In the negative feedback model, loss of endogenous glucocorticoids up-regulates the expression of glucocorticoid receptor mRNA. To elucidate further the effect of chronic lack of glucocorticoids on the expression of glucocorticoid receptor mRNA and protein, in situ hybridization and immunohistochemical methods were used to examine the long-term alteration of glucocorticoid receptor mRNA and its immunoreactivity in the forebrain of adrenalectomized rats. Constant lack of glucocorticoids resulted in marked decrease in the expression of glucocorticoid receptor mRNA and disappearance of glucocorticoid receptor immunoreactivity in many forebrain structures. In particular, in the suprapyramidal blade of the hippocampal granule cell layer and cerebral cortex, many cells showed almost no glucocorticoid receptor mRNA signals. These results suggest that long-term loss of endogenous glucocorticoids down-regulates the levels of glucocorticoid receptor mRNA, leading to reduction in the synthesis of glucocorticoid receptors in the rat forebrain. Therefore, the presence of endogenous glucocorticoids is vital to the continued expression of glucocorticoid receptor mRNA.