Corticotropin-releasing factor (CRF), a 41 amino acidcontaining peptide, appears to mediate not only the endocrine but also the autonomic and behavioral responses to stress. Stress, in particular early-life stress such as childhood abuse and neglect, has been associated with a higher prevalence rate of affective and anxiety disorders in adulthood. In the present review, we describe the evidence suggesting that CRF is hypersecreted from hypothalamic as well as from extrahypothalamic neurons in depression, resulting in hyperactivity of the hypothalamic-pituitaryadrenal (HPA) axis and elevations of cerebrospinal fluid (CSF) concentrations of CRF. This increase in CRF neuronal activity is also believed to mediate certain of the behavioral symptoms of depression involving sleep and appetite disturbances, reduced libido, and psychomotor changes. The hyperactivity of CRF neuronal systems appears to be a state marker for depression because HPA axis hyperactivity normalizes following successful antidepressant treatment. Similar biochemical and behavioral findings have been observed in adult rats and monkeys that have been subjected to early-life stress. In contrast, clinical studies have not revealed any consistent changes in CSF CRF concentrations in patients with anxiety disorders; however, preclinical findings strongly implicate a role for CRF in the pathophysiology of certain anxiety disorders, probably through its effects on central noradrenergic systems. The findings reviewed here support the hypothesis that CRF receptor antagonists may represent a novel class of antidepressants and/or anxiolytics.

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Postnatal handling of rat pups is known to alter permanently hypothalamic-pituitary-adrenal (HPA) responses to a wide variety of stressors. As adults, handled (H) and nonhandled (NH) animals also differ in sensitivity to the delayed negative-feedback effects of glucocorticoids on stress-induced HPA activity. However, it is not understood how handling alters neuroendocrine responses to stressful stimuli, and how differences in feedback sensitivity might account for changes in HPA activity both during and following stress. In the present studies, plasma ACTH responses to both restraint and ether stress were significantly greater in NH compared with H animals. Administration of 100 micrograms/kg corticosterone (B) immediately prior to restraint stress significantly decreased subsequent plasma ACTH responses to restraint to the same extent in H and NH animals, suggesting that H and NH animals do not differ in glucocorticoid fast feedback. H and NH animals adrenalectomized (ADX) 5 d prior to testing did not differ in plasma ACTH responses to restraint stress, demonstrating that the differences between the groups are dependent upon the presence of circulating B. However, the handling effect was apparent in ADX animals provided with a low level of B replacement (approximately 5-6 micrograms/dl). B replacement significantly decreased plasma ACTH levels under both basal conditions and in response to restraint stress in H/ADX rats. In contrast, although B replacement also decreased basal ACTH levels in ADX/NH rats, there were no differences in plasma ACTH responses to restraint between NH/ADX and NH/ADX+B animals.(ABSTRACT TRUNCATED AT 250 WORDS)

The development of many endocrine, metabolic, and behavioral abnormalities characteristic of genetically obese Zucker rats is dependent upon the presence of glucocorticoids, the secretion of which is regulated by a neuroendocrine cascade initiated by hypothalamic release of CRF. Recent reports have inferred alterations in central CRF tone as a putative factor contributing to dysregulation of the pituitary-adrenal axis and of metabolic processes in this phenotype. In the current study the hypothalamic CRF system in Zucker lean (FA/?) and obese (fa/fa) phenotypes was functionally evaluated. Neither the stalk median eminence content of CRF or arginine vasopressin (AVP) nor hypothalamic levels of CRF or AVP mRNA differed in the lean and obese phenotypes. No phenotypic differences were observed in either basal or stimulated CRF release from hypothalamic tissue obtained from lean and obese rats. Furthermore, in intact rats the magnitude of pituitary-adrenal responses to various stressors was also similar between phenotypes. However, secretion of CRF and AVP into the hypophysial-portal circulation of obese rats was, respectively, 73% and 35% lower than that of the lean rats. Adrenalectomy was associated with a 3-fold elevation of hypophysial-portal CRF levels in obese rats compared to intact controls. Corticosterone infusion was more effective in suppressing portal CRF levels in adrenalectomized obese compared to adrenalectomized lean rats. Finally, neither CRF receptor number and affinity nor the magnitude of pituitary-adrenal responses to rat CRF challenge (1 micrograms, iv) differed between Zucker phenotypes. These observations lead us to infer that rats of the obese phenotype exhibit reduced hypothalamic CRF tone due to dysregulation of the HPA axis at a site proximal to the hypophysiotropic CRF system that mediates glucocorticoid feedback regulation.