On Site Link: Norepinephrine, CRF, and Unipolar Depression
On Site Link: Corticosteroid Receptors and Unipolar Depression

Arborelius L, Owens MJ, Plotsky PM, Nemeroff CB.
The role of corticotropin-releasing factor in depression and anxiety disorders.
J Endocrinol 1999 Jan;160(1):1-12
"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-pituitary-adrenal (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." [Abstract]

Boyer P.
Do anxiety and depression have a common pathophysiological mechanism?
Acta Psychiatr Scand Suppl 2000;(406):24-9
"OBJECTIVE: To review, examine and propose a common mechanism for anxiety and depression based on modifications observed in neurotransmitter systems (mainly noradrenergic and serotonergic) and dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis. METHOD: The relevant papers were identified by searches in Medline, Excerpta Medica, PsychLIT and other databases. The primary reports were reviewed and classified into animal and human data concerning: modifications of the monoamine receptors in anxiety and depression, pathophysiology of endocrine factors in anxiety and depression, pathophysiology of the hypothalamic-pituitary-adrenal (HPA) axis and the pathophysiology of the HPA dysregulation in anxiety and in depression. In addition, a proposed model of a neuroendocrine continuum for anxiety and depression, in which anxiety occurs first during the life course and major depressive episodes occur later, was examined. RESULTS: Based on the available literature, increased concentrations of corticotropin-releasing factor (CRF) in the cerebrospinal fluid has been reported in both anxiety and depression. However, release of other peptides or hormones of the HPA axis is regulated differently in the two disorders. Anxiety is characterized by hypocortisolemia, supersuppression after dexamethasone and increased numbers of glucocorticoid receptors, whereas depression is characterized by hypercortisolemia, nonsuppression after dexamethasone and decreased numbers of glucocorticoid receptors. A 'neuroendocrine continuum' model is proposed to explain these differences. A general desensitization of CRF receptors at pituitary, limbic (amygdala) and cortical as well as hippocampal levels could be secondary to the loss of hippocampal inhibition resulting from hippocampal damage linked to repeated stressing events. CONCLUSION: The proposed hypothesis remains to be tested by examination of either the changes in receptors and neurotransmission or the mechanisms underlying the dysregulation of endocrine factors." [Abstract]

Alonso R, Griebel G, Pavone G, Stemmelin J, Le Fur G, Soubrie P.
Blockade of CRF(1) or V(1b) receptors reverses stress-induced suppression of neurogenesis in a mouse model of depression.
Mol Psychiatry. 2003 Dec 23 [Epub ahead of print]
"Repeated exposure to stress is known to induce structural remodelling and reduction of neurogenesis in the dentate gyrus. Corticotrophin-releasing factor (CRF) and vasopressin (AVP) are key regulators of the stress response via activation of CRF(1) and V(1b) receptors, respectively. The blockade of these receptors has been proposed as an innovative approach for the treatment of affective disorders. The present study aimed at determining whether the CRF(1) receptor antagonist SSR125543A, the V(1b) receptor antagonist SSR149415, and the clinically effective antidepressant fluoxetine may influence newborn cell proliferation and differentiation in the dentate gyrus of mice subjected to the chronic mild stress (CMS) procedure, a model of depression with predictive validity. Repeated administration of SSR125543A (30 mg/kg i.p.), SSR149415 (30 mg/kg i.p.), and fluoxetine (10 mg/kg i.p.) for 28 days, starting 3 weeks after the beginning of the stress procedure, significantly reversed the reduction of cell proliferation produced by CMS, an effect which was paralleled by a marked improvement of the physical state of the coat of stressed mice. Moreover, mice subjected to stress exhibited a 53% reduction of granule cell neurogenesis 30 days after the end of the 7-week stress period, an effect which was prevented by all drug treatments. Collectively, these results point to an important role of CRF and AVP in the regulation of dentate neurogenesis, and suggest that CRF(1) and V(1b) receptor antagonists may affect plasticity changes in the hippocampal formation, as do clinically effective antidepressants." [Abstract]

Kristen L. Brunson, Mariam Eghbal-Ahmadi, Roland Bender, Yuncai Chen, and Tallie Z. Baram
Long-term, progressive hippocampal cell loss and dysfunction induced by early-life administration of corticotropin-releasing hormone reproduce the effects of early-life stress
PNAS 98: 8856-8861; published online before print as 10.1073/pnas.151224898
"Stress early in postnatal life may result in long-term memory deficits and selective loss of hippocampal neurons. The mechanisms involved are poorly understood, but they may involve molecules and processes in the immature limbic system that are activated by stressful challenges. We report that administration of corticotropin-releasing hormone (CRH), the key limbic stress modulator, to the brains of immature rats reproduced the consequences of early-life stress, reducing memory functions throughout life. These deficits were associated with progressive loss of hippocampal CA3 neurons and chronic up-regulation of hippocampal CRH expression. Importantly, they did not require the presence of stress levels of glucocorticoids. These findings indicate a critical role for CRH in the mechanisms underlying the long-term effects of early-life stress on hippocampal integrity and function." [Full Text]

Hugin-Flores ME, Steimer T, Schulz P, Vallotton MB, Aubert ML.
Chronic corticotropin-releasing hormone and vasopressin regulate corticosteroid receptors in rat hippocampus and anterior pituitary.
Brain Res. 2003 Jun 27;976(2):159-70.
"Corticotropin-releasing hormone (CRH) and vasopressin (AVP) participate in the endocrine, autonomic, immunological and behavioral response to stress. CRH and AVP receptors are found in hippocampus and anterior pituitary, where mineralocorticoid (MR) and glucocorticoid (GR) receptors are abundant. We investigated the possible influence of CRH and AVP on the regulation of MR and GR in both tissues. CRH, AVP, or their antagonists were administered to adrenalectomized rats substituted with corticosterone, to avoid interference with adrenal secretion. Repeated i.c.v. oCRH injections (10 microgram) for 5 days significantly decreased MR and GR mRNA in hippocampus and MR mRNA in anterior pituitary. AVP significantly increased both corticosteroid receptor mRNAs, as repeated i.c.v. injections (5 microgram) for 5 days in hippocampus, and as continuous i.c.v. infusion (10 ng/h/5 days) in anterior pituitary. The i.c.v. infusion of 5 or 10 microgram/day of the alpha-helical CRH antagonist during intermittent restraint stress (5 days), induced a significant decrease in hippocampal MR binding. In anterior pituitary, 5 microgram/day significantly decreased MR binding, while 10 microgram/day significantly increased GR binding. Under the same conditions of stress, the infusion of 15 microgram/day of the vasopressin V1a/1b receptor antagonist [dP Tyr (Me)(2)AVP] significantly increased MR and GR binding in hippocampus and anterior pituitary; 5 microgram/day significantly decreased pituitary MR binding. Our results show that CRH and AVP regulate MR and GR in hippocampus and anterior pituitary. This reveals another important function of CRH and AVP, which could be relevant to understand stress adaptation and the pathophysiology of stress-related disorders like major depression." [Abstract]

Hatzinger M.
Neuropeptides and the hypothalamic-pituitary-adrenocortical (HPA) system: review of recent research strategies in depression.
World J Biol Psychiatry 2000 Apr;1(2):105-11
"Depressed patients show a variety of alterations in hypothalamic-pituitary-adrenocortical (HPA) system regulation which is reflected by increased pituitary-adrenocortical hormone secretion at baseline and a number of aberrant neuroendocrine function tests. The latter include the combined dexamethasone (DEX) suppression/corticotropin-releasing hormone (CRH) challenge test, in which CRH was able to override DEX induced suppression of ACTH and cortisol secretion. Whereas the abnormal HPA activation in these patients improved in parallel with clinical remission, persistent HPA dysregulation was associated with an increased risk of relapse. Moreover, healthy subjects at high genetic risk for depression also showed this phenomenon as a trait marker. In consequence, it has been concluded that HPA alteration and development as well as course of depression may be causally related. As evidenced from clinical and preclinical studies, underlying mechanisms of these abnormalities involve impairment of central corticosteroid receptor function which leads to enhanced activity of hypothalamic neurons synthesising and releasing vasopressin and CRH. These neuropeptides mediate not only neuroendocrine but also behavioural effects. Recent research provided evidence that CRH can induce depression-like symptoms in animals and that these signs are mediated through the CRH1 receptor subtype. Hence, therapeutical application of new compounds acting more specifically on the HPA system such as CRH1 receptor antagonists appear to be a promising approach for future treatment options of depression. In conclusion, research in neuroendocrinology provided new insights into the underlying pathophysiology of depression and, in consequence, may lead to the development of new therapeutic tools." [Abstract]

Stout SC, Owens MJ, Nemeroff CB.
Regulation of corticotropin-releasing factor neuronal systems and hypothalamic-pituitary-adrenal axis activity by stress and chronic antidepressant treatment.
J Pharmacol Exp Ther 2002 Mar;300(3):1085-92
"In a series of experiments, we tested the hypothesis that chronic antidepressant drug administration reduces the synaptic availability of corticotropin-releasing factor (CRF) through one or more effects on CRF gene expression or peptide synthesis. We also determined whether effects of acute or chronic stress on CRF gene expression or peptide concentration are influenced by antidepressant drug treatment. Four-week treatment with venlafaxine, a dual serotonin (5-HT)/norepinephrine (NE) reuptake inhibitor, and tranylcypromine, a monoamine oxidase inhibitor, resulted in an attenuation of acute stress-induced increases in CRF heteronuclear RNA (hnRNA) synthesis in the paraventricular nucleus (PVN). Trends toward the same effect were observed after treatment with the 5-HT reuptake inhibitor fluoxetine, or the NE reuptake inhibitor reboxetine. CRF mRNA accumulation in the PVN during exposure to chronic variable stress was attenuated by concurrent antidepressant administration. Basal CRF hnRNA and mRNA expression were not affected by antidepressant treatment in the PVN or in other brain regions examined. Chronic stress reduced CRF concentrations in the median eminence, but there were no consistent effects of antidepressant drug treatment on CRF, serum corticotropin, or corticosterone concentrations. CRF receptor expression and basal and stress-stimulated HPA axis activity were unchanged after antidepressant administration. These results suggest that chronic antidepressant administration diminishes the sensitivity of CRF neurons to stress rather than alters their basal activity. Additional studies are required to elucidate the functional consequences and mechanisms of this interaction." [Abstract]

