Although both MK-801 (dizocilpine: 0.1 mg/kg, IP) and ethanol (1.6 nd 2.4 g/kg, PO) only slightly increased ambulatory activity in mice, their combination produced a marked enhancement of the ambulation-increasing effect. The combination of MK-801 (0.03 mg/kg) with ethanol (1.6 and 2.4 g/kg) also elicited a significant increase in the mouse's ambulation. A significant enhancement of the effect was produced by the combination of ketamine (3 and 10 mg/kg) with ethanol only (2.4 g/kg). The ambulation increment induced by the combination of MK-801 (0.1 mg/kg) plus ethanol (1.6 g/kg) was dose-dependently inhibited by YM-09151-2 (0.0001-0.01 mg/kg IP), SCH 23390 (0.001-1 mg/kg IP), reserpine (0.1-1 mg/kg, IP) and ceruletide (0.00001-0.001 mg/kg, IP), and the highest dose of each drug was effective for complete inhibition of the ambulation. Naloxone (0.05-5 mg/kg IP), apomorphine (0.001-0.1 mg/kg IP) and alpha-methyl-p-tyrosine (50-200 mg/kg, IP) partially reduced the ambulatory activity induced by the combination of MK-801 with ethanol. These results suggest that the dopaminergic system, particularly via presynaptic changes in the release of stored dopamine, as well as the opioid system, are involved in the interaction of MK-801 with ethanol.