Circadian Rhythms in Toxic Effects of the Serotonin Antagonist Ondansetron in Mice

Achraf Khedhaier, Mossadok Ben Attia, Wafa Gadacha, Mamane Sani, Kamel Bouzouita, Lotfi Chouchane, Mohamed Mechkouri, Alain Reinberg, Naceur A. Boughattass

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

The aim of the study was to learn whether the lethal and the motor incoordination (ataxia) side effect of ondansetron (Zophren®) administration is dosing-time dependent. Ondansetron is a serotonin 5-HT 3 receptor antagonist used primarily to control nausea and vomiting arising from cytotoxic chemo- and radiotherapy. A total of 210 male Swiss mice 10 to 12 weeks of age were synchronized for 3 weeks by 12h light (rest span)/ 12h dark (activity span). Different doses of ondansetron were injected intraperitoneally (i.p.) at fixed times during the day to determine both the sublethal (TD50) and lethal (LD50) doses, which were, respectively, 3.7 ± 0.6 mg/kg and 4.6 ± 0.5 mg/kg. In the chronotoxicologic study a single dose of ondansetron (3.5 mg/kg, i.p.) was administered to different and comparable groups of animals at four different circadian stages [1, 7, 13, and 19h after light onset (HALO)]. The lethal toxicity was statistically significantly dosing time-dependent (χ 2 = 21.51, p < 0.0001). Drug dosing at 1 HALO resulted in 100% survival rate whereas drug dosing at 19 HALO was only one-half that (52%). Similarly, lowest and highest ataxia occurred when ondansetron was injected at 1 and 19 HALO, respectively (χ2 = 22.24, p < 0.0001). Effects on rectal temperature were also dosing-time related (Cosinor analysis, p < 0.0001). The characteristics of the waveform describing the temporal patterns differed between the studied variables, e.g., lethal toxicity and survival rate showing two peaks and rectal temperature showing one peak in the 24h time series waveform pattern. Cosinor analysis also revealed a statistically significant ultradian (r ≡ 8h) rhythmic component in the considered variables. Differences in curve patterns in toxicity elicited by ondansetron on a per end point basis are hypothesized to represent the phase relations between the identified 24h and 8h periodicities.

Original languageEnglish
Pages (from-to)1103-1116
Number of pages14
JournalChronobiology International
Volume20
Issue number6
DOIs
Publication statusPublished - 2003
Externally publishedYes

Fingerprint

Ondansetron
Serotonin Antagonists
Poisons
Circadian Rhythm
serotonin
circadian rhythm
antagonists
toxicity
mice
Ataxia
dosage
survival rate
ataxia (disorder)
drugs
nausea
radiotherapy
vomiting
lethal dose 50
periodicity
drug therapy

Keywords

  • Ataxia
  • Circadian rhythm
  • Lethality
  • Mice
  • Motor incoordination
  • Ondansetron
  • Serotoninrgic system

ASJC Scopus subject areas

  • Agricultural and Biological Sciences (miscellaneous)
  • Physiology
  • Physiology (medical)

Cite this

Khedhaier, A., Attia, M. B., Gadacha, W., Sani, M., Bouzouita, K., Chouchane, L., ... Boughattass, N. A. (2003). Circadian Rhythms in Toxic Effects of the Serotonin Antagonist Ondansetron in Mice. Chronobiology International, 20(6), 1103-1116. https://doi.org/10.1081/CBI-120025532

Circadian Rhythms in Toxic Effects of the Serotonin Antagonist Ondansetron in Mice. / Khedhaier, Achraf; Attia, Mossadok Ben; Gadacha, Wafa; Sani, Mamane; Bouzouita, Kamel; Chouchane, Lotfi; Mechkouri, Mohamed; Reinberg, Alain; Boughattass, Naceur A.

In: Chronobiology International, Vol. 20, No. 6, 2003, p. 1103-1116.

Research output: Contribution to journalArticle

Khedhaier, A, Attia, MB, Gadacha, W, Sani, M, Bouzouita, K, Chouchane, L, Mechkouri, M, Reinberg, A & Boughattass, NA 2003, 'Circadian Rhythms in Toxic Effects of the Serotonin Antagonist Ondansetron in Mice', Chronobiology International, vol. 20, no. 6, pp. 1103-1116. https://doi.org/10.1081/CBI-120025532
Khedhaier, Achraf ; Attia, Mossadok Ben ; Gadacha, Wafa ; Sani, Mamane ; Bouzouita, Kamel ; Chouchane, Lotfi ; Mechkouri, Mohamed ; Reinberg, Alain ; Boughattass, Naceur A. / Circadian Rhythms in Toxic Effects of the Serotonin Antagonist Ondansetron in Mice. In: Chronobiology International. 2003 ; Vol. 20, No. 6. pp. 1103-1116.
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