Inbred mouse strains differ in sensitivity to a first dose of nicotine and in the development of tolerance to nicotine. The experiments reported here used six inbred mouse strains (A, BUB, C3H, C57BL/6, DBA/2, ST/b) that differ in sensitivity to an acute challenge dose of nicotine to determine whether differences in oral self-selection of nicotine exist. Animals were presented with solutions containing nicotine or vehicle (water or 0.2% saccharin) and their daily intake of the two fluids was measured for 4 days starting with a 10 micrograms/ml nicotine solution. This was followed by sequential 4-day testing with 20, 35, 50, 65, 80, 100, 125, 160 and 200 micrograms/ml nicotine solutions. The strains differed dramatically in their self-selection of nicotine and in maximal daily dose (mg/kg); the rank order of the strains was C57BL/6 > DBA > BUB > A > or = C3H > or = ST/b for both the tap water and 0.2% saccharin choice experiments. Correlations between nicotine consumption and sensitivity to nicotine, as measured by a battery of behavioral and physiological responses, were also calculated. Strain differences in nicotine intake were highly correlated with sensitivity to nicotine-induced seizures. As sensitivity to nicotine-induced seizures increases, oral self-selection of nicotine decreases. This finding may suggest that this toxic action of nicotine serves to limit intake.