Heuser I, Bissette G, Dettling M, Schweiger U, Gotthardt U, Schmider J, Lammers CH, Nemeroff CB, Holsboer F.
Cerebrospinal fluid concentrations of corticotropin-releasing hormone, vasopressin, and somatostatin in depressed patients and healthy controls: response to amitriptyline treatment.
Depress Anxiety 1998;8(2):71-9
"The effect of amitriptyline upon hypothalamic-pituitary-adrenal [HPA]-system-regulating neuropeptides (corticotropin-releasing hormone [CRH], vasopressin, somatostatin) was studied in a group of depressed elderly patients and controls. A first lumbar puncture was performed in 37 depressed in-patients. This was followed by a 6-week medication phase with amitriptyline. Upon its completion a second cerebrospinal fluid (CSF) sample was obtained in 18 of these 37 patients. In 25 healthy controls a first lumbar puncture was done eleven of these individuals agreed to take 75 mg/d amitriptyline for 6 weeks and to participate in the follow-up CSF study. Within the group of depressed patients amitriptyline led to a significant decrease of CSF CRH in treatment responders only (F1, 16 = 5.2; P < 0.02). Also, in normal controls CSF CRH concentration tended to decrease with amitriptyline treatment (t-test; P < 0.09). No effects of amitriptyline upon vasopressin or somatostatin were observed. In normal controls (r = 0.4; P < 0.02) and in patients (r = 0.4; P < 0.03) age correlated positively with baseline CSF somatostatin. A trend for CSF CRH to increase with aging was found only in controls (r = 0.3; P < 0.09); patients did not show a significant association here. Finally, CSF neuropeptide concentration at baseline did not differ between the group of depressed patients and healthy controls. Our study corroborates the evolving concept that antidepressants effect various components of the HPA system with the net result of a reduction in its activity. In addition, we found CSF CRH and CSF somatostatin concentrations to be better reflections of age than of depression and, finally, that during aging and during depression the HPA system changes in similar directions." [Abstract]

Hassan A, Chacko S, Mason D.
Desensitization of the adrenocorticotrophin responses to arginine vasopressin and corticotrophin-releasing hormone in ovine anterior pituitary cells.
J Endocrinol. 2003 Sep;178(3):491-501.
"Following repeated or prolonged exposure to either corticotrophin-releasing hormone (CRH) or arginine vasopressin (AVP), pituitary adrenocorticotrophin (ACTH) responsiveness is reduced. This study compared the characteristics of desensitization to CRH and AVP in perifused ovine anterior pituitary cells. Desensitization to AVP occurred at relatively low AVP concentrations and was both rapid and readily reversible. Treatment for 25 min with AVP at concentrations greater than 2 nM caused significant reductions in the response to a subsequent 5 min 100 nM AVP pulse (IC(50)=6.54 nM). Significant desensitization was observed following pretreatment with 5 nM AVP for as briefly as 5 min. Desensitization was greater following a 10 min pretreatment, but longer exposures caused no further increase. Resensitization was complete within 40 min following 15 min treatment with 10 nM AVP. Continuous perifusion with 0.01 nM CRH had no effect on AVP-induced desensitization. Treatment with 0.1 nM CRH for either 25 or 50 min caused no reduction in the response to a subsequent 5 min stimulation with 10 nM CRH. When the pretreatment concentration was increased to 1 nM significant desensitization was observed, with a greater reduction in response occurring after 50 min treatment. Recovery of responsiveness was progressive following 50 min treatment with 1 nM CRH and was complete after 100 min. Our data show that in the sheep AVP desensitization can occur at concentrations and durations of AVP exposure within the endogenous ranges. This suggests that desensitization may play a key role in regulating ACTH secretion in vivo. If, as has been suggested, CRH acts to set corticotroph gain while AVP is the main dynamic regulator, any change in responsiveness to CRH may significantly influence the overall control of ACTH secretion." [Abstract]

O'Brien D, Skelton KH, Owens MJ, Nemeroff CB.
Are CRF receptor antagonists potential antidepressants?
Hum Psychopharmacol 2001 Jan;16(1):81-87
"Corticotropin-releasing factor (CRF) is the major regulator of the hypothalamic-pituitary-adrenal (HPA) axis, and plays a key role in coordinating the endocrine, as well as autonomic and behavioral responses of an organism to stress. Direct CNS administration of CRF to laboratory animals produces an aggregate of effects that mimic the mammalian stress response. Impeding CRF function with CNS administration of a peptidergic CRF antagonist can block these manifestations of the stress response whether produced by exogenous CRF or occurring naturally in response to a stressor. A role for hypersecretion of CRF in the pathophysiology of depression is suggested by the finding that CNS administration of CRF mirrors many of the signs and symptoms utilized as diagnostic criteria for major depression. In addition, a large body of clinical evidence points to excess hypothalamic secretion of CRF and an accompanying HPA axis hyperactivity in patients with major depression. The recent development of selective, small molecule CRF(1) receptor antagonists, which block the effects of CRF both in vitro and in vivo, suggest that these compounds may be effective in the treatment of affective and anxiety disorders. Early evidence indicates that these agents possess anxiolytic and antidepressant activity in animal behavioral models." [Abstract]

Zobel AW, Nickel T, Kunzel HE, Ackl N, Sonntag A, Ising M, Holsboer F.
Effects of the high-affinity corticotropin-releasing hormone receptor 1 antagonist R121919 in major depression: the first 20 patients treated.
J Psychiatr Res 2000 May-Jun;34(3):171-81
"Clinical and preclinical data suggest that unrestrained secretion of corticoctropin-releasing hormone (CRH) in the CNS produces several signs and symptoms of depression and anxiety disorders through continuous activation of CRH(1) receptors. This led to the development of drugs that selectively antagonize CRH(1) receptors suppressing anxiety-like behavior in rats and also in monkey models of anxiety. These findings led to a clinical development program exploring the antidepressive potential of R121919, a water-soluble pyrrolopyrimidine that binds with high affinity to human CRH(1) receptors and is well absorbed in humans. This compound was administered to 24 patients with a major depressive episode primarily in order to investigate whether its endocrine mode of action compromises the stress-hormone system or whether other safety and tolerability issues exist. The patients were enrolled in two dose-escalation panels: one group (n=10) where the dose range increased from 5-40 mg and another group (n=10) where the dose escalated from 40 to 80 mg within 30 days each. Four patients dropped out because of withdrawal of consent to participate (three cases) or worsening of depressive symptomatoloy in one case. We found that R121919 was safe and well tolerated by the patients during the observation period. Moreover, the data suggested that CRH(1)-receptor blockade does not impair the corticotropin and cortisol secretory activity either at baseline or following an exogenous CRH challenge. We also observed significant reductions in depression and anxiety scores using both, patient and clinician ratings. These findings, along with the observed worsening of affective symptomatology after drug discontinuation, suggests that the pharmacological principle of CRH(1)-receptor antagonism has considerable therapeutic potential in the treatment and the prevention of diseases where exaggerated central CRH activity is present at baseline or following stress exposure." [Abstract]

Kunzel HE, Zobel AW, Nickel T, Ackl N, Uhr M, Sonntag A, Ising M, Holsboer F.
Treatment of depression with the CRH-1-receptor antagonist R121919: endocrine changes and side effects.
J Psychiatr Res. 2003 Nov-Dec;37(6):525-33.
"A dysregulation of the hypothalamus-pituitary-adrenocortical (HPA) system has been hypothesized to account for a myriad of cardinal symptoms of affective disorders. Specifically, increased CRH signalling via CRH type 1 receptors is thought to be an important factor in the pathogenesis of major depression and anxiety disorders. Consequently, a number of drugs have been developed in order to target the postulated increase in CRH/CRH 1 receptor signalling. One of these compounds, R121919, binds with high affinity to CRH1 receptors antagonising the action of CRH. R121919 was recently tested in an open-label study conceptualized as a safety and tolerability study. As part of this study, a thorough endocrine evaluation and detailed clinical laboratory analysis were assessed several times during 30 days of treatment with two different dose regimens of R121919 (5-40 mg vs. 40-80 mg) in 24 patients with a major depressive episode. During treatment with the experimental drug no serious side effects were noted. In particular, there were no adverse effects or impairment of the hypothalamic-pituitary-gonadal system, the hypothalamic-pituitary-thyroid axis, the renin-angiotensin system, prolactin or vasopressin secretion. Furthermore, no changes in the serum corticotropin and cortisol concentrations and in the responsivity of corticotropin and cortisol following a CRH stimulation test were noted. No effects of R121919 on clinical laboratory parameters including liver enzymes, EEG and ECG were observed. These results encourage the development of other CRH-1-R antagonists as a novel class of antidepressive drugs." [Abstract]

