Involvement of 5-HT2A receptor hyperfunction in the anxiety-like behavior induced by doxorubicin and cyclophosphamide combination treatment in rats

Yuka Nakamura, Yoshihisa Kitamura, Yusuke Sumiyoshi, Nanami Naito, Shiho Kan, Soichiro Ushio, Ikuko Miyazaki, Masato Asanuma, Toshiaki Sendo

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Abstract

We examined whether combination treatment with doxorubicin and cyclophosphamide, a traditional chemotherapy for breast cancer, induced anxiety-like behavior in rats. Furthermore, we evaluated the role of the serotonin (5-HT)2A receptor subtype in the anxiety-like behavior induced by such chemotherapy. Rats were intraperitoneally injected with doxorubicin and cyclophosphamide once a week for 2 weeks. This caused the rats to display anxiety-like behavior during the light–dark test. In addition, we examined the rats’ 5-HT2A receptor-mediated behavioral responses. Combination treatment with doxorubicin and cyclophosphamide significantly increased (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane, (a 5-HT2A receptor agonist)-induced wet-dog shake activity. This anxiety-like behavior was significantly inhibited by mirtazapine, a 5-HT2A receptor antagonist/5-HT1A receptor agonist, and tandospirone, a partial 5-HT1A receptor agonist, but not by fluoxetine, a selective serotonin reuptake inhibitor. The anxiety-like behavior induced by doxorubicin and cyclophosphamide combination treatment is mediated by hyperfunctioning of the 5-HT2A receptor. Thus, 5-HT2A receptor antagonists or 5-HT1A receptor agonists might be useful for treating chemotherapy-induced anxiety disorders.

Original languageEnglish
JournalJournal of Pharmacological Sciences
DOIs
Publication statusAccepted/In press - Jan 1 2018

Fingerprint

Receptor, Serotonin, 5-HT2A
Doxorubicin
Cyclophosphamide
Anxiety
Serotonin 5-HT1 Receptor Agonists
Receptor, Serotonin, 5-HT1A
Serotonin 5-HT2 Receptor Antagonists
Drug Therapy
Therapeutics
Serotonin 5-HT2 Receptor Agonists
Fluoxetine
Serotonin Uptake Inhibitors
Anxiety Disorders
Serotonin
Dogs
Breast Neoplasms

Keywords

  • 5-HT receptor
  • Anxiety
  • Cyclophosphamide
  • Doxorubicin

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

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title = "Involvement of 5-HT2A receptor hyperfunction in the anxiety-like behavior induced by doxorubicin and cyclophosphamide combination treatment in rats",
abstract = "We examined whether combination treatment with doxorubicin and cyclophosphamide, a traditional chemotherapy for breast cancer, induced anxiety-like behavior in rats. Furthermore, we evaluated the role of the serotonin (5-HT)2A receptor subtype in the anxiety-like behavior induced by such chemotherapy. Rats were intraperitoneally injected with doxorubicin and cyclophosphamide once a week for 2 weeks. This caused the rats to display anxiety-like behavior during the light–dark test. In addition, we examined the rats’ 5-HT2A receptor-mediated behavioral responses. Combination treatment with doxorubicin and cyclophosphamide significantly increased (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane, (a 5-HT2A receptor agonist)-induced wet-dog shake activity. This anxiety-like behavior was significantly inhibited by mirtazapine, a 5-HT2A receptor antagonist/5-HT1A receptor agonist, and tandospirone, a partial 5-HT1A receptor agonist, but not by fluoxetine, a selective serotonin reuptake inhibitor. The anxiety-like behavior induced by doxorubicin and cyclophosphamide combination treatment is mediated by hyperfunctioning of the 5-HT2A receptor. Thus, 5-HT2A receptor antagonists or 5-HT1A receptor agonists might be useful for treating chemotherapy-induced anxiety disorders.",
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author = "Yuka Nakamura and Yoshihisa Kitamura and Yusuke Sumiyoshi and Nanami Naito and Shiho Kan and Soichiro Ushio and Ikuko Miyazaki and Masato Asanuma and Toshiaki Sendo",
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AU - Nakamura, Yuka

AU - Kitamura, Yoshihisa

AU - Sumiyoshi, Yusuke

AU - Naito, Nanami

AU - Kan, Shiho

AU - Ushio, Soichiro

AU - Miyazaki, Ikuko

AU - Asanuma, Masato

AU - Sendo, Toshiaki

PY - 2018/1/1

Y1 - 2018/1/1

N2 - We examined whether combination treatment with doxorubicin and cyclophosphamide, a traditional chemotherapy for breast cancer, induced anxiety-like behavior in rats. Furthermore, we evaluated the role of the serotonin (5-HT)2A receptor subtype in the anxiety-like behavior induced by such chemotherapy. Rats were intraperitoneally injected with doxorubicin and cyclophosphamide once a week for 2 weeks. This caused the rats to display anxiety-like behavior during the light–dark test. In addition, we examined the rats’ 5-HT2A receptor-mediated behavioral responses. Combination treatment with doxorubicin and cyclophosphamide significantly increased (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane, (a 5-HT2A receptor agonist)-induced wet-dog shake activity. This anxiety-like behavior was significantly inhibited by mirtazapine, a 5-HT2A receptor antagonist/5-HT1A receptor agonist, and tandospirone, a partial 5-HT1A receptor agonist, but not by fluoxetine, a selective serotonin reuptake inhibitor. The anxiety-like behavior induced by doxorubicin and cyclophosphamide combination treatment is mediated by hyperfunctioning of the 5-HT2A receptor. Thus, 5-HT2A receptor antagonists or 5-HT1A receptor agonists might be useful for treating chemotherapy-induced anxiety disorders.

AB - We examined whether combination treatment with doxorubicin and cyclophosphamide, a traditional chemotherapy for breast cancer, induced anxiety-like behavior in rats. Furthermore, we evaluated the role of the serotonin (5-HT)2A receptor subtype in the anxiety-like behavior induced by such chemotherapy. Rats were intraperitoneally injected with doxorubicin and cyclophosphamide once a week for 2 weeks. This caused the rats to display anxiety-like behavior during the light–dark test. In addition, we examined the rats’ 5-HT2A receptor-mediated behavioral responses. Combination treatment with doxorubicin and cyclophosphamide significantly increased (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane, (a 5-HT2A receptor agonist)-induced wet-dog shake activity. This anxiety-like behavior was significantly inhibited by mirtazapine, a 5-HT2A receptor antagonist/5-HT1A receptor agonist, and tandospirone, a partial 5-HT1A receptor agonist, but not by fluoxetine, a selective serotonin reuptake inhibitor. The anxiety-like behavior induced by doxorubicin and cyclophosphamide combination treatment is mediated by hyperfunctioning of the 5-HT2A receptor. Thus, 5-HT2A receptor antagonists or 5-HT1A receptor agonists might be useful for treating chemotherapy-induced anxiety disorders.

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