Repeated exposure to morphine and amphetamine induces long-lasting sensitization of their psychomotor stimulant properties, whereas pretreatment with morphine causes cross-sensitization of the locomotor effects of amphetamine. Here, we investigated whether pre-exposure to amphetamine also results in cross-sensitization to morphine. Rats pretreated with amphetamine (5 x 2.5 mg/kg, i.p.) displayed neither short-term (3 days post-treatment) nor long-term (3 weeks post-treatment) cross-sensitization of the locomotor effects of morphine (2 or 5 mg/kg, s.c.). Two other amphetamine pretreatment protocols (1 x 5 mg/kg, i.p. and 14 x 2.5 mg/kg, i.p.) also failed to induce cross-sensitization to morphine. In contrast, all amphetamine pretreatment regimens induced sensitization of the locomotor effects of amphetamine (1 mg/kg, i.p.) and pretreatment with morphine (14 x 10 mg/kg, s.c.) induced both short- and long-term sensitization of the locomotor effects of both morphine and amphetamine. These data suggest that the expression of sensitization of the locomotor effects of morphine and amphetamine, at least partially, involves distinct neuroadaptive phenomena. Copyright (C) 1999 American College of Neuropsychopharmacology.