Characteristics of the ambulation-increasing effect of MK-801, a non-competitive NMDA antagonist, were assessed through the coadministration of MK-801 with various central-acting drugs in mice. The MK-801 (0.3 mg/kg, i.p.)-induced ambulation-increment with a slight ataxia was maximum at around 50 min, and ambulation returned to the control level at about 3 hr after the administration. At 1 mg/kg, the mouse''s activity transiently increased, followed by a decrease due to a marked ataxia, which was due to neither stereotypy nor convulsion, for 20-50 min, and then increased again; the ambulation-increment continued even at 4 hr after the administration. Coadministration of MK-801 (0.3 mg/kg, i.p.) with either methamphetamine (2 mg/kg, s.c.), cocaine (20 mg/kg, s.c.), GBR-12909 (10 mg/kg, i.p.), scopolamine (0.5 mg/kg, s.c.), caffeine (10 mg/kg, s.c.) or morphine (10 mg/kg, s.c.) produced a significant enhancement of the effect. However, 0.1 mg/kg of MK-801 had no effect on the interaction with these drugs. On the other hand, the ambulation-increas ing effect of MK-801 (0.3 mg/kg) was significantly reduced by haloperidol (0.03 and 0.1 mg/kg, s.c.), ceruletide (0.01 and 0.1 mg/kg, i.p.), reserpine (0.05 and 2 mg/kg, s.c., pretreatment 4 hr before) and nimodipine (1 and 3 mg/kg, i.p.), but it was scarcely modified by α-methyl-p-tyrosine (100 and 200 mg/kg, i.p., pretreatment 24 hr and 4 hr before), imipramine (20 mg/kg, i.p.), 6R-L-erythro-5, 6, 7, 8-tetrahydro-biopterin (100 mg/kg, i.p.), pilocarpine (1 and 4 mg/kg, s.c.), N⁶-(L-2-phenylisopropyl)-adenosine (0.03 and 0.1 mg/kg, s.c.) and naloxone (1 and 5 mg/kg, s.c.). These results indicate the MR-801 increases the mouse''s ambulatory activity through stimulation of the dopaminergic system which is strongly affected by a calcium-dependent mechanism.