Mansbach RS, Brooks EN, Chen YL.
Antidepressant-like effects of CP-154,526, a selective CRF1 receptor antagonist.
Eur J Pharmacol 1997 Mar 26;323(1):21-6
"The effects of CP-154,526 (butyl-ethyl-[2,5-dimethyl-7-(2,4,6 -trimethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine), a selective corticotropin releasing factor (CRF1) receptor antagonist, were examined in the learned helplessness procedure, a putative model of depression with documented sensitivity to diverse classes of antidepressant drugs. Rats were exposed to a series of inescapable foot shocks on three consecutive days and tested in a shock-escape procedure on the fourth day. Animals exposed to 'helplessness' training performed poorly in the shock-escape test compared with control animals not receiving inescapable shocks. CP-154,526 (10-32 mg/kg, intraperitoneally) dose-dependently reversed the escape deficit when administered 60 min prior to the test session, but had no effect on the performance of control rats not receiving prior exposure to inescapable stress. In comparison, the tricyclic antidepressant imipramine (17.8 mg/kg) reversed the escape deficit after repeated, but not acute, administration. These data support evidence implicating stress systems in the pathophysiology of depression, and suggest potential efficacy of small-molecule CRF receptor antagonists in the treatment of affective disorders." [Abstract]

Griebel G, Simiand J, Steinberg R, Jung M, Gully D, Roger P, Geslin M, Scatton B, Maffrand JP, Soubrie P.
4-(2-Chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-
1-(3-fluoro-4-methylphenyl)ethyl]5-methyl-N-(2-propynyl)-1, 3-
thiazol-2-amine hydrochloride (SSR125543A), a potent and selective corticotrophin-releasing factor(1) receptor antagonist. II. Characterization in rodent models of stress-related disorders.
J Pharmacol Exp Ther 2002 Apr;301(1):333-45
"The present study investigated the effects of the novel corticotrophin-releasing factor (CRF)(1) receptor antagonist 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-
cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]5-methyl-N-(2-propynyl)-1,3-thiazol-
2-amine hydrochloride (SSR125543A) in a variety of rodent models of anxiety, including conflict procedures (punished drinking and four-plate), exploration models (elevated plus-maze and light/dark), a fear/anxiety defense test battery, and several procedures based on stress-induced changes in physiological (isolation-induced hyperthermia and tail pinch-induced cortical norepinephrine release) or behavioral (social defeat-induced anxiety, maternal separation-induced vocalization) parameters. Moreover, the effects of SSR125543A were investigated in acute (forced swimming) and chronic (chronic mild stress; CMS) models of depression. SSR125543A and the CRF(1) receptor antagonist antalarmin displayed limited efficacy in exploration-based anxiety models. In contrast, both compounds produced clear-cut anxiolytic-like activity in models involving inescapable stress, including the conflict procedures, the social defeat-induced anxiety paradigm and the defense test battery (3-30 mg/kg i.p. or p.o.). These effects paralleled those of the anxiolytic diazepam. In addition, SSR125543A and antalarmin antagonized stress-induced hyperthermia, distress vocalization, and cortical norepinephrine release. In the forced swimming test, 30 mg/kg p.o. SSR125543A and 3 to 30 mg/kg p.o. antalarmin produced clear antidepressant-like effects. These latter results were strengthened by the findings from the CMS, which showed that repeated administration of 10 mg/kg i.p. SSR125543A for 30 days improved the degradation of the physical state, the reduction of body weight gain, and anxiety produced by stress. Together, these data indicate that SSR125543A shows good activity in acute and chronic tests of unavoidable stress exposure, suggesting that it may have a potential in the treatment of depression and some forms of anxiety disorders." [Abstract]

Arborelius, Lotta, Skelton, Kelly H., Thrivikraman, Karacheri V., Plotsky, Paul M., Schulz, David W., Owens, Michael J.
Chronic Administration of the Selective Corticotropin-Releasing Factor 1 Receptor Antagonist CP-154,526: Behavioral, Endocrine and Neurochemical Effects in the Rat
J Pharmacol Exp Ther 2000 294: 588-597
"Corticotropin-releasing factor 1 (CRF1) receptor antagonists may represent a novel group of drugs for the pharmacotherapy of depression and/or anxiety disorders. We have investigated the behavioral, endocrine, and neurochemical effects of chronic administration of a selective CRF1 receptor antagonist, CP-154,526. After 9 to 10 days of treatment with CP-154,526 (3.2 mg/kg/day), defensive withdrawal behavior was significantly decreased suggesting anxiolytic activity. In animals treated for 14 days with the low dose of CP-154,526, serum corticosterone concentrations returned to baseline levels faster after application of an airpuff startle. Using in situ hybridization, no changes in CRF1 receptor mRNA expression were detected in parietal cortex, basolateral amygdala, or cerebellum after chronic treatment with CP-154,526. A dose-dependent decrease in CRF mRNA expression was observed in the hypothalamic paraventricular nucleus (PVN) and the Barrington's nucleus, an effect that was significant at the high but not the low dose of CP-154,526. CP-154,526 did not alter central CRF2A receptor binding or mRNA expression, or urocortin mRNA expression. The present findings suggest that chronic administration of CP-154,526 produces anxiolytic-like effects but no evidence of adrenal insufficiency. Previous postmortem studies revealed increased CRF peptide and mRNA levels in the PVN of depressed patients, which may mediate the hyperactivity of the hypothalamic-pituitary-adrenal axis observed in such patients. In view of a possible use for CRF1 receptor antagonists in the treatment of depression, the present finding that CP-154,526 decreases CRF synthesis in the PVN is of considerable interest." [Full Text]

Willenberg HS, Bornstein SR, Hiroi N, Path G, Goretzki PE, Scherbaum WA, Chrousos GP.
Effects of a novel corticotropin-releasing-hormone receptor type I antagonist on human adrenal function.
Mol Psychiatry 2000 Mar;5(2):137-41
"Corticotropin-releasing hormone (CRH) is the principal regulator of the hypothalamic-pituitary-adrenal (HPA) axis and an activator of the sympathoadrenal (SA) and systemic sympathetic (SS) systems. Mental disorders, including major depression and, more recently, Alzheimer's disease have been associated with dysregulation of the HPA axis and the SA/SS systems. Treatment of rats or monkeys with the novel CRH receptor type 1 (CRH-R1) antagonist antalarmin inhibits the HPA and/or the SA/SS axes. This is the first study to examine the potential direct effect of antalarmin on human adrenal function. Adrenocortical and adrenomedullary cells were characterized by double-immunohistochemistry with anti-17 alpha hydroxylase (cortical cells) and anti-chromogranin A (chromaffin cells). Expression of CRH, ACTH, CRH type I and type II receptor mRNA were analyzed by reverse-transcription (RT) PCR. Human adrenal cortical and/or chromaffin cells in co-culture were incubated with CRH, antalarmin, and both CRH and antalarmin in vitro. Exposure of these cells to corticotropin or vehicle medium served as positive and negative controls, respectively. Cortical and chromaffin tissues were interwoven in the human adrenals, and both in situ and in the co-culture system the endocrine cell types were in close cellular contact. ACTH, CRH, and CRH-R1 and CRH-R2 mRNAs were expressed in the human adrenal as determined by RT-PCR. CRH (10-8 M) led to a moderate increase of cortisol release (145.7 +/- 20.0%) from cortical and chromaffin adrenal cells in co-culture. This effect corresponded to 41.8% of the maximal increase induced by ACTH (10-8 M). The action of CRH was completely inhibited by antalarmin. CRH, ACTH, and both CRH-R1 and CRH-R2 mRNAs are expressed in the adult human adrenal gland. CRH stimulates cortisol production in cortical and chromaffin cell co-cultures. This effect is blocked by antalarmin, a selective CRH-R1 receptor antagonist, suggesting that CRH-R1 receptors are involved in an intraadrenal CRH/ACTH control system in humans." [Abstract]

Arlt J, Jahn H, Kellner M, Strohle A, Yassouridis A, Wiedemann K.
Modulation of sympathetic activity by corticotropin-releasing hormone and atrial natriuretic peptide.
Neuropeptides. 2003 Dec;37(6):362-8.
"BACKGROUND: Heart rate variability represents a reliable marker to delineate the status of autonomic nervous system (ANS) function and alterations due to stress in vivo. Interestingly, up to now the effects of corticotropin-releasing hormone (CRH), a key regulator of the stress hormone system, upon heart rate variability are not sufficiently described. Hence, we attempted to investigate the ANS-effects of a CRH bolus and the modulatory influences of atrial natriuretic peptide (ANP), one of the most important functional antagonist of CRH actions.METHODS: 12 healthy male volunteers were administered 100 microg CRH as bolus injection at 15:00. Six randomly chosen subjects received 150 microg ANP dissolved in normal saline and six subjects a normal saline infusion from 14:45 to 15:15. From 13:00 to 17:00 an ECG was recorded and mean heart rate (HR), total power (TP), very low frequency (VLF), low frequency (LF), LF in normalized units (LF [nu]), high frequency (HF) domains and the LF/HF-ratio in the interval from 14:00 to 16:00 were determined.RESULTS: After administration of CRH a significant increase in HR and a fast reduction of TP were observed, which lasted about 1 h. Based upon spectral domain analyses the sympathetic activity after CRH administration as indicated by LF [nu] increased by 31% (mean location) during saline. Applying ANP this increase was reduced to 19% (mean location). The VLF component, which is considered to be based in part also on sympathetic influences, indicates comparable effect. During saline the VLF after CRH bolus remained largely unchanged, but was reduced to 66% by ANP. Though the vagal activity indicated by the HF component was reduced after CRH, no significant differences emerged between both treatments. The changes of the LF/HF-ratio were pronounced in both groups. During saline this ratio increased by about 111%, during ANP only by 43% (mean location).CONCLUSIONS: Based upon HRV analysis the CRH administration induced sympathotonic effects which were antagonized by ANP. The observed vagal changes were less pronounced and need further investigation. Further studies of autonomic effects by alterations of CRH secretion in depression and anxiety disorder are strongly warranted." [Abstract]

