Secretion of glucocorticoids seems to control stress-induced sensitization of the behavioral effects of drugs of abuse by acting on the mesencephalic dopaminergic transmission, the principal neural substrate of sensitization. In order to investigate the mechanisms of this interaction between glucocorticoids and dopamine, we studied the sensitization of the increase in extracellular concentration of dopamine induced by cocaine in male rats in which corticosterone secretion was either intact or blocked. Extracellular concentrations of dopamine were evaluated in the nucleus accumbens of freely moving animals by means of microdialysis. Metyrapone, an inhibitor of corticosterone synthesis, was used to block stress-induced corticosterone secretion. Food-restriction (90% of the initial body weight) was the stressor used to induce sensitization. It was found that metyrapone (100 mg/kg s.c. twice a day for 8 d) suppressed stress- induced sensitization of the increase in accumbens dopamine induced by cocaine (10 mg/kg, i.p.) and sensitization of cocaine-induced locomotion Metyrapone suppressed both the development and the expression of sensitization. Thus, sensitization was equally blocked when the metyrapone treatment started either 1 d before the start of food-restriction or 8 d later, that is, when food-restriction-induced sensitization to cocaine was already established. In conclusion, our results suggest that glucocorticoids modify sensitization of the behavioral effects of cocaine by acting on extracellular concentrations of dopamine. Since addictive properties of psychostimulants seem mediated by the increase in extracellular concentrations of dopamine they induce, these findings may have implications for the development of new therapeutic strategies of addiction.