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Ketamine elicits sustained antidepressant-like activity via a serotonin-dependent mechanism

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Abstract

Rationale

Behavioural antidepressant-like effects of ketamine have been reported in the forced swimming test (FST). The mechanisms mediating such effects are unknown.

Objectives

As serotonin (5-HT) is an important transmitter mediating antidepressant responsiveness in the FST, the influence of 5-HT depletion on the antidepressant-like effect of ketamine was assessed.

Methods

The effect of ketamine (25 mg/kg, i.p., 1 or 24 h prior to test) was assessed in the FST in naive rats or animals subjected to 5-HT depletion, repeated stress or following a combination of 5-HT depletion and stress. Endogenous 5-HT was depleted using the tryptophan hydroxylase inhibitor para-chlorophenylalanine (3 × 150 mg/kg, i.p.). Stress was induced by physical restraint (2 h/day for 10 days).

Results

In naive rats, ketamine administered 24 or 1 h prior to test produced a characteristic antidepressant-like reduction in immobility time in the FST. Depletion of 5-HT blocked this reduction in immobility when ketamine was administered 24 h prior FST, indicative of 5-HT dependency. The increase in immobility provoked by repeated restraint stress (2 h/day for 10 days) was blocked by ketamine when administered 24 h prior to FST, but this effect dissipated when animals were subjected to 5-HT depletion.

Conclusions

These observations are consistent with a role for 5-HT in mediating sustained antidepressant activity of ketamine in the FST. Molecular and cellular changes induced by ketamine may produce a rapid adaptation of 5-HT transmission which underlies the antidepressant response.

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Acknowledgments

The authors gratefully acknowledge support from the Health Research Board of Ireland.

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Authors and Affiliations

  1. Neuropsychopharmacology Research Group, School of Pharmacy & Pharmaceutical Sciences and Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin 2, Ireland

    Valentina Gigliucci, Grainne O’Dowd, Sheena Casey, Danielle Egan, Sinead Gibney & Andrew Harkin

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  1. Valentina Gigliucci
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  2. Grainne O’Dowd
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  3. Sheena Casey
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  4. Danielle Egan
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  5. Sinead Gibney
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  6. Andrew Harkin
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Correspondence to Andrew Harkin.

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Gigliucci, V., O’Dowd, G., Casey, S. et al. Ketamine elicits sustained antidepressant-like activity via a serotonin-dependent mechanism. Psychopharmacology 228, 157–166 (2013). https://doi.org/10.1007/s00213-013-3024-x

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  • DOI: https://doi.org/10.1007/s00213-013-3024-x

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