Gold PW, Calabrese JR, Kling MA, Avgerinos P, Khan I, Gallucci WT, Tomai TP, Chrousos GP.
Abnormal ACTH and cortisol responses to ovine corticotropin releasing factor in patients with primary affective disorder.
Prog Neuropsychopharmacol Biol Psychiatry 1986;10(1):57-65
"To further explore hypothalamic pituitary adrenal regulation in patients with affective illness, we administered 1 microgram/kg of synthetic ovine corticotropin releasing factor at 2000h to 26 drug-free patients with this disorder and to 15 healthy controls. Compared to controls, depressed patients (N = 12) showed a significant elevation in baseline cortisol and significant reductions in the net ACTH and cortisol responses to corticotropin releasing factor. These findings were normal in manic (N = 6) and improved (N = 8) subjects. An additional finding was that baseline cortisol and net ACTH and cortisol responses to CRF were negatively correlated in the entire group of patients and controls as well as in the patients alone. These data indicate that the reduced ACTH and cortisol responses to CRF in depression reflect normal functioning of the pituitary corticotroph cell (i.e., that the negative feedback effect of cortisol on ACTH secretion in depression is physiologically intact, effectively serving as a brake on the ACTH response to exogenous CRF. Thus, the hypercortisolism of depression may be due to a hypothalamic defect, possibly involving hypersecretion of endogenous CRF. This possibility may be of particular interest in light of clinical observations that depression can often be precipitated by stress and by data in experimental animals that CRF may influence several processes known to be altered in the overall symptom complex of depression." [Abstract]

Nerozzi D, Bersani G, Melia E, Magnani A, Antonozzi I, Frajese G.
Corticotropin-releasing factor and adrenal function in major depression.
J Endocrinol Invest 1988 Nov;11(10):697-701
"We investigated ACTH and cortisol responses after ovine CRF injection (1 microgram/kg one bolus) in a group of 11 drug-free patients suffering from major depression. When compared to sex- and age-matched normal controls, our depressed patients showed: Higher ACTH basal values (p less than 0.002); higher cortisol basal values (p less than 0.009); blunted ACTH response to oCRF administration (p less than 0.23); higher cortisol response to oCRF (p less than 0.001). Our data show that in depressed patients the feed-back mechanism is functionally intact at the pituitary level on one hand, while on the other, a hyperresponsiveness of adrenal cortex (even to minimal stimuli) seems to be present. Moreover, a hypersecretion of endogenous CRF in these patients seems to be likely." [Abstract]

Mitchell AJ.
The role of corticotropin releasing factor in depressive illness: a critical review.
Neurosci Biobehav Rev 1998 Sep;22(5):635-51
"Corticotropin-releasing factor (CRF) is the principal neuropeptide involved in regulating the stress response. When centrally administered to animals it produces somatic changes analogous to those seen in both depression and anxiety. In humans, it is capable of reproducing the hormonal changes which are characteristically seen in depressed patients. A literature search using Medline, Embase Psychiatry, PsycLIT and BIDS from 1996-1997 revealed 25 studies that have examined CRF concentrations in patients with affective disorder. The methodology of these studies varies and they can be criticised, in particular, for failing to consider the stress response of the lumbar puncture. Recently, post-mortem immunocytochemical techniques have been employed to help clarify the nature of these abnormalities in depression. On balance, evidence from CSF sampling, post-mortem findings and dynamic endocrine studies suggests that both hypothalamic and extra-hypothalamic concentrations of CRF are moderately elevated in a proportion of currently antidepressant treatment, high CRF concentrations tend to normalise. The causes of increased CRF output in depression are also unknown but may involve an integration of remote vulnerability factors and recent stressors perhaps mediated through impaired function of glucocorticoid receptors. Ultimately, the careful manipulation of CRF may hold therapeutic promise for sufferers of mood disorders." [Abstract]

Nemeroff CB, Bissette G, Akil H, Fink M.
Neuropeptide concentrations in the cerebrospinal fluid of depressed patients treated with electroconvulsive therapy. Corticotrophin-releasing factor, beta-endorphin and somatostatin.
Br J Psychiatry 1991 Jan;158:59-63
"The CSF concentrations of CRF, somatostatin and beta-endorphin were determined in nine patients who fulfilled DSM-III criteria for major depression with psychotic features. CSF samples were obtained at baseline in the depressed state, and again after a course of ECT. Concentrations of both CRF and beta-endorphin decreased after ECT, while the concentration of somatostatin increased, although the latter difference did not attain statistical significance. The increase in CSF concentrations of CRF and beta-endorphin in depressed patients is therefore seen to be state-dependent." [Abstract]

Owens MJ, Bissette G, Nemeroff CB.
Acute effects of alprazolam and adinazolam on the concentrations of corticotropin-releasing factor in the rat brain.
Synapse 1989;4(3):196-202
"Corticotropin-releasing factor (CRF) is the major physiological regulator of the hypothalamic-pituitary-adrenal (HPA) axis. However, considerable evidence indicates that CRF may be responsible for integrating not only the endocrine, but the autonomic and behavioral responses of an organism to stress as well. In addition, clinical studies indicate that CRF of both hypothalamic and extrahypothalamic origin may be hypersecreted in major depression as well as other psychiatric disorders. These findings, taken together, led to the hypothesis that the efficacy of antidepressant and/or anxiolytic drugs may be related to their actions on CRF-containing neural pathways in the central nervous system (CNS). Therefore, alterations of CRF concentrations in 18 rat brain regions were studied after acute administration of a tricyclic antidepressant (imipramine) or one of two triazolobenzodiazepines (alprazolam or adinazolam) that possess anxiolytic properties typical of benzodiazepines, as well as purported antidepressant activity unique to these compounds. Treatment with alprazolam or adinazolam increased hypothalamic CRF concentrations, which was associated with lower plasma ACTH concentrations. In contrast, the concentration of CRF was markedly reduced in the locus coeruleus, amygdala, and several cortical regions by either triazalobenzodiazepine. Acute treatment with imipramine was without effect on CRF concentrations in any brain region studied. Of particular interest is the finding that the two triazolobenzodiazepines exert effects on CRF concentrations in the locus coeruleus and hypothalamus that are opposite to CRF changes seen after stress." [Abstract]

Hiroi N, Wong ML, Licinio J, Park C, Young M, Gold PW, Chrousos GP, Bornstein SR.
Expression of corticotropin releasing hormone receptors type I and type II mRNA in suicide victims and controls.
Mol Psychiatry 2001 Sep;6(5):540-6
"Corticotropin-releasing hormone (CRH) is a key neuroendocrine factor implementing endocrine, immune and behavioral responses to stress. CRH exerts its action through two major receptors, CRH-R1 and CRH-R2. Recently novel non-peptidic antagonists directed against CRH-R1 or CRH-R2 have been proposed as promising agents in the treatment of depression, anxiety and eating disorder. However, so far the CRH-receptor system has not been widely studied in humans. Therefore, we employed quantitative TaqMan PCR to analyze the expression and distribution of both CRH-R1 and CRH-R2 in human brain tissue and peripheral organs. Furthermore the expression of CRH receptors was analyzed for the first time in pituitaries of suicide victims by in situ hybridization and quantitative PCR. Our data demonstrated a different expression pattern in humans as compared to rodents. Both CRH-R1 and CRH-R2 were expressed in high amounts in the brain with the strongest expression in the pituitary. As described in rodents, however the CRH-R1 in human was the predominant receptor in the brain (82.7 +/- 11.0%), whilst CRH-R2 was the predominant receptor in peripheral organs (77.0 +/- 15.8%). There was a shift in the ratio of CRH-R1/R2 in the pituitaries of suicide victims. In conclusion, both CRH-R1 and CRH-R2 are widely expressed in human tissues with a distribution substantially different from rodents. Strong expression of both CRH-R1 and CRH-R2 in human pituitaries suggests that particularly under stress, activation of the HPA axis can be maintained through both receptors." [Abstract]

Merali Z, Du L, Hrdina P, Palkovits M, Faludi G, Poulter MO, Anisman H.
Dysregulation in the suicide brain: mRNA expression of corticotropin-releasing hormone receptors and GABA(A) receptor subunits in frontal cortical brain region.
J Neurosci. 2004 Feb 11;24(6):1478-85.
"Corticotropin-releasing hormone (CRH) and GABA have been implicated in depression, and there is reason to believe that GABA may influence CRH functioning. The levels of CRH, and mRNA for CRH-binding protein, CRH1, and CRH2 receptors, as well as various GABA(A) receptor subunits (alpha1, alpha2, alpha3, alpha4, alpha5, delta, and gamma2), were determined in several frontal cortical brain regions of depressed suicide victims and nondepressed individuals who had not died by suicide. Relative to the comparison group, CRH levels were elevated in frontopolar and dorsomedial prefrontal cortex, but not in the ventrolateral prefrontal cortex of suicide victims. Conversely, using quantitative PCR analyses, it was observed that, in frontopolar cortex, mRNA for CRH1, but not CRH2, receptors were reduced in suicide brains, possibly secondary to the high levels of CRH activity. In addition, mRNA of the alpha1, alpha3, alpha4, and delta receptor subunits was reduced in the frontopolar region of suicide victims. Interestingly, a partial analysis of the GABA(A) receptor functional genome revealed high cross-correlations between subunit expression in cortical regions of nondepressed individuals, suggesting a high degree of coordinated gene regulation. However, in suicide brains, this regulation was perturbed, independent of overall subunit abundance. These findings raise the possibility that the CRH and GABA(A) receptor subunit changes, or the disturbed coordination between these GABA(A) receptor subunits, contribute to depression and/or suicidality or are secondary to the illness/distress associated with it." [Abstract]

