Effects of 5 subcutaneous injections of cocaine (COC) at 10, 20 or 40 mg/kg at intervals of 1 to 7 days were investigated by placing mice individually into tilting activity cages (20cm in diameter and 18 cm height). A progressive enhancement of the ambulation-increasing effect was noted for 3 to 4 hrs after each administration, showing marked sensitization (reverse tolerance). The enhancement of the effect progressed rapidly and the maximum sensitization was observed after the 3rd to 4th administration of 10 to 20 mg/kg at intervals of 3 to 7 days. The peak effect of the enhancement was of short duration. Sensitization lasted for at least one month. However, 40 mg/kg of COC produced stereotyped behaviors concurrent with preconvulsive signs which were also enhanced by serial administration. In contrast, pretreatment with COC in a narrow environment (glass jar, 5.5 cm in diameter and 15 cm height) did not cause the enhancement to the ambulation-increasing effect of the drug. Cross-sensitization was observed from COC to methamphetamine.