Both the acute psychomotor response and the development of sensitization to amphetamine are attenuated if i.p. injections are given in the cage where animals live (HOME), relative to when injections are given in a novel (NOVEL), but otherwise physically identical cage. It was suggested that this effect of environment on sensitization may be due to the relative availability of cues predictive of drug administration in the two conditions. It was hypothesized, therefore, that removal of all environmental cues predictive of drug administration would attenuate the development of sensitization even further. This was accomplished by comparing the psychomotor activating effects (rotational behavior) of repeated unsignalled intravenous (i.v.) infusions of 1.0 mg/kg amphetamine given in a HOME environment with those of signalled i.v. infusions given in a NOVEL environment. It was found that signalled i.v. amphetamine administration (NOVEL) produced a large acute psychomotor response, and repeated administrations resulted in a significant increase in psychomotor response (i.e., sensitization). In contrast, the same treatment in the HOME condition produced only a very small acute response and no sensitization. Indeed, the magnitude of the psychomotor response to an amphetamine challenge varied approximately 23-fold as a function of past drug history and environmental condition. It is suggested that this paradigm provides a powerful new model to study how environmental factors modulate responsiveness to psychoactive drugs.