We have studied biochemical and behavioral effects of chronic corticosterone administration in two inbred rat stains (Fischer 344 and Lewis), known to differ in their hypothalamic-pituitary-adrenal axis and in their behavioral responses to drugs of abuse. First, we studied corticosterone regulation of phosphoproteins in the ventral tegmental area of sham- and corticosterone-treated Fischer and Lewis rats, by means of back-phosphorylation and two-dimensional gel electrophoresis and Western blotting analysis. Corticosterone administration upregulated tyrosine hydroxylase immunoreactivity and decreased glial-fibrillary acidic protein phosphorylation state in the ventral tegmental area of Fischer rats only, with no changes seen in Lewis rats. We also studied corticosterone effects on locomotor sensitization to cocaine, a behavior known to be regulated by the ventral tegmental area. In Fischer rats, chronic corticosterone pretreatment resulted in development of cocaine sensitization, which was absent in sham-pretreated Fischer rats. In contrast, Lewis rats developed cocaine sensitization either with or without corticosterone pretreatment. Thus, both biochemical and behavioral effects of corticosterone observed in Fischer rats were absent in Lewis rats. We next studied the possibility that certain transcription factors, thought to play a role in tyrosine hydroxylase expression, could be involved in these strain-selective effects of corticosterone. Corticosterone treatment decreased levels of glucocorticoid receptor immunoreactivity in the ventral tegmental area of Lewis rats, but not of Fischer rats. In addition, drug-naive Fischer rats showed higher ventral tegmental area levels of immunoreactivity of cyclic AMP response element binding protein than Lewis rats, with no effect of corticosterone observed in either strain. These findings suggest that hypothalamic-pituitary-adrenal axis modulation of responses to drugs of abuse is a genetically determined characteristic seen in Fischer rats, but absent in Lewis rats. We propose that corticosterone administration down-regulates the glucocorticoid receptor in the ventral tegmental area of Lewis rats, and thereby prevents other adaptations to corticosterone treatment, while in the ventral tegmental area of Fischer rats the lack of glucocorticoid receptor down-regulation and the high basal levels of cyclic AMP response element binding protein could facilitate the transcriptional, biochemical and behavioral actions of glucocorticoids.