Active Clearance of Corticotropin-Releasing Factor from the Cerebrospinal Fluid

Oldfield, Edward H.; Schulte, Heinrich M.; Chrousos, George P.; Rock, Jack; Kornblith, Paul L.; O'Neill, Dondra; Poplack, David G.; Gold, Philip W.; Cutler, Gordon B.; Loriaux, Lynn

doi:10.1159/000124056

Cited by 29 publications

(10 citation statements)

References 15 publications

(19 reference statements)

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“…The portal CRH concentration after hemorrhagic (Caraty et al 1988) and audiovisual (Canny et al 1989) stress remained at a high level for more than 30 min. Because the neurons and receptors for CRH are distributed widely in the brain (Hannaka & Otsuka 1993), intracerebroventricularly infused CRH could stimulate neuroendocrine function not only at the hypothalamic-anterior pituitary level (Oldfield et al 1985;Ono et al 1985) but also in other brain areas by diffusing in the extra-cellular compartment of the brain. Considering that the rate of CSF formation in the goat is 160 mL/min (Pollay 1975) and that CRH is actively cleared from the CSF (Oldfield et al 1985), a bolus injection of CRH cannot precisely mimic the condition above.…”

Section: Discussionmentioning

confidence: 99%

Effects of intracerebroventricular infusions of corticotropin‐releasing hormone in sheep

Yayou

Otani

Takusari

et al. 2003

Animal Science Journal

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To provide new insights into the neural mechanisms of physiological and behavioral responses to stressors in sheep, acute changes in endocrine, autonomic and behavioral functions following 30 min infusions of ovine-corticotropin-releasing hormone (oCRH; 0, 0.5, 5 or 50 m g/0.5 mL of artificial cerebrospinal fluid/30 min) into the third ventricle of sheep ( n = 7-8) were examined. Serial blood samples were collected through indwelling jugular catheters to determine plasma cortisol concentrations (CORT). Heart rate (HR) and rectal temperature (RT) were obtained via telemetry systems. The behaviors of the animal were monitored simultaneously. Intracerebroventricular infusions of CRH dose-dependently induced an increase in CORT; there was a time-treatment interaction in CORT ( P < 0.001). There was not a time-treatment interaction either in HR ( P = 0.29) or in RT ( P = 0.28). That RT showed a tendency to decrease with higher doses of CRH in sheep was in contradiction to previous reports in rats and pigs. As to changes in behavioral function, only the induction of bleating was marked. These results suggest that in physiological and behavioral responses of sheep to stressors, CRH regulates the increase in CORT and the induction of bleating. However, CRH might have little function in sympathetic nervous activation during physiological responses to stressors in sheep.

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Section: Discussionmentioning

confidence: 99%

Effects of intracerebroventricular infusions of corticotropin‐releasing hormone in sheep

Yayou

Otani

Takusari

et al. 2003

Animal Science Journal

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“…For example, CRF concentrations in lumbar CSF were highly correlated to those in cisternal CSF (Geracioti et al, 1997). Furthermore, because active transport mechanisms may exist to rapidly clear CRF and other neuropeptides from the cerebral ventricles to lower regions of the CNS (Oldfield et al, 1985), analyses based upon CSF bulk flow rates may underestimate the contribution of higher CNS centers to the CRF present in lumbar CSF. Such mechanisms may underlie the numerous reports of elevated CSF CRF concentrations in patients with stress-related psychiatric disorders (cf Newport and Nemeroff, 2001 for a review) and the association of higher CSF CRF concentrations with brain activation patterns in experimental animals that accompany fearful temperament (Kalin et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

Cerebrospinal Fluid Corticotropin-Releasing Factor (CRF) and Vasopressin Concentrations Predict Pituitary Response in the CRF Stimulation Test: A Multiple Regression Analysis

