Abstract

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 D₂receptor 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.