To investigate the neuroendocrine alterations linked to inborn emotionality in two Wistar rat lines selectively bred for either high (HAB) or low (LAB) anxiety-related behavior, we administered the combined dexamethasone (DEX)/corticotropin-releasing hormone (CRH)testNeuroendocrine studies provide strong indications that hyperactivity of central corticotropin-releasing hormone (CRH) circuits, resulting in a characteristic dysregulation of the hypothalamic-pituitary-adrenocortical (HPA) system, plays a causal role in the symptomatology of affective and anxiety disorders (review: Keck and Holsboer 2001). The effects of CRH are modulated by vasopressin (AVP), which, after prolonged stress and in senescence, is increasingly coexpressed and secreted from hypothalamic CRH neurons in both humans and rodents (Antoni 1993;Tilders et al. 1993;Hatzinger et al. 2000;Keck et al. 2000). Similarly, increased numbers of CRH neurons that coexpress AVP mRNA have been found in the hypothalamus of depressed patients (Raadsheer et al. 1993;Purba et al. 1996). The excessive release of CRH and AVP into hypophysial portal blood is thought to increase the secretion of corticotropin (ACTH) from pituitary corticotrope cells, and this in turn to increase the release of corticosteroids from the adrenal gland. In this context, a variety of changes in HPA system regulation have been demonstrated in psychiatric disorders such as major depression, among them defective negative feedback of the HPA system, basal hypercortisolemia, inappropriate HPA suppression by the synthetic corticosteroid dexamethasone (DEX) and a paradoxical stimulation of ACTH secretion by CRH after DEX pretreatment (review: Holsboer and Barden 1996;Holsboer 2000). In depression, the combined DEX/CRH test, in which DEX-pretreated subjects receive a single dose of CRH, has proven to be the most sensitive tool for the detection of altered HPA regulation. Depending on age and gender, up to 90% of patients with depression show this neuroendocrine phenomenon (Heuser et al. 1994). Moreover, studies using the DEX/CRH test not only agree that normalization of an initial aberrance is predictive of a favorable treatment response but also corroborate other evidence that a persistent HPA abnormality correlates with chronicity or relapse (Heuser et al. 1996;Zobel et al. 1999). Since activation of corticosteroid receptors suppresses the synthesis and release of CRH and AVP from the hypothalamic paraventricular nucleus (PVN) , these findings are consistent with the hypothesis of functionally impaired corticosteroid receptor signaling in both depressed patients (Modell et al. 1997) and healthy subjects at genetic risk for depression Modell et al. 1998).As the mechanisms underlying the abnormal HPA reactivity in patients with certain psychiatric disorders are not fully understood, animal models are needed to further investigate the hypothesized linkage between these disorders and changes in the regulation of the HPA system. After several generations of selective breeding, we could establish ...