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Antidepressant effects of AMPA and ketamine combination: role of hippocampal BDNF, synapsin, and mTOR

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Abstract

Rationale

A number of preclinical and clinical studies suggest that ketamine, a glutamate N-methyl-d-aspartate receptor antagonist, has a rapid and lasting antidepressant effect when administered either acutely or chronically. It has been postulated that this effect is due to stimulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors.

Objective

In this study, we tested whether AMPA alone has an antidepressant effect and if the combination of AMPA and ketamine provides added benefit in Wistar-Kyoto rats, a putative animal model of depression.

Results

Chronic AMPA treatment resulted in a dose-dependent antidepressant effect in both the forced swim test and sucrose preference test. Moreover, chronic administration (10–11 days) of combinations of AMPA and ketamine, at doses that were ineffective on their own, resulted in a significant antidepressant effect. The behavioral effects were associated with increases in hippocampal brain-derived neurotrophic factor, synapsin, and mammalian target of rapamycin.

Conclusion

These findings are the first to provide evidence for an antidepressant effect of AMPA and suggest the usefulness of AMPA–ketamine combination in treatment of depression. Furthermore, these effects appear to be associated with increases in markers of hippocampal neurogenesis and synaptogenesis, suggesting a mechanism of their action.

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Acknowledgments

This study was supported by NIH/NIGMS (2 SO6 GM08016-39).

Conflict of interest

The authors declare no conflict of interest.

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Authors and Affiliations

  1. Department of Pharmacology, Howard University College of Medicine, 520 W Street NW, Washington, DC, 20059, USA

    Luli Akinfiresoye & Yousef Tizabi

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  1. Luli Akinfiresoye
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  2. Yousef Tizabi
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Correspondence to Yousef Tizabi.

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Akinfiresoye, L., Tizabi, Y. Antidepressant effects of AMPA and ketamine combination: role of hippocampal BDNF, synapsin, and mTOR. Psychopharmacology 230, 291–298 (2013). https://doi.org/10.1007/s00213-013-3153-2

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  • DOI: https://doi.org/10.1007/s00213-013-3153-2

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