Although our lab, as well as several others, has demonstrated a role for corticosterone in cocaine self-administration, there are no studies of the central dynamics of this hormone over the course of a behavioral session when rats are self-administering cocaine or receiving passive injections. The assay of corticosterone in microdialysates collected during such sessions allows for determinations of changes in brain corticosterone during drug-taking behavior. By using the combination of microdialysis in terminal fields for the mesocorticolimbic dopaminergic system and the yoked-triad model, one can distinguish between the direct cocaine-induced activation of the hypothalamo-pituitary-adrenal (HPA) axis from the activation of the HPA axis related to drug-taking. In these experiments, we measured corticosterone in microdialysis samples collected from probes aimed at the medial prefrontal cortex, nucleus accumbens and basolateral amygdala in rats self-administering cocaine and receiving identical, passive infusions of cocaine or saline. While corticosterone was increased in all three brain regions in rats receiving cocaine, medial prefrontal cortex corticosterone was increased significantly more in rats receiving non-contingent infusions of the drug compared to rats self-administering cocaine. The results of these experiments demonstrate that control over drug delivery can affect the influence of a hormonal input on the functional characteristics of specific anatomical projections of the central nervous system. These results also provide evidence of the role steroid hormones play in shaping the functional activity of the brain.