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Influence of nicotine on doxorubicin and cyclophosphamide combination treatment-induced spatial cognitive impairment and anxiety-like behavior in rats

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Abstract

In the present study, we examined the effects of nicotine on cognitive impairment, anxiety-like behavior, and hippocampal cell proliferation in rats treated with a combination of doxorubicin and cyclophosphamide. Combined treatment with doxorubicin and cyclophosphamide produced cognitive impairment and anxiety-like behavior in rats. Nicotine treatment reversed the inhibition of novel location recognition induced by the combination treatment. This effect of nicotine was blocked by methyllycaconitine, a selective α7 nicotinic acetylcholine receptor (nAChR) antagonist, and dihydro-β-erythroidine, a selective α4β2 nAChR antagonist. In addition, nicotine normalized the amount of spontaneous alternation seen during the Y-maze task, which had been reduced by the combination treatment. This effect of nicotine was inhibited by dihydro-β-erythroidine. In comparison, nicotine did not affect the anxiety-like behavior induced by the combination treatment. Furthermore, the combination treatment reduced the number of proliferating cells in the subgranular zone of the hippocampal dentate gyrus, and this was also prevented by nicotine. Finally, the combination of doxorubicin and cyclophosphamide significantly reduced hippocampal α7 nAChR mRNA expression. These results suggest that nicotine inhibits doxorubicin and cyclophosphamide-induced cognitive impairment via α7 nAChR and α4β2 nAChR, and also enhances hippocampal neurogenesis.

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Acknowledgements

This study was supported by a grant from the Smoking Research Foundation in Japan (YK). The funders had no role in the study design, data collection, analysis, or the decision to prepare or submit the manuscript.

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Authors and Affiliations

  1. Department of Clinical Pharmacy; Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-cho; Kita-ku, Okayama, 700-8558, Japan

    Yoshihisa Kitamura, Erika Kanemoto, Misaki Sugimoto, Ayumi Machida, Yuka Nakamura, Nanami Naito, Hirotaka Kanzaki & Toshiaki Sendo

  2. Department of Medical Neurobiology; Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-cho; Kita-ku, Okayama, 700-8558, Japan

    Ikuko Miyazaki & Masato Asanuma

Authors
  1. Yoshihisa Kitamura
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  2. Erika Kanemoto
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  3. Misaki Sugimoto
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  4. Ayumi Machida
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  5. Yuka Nakamura
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  6. Nanami Naito
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  7. Hirotaka Kanzaki
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  8. Ikuko Miyazaki
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  9. Masato Asanuma
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  10. Toshiaki Sendo
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Corresponding author

Correspondence to Yoshihisa Kitamura.

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The authors declare that they have no conflict of interest.

Authors’ contributions

Conceived and designed the experiments: YK, EK, MS, HK, IM, MA, and TS. Performed the experiments: YK, EK, MS, AM, YN, NN, and HK. Analyzed the data: YK, EK, MS, AM, and HK. Contributed reagents/materials/analysis tools: YK, EK, MS, HK, IM, and MA. Wrote the paper: YK, EK, and MS.

Funding

This work was supported by a grant from the Smoking Research Foundation in Japan (YK). The funders had no role in the study design, data collection, or analysis, or the decision to prepare or submit the manuscript.

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Kitamura, Y., Kanemoto, E., Sugimoto, M. et al. Influence of nicotine on doxorubicin and cyclophosphamide combination treatment-induced spatial cognitive impairment and anxiety-like behavior in rats. Naunyn-Schmiedeberg's Arch Pharmacol 390, 369–378 (2017). https://doi.org/10.1007/s00210-016-1338-z

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  • DOI: https://doi.org/10.1007/s00210-016-1338-z

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