Vol. 298, Issue 3, 964-969, September 2001

Dosing Time-Dependent Tolerance of Catalepsy by Repetitive Administration of Haloperidol in Mice

Jarupa Viyoch, Shigehiro Ohdo, Eiji Yukawa and Shun Higuchi

Department of Clinical Pharmacokinetics, Division of Pharmaceutical Sciences, Graduate School, Kyushu University, Higashi-Ku, Fukuoka, Japan

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 mid-light 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.