Chronic administration of d-amphetamine to young guinea pigs results in an increased behavioral response to this drug. After 6 months of daily amphetamine exposure, animals demonstrated behavioral hypersensitivity and developed full amphetamine-induced stereotyped behavior with decreased latency. The data suggest that chronic agonism with amphetamine can produce dopaminergic hypersensitivity, a behavior that contrasts with the development of drug tolerance to other pharmacologic agents. The mechanism of this induced hypersensitivity was studied by comparing brain amphetamine levels after acute and chronic amphetamine treatment. The two groups of guinea pigs showed no significant difference in amphetamine levels or drug distribution. These results suggest that altered amphetamine metabolism cannot account for the hypersensitivity seen after amphetamine exposure. Guinea pigs chronically pretreated with d-amphetamine were hypersensitive to another dopaminergic agonist whose metabolic pathway is distinct from that of amphetamine. These results have therapeutic implications in the management of clinical conditions related to chronic agonist-induced hypersensitivity.