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

Abstract

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.

Long-Term Consequences of Neonatal Rearing on Central Corticotropin-Releasing Factor Systems in Adult Male Rat Offspring

“…Indeed, lesions to the CeA produce an 80-85% decrease in CRFir in the region of the LC (Koegler-Muly et al, 1993). The elevation of CSF CRFir in HMS180 rats is consistent with reports from clinical studies of depression and abuse (Banki et al, 1987;De Bellis et al, 1993;Geracioti et al, 1992;Nemeroff et al, 1991;Newport et al, 2003). Taken together with our previous reports showing increased hypothalamic and median eminence CRFir in HMS180 animals , these findings suggest that CRF gene expression and peptide synthesis within the PVN and CeA-LC systems may represent a common target in animals exposed to what may be considered abnormal neonatal rearing conditions regardless of which end of the rearing spectrum they fall intoFmonotonous housing and care (ie HMS0) vs extended periods of neonatal maternal separation (ie HMS180).…”

“…This pattern of hyperresponsiveness has also been reported in several nonhuman primate models of early adversity (Coplan et al, 1996;Smith et al, 2002) and in adult women with a history of prepubertal abuse (Heim et al, 2000(Heim et al, , 2002Heim and Nemeroff, 2001). Changes in nervous system CRF tone appear to be associated with these changes in HPA responsiveness, as illustrated by elevations in CSF CRFir in the adult HMS180 rats (Figure 2), in several primate models of early adversity (Coplan et al, 1996;Maestripieri et al, 2005), primates with fearful temperaments (Kalin et al, 2000), and in abused children as well as in adult women with a history of abuse (Heim and Nemeroff, 2001;Newport et al, 2003;Carpenter et al, 2004). Alternatively, we recently reported blunting of the diurnal cortisol rhythm in rhesus monkeys exposed to early adversity without accompanying changes in CSF CRFir (Sanchez et al, 2005).…”

“…Thus, it appears that central CRF systems represent a major target of neonatal rearing conditions in the rat. In fact, this may represent a general response to a wide range of early life stressors in rodents (Dent et al, 2000;Ladd et al, 2000;Schmidt et al, 2002;Fenoglio et al, 2004), monkeys (Coplan et al, 1996), and humans (Raadsheer et al, 1994(Raadsheer et al, , 1995Austin et al, 2003;Newport et al, 2003;Carpenter et al, 2004).…”

Effects of cortisol on cognition in major depressive disorder, posttraumatic stress disorder and borderline personality disorder - 2014 Curt Richter Award Winner

“…Using the dexamethasone suppression test and the combined DEX/CRF test in MDD, a reduced feedback sensitivity of the HPA axis was shown and has been interpreted as reduction of GR functioning (Holsboer, 2000). In this context vasopressin has been also emphasized to play an important role in MDD (Scott and Dinan, 1998;Newport et al, 2003;Dinan et al, 2004). Other authors have demonstrated that GR signalling is reduced in depression, suggesting that the brain is in a state of glucocorticoid resistance (Pariante et al, 2004).…”

Estados de pseudo-Cushing

“…A resposta da ACTH ao teste do CRH está diminuída na depressão endógena e alguns trabalhos demonstram inclusive down regulation dos receptores CRHR-1, refletindo o aumento nos níveis de CRH (48).…”