The effects of cocaine on Y-maze activity and heart rate have been examined in four inbred strains of mouse (BALB, C57BL, C3H and DBA). In addition, brain [3H]-cocaine concentrations were measured at the time of maximal response to cocaine. Cocaine produced a dose-related increase in Y-maze cross activity in C3H, DBA and C57BL, with C3H mice being considerably more sensitive than DBA or C57BL. Cocaine was without effect on Y-maze cross activity in BALB mice. Cocaine produced a biphasic effect on rearing activity in C3H mice, a dose related depression in BALB mice, and was without effect on C57BL and DBA mice. At the highest dose studied (15 mg/kg), cocaine produced a small decrease in heart rate in C3H mice. Strain differences in behavior were maximal 15 minutes after a dose of 5 mg/kg, IP. At this dose and time interval, brain [3H]-cocaine concentrations were not significantly different among the four strains of mice. The results suggest a genetically-determined difference in CNS sensitivity to cocaine.