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Anxiolytic effects of ketamine in animal models of posttraumatic stress disorder

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Abstract

This study investigated the effectiveness of ketamine, a noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist, in alleviating the enhanced anxiety and fear response in both a mouse model of PTSD induced by inescapable electric foot shocks and a rat model of PTSD induced by a time-dependent sensitization (TDS) procedure. First, we evaluated the effect of ketamine on behavioral deficits in a mouse model of PTSD that consisted of foot shocks followed by three situational reminders. Our results showed that the aversive procedure induced several behavioral deficiencies, such as increased freezing behavior and anxiety, as well as reduced time spent in an aversive-like context, which were reversed by repeated treatment with ketamine. The effect of ketamine on behavioral changes after exposure to TDS was also investigated, and the levels of brain-derived neurotrophic factor (BDNF) in the hippocampus were measured. The results revealed that after TDS, the rats showed a significant increase in contextual freezing and a decrease in the percentage of time spent in and numbers of entries into open arms in the elevated plus maze test. As a positive control drug, sertraline (Ser, 15 mg/kg, i.g.), a selective serotonin reuptake inhibitor (SSRI) ameliorated these behavioral deficits. These behavioral effects were mimicked by chronic ketamine treatment. Furthermore, ketamine normalized the decreased BDNF level in the hippocampus in post-TDS rats. Taken together, these results suggest that ketamine exerts a therapeutic effect on PTSD that might be at least partially mediated by an influence on BDNF signaling in the hippocampus.

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Abbreviations

ANOVA:

Analysis of variance

BDNF:

Brain-derived neurotrophic factor

NMDA:

N-methyl-d-aspartate

PTSD:

Posttraumatic stress disorder

TDS:

Time-dependent sensitization

SSRIs:

Selective serotonin reuptake inhibitors

EPM:

Elevated plus maze

ST:

Staircase test

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Acknowledgments

This study was supported by the National Natural Science Foundation of China (No. 81001653, 30973516, 81102423, 81102498, 81072624, and 81173036) and the National Key New Drug Creation Program (No. 2012ZX09102101-004, 2012ZX09J12110-02C, and 2012ZX09J12201-004).

Conflicts of interest

The authors report no conflicts of interest.

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Authors and Affiliations

  1. Department of New Drug Evaluation, Beijing Institute of Pharmacology and Toxicology, 27 Taiping Road, Haidian, Beijing, 100850, China

    Li-Ming Zhang, Wen-Wen Zhou, Ya-Jun Ji, Nan Zhao, Hong-Xia Chen, Rui Xue, You-Zhi Zhang & Yun-Feng Li

  2. Department of Anesthesiology, 309 Hospital of PLA, 17 Heishanhu Road, Haidian, Beijing, 100091, China

    Wen-Wen Zhou, Ya-Jun Ji & Heng-Lin Wang

  3. Hebei North University, No. 11 Diamond Road, New District, Zhangjiakou, 075000, China

    Wen-Wen Zhou, Ya-Jun Ji & Heng-Lin Wang

  4. Pharmaceutical Department, Beijing Institute of Pharmacology and Toxicology, 27 Taiping Road, Haidian, Beijing, 100850, China

    Ying Li & Xin-Guo Mei

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  1. Li-Ming Zhang
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  2. Wen-Wen Zhou
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  9. You-Zhi Zhang
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  10. Heng-Lin Wang
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  11. Yun-Feng Li
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Correspondence to You-Zhi Zhang or Heng-Lin Wang.

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Author contributions

Author Zhang (Li-ming Zhang) performed the research design, data analysis, and manuscript writing. Authors Wen-Wen Zhou, Ya-Jun Ji, and Ying Li performed the behavioral tests and Western blotting. Nan-Zhao, Hong-Xia Chen, and Rui Xue participated in behavioral tests. Authors Zhang (You-Zhi Zhang) and Wang contributed to research design, data analysis, and manuscript revision. Authors Mei and Li contributed to research design and manuscript revision.

Li-Ming Zhang and Wen-Wen Zhou contributed equally to this study.

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Zhang, LM., Zhou, WW., Ji, YJ. et al. Anxiolytic effects of ketamine in animal models of posttraumatic stress disorder. Psychopharmacology 232, 663–672 (2015). https://doi.org/10.1007/s00213-014-3697-9

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