Dysregulation of CRF pathways in human disease states

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Imbalances of the HPA axis and central CRF pathways have been associated with allostatic load and subsequent pathological states (Schulkin et al., 1998). In the periphery, excess circulating glucocorticoids caused by prolonged activation of the HPA axis or long-term treatment with exogenous glucocorticoids results in Cushing's disease or syndrome (Nelson, 1989). Continued exposure to high levels of glucocorticoids eventually leads to metabolic dysfunction that may include muscle wasting, abnormal fat deposits, brittle bones, thin skin, hair loss, and hyperglycemia.

In the central nervous system (CNS), dysregula-tion of the HPA system may be causally involved in the pathogenesis of stress-related affective disorders such as anorexia, anxiety and major melancholic depression (Nemeroff et al, 1984; Keck and Holsboer, 2001). Several of these disorders, particularly depression, are characterized by increased central CRF drive, as revealed from measurements of circulating Cortisol, CRF in cerebrospinal fluid, and CRF challenge tests (Gold et al, 1986). It has been postulated that an initial defect in glucorticoid negative feedback mechanisms ultimately leads to

Table 1. Animal models of corticotropin pathway dysregulation

Basal HPA activity

Hypothalamic Plasma Plasma CRF ACTH CORT

pathological emotional states (Holsboer, 2000; Holsboer and Barden, 1996). In this model, disinhibition of HPA activity results in elevated glucorticoids, which in turn positively regulate CRF synthesis in the central nucleus of the amygdala and BNST. Consequent elevations in limbic CRF may be responsible for increased emotionality and anxiety and when prolonged, lead to affective pathology. Thus, normalization of HPA system function may be required for stable remission of depression and/or anxiety (Holsboer, 2000).

Mouse models with targeted mutations of corticotropin pathways

We discuss prominent neuroendocrine and behavioral features of various genetic models that harbor specific genomic alterations in the corticotropin system (Table 1). The high degree of molecular and cellular specificity of genetically engineered mice,

Stress HPA activity Behavior

Plasma Plasma Anxiety Other

ACTH CORT impairments

CRF ligand/receptor

CRF-Tg

normal

t

t

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