The locomotor activity (LMA) effects of morphine (MRP) and (+/-)-ethylketocyclazocine (EKC) were studied in two inbred mouse strains, C57B1/6J (C57) and DBA/2J (DBA). MRP (3.2-100 mg/kg) caused a monophasic stimulation, a "running fit," in naive C57 mice and a biphasic, depression-stimulation in DBA mice. In contrast, EKC (3.2-100 mg/kg) elicited a biphasic, catalepsy-stereotypy in both strains. The later stereotypic actions of acute EKC, although including sporadic running, were clearly unlike the persistent circling of MRP-stimulation. The LMA responses to MRP and EKC were stereoselective and antagonized by naloxone. Tolerance to the initial depression of activity by MRP in DBA mice developed after chronic administration of either MRP or EKC (32 mg/kg s.c., b.i.d. for 1 week); the intensity of MRP-stimulation, however, increased in both strains. This sensitization to MRP was not overcome with a chronic treatment schedule of 100 mg/kg t.i.d. for 10 days of MRP or EKC. Mice treated chronically with EKC were completely tolerant to its cataleptic and stereotypic effects. Moreover, in these mice EKC elicited a vigorous, MRP-like running fit. Prolonged MRP administration, on the other hand, conferred no tolerance whatsoever to the cataleptic effect of EKC. Taken together with the genetic differences in the acute actions of MRP, this lack of cross-tolerance indicates that distinct neural mechanisms mediate the acute LMA responses to the two narcotics in these mice.