Hucks D, Lowter S, Crompton MR, Katona CL, Horton RW.
Corticotropin-releasing factor binding sites in cortex of depressed suicides.
Psychopharmacology (Berl) 1997 Nov;134(2):174-8
"Corticotropin-releasing factor (CRF) receptors were measured by saturation binding in frontal and motor cortex of suicides with a firm retrospective diagnosis of depression, and matched controls. The suicides were divided into those who were free of antidepressant drugs, and those in whom prescription of antidepressant drugs was clearly documented. There were no differences in the number or affinity of CRF receptors between antidepressant-free or antidepressant-treated suicides and matched controls in either brain region. When suicides were divided according to violence of death, again there were no differences between violent or non-violent suicides and controls." [Abstract]

Nemeroff CB, Owens MJ, Bissette G, Andorn AC, Stanley M.
Reduced corticotropin releasing factor binding sites in the frontal cortex of suicide victims.
Arch Gen Psychiatry 1988 Jun;45(6):577-9
"Previous studies have provided evidence that corticotropin releasing factor (CRF) is hypersecreted in patients with major depression. This CRF hypersecretion is believed to contribute at least in part to hyperactivity of the hypothalamic-pituitary-adrenal axis in depressed patients. If CRF is chronically hypersecreted in depressed patients, then, due to down-regulation, a reduced number of CRF receptor binding sites should be present in patients with profound depressive disorder. To test this hypothesis, we measured the number and affinity of CRF binding sites in the frontal cortex of 26 suicide victims and 29 controls who died of a variety of causes. There was a marked (23%) reduction in the number of CRF binding sites in the frontal cortex of the suicide victims compared with the controls. These data are consistent with the hypothesis that CRF is hypersecreted in depression." [Abstract]

Owens MJ, Nemeroff CB.
The role of corticotropin-releasing factor in the pathophysiology of affective and anxiety disorders: laboratory and clinical studies.
Ciba Found Symp 1993;172:296-308; discussion 308-16
"The unique distribution of corticotropin-releasing factor (CRF) and its receptors within the central nervous system, its pre-eminent role in mediating the endocrine, behavioural, autonomic and immunological effects of stress and its potent effects after direct administration into the CNS all support the hypothesis that alterations in CRF neuronal systems contribute to the pathophysiology of depression and certain anxiety disorders. This report summarizes a series of preclinical and clinical investigations which have sought to test the hypothesis that CRF-containing neurons show alterations in depression and anxiety, and that drugs used to treat these disorders alter CRF neuronal circuits. Direct injection of CRF into the locus ceruleus or nearby parabrachial nucleus evokes an anxiogenic response. Stress increases CRF concentrations in the locus ceruleus, whereas alprazolam, a benzodiazepine anxiolytic, decreases the concentration of the peptide in the same area. Clinical studies reveal that drug-free depressed patients show: (1) hyperactivity of the hypothalamo-pituitary-adrenal axis; (2) increased CRF concentrations in the cerebrospinal fluid; (3) a blunted release of ACTH in response to CRF; (4) a reduced density of CRF receptors in the frontal cortex; (5) pituitary and adrenal gland hypertrophy. These findings are all concordant with hypersecretion of CRF from hypothalamic and extrahypothalamic CRF neurons in depression." [Abstract]

Kasckow JW, Baker D, Geracioti TD Jr.
Corticotropin-releasing hormone in depression and post-traumatic stress disorder.
Peptides 2001 May;22(5):845-51
"Corticotropin-releasing hormone (CRH) has been implicated in the regulation of a wide range of behaviors including arousal, motor function, feeding, and reproduction. Because depressed patients are often hypercortisolemic and intracerebroventricular administration of CRH to experimental animals produces a syndrome reminiscent of depression, dysregulation of this compound has been suggested to be involved in the pathogenesis of depressive and anxiety disorders. Studies of cerebrospinal fluid CRH levels and clinical neuroendocrine tests in patients with anxiety and affective disorders have supported this hypothesis. This review discusses these neuroendocrine findings in melancholic and atypical depression as well as post-traumatic stress disorder (PTSD). Overall, the data suggest that melancholic depression is characterized by hyperactive central CRH systems with overactivity of the pituitary-adrenal (HPA) axis. On the other hand, atypical depression is characterized by hypoactive central CRH systems and accompanying underactivity of the hypothalamic-pituitary-adrenal axis. Furthermore, the neuroendocrinology of PTSD appears to be unique, in that patients have hyperactive central CRH systems with underactivity of the pituitary-adrenal axis." [Abstract]

Licinio J, Gold PW.
Role of corticotrophin releasing hormone 41 in depressive illness.
Baillieres Clin Endocrinol Metab 1991 Mar;5(1):51-8
"CRH seems to be of fundamental importance in depressive illness. Melancholic depressed patients, with a syndrome of hyperarousal, have increased activity of CRH-producing neurones. Conversely, there is evidence to support the notion that patients with atypical depression, a syndrome of hypoarousal, have decreased activity of CRH-producing neurones. CRH-induced kindling is a possible model for the natural history of depressive illness. Finally, effective treatments for depressive illness, such as tricyclic antidepressants, decrease CRH production, and drugs, such as carbamazepine, effective in preventing the recurrence of affective disorder, also decrease CRH production. Interestingly, these drugs are not particularly effective in the treatment of atypical depression, which seems to be related not to an activation of CRH-producing neurones, but rather to a decrease of CRH secretion." [Abstract]

McGinn LK, Asnis GM, Rubinson E.
Biological and clinical validation of atypical depression.
Psychiatry Res 1996 Mar 29;60(2-3):191-8
"Depressed patients with (a) mood reactivity alone (MR group), (b) mood reactivity plus one or more associated features (atypical depression, AD group), and (c) patients with neither mood reactivity nor atypical depression (non-MR/AD group) were compared on their cortisol response to 75 mg of desipramine (DMI), a relatively selective norepinephrine reuptake inhibitor. AD patients exhibited a significantly higher cortisol response to DMI compared with MR and non-MR/AD patients, suggesting that atypical depression may be associated with a less impaired norepinephrine system. MR and non-MR/AD patients did not differ, suggesting that mood reactivity alone is not associated with the biological profile observed in atypical depression. Results indicate that while mood reactivity may be necessary for the diagnosis of atypical depression, the additional presence of at least one associated symptom is required for a distinct biological profile. Our findings provide further biological validation of the concept of atypical depression." [Abstract]

Levitan RD, Vaccarino FJ, Brown GM, Kennedy SH.
Low-dose dexamethasone challenge in women with atypical major depression: pilot study.
J Psychiatry Neurosci 2002 Jan;27(1):47-51
"OBJECTIVE: To examine if atypical depression may be associated with hypersuppression of the hypothalamic-pituitary-adrenal (HPA) axis. METHOD: Eight women with atypical major depression and 11 controls with no history of psychiatric illness, matched on age and body mass index, were challenged with low-dose dexamethasone (0.25 mg and 0.50 mg in random order and 1 week apart). Dexamethasone was self administered at 11 pm, and plasma cortisol samples were drawn at 8 am and 3 pm on the following day. RESULTS: After the 0.50-mg dexamethasone challenge, mean suppression of morning cortisol was significantly greater in patients with atypical depression (91.9%, standard deviation [SD] 6.8%) than in the controls (78.3%, SD 10.7%; p < 0.01). CONCLUSION: These preliminary data add to the growing body of literature that suggests atypical depression, in contrast to classic melancholia, may be associated with exaggerated negative feedback regulation of the HPA axis." [Abstract]

Capuron L, Raison CL, Musselman DL, Lawson DH, Nemeroff CB, Miller AH.
Association of exaggerated HPA axis response to the initial injection of interferon-alpha with development of depression during interferon-alpha therapy.
Am J Psychiatry. 2003 Jul;160(7):1342-5.
"OBJECTIVE: The authors assessed the relationship between the hypothalamic-pituitary-adrenal (HPA) axis response to interferon-alpha (IFN-alpha) and the development of major depression during IFN-alpha treatment. METHOD: Adrenocorticotropic hormone (ACTH), cortisol, and interleukin-6 (IL-6) plasma concentrations were measured in 14 patients with malignant melanoma at regular intervals during the first 12 weeks of IFN-alpha therapy, both immediately before and 1, 2, and 3 hours after IFN-alpha administration. Symptom criteria for major depression were also evaluated at each visit. RESULTS: ACTH and cortisol responses but not IL-6 responses to the initial administration of IFN-alpha were significantly higher in the seven patients who subsequently developed symptom criteria for major depression than in those who did not. No differences in hormonal or cytokine responses were found between these two groups during chronic IFN-alpha administration. CONCLUSIONS: The HPA axis response to the acute administration of IFN-alpha reveals a vulnerability to IFN-alpha-induced depression, possibly due to sensitization of corticotropin-releasing factor pathways." [Abstract]

