1. Locomotor activating effects of D-amphetamine, cocaine, and scopolamine were determined alone and after pretreatment with K-channel modulators in mice. 2. When administered alone, D-amphetamine (1.0- 30 mg/kg) and cocaine (3.0- 56 mg/kg) produced inverted U-shaped dose-effect curves characteristic of psychomotor stimulant drugs. 3. When administered alone, scopolamine (3.0-56 mg/kg) also produced dose-dependent increases in locomotor activity but these effects plateaued with similar increases in locomotor activity induced by 10-56 mg/kg of scopolamine. 4. Pretreatment with the K-channel blockers 4-aminopyridine (0.3-1.7 mg/kg), quinine (30-100 mg/kg) or apamin (0.3-1.0 mg/kg) attenuated the locomotor increases induced by d-amphetamine, cocaine, and scopolamine. 5. Like the K-channel blockers, pretreatment with the K-channel openers cromakalim (1.0-3.0 mg/kg) and pinacidil (3.0-10 mg/kg) also attenuated the locomotor increases induced by D-amphetamine and scopolamine but did not modify the locomotor activating effects of cocaine. 6. These results demonstrate that K-channel modulation modifies the effects of D-amphetamine, cocaine, and scopolamine. 7. The results also demonstrate that K-channel openers can differentially alter the behavioral effects of cocaine and D-amphetamine.