The behavioral and neurochemical effects of acute and chronic ethanol administration were studied in BALB/c, C57B1/6 and DBA/2 mice. The rates of dopamine synthesis and release in the striatum were estimated by measuring the accumulation of DOPA and DOPAC, respectively, after inhibition of aromatic amino acid decarboxylase with NSD-1024. Biphasic behavioral effects were found in BALB/c and DBA/2 mice, but not in C57B1/6 mice, with low doses of ethanol producing activation and high doses, depression. Biphasic effects were also found in the dopamine response to acute doses of ethanol. The BALB/c and DBA/2 mice showed larger suppressions of DA release in the lower dose ranges of ethanol, and smaller increases at the higher doses than did the C57B1/6 mice. Ethanol stimulated dopamine synthesis in a monophasic, dose-dependent manner, and C57B1/6 mice were less sensitive to this effect of ethanol compared to the other tested strains of mice. Chronic ethanol feeding produced behavioral tolerance to the high-dose depressant effects of ethanol, but not to the low-dose activating effects. Similarly, tolerance developed in the dopaminergic responses to a higher challenge dose of ethanol (3.5 g/kg). These findings demonstrate that genetically determined differences exist in the sensitivity of the dopaminergic systems of mice to ethanol, and suggest that central dopamine neurons may be important in the behavioral effects of ethanol.