It has been suggested that individual predisposition to develop amphetamine self-administration is associated with impairment in corticosteroid negative feedback mechanisms. Since corticosteroid receptors, particularly those in the hippocampus, are involved in corticosterone feedback sensitivity, we examined the relation between individual differences in amphetamine self-administration and characteristics of hippocampal corticosteroid receptors. Rats were selected on the basis of likelihood to self-administer amphetamine and designed as: (1) High Responding (HR) rats, who quickly acquire the response and (2) Low Responding (LR), who fail to self-administer amphetamine. We found lower affinities both for hippocampal type I and type II corticosteroid receptors in the HR animals. These data suggest that modification of hippocampal corticosteroid receptors may be responsible for the predisposition of some animals for amphetamine self-administration. Because HR rats also show a greater behavioral and endocrinological response in a novel environment, these differences in affinities suggest a relation among amphetamine self-administration, control of the corticosterone feedback loop, serum levels of corticosterone and characteristics of hippocampal corticosteroid receptors. The implication is that pharmacological manipulations of corticosteroid receptors may reveal new therapeutic strategies for drug abuse.