Influence of 5-HT2A receptor function on anxiety-like behavior induced by a combination treatment with doxorubicin and cyclophosphamide in rats

• Published in: Psychopharmacology Vol. 238; no. 12; pp. 3607 - 3614
• Main Authors: Tabuchi, Hironori, Kitamura, Yoshihisa, Ushio, Soichiro, Kan, Shiho, Wada, Yudai, Sumiyoshi, Yusuke, Izushi, Yasuhisa, Miyazaki, Ikuko, Asanuma, Masato, Sendo, Toshiaki
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01-12-2021; Springer Nature B.V
• Subjects: Anxiety; Biomedical and Life Sciences; Biomedicine; Chemotherapy; Cortex (frontal); Cyclophosphamide; Doxorubicin; Extracellular signal-regulated kinase; Fluoxetine; Hippocampus; Hyperactivity; Microdialysis; Neurosciences; Original Investigation; Pharmacology/Toxicology; Phosphorylation; Psychiatry; Serotonin S2 receptors; Western blotting; Cyclophosphamide; Anxiety; receptor; 5-HT; Fluoxetine; Doxorubicin
• ISSN: 0033-3158; 1432-2072
• DOI: 10.1007/s00213-021-05979-5

Anxiety-like behavior induced by a combination of doxorubicin and cyclophosphamide may be mediated by serotonin (5-HT)
2A
receptor hyperactivity. The anxiolytic effects of fluoxetine may be inhibited by this combination. The present study examined the mechanisms underlying anxiety-like behavior induced by the combination doxorubicin and cyclophosphamide in rats. Anxiety-like behavior was induced during a light–dark test by the doxorubicin and cyclophosphamide treatment (once a week for 2 weeks). 5-HT
2A
receptor and 5-HT
2A
receptor-mediated extracellular signal-related kinase (ERK)1/2 levels were measured using Western blotting. 5-HT reuptake activity in fluoxetine-treated rats was also examined using microdialysis. ( ±)-1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane, a 5-HT
2A
receptor agonist, induced anxiety-like behavior. The fluoxetine treatment increased extracellular 5-HT concentrations in the hippocampus of vehicle- and doxorubicin and cyclophosphamide-treated rats. 5-HT transporter levels in the hippocampus were not affected by chemotherapy. The doxorubicin and cyclophosphamide treatment did not alter 5-HT
2A
receptor levels in the frontal cortex. However, chemotherapy increased 5-HT
2A
receptor-mediated ERK1/2 phosphorylation levels significantly more than the vehicle treatment. The present results suggest that anxiety-like behavior induced by the combination of doxorubicin and cyclophosphamide is mediated by 5-HT
2A
receptor hyperactivity without an increase in 5-HT
2A
receptor levels in rats.