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

May 30, 2016Psychopharmacology

Different effects of S-ketamine, vortioxetine, and fluoxetine on the serotonin system in a genetic rat model of depression

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Abstract

Vortioxetine improved memory deficits in depressed rats, while s-ketamine showed sustained antidepressant effects.

The behavioral phenotype of depressed rats remained unchanged despite serotonin depletion.
Vortioxetine acutely improved memory in depressed rats, independent of serotonin levels.
No long-lasting effects on memory were observed for vortioxetine.
All three antidepressants exhibited acute effects in a forced swim test, indicating immediate antidepressant-like activity.
Only s-ketamine maintained its antidepressant-like effects over time, while those of fluoxetine and s-ketamine were diminished by serotonin depletion.

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

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