acknowledge Pia Høgh Plougmann for the skillful technical assistance.

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Authors and Affiliations

  1. Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Skovagervej 2, 8240, Risskov, Denmark

    Kristian Gaarn du Jardin, Nico Liebenberg, Heidi Kaastrup Müller, Betina Elfving, Connie Sanchez & Gregers Wegener

  2. Lundbeck US LLC, 215 College Rd, Paramus, NJ, 07652, USA

    Connie Sanchez

  3. School of Pharmacy (Pharmacology), North-West University, 11 Hoffman St, Potchefstroom, 2531, South Africa

    Gregers Wegener

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  1. Kristian Gaarn du Jardin
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  2. Nico Liebenberg
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Correspondence to Kristian Gaarn du Jardin.

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Kristian Gaarn du Jardin has received travel grants from H. Lundbeck A/S. Connie Sanchez is a fulltime employee of Lundbeck US LLC. Gregers Wegener declares having received lecture fees from H. Lundbeck A/S, Servier SA, Astra Zeneca AB, Eli Lilly A/S, Sun Pharma Pty Ltd, and Pfizer Inc.

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du Jardin, K.G., Liebenberg, N., Müller, H.K. et al. Differential interaction with the serotonin system by S-ketamine, vortioxetine, and fluoxetine in a genetic rat model of depression. Psychopharmacology 233, 2813–2825 (2016). https://doi.org/10.1007/s00213-016-4327-5

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