Dosing time-dependent tolerance of catalepsy by repetitive administration of haloperidol in mice

Jarupa Viyoch, Shigehiro Ohdo, Eiji Yukawa, Shun Higuchi

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19 Citations (Scopus)


To investigate the effect of repeated administration time on the development of tolerance, male ICR mice, housed under 12: 12-h light/dark cycle (7:00 AM, lights on), were treated with haloperidol 4 mg/kg/day i.p. at 9:00 AM or 9:00 PM, the time nearly corresponding to the maximal or minimal catalepsy responses to a single dose, respectively, for 14 days and catalepsy responses were monitored at 1 h after administration each day. The findings indicated that, on day 1 to day 6, a greater development of tolerance was seen in the group of mice treated at 9:00 AM, and catalepsy behavior exhibited a significant difference between the two dosing times (P < 0.01). The study of D2 receptor mRNA expression in mouse striatum revealed that the phase of D2 receptor mRNA rhythm was similar to that of catalepsy response, with the maximum around midlight and the minimum around mid-dark. After repeated administration, the increase in D2 receptor mRNA levels in mice treated with haloperidol at 9:00 AM was higher than that of mice treated with haloperidol at 9:00 PM. In addition, from a [3H]spiperone binding study, the amount of binding site [3H]spiperone after repeated injection of haloperidol at 9:00 AM was greater than that after repeated injection at 9:00 PM. These findings demonstrate the importance of dosing time on the susceptibility to extrapyramidal effects and the relation of administration time to D2 receptor change and tolerance.

Original languageEnglish
Pages (from-to)964-969
Number of pages6
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number3
Publication statusPublished - 2001

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology


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