Budziszewska B, Jaworska-Feil L, Tetich M, Basta-Kaim A, Kubera M, Leskiewicz M, Lason W.
Regulation of the Human Corticotropin-Releasing-Hormone Gene Promoter Activity by Antidepressant Drugs in Neuro-2A and AtT-20 Cells.
Neuropsychopharmacology. 2004 Jan 21 [Epub ahead of print]
"Major depression is frequently associated with hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis. Clinically effective therapy with antidepressant drugs normalizes the disturbed activity of HPA axis, in part, by decreasing corticotropin-releasing hormone (CRH) synthesis, but the mechanism of this action is poorly recognized. In order to find out whether antidepressants directly affect CRH gene promoter activity, we studied their effect on undifferentiated and differentiated Neuro-2A cells, and for comparison the effect of the selected antidepressants on AtT-20 cells was also determined. The cells were stably transfected with a human CRH promoter fragment (-663 to +124 bp) linked to the chloramphenicol acetyltransferase (CAT) reporter gene. The regulation of CRH gene promoter activity is similar in Neuro-2A cells, both intact and differentiated, and in AtT-20 cell line, and cAMP/PKA-dependent pathway plays an important role in the stimulation of CRH gene. It was found that imipramine, amitryptyline, desipramine, fluoxetine, and mianserin, present in the culture medium for 5 days, in a concentration-dependent manner inhibited basal hCRH gene promoter activity in undifferentiated Neuro-2A cells, while other drugs under study (citalopram, tianeptine, moclobemide, venlafaxine, reboxetine, mirtazapine, and milnacipram) were inactive. In the differentiated cells, all examined antidepressants, except moclobemide (no effect) and tianeptine (increase), inhibited hCRH gene transcription. Moreover, in differentiated cells, the drugs acted stronger and were effective at lower concentrations. Forskolin-induced CAT activity was attenuated by imipramine and fluoxetine and to a lesser degree by amitriptyline and desipramine in differentiated cells, whereas other drugs were inactive. Moreover, imipramine and fluoxetine, but not tianeptine, showed moderate inhibitory effect on CRH gene promoter activity also in AtT-20 cell line, commonly used in CRH gene regulation studies. These results indicate that neuron-like differentiated Neuro-2A cells are a better model than pituitary and intact neuroblastoma to investigate the mechanism of psychotropic drug action. Inhibition of CRH gene promoter activity by antidepressant drugs may be a molecular mechanism by which these drugs inhibit the activity of HPA axis." [Abstract]

Brunson KL, Grigoriadis DE, Lorang MT, Baram TZ.
Corticotropin-releasing hormone (CRH) downregulates the function of its receptor (CRF1) and induces CRF1 expression in hippocampal and cortical regions of the immature rat brain.
Exp Neurol 2002 Jul;176(1):75-86
"In addition to regulating the neuroendocrine stress response, corticotropin-releasing hormone (CRH) has been implicated in both normal and pathological behavioral and cognitive responses to stress. CRH-expressing cells and their target neurons possessing CRH receptors (CRF1 and CRF2) are distributed throughout the limbic system, but little is known about the regulation of limbic CRH receptor function and expression, including regulation by the peptide itself. Because CRH is released from limbic neuronal terminals during stress, this regulation might play a crucial role in the mechanisms by which stress contributes to human neuropsychiatric conditions such as depression or posttraumatic stress disorder. Therefore, these studies tested the hypothesis that CRH binding to CRF1 influenced the levels and mRNA expression of this receptor in stress-associated limbic regions of immature rat. Binding capacities and mRNA levels of both CRF1 and CRF2 were determined at several time points after central CRH administration. CRH downregulated CRF1 binding in frontal cortex significantly by 4 h. This transient reduction (no longer evident at 8 h) was associated with rapid increase of CRF1 mRNA expression, persisting for >8 h. Enhanced CRF1 expression-with a different time course-occurred also in hippocampal CA3, but not in CA1 or amygdala, CRF2 binding and mRNA levels were not altered by CRH administration. To address the mechanisms by which CRH regulated CRF1, the specific contributions of ligand-receptor interactions and of the CRH-induced neuronal stimulation were examined. Neuronal excitation without occupation of CRF1 induced by kainic acid, resulted in no change of CRF1 binding capacity, and in modest induction of CRF1 mRNA expression. Furthermore, blocking the neuroexcitant effects of CRH (using pentobarbital) abolished the alterations in CRF1 binding and expression. These results indicate that CRF1 regulation involves both occupancy of this receptor by its ligand, as well as "downstream" cellular activation and suggest that stress-induced perturbation of CRH-CRF1 signaling may contribute to abnormal neuronal communication after some stressful situations." [Abstract]

Dautzenberg FM, Hauger RL.
The CRF peptide family and their receptors: yet more partners discovered.
Trends Pharmacol Sci 2002 Feb;23(2):71-7
"Abnormal signaling at corticotropin-releasing factor CRF1 and CRF2 receptors might contribute to the pathophysiology of stress-related disorders such as anxiety, depression and eating disorders, in addition to cardiac and inflammatory disorders. Recently, molecular characterization of CRF1 and CRF2 receptors and the cloning of novel ligands--urocortin, stresscopin-related peptide/urocortin II, and stresscopin/urocortin III--have revealed a far-reaching physiological importance for the family of CRF peptides. Although the physiological roles of the CRF2 receptor remain to be defined, the preclinical and clinical development of specific small-molecule antagonists of the CRF1 receptor opens new avenues for the treatment of psychiatric and neurological disorders." [Abstract]

Gold PW, Chrousos GP.
Organization of the stress system and its dysregulation in melancholic and atypical depression: high vs low CRH/NE states.
Mol Psychiatry 2002;7(3):254-75
"Stress precipitates depression and alters its natural history. Major depression and the stress response share similar phenomena, mediators and circuitries. Thus, many of the features of major depression potentially reflect dysregulations of the stress response. The stress response itself consists of alterations in levels of anxiety, a loss of cognitive and affective flexibility, activation of the hypothalamic-pituitary-adrenal (HPA) axis and autonomic nervous system, and inhibition of vegetative processes that are likely to impede survival during a life-threatening situation (eg sleep, sexual activity, and endocrine programs for growth and reproduction). Because depression is a heterogeneous illness, we studied two diagnostic subtypes, melancholic and atypical depression. In melancholia, the stress response seems hyperactive, and patients are anxious, dread the future, lose responsiveness to the environment, have insomnia, lose their appetite, and a diurnal variation with depression at its worst in the morning. They also have an activated CRH system and may have diminished activities of the growth hormone and reproductive axes. Patients with atypical depression present with a syndrome that seems the antithesis of melancholia. They are lethargic, fatigued, hyperphagic, hypersomnic, reactive to the environment, and show diurnal variation of depression that is at its best in the morning. In contrast to melancholia, we have advanced several lines of evidence of a down-regulated hypothalamic-pituitary adrenal axis and CRH deficiency in atypical depression, and our data show us that these are of central origin. Given the diversity of effects exerted by CRH and cortisol, the differences in melancholic and atypical depression suggest that studies of depression should examine each subtype separately. In the present paper, we shall first review the mediators and circuitries of the stress system to lay the groundwork for placing in context physiologic and structural alterations in depression that may occur as part of stress system dysfunction." [Abstract] [Note that the authors use the atypical acronym CRH rather than the equivalent acronym CRF.]

Newport DJ, Heim C, Owens MJ, Ritchie JC, Ramsey CH, Bonsall R, Miller AH, Nemeroff CB.
Cerebrospinal Fluid Corticotropin-Releasing Factor (CRF) and Vasopressin Concentrations Predict Pituitary Response in the CRF Stimulation Test: A Multiple Regression Analysis.
Neuropsychopharmacology 2003 Mar;28(3):569-576
"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 &mgr;g/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." [Abstract]

Baghai TC, Schule C, Zwanzger P, Minov C, Holme C, Padberg F, Bidlingmaier M, Strasburger CJ, Rupprecht R.
Evaluation of a salivary based combined dexamethasone/CRH test in patients with major depression.
Psychoneuroendocrinology 2002 Apr;27(3):385-99
"The combined dexamethasone/corticotropin releasing hormone (Dex/CRH) test is one of the most reliable neuroendocrine function tests for investigation of hypothalamic-pituitary-adrenocortical (HPA) system dysregulation in depression. Persistent high HPA system activity reflected by an enhanced cortisol secretion during the Dex/CRH test after successful antidepressant treatment is correlated with an enhanced risk for relapse in remitted depressives. Thus, the Dex/CRH test might be a useful neuroendocrinological tool for treatment monitoring. However, the performance of the test requiring multiple blood samplings renders this test difficult for routine clinical use. Thus, a simplified test procedure using a saliva based test without the necessity of multiple blood samplings would be desirable.Therefore, we compared matched saliva and serum probes of Dex/CRH tests of 73 depressed patients who underwent a total of 157 tests. Both saliva and serum cortisol concentrations showed a significant stimulation pattern during the test and were highly correlated. This correlation was not influenced by either antidepressive treatment. In patients with high cortisol secretion patterns during the Dex/CRH test there was a decrease in HPA system activity after successful antidepressant treatment that was reflected by both the saliva and the serum Dex/CRH test.Thus, the saliva based combined Dex/CRH test appears to be a suitable tool for monitoring HPA system activity during the course of depressive illness. The easier performance of the saliva Dex/CRH test in comparison to the standard test procedure for both patients and hospital staff opens the door for routine clinical use of the Dex/CRH test for treatment monitoring and estimation of relapse risk." [Abstract]

Banki CM, Bissette G, Arato M, O'Connor L, Nemeroff CB.
CSF corticotropin-releasing factor-like immunoreactivity in depression and schizophrenia.
Am J Psychiatry 1987 Jul;144(7):873-7
"To further investigate the hypothesis that hyperactivity of the hypothalamic-pituitary-adrenal axis in patients with depression may be mediated by hypersecretion of corticotropin-releasing factor (CRF), the authors measured CRF-like immunoreactivity in CSF samples from 138 neurological control, 54 depressed, and 27 nondepressed (23 schizophrenic and four manic) subjects. The CSF CRF concentration was markedly higher (almost twofold) in depressed patients than in control subjects and nondepressed psychiatric patients. The concentration of CSF CRF was slightly but significantly higher in schizophrenic patients than in control subjects. These findings provide further support for the hypothesis that CRF hypersecretion occurs in major depression." [Abstract]

