Glucocorticoid receptors (GR) mediate the direct effects of glucocorticoids released in response to stress and the regulation of the hypothalamic-pituitary-adrenocortical (HPA) system through a negative feedback mechanism. Individuals with major mental illness, who often exhibit hypercortisolemia, may have down-regulated levels of GR mRNA. In situ hybridization for GR mRNA was performed on post-mortem specimens from patients suffering from depression, bipolar disorder, schizophrenia and from normal controls (n = 15 per group). In frontal cortex, GR mRNA levels were decreased in layers III-VI in the subjects with depression and schizophrenia. In inferior temporal cortex, GR mRNA levels were decreased in layer IV in all three diagnostic groups. In the entorhinal cortex, GR mRNA levels were decreased in layers III and VI in the bipolar group. In hippocampus, GR mRNA levels were reduced in the dentate gyrus, CA(4), CA(3) and CA(1) in the schizophrenia group. In the subiculum, GR mRNA levels were reduced in the bipolar group. These results suggest that GR dysregulation occurs in all three major psychiatric illnesses with variability according to anatomical site. The severity and heterogeneity of this reduction may underlie some of the clinical heterogeneity seen in these disorders.