Circadian variation in the ambulation-increasing effect of apomorphine was investigated after repeated administration in mice. The mice housed in a 12 hr light-dark situation (light period; 6:00-18:00) were treated with apomorphine (0.5 mg/kg) or physiological saline vehicle sc at one of 6 times of day (3:30, 7:30, 11:30, 15:30, 19:30 and 23:30). The same treatment was carried out 5 times at intervals of 7 days, and the ambulatory activity was measured for 1 hr after each administration. Repeated administration of apomorphine produced a reverse tolerance (an augmentation in the activity) to the drug. However, the circadian variation in the activity, which was at maximum during the late dark period (administration at 3:30) and at minimum during the late light period (administration at 15:30), was well maintained even after the repeated administration. The circadian variation in the ambulatory activity observed at the 1st administration in the saline-treated control mice, which was at maximum and minimum during the late dark period and mid light period (administration at 11:30), respectively, tended to abolish after the repeated saline administration. The mice that experienced repeated administration of apomorphine exhibited a cross reverse tolerance to methamphetamine (1 mg/kg sc). The cross reverse tolerance occurred throughout the day, and the circadian variation in the effect of methamphetamine, which was similar to that of apomorphine, was also maintained.