Newport

Heim

Owens

et al. 2002

Neuropsychopharmacol

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There is considerable evidence that stress-related psychiatric disorders, including depression and post-traumatic stress disorder (PTSD), are associated with hypersecretion of corticotropin-releasing factor (CRF) within the central nervous system (CNS). One line of evidence that is consistent with central CRF hypersecretion in these disorders is the blunted adrenocorticotropin hormone (ACTH) response to intravenous CRF administration, likely a consequence, at least in part, of downregulation of anterior pituitary CRF receptors. The present study tests the hypothesis that elevated cerebrospinal fluid (CSF) concentrations of CRF and a secondary ACTH secretagogue, arginine vasopressin (AVP), are associated with diminished adenohypophyseal responses in a standard CRF stimulation test. CSF concentrations of CRF and AVP, and plasma ACTH responses to the administration of 1 mg/kg ovine CRF (oCRF) were measured in healthy adult women with and without current major depression and/or a history of significant childhood abuse. The primary outcome measure was ACTH area under the curve (AUC) in the CRF stimulation test. Multiple linear regression was performed to identify the impact of CSF CRF and AVP concentrations upon the pituitary response to CRF stimulation. The regression model explained 56.5% of the variation in the ACTH response to CRF stimulation. The relationship of CSF concentrations of CRF to ACTH responses to CRF were best described by a third-order function that was inversely correlated over most of the range of studied values. The association of ACTH response with CSF concentration of AVP and the dose of oCRF followed second-order kinetics. These findings support the hypothesis that central CRF hypersecretion is associated with a blunted ACTH response to exogenously administered CRF, explaining almost 60% of the variation in the ACTH response to CRF.

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“…Moreover, peripheral infusion of CRH for ϳ2 d reduces pituitary CRH receptor concentrations (Tizabi and Aguilera, 1992). Alternatively, changes in CRH binding protein activity and /or clearance of CRH may have affected CRH bioavailability (Oldfield et al, 1985;Behan et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

Long-Term Intracerebroventricular Infusion of Corticotropin-Releasing Hormone Alters Neuroendocrine, Neurochemical, Autonomic, Behavioral, and Cytokine Responses to a Systemic Inflammatory Challenge

et al. 1997

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Corticotropin-releasing hormone (CRH) was infused intracerebroventricularly into rats for 7 d via a miniosmotic pump (1 g ⅐ l Ϫ1 ⅐ hr Ϫ1 ). Body temperature and locomotor activity were recorded during the treatment using biotelemetry, whereas hippocampal serotonergic neurotransmission and free corticosterone levels were monitored using in vivo microdialysis on day 7 of CRH treatment. During the microdialysis experiment, behavioral activity was scored by assessing the time during which rats were active (locomotion, grooming, eating, drinking). Continuous intracerebroventricular infusion of CRH produced a transient increase in body temperature and locomotion. Moreover, intracerebroventricularly CRH-treated rats showed elevated free corticosterone levels with no apparent diurnal rhythm.Intraperitoneal administration of bacterial endotoxin [lipopolysaccharide (LPS); 100 g/kg body weight] on day 7 of CRH/ vehicle treatment produced a marked fever response in control animals, which was significantly blunted in intracerebroventricularly CRH-treated rats. Although free corticosterone levels reached similar peak concentrations in both intracerebroventricularly vehicle-and CRH-infused groups after LPS, this response was delayed significantly by ϳ1 hr in the intracerebroventricularly CRH-treated animals. Microdialysis experiments showed no changes in basal extracellular levels of serotonin and 5-hydroxyindoleacetic acid in intracerebroventricularly CRHinfused animals. Injection of LPS in intracerebroventricularly CRHtreated rats produced a blunted 5-HT response and a delayed onset of behavioral inhibition and other signs of sickness behavior. Assessment of the endotoxin-induced cytokine responses showed significantly enhanced plasma interleukin-1 (IL-1) and IL-6 bioactivities in the intracerebroventricularly CRH-infused animals 3 hr after injection of LPS, whereas tumor necrosis factor bioactivity responses were not different.Our data demonstrate that chronically elevated brain CRH levels produce marked changes in basal (largely CRH regulated) physiological and behavioral processes accompanied by aberrant responses to an acute challenge. The present study provides evidence that chronic CRH hypersecretion is an important factor in the etiology of stress-related disorders.

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Active Clearance of Corticotropin-Releasing Factor from the Cerebrospinal Fluid

Cited by 29 publications

References 15 publications

Effects of intracerebroventricular infusions of corticotropin‐releasing hormone in sheep

Effects of intracerebroventricular infusions of corticotropin‐releasing hormone in sheep

Cerebrospinal Fluid Corticotropin-Releasing Factor (CRF) and Vasopressin Concentrations Predict Pituitary Response in the CRF Stimulation Test: A Multiple Regression Analysis

Long-Term Intracerebroventricular Infusion of Corticotropin-Releasing Hormone Alters Neuroendocrine, Neurochemical, Autonomic, Behavioral, and Cytokine Responses to a Systemic Inflammatory Challenge

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