Mice trained to discriminate 1 mg/kg d-amphetamine from saline, or the selective norepinephrine uptake inhibitor, nisoxetine, from saline, cross-generalized to the alternate drug. They also generalized to 5.6 mg/kg cocaine. The cues produced by amphetamine were antagonized by the selective alpha 1-adrenoceptor antagonist, prazosin, and slightly potentiated by the selective alpha 2-adrenoceptor antagonist, yohimbine. The nisoxetine cue was also antagonized by prazosin. In contrast, the peripherally acting sympathomimetics, p-hydroxyamphetamine and phenylpropranolamine, failed to substitute for, and pimozide and propranolol failed to block, either drug cue. In addition, prazosin, at a dose that did not affect either saline-associated locomotor behavior in mice or the locomotor-activity increase produced by the dopamine uptake inhibitor, bupropion, also antagonized the locomotor stimulation produced by amphetamine and cocaine. Thus, in mice, both the cues and locomotor stimulation produced by amphetamine and cocaine appear to be at least partially mediated by central alpha 1-adrenoceptor activation secondary to increased central synaptic concentrations of norepinephrine.