Stress represents a complex stimulus to neuroendocrine systems regulating homeostasis. By and large, stress effects are mediated by stress-integrative corticotropin-releasing hormone (CRH) neurons present in the medial parvocellular division of the hypothalamic paraventricular nucleus (PVN). These neurons summate a large variety of neuronal and hormonal signals to eventually yield a physiologically meaningful level of circulating glucocorticoids. In the present experiments, we examined the effects of a chronic variable-stressor paradigm on indices of adrenocorticotropic hormone (ACTH) secretagogue biosynthesis in the PVN and adrenocorticosteroid receptor mRNA expression in the hippocampal formation, PVN and cortex. The variable-stressor paradigm produces a syndrome consistent with chronic stress, including baseline hypersecretion of corticosterone, ACTH and prolactin, and adrenal hypertrophy. CRH mRNA levels in the PVN are increased some 61%, consistent with the observed hypothalamo-pituitary-adrenal (HPA) up-regulation. There was a small but significant increase in arginine vasopressin (AVP) mRNA expression in individual parvocellular PVN neurons (16%), and no demonstrable increase in the number of AVP mRNA-containing neurons. No change in AVP expression was seen in the magnocellular PVN, supraoptic or suprachiasmatic nuclei. In all, these data highlight the importance of CRH in maintaining HPA up-regulation in the face of prolonged challenge. To investigate effects of chronic stress on the regulation of glucocorticoid receptivity, mineralocorticoid receptor (MR) and glucocorticoid receptor mRNA expression was assessed in the hippocampus, frontoparietal cortex and PVN. Chronic stress significantly down-regulated MR mRNA expression in subfields CA1, CA3 and the dentate gyrus (DG), and GR mRNA expression in subfields CA1, the DG and frontoparietal cortex. The reduction in receptor biosynthesis suggests the capacity for stress to modulate the impact of glucocorticoid on hippocampal cell physiology at the genomic level, potentially influencing processes ranging from cognition to feedback regulation of the HPA axis. At the level of the parvocellular PVN, GR mRNA expression was decreased to 60% of control values. GR mRNA expression was negatively correlated with PVN CRH mRNA expression, suggesting a relationship between elevated CRH gene expression and down-regulation of GR at the level of the PVN.