Nemeroff CB, Widerlov E, Bissette G, Walleus H, Karlsson I, Eklund K, Kilts CD, Loosen PT, Vale W.
Elevated concentrations of CSF corticotropin-releasing factor-like immunoreactivity in depressed patients.
Science 1984 Dec 14;226(4680):1342-4
"The possibility that hypersecretion of corticotropin-releasing factor (CRF) contributes to the hyperactivity of the hypothalamo-pituitary-adrenal axis observed in patients with major depression was investigated by measuring the concentration of this peptide in cerebrospinal fluid of normal healthy volunteers and in drug-free patients with DSM-III diagnoses of major depression, schizophrenia, or dementia. When compared to the controls and the other diagnostic groups, the patients with major depression showed significantly increased cerebrospinal fluid concentrations of CRF-like immunoreactivity; in 11 of the 23 depressed patients this immunoreactivity was greater than the highest value in the normal controls. These findings are concordant with the hypothesis that CRF hypersecretion is, at least in part, responsible for the hyperactivity of the hypothalamo-pituitary-adrenal axis characteristic of major depression." [Abstract]

Catalan R, Gallart JM, Castellanos JM, Galard R.
Plasma corticotropin-releasing factor in depressive disorders.
Biol Psychiatry 1998 Jul 1;44(1):15-20
"BACKGROUND: The aim of this work was to investigate alterations of plasma corticotropin-releasing factor (CRF) levels in depressive states. We have also measured plasma cortisol and corticotropin (ACTH) concentrations and examined their correlation with the peripheral CRF values. METHODS: Thirty-six outpatients from the psychiatric department of a Barcelona hospital who were diagnosed as having major depressive disorder (n = 26) and dysthymic depressive disorder (n = 10) were studied. Among the major depressed patients, 10 suffered from severe depressive disorder and 16 from mild or moderate depressive disorder. The comparison group consisted of 17 healthy volunteers. Cortisol, ACTH, and CRF concentrations were determined by iodine-125 radioimmunoassay; CRF measurements were performed on C18 extracted samples. RESULTS: CRF and cortisol plasma concentrations were significantly higher in major depression and dysthymia than in the comparison group. The major depressed patients did not show significantly different CRF and cortisol levels than the dysthymic. Severe major depressive disorder exhibited significantly higher CRF plasma levels than the mild or moderate episodes. Plasma cortisol and CRF concentrations correlated significantly. CONCLUSIONS: The results obtained indicate that plasma CRF values are altered in depressive disorders and suggest that these determinations could be important for understanding the pathophysiology in affective illness." [Abstract]

Claes S, Villafuerte S, Forsgren T, Sluijs S, Del-Favero J, Adolfsson R, Van Broeckhoven C.
The corticotropin-releasing hormone binding protein is associated with major depression in a population from Northern Sweden.
Biol Psychiatry. 2003 Nov 1;54(9):867-72.
"BACKGROUND: Recent research suggests that central corticotropin releasing hormone hyperdrive is an important neurobiological risk factor for developing major depression. The availability of free corticotropin releasing hormone in the central nervous system is tightly regulated by the expression of corticotropin releasing hormone binding protein. Therefore, the gene encoding for corticotropin releasing hormone binding protein is a functional candidate gene for major depression. METHODS: We present a systematic study of single nucleotide polymorphisms in the corticotropin releasing hormone binding protein gene and their role in the liability for major depression. Seven single nucleotide polymorphisms were genotyped in a well-diagnosed sample of 89 patients with recurrent major depressions and matched controls. RESULTS: Two single nucleotide polymorphisms within the corticotropin releasing hormone binding protein gene were significantly associated with the disease (p <.05). An expectation-maximization algorithm estimated a specific haplotype to have a frequency of 53% in patients and 35% in controls (p <.001). CONCLUSIONS: The corticotropin releasing hormone binding protein gene is likely to be involved in the genetic vulnerability for major depression." [Abstract]

Raadsheer FC, Hoogendijk WJ, Stam FC, Tilders FJ, Swaab DF.
Increased numbers of corticotropin-releasing hormone expressing neurons in the hypothalamic paraventricular nucleus of depressed patients.
Neuroendocrinology 1994 Oct;60(4):436-44
"The hypothalamo-pituitary-adrenal (HPA) axis is known to be activated in depressed patients. Although direct evidence is lacking, this activation is hypothesized to be due to hyperactivity of corticotropin-releasing hormone (CRH) neurons of the hypothalamic paraventricular nucleus (PVN). Recent immunocytochemical studies in experimental animals and in humans showed that the number of CRH-expressing neurons correlated with the activity of these neurons. In addition, colocalization of AVP in CRH neurons has been shown to be an index for the secretory activity. Therefore, we estimated the total number of CRH-immunoreactive neurons and their fraction showing colocalization with AVP in the PVN of 10 control subjects and of 6 depressed patients who were diagnosed to be suffering from a major depression or a bipolar disorder. The mean total number of CRH-expressing neurons of the 6 depressed patients was four times higher, and the number of CRH neurons co-expressing AVP was almost three times higher than those in the control group. We also determined the two activity parameters of CRH neurons in the PVN of 2 subjects with a depressive organic mood syndrome or a depressive disorder not otherwise specified. In these two 'non-major depressed' subjects, the activity parameters of CRH neurons were comparable to those of control subjects. Our observations strongly support the hypothesis that CRH neurons in the PVN are hyperactivated in major depressed patients. This hyperactivity might be causally related to at least part of the symptomatology of depression." [Abstract]

Austin MC, Janosky JE, Murphy HA.
Increased corticotropin-releasing hormone immunoreactivity in monoamine-containing pontine nuclei of depressed suicide men.
Mol Psychiatry. 2003 Mar;8(3):324-32.
"A number of clinical investigations and postmortem brain studies have provided evidence that excessive corticotropin-releasing hormone (CRH) secretion and neurotransmission is involved in the pathophysiology of depressive illness, and several studies have suggested that the hyperactivity in CRH neurotransmission extends beyond the hypothalamus involving several extra-hypothalamic brain regions. The present study was designed to test the hypothesis that CRH levels are increased in specific brainstem regions of suicide victims with a diagnosis of major depression. Frozen tissue sections of the pons containing the locus coeruleus and caudal raphe nuclei from 11 matched pairs of depressed suicide and control male subjects were processed for radioimmunocytochemistry using a primary antiserum to CRH and a ([125])I-IgG secondary antibody. The optical density corresponding to the level of CRH-immunoreactivity (IR) was quantified in specific pontine regions from the film autoradiographic images. The level of CRH-IR was increased by 30% in the locus coeruleus, 39% in the median raphe and 45% in the caudal dorsal raphe in the depressed suicide subjects compared to controls. No difference in CRH-IR was found in the dorsal tegmentum or medial parabrachial nucleus between the subject groups. These findings reveal that CRH-IR levels are specifically increased in norepinephrine- and serotonin-containing pontine nuclei of depressed suicide men, and thus they are consistent with the hypothesis that CRH neurotransmission is elevated in extra-hypothalamic brain regions of depressed subjects." [Abstract]

van Gaalen MM, Reul JH, Gesing A, Stenzel-Poore MP, Holsboer F, Steckler T.
Mice overexpressing CRH show reduced responsiveness in plasma corticosterone after a5-HT1A receptor challenge.
Genes Brain Behav. 2002 Aug;1(3):174-7.
"Corticotropin-releasing hormone (CRH) overproduction and serotonergic dysfunction have both been implicated in a range of psychiatric disorders, such as anxiety and depression, and several studies have shown interactions between these two neurotransmitter systems. In this study, we investigated the effects of CRH challenge on hypothalamo-pituitary-adrenal (HPA) axis activity in female transgenic mice overproducing CRH. Furthermore, the effects of mild stress on HPA axis activity and body temperature were investigated in these mice. Pre- and post-synaptic 5-HT1A receptor function were studied by monitoring body temperature and plasma corticosterone levels after challenge with the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propyl-amino)-tetralin (8-OH-DPAT). Hypothermia in response to 8-OH-DPAT treatment did not differ between transgenic and wild type mice, indicating unaltered somatodendritic 5-HT1A autoreceptor function in mice overproducing CRH. In wild type mice 8-OH-DPAT increased plasma corticosterone levels, but not in transgenic animals. CRH injection, however, increased corticosterone levels in both groups. These data suggest desensitization of post-synaptic, but not pre-synaptic, 5-HT1A receptors in mice overproducing CRH. These findings resemble those seen in depressed patients following 5-HT1A challenge, which is in accord with the hypothesized role of CRH in the pathogenesis of depression." [Abstract]

Bissette G, Klimek V, Pan J, Stockmeier C, Ordway G.
Elevated concentrations of CRF in the locus coeruleus of depressed subjects.
Neuropsychopharmacology. 2003 Jul;28(7):1328-35. Epub 2003 May 21.
"Research evidence that corticotropin-releasing factor (CRF) plays a role in the pathophysiology of major depressive disorder (MDD) has accumulated over the past 20 years. The elevation of lumbar cerebrospinal fluid (CSF) concentrations of CRF decreased responsiveness of pituitary CRF receptors to challenge with synthetic CRF, and increased levels of serum cortisol in MDD subjects support the hypothesis that CRF is chronically hypersecreted in at least the endocrine circuits of the hypothalamic-pituitary-adrenal (HPA) axis and may also involve other CRF brain circuits mediating emotional responses and/or arousal. One such circuit includes the excitatory CRF input to the locus coeruleus (LC), the major source of norepinephrine in the brain. Furthermore, there are now reports of decreased levels of CRF in lumbar CSF from MDD patients after symptom relief from chronic treatment with antidepressant drugs or electroconvulsive therapy. Whether this normalization reflects therapeutic effects on both endocrine- and limbic-associated CRF circuits has not yet been effectively addressed. In this brief report, we describe increased concentrations of CRF-like immunoreactivity in micropunches of post-mortem LC from subjects with MDD symptoms as established by retrospective psychiatric diagnosis compared to nondepressed subjects matched for age and sex." [Abstract]

