The repeated intermittent administration of amphetamine (AMP) produces an enduring enhancement in the response of dopamine (DA) systems in the brain to a subsequent "challenge" with amphetamine. However, former amphetamine addicts are not only hypersensitive to amphetamine, but also to "physical or psychological stress". This suggests that sensitization to amphetamine may change the response of DA neurons in brain to subsequent stress. To explore this idea, the effects of footshock stress on regional metabolism of DA in brain, and on the concentrations of plasma beta-endorphin and N-acetylated beta-endorphin, were studied in rats previously exposed to amphetamine or saline. It was found that: Prior treatment with amphetamine produced enduring (at least 7 days) changes in the dopaminergic response to footshock in the medial frontal cortex, hypothalamus, dorsolateral striatum and nucleus accumbens. Generally, rats pretreated with amphetamine showed a greater initial reduction in concentrations of DA in response to footshock, and a greater elevation in concentrations of metabolites of DA and/or metabolite/transmitter ratios, compared to nonhandled control rats. In some regions of the brain repeated injections of saline produced changes in the response to subsequent footshock that were comparable to those produced by amphetamine. Prior treatment with amphetamine enhanced the release of beta-endorphin and N-acetylated beta-endorphin from the pituitary elicited by footshock stress. It is concluded that repeated intermittent treatment with amphetamine or stress (injections of saline) produce enduring changes in the response of DA neurons and the pituitary to subsequent stress. These changes may be responsible for the hypersensitivity to stress reported in former amphetamine addicts, and in rats previously sensitized to amphetamine.