The present study investigated the effects of HPE on caffeine-induced locomotor activity in mice. Caffeine (416 mg/kg) or saline were given to adult male Swiss-Webster mice, and the locomotor activity was immediately measured for 30 min. HPE (6-48 mg/kg) and saline were injected to another group (,of mice and the locomotor activity was measured 20 min later. HPE (6-24 mg/kg) was also administered to another group of mice 20 min before caffeine (16 mg/kg) injections and the locomotor activity was recorded for 30 min immediately after caffeine administrations. Finally L-arginine (1 g/kg) was administered i.p. 20 min before HPE (6 mg/kg) and the locomotor activity was measured as mentioned above. Each group of mice was used only once. Caffeine produced some significant increases in locomotor activity of the mice. HPE (6-24 mg/kg) significantly blocked the caffeine-induced locomotor hyperactivity. Pretreatment of L-arginine (1 g/kg) reversed the inhibitory effect of HPE (6 mg/kg) on caffeine-induced locomotor activity without producing any significant effect on locomotor activity of the mice when it was administered alone. The results suggest that HPE, blocks caffeine-induced locomotor hyperactivity in mice. Furthermore, the inhibitory effect of HPE on caffeine-induced locomotor activity may be related to its NOS inhibitory property. Copyright (c) 2007 John Wiley & Sons, Ltd.