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Rapamycin blocks the antidepressant effect of ketamine in task-dependent manner

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Abstract

Objective

The aim of our study was to test whether ketamine produces an antidepressant effect in animal model of olfactory bulbectomy and assess the role of mammalian target of rapamycin (mTOR) pathway in ketamine’s antidepressant effect.

Methods

Bulbectomized (OBX) rats and sham controls were assigned to four subgroups according to the treatment they received (ketamine, saline, ketamine + rapamycin, and saline + rapamycin). The animals were subjected to open field (OF), elevated plus maze (EPM), passive avoidance (PA), Morris water maze (MWM), and Carousel maze (CM) tests. Blood samples were collected before and after drug administration for analysis of phosphorylated mTOR level. After behavioral testing, brains were removed for evaluation of brain-derived neurotrophic factor (BDNF) in prefrontal cortex (PFC) and hippocampus.

Results

Ketamine normalized hyperactivity of OBX animals in EPM and increased the time spent in open arms. Rapamycin pretreatment resulted in elimination of ketamine effect in EPM test. In CM test, ketamine + rapamycin administration led to cognitive impairment not observed in saline-, ketamine-, or saline + rapamycin-treated OBX rats. Prefrontal BDNF content was significantly decreased, and level of mTOR was significantly elevated in OBX groups.

Conclusions

OBX animals significantly differed from sham controls in most of the tests used. Treatment had more profound effect on OBX phenotype than controls. Pretreatment with rapamycin eliminated the anxiolytic and antidepressant effects of ketamine in task-dependent manner. The results indicate that ketamine + rapamycin application resulted in impaired stress responses manifested by cognitive deficits in active place avoidance (CM) test. Intensity of stressor (mild vs. severe) used in the behavioral tests had opposite effect on controls and on OBX animals.

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Acknowledgments

This study was supported by grant IGAMZCR NT13403-4/2012 and institutional support RVO:67985823 and NIMH-CZ ED2.1.00/03.0078 and the European Regional Development Fund. We would like to thank Michaela Fialova for the technical assistance and Barbara Stuchlikova for the graphical assistance with the figures.

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Authors and Affiliations

  1. The Institute of Physiology, Academy of Sciences of the Czech Republic, v.v.i., Videnska 1083, 14220, Prague, Czech Republic

    Kristina Holubova, Lenka Kleteckova, Martina Skurlova, Ales Stuchlik & Karel Vales

  2. National Institute of Mental Health, Topolova 748, 250 67 Klecany, Prague East, Czech Republic

    Kristina Holubova, Lenka Kleteckova, Martina Skurlova, Jan Ricny & Karel Vales

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  1. Kristina Holubova
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  2. Lenka Kleteckova
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  6. Karel Vales
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Correspondence to Karel Vales.

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Holubova, K., Kleteckova, L., Skurlova, M. et al. Rapamycin blocks the antidepressant effect of ketamine in task-dependent manner. Psychopharmacology 233, 2077–2097 (2016). https://doi.org/10.1007/s00213-016-4256-3

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