Roy A, Pickar D, Linnoila M, Chrousos GP, Gold PW.
Cerebrospinal fluid corticotropin-releasing hormone in depression: relationship to noradrenergic function.
Psychiatry Res 1987 Mar;20(3):229-37
"We investigated the neurotransmitter regulation of corticotropin-releasing hormone (CRH). Among 21 depressed patients cerebrospinal fluid (CSF) levels of CRH significantly correlated with urinary outputs of norepinephrine and its major metabolites, and there were trends for significant correlations with both CSF and plasma levels of norepinephrine. These results suggest that CRH may be associated with the dysregulation of the norepinephrine system that is found in [depression]." [Abstract]

Valentino RJ, Foote SL, Page ME.
The locus coeruleus as a site for integrating corticotropin-releasing factor and noradrenergic mediation of stress responses.
Ann N Y Acad Sci 1993 Oct 29;697:173-88
"It could be predicted that the effects of CRF neurotransmission in the LC during stress would enhance information processing concerning the stressor or stimuli related to the stressor by LC target neurons. One consequence of this appears to be increased arousal. Although this may be adaptive in the response to an acute challenge, it could be predicted that chronic CRF release in the LC would result in persistently elevated LC discharge and norepinephrine release in targets. This could be associated with hyperarousal and loss of selective attention as occurs in certain psychiatric diseases. Manipulation of endogenous CRF systems may be a novel way in which to treat psychiatric diseases characterized by these maladaptive effects." [Abstract]

Curtis AL, Valentino RJ.
Corticotropin-releasing factor neurotransmission in locus coeruleus: a possible site of antidepressant action.
Brain Res Bull 1994;35(5-6):581-7
"Hypersecretion of corticotropin-releasing factor (CRF), has been hypothesized to occur in depression. Because CRF may serve as a neurotransmitter in the locus coeruleus (LC), it was proposed that CRF hypersecretion in the LC is responsible for some characteristics of depression, and that antidepressants act by interfering with CRF neurotransmission in the LC. To test this hypothesis, the acute and chronic effects of four antidepressants and cocaine were characterized on LC spontaneous and sensory-evoked discharge, LC activation by a stressor that requires CRF release, and LC activation by exogenously administered CRF. None of the antidepressants or cocaine altered LC activation by intracerebroventricularly administered CRF (3.0 microgram) after chronic administration. However, chronic administration of desmethylimipramine and mianserin inhibited LC activation by a hypotensive stress that requires endogenous CRF release, suggesting that they decrease CRF release in the LC. Chronic administration of sertraline and phenelzine altered LC responses to repeated sciatic nerve stimulation in a manner opposite to the effect produced by CRF, suggesting that these drugs may functionally antagonize CRF actions in the LC. Cocaine did not appear to interfere with CRF actions in the LC. In conclusion, chronic administration of antidepressants may have the potential to interfere with CRF neurotransmission in the LC." [Abstract]

Valentino RJ, Curtis AL.
Pharmacology of locus coeruleus spontaneous and sensory-evoked activity.
Prog Brain Res 1991;88:249-56
"Neuroendocrine and catecholamine dysfunctions in depression may be linked by corticotropin-releasing factor (CRF) effects on locus coeruleus (LC) neurons. One consequence of CRF hypersecretion in depression would be persistent elevated levels of LC discharge and diminished responses to phasic sensory stimuli. The hypothesis that antidepressants could reverse these changes was tested by characterizing effects of pharmacologically distinct antidepressants on LC sensory-evoked discharge, LC activation by stress, and LC activation by CRF. The most consistent effect of all of the antidepressants tested was a decrease in LC sensory-evoked discharge after acute administration. However, tolerance occurs to these effects after chronic administration. With chronic administration each of the antidepressants produced effects which could potentially interfere with CRF function in the LC. Desmethylimipramine and mianserin attenuated LC activation by a stressor which requires endogenous CRF, suggesting that these antidepressants attenuate stress-elicited release of CRF and perhaps the hypersecretion that occurs in depression. The serotonin reuptake inhibitor, sertraline (SER), enhanced the signal-to-noise ratio of the LC sensory response, an effect opposite to that of CRF. Thus, SER could serve as a functional antagonist of CRF that is hypersecreted in depression. The finding that three pharmacologically distinct antidepressants share the potential to interfere with CRF function in the LC implies that this may be an important common mechanism for antidepressant activity." [Abstract]

Curtis, Andre L., Pavcovich, Luis A., Valentino, Rita J.
Long-Term Regulation of Locus Ceruleus Sensitivity to Corticotropin-Releasing Factor by Swim Stress
J Pharmacol Exp Ther 1999 289: 1211-1219
"Corticotropin-releasing factor (CRF) acts as a putative neurotransmitter in the locus ceruleus (LC) to mediate its activation by certain stressors. In this study, we quantified LC sensitivity to CRF 24 h after swim stress, at a time when behavioral depression that is sensitive to antidepressants is apparent. Rats were placed in a tank with 30 cm (swim stress) or 4 cm water and 24 h later, either behavior was monitored in a forced swim test or LC discharge was recorded. Swim stress rats were more immobile than control animals in the swim test. LC neurons of swim stress rats were sensitized to low doses of CRF (0.1-0.3 µg i.c.v.) that were ineffective in control animals and were desensitized to higher doses. Swim stress selectively altered LC sensitivity to CRF because neither LC spontaneous discharge nor responses to other agents (e.g., carbachol, vasoactive intestinal peptide) were altered. Finally, the mechanism for sensitization was localized to the LC because neuronal activation by low doses of CRF was prevented by the intracerulear administration of a CRF antagonist. CRF dose-response curves were consistent with a two-site model with similar dissociation constants under control conditions but divergent dissociation constants after swim stress. The results suggest that swim stress (and perhaps other stressors) functionally alters CRF receptors that have an impact on LC activity. Stress-induced regulation of LC sensitivity to CRF may underlie behavioral aspects of stress-related psychiatric disorders." [Full Text]

Zeng J, Kitayama I, Yoshizato H, Zhang K, Okazaki Y.
Increased expression of corticotropin-releasing factor receptor mRNA in the locus coeruleus of stress-induced rat model of depression.
Life Sci. 2003 Jul 18;73(9):1131-9.
"Hypersecretion of corticotropin-releasing factor (CRF) has been hypothesized to occur in depression. To investigate CRF receptor (CRFR) response to the increased production of CRF in chronically stressed rats, we measured by in situ hybridization the expression of CRFR mRNA in the locus coeruleus (LC) concomitant with measuring plasma adrenocorticotropin (ACTH). The expression of both CRFR mRNA in the LC and the plasma level of ACTH increased significantly in "depression-model rats" which exhibit reduced activity following exposure to 14 days forced walking stress (FWS), but not in "spontaneous recovery rats" whose activity was restored after the long-term stress. These results suggest that the LC neurons continue to be stimulated by CRF, and that the hypothalamic-pituitary-adrenal (HPA) axis is hyperfunctioning in the depression-model rats." [Abstract]

Heim C, Nemeroff CB.
The impact of early adverse experiences on brain systems involved in the pathophysiology of anxiety and affective disorders.
Biol Psychiatry 1999 Dec 1;46(11):1509-22
"The relative contribution of genetic and environmental factors to the development of the major psychiatric disorders has long been debated. Recently, considerable attention has been given to the observations that adverse experiences early in life predispose individuals to the development of affective and anxiety disorders in adulthood. Corticotropin-releasing factor (CRF) is the central coordinator of the endocrinologic, autonomic, immunologic, and behavioral stress responses. When centrally administered, CRF produces many physiologic and behavioral changes reminiscent of both acute stress and depression. Moreover, CRF has also been implicated in the pathogenesis of a variety of anxiety disorders, mainly through CRF neurocircuits connecting the amygdala and the locus ceruleus. Clinical studies have provided convincing evidence for central CRF hypersecretion in depression, and, to a lesser extent, in some anxiety disorders. Evidence mainly from preclinical studies suggests that stress early in life results in persistent central CRF hyperactivity and increased stress reactivity in adulthood. Thus, genetic disposition coupled with early stress in critical phases of development may result in a phenotype that is neurobiologically vulnerable to stress and may lower an individual's threshold for developing depression and anxiety upon further stress exposure. This pathophysiologic model may provide novel approaches to the prevention and treatment of psychopathology associated with stress early in life." [Abstract]

Heim C, Nemeroff CB.
The role of childhood trauma in the neurobiology of mood and anxiety disorders: preclinical and clinical studies.
Biol Psychiatry 2001 Jun 15;49(12):1023-39
"Epidemiologic studies indicate that children exposed to early adverse experiences are at increased risk for the development of depression, anxiety disorders, or both. Persistent sensitization of central nervous system (CNS) circuits as a consequence of early life stress, which are integrally involved in the regulation of stress and emotion, may represent the underlying biological substrate of an increased vulnerability to subsequent stress as well as to the development of depression and anxiety. A number of preclinical studies suggest that early life stress induces long-lived hyper(re)activity of corticotropin-releasing factor (CRF) systems as well as alterations in other neurotransmitter systems, resulting in increased stress responsiveness. Many of the findings from these preclinical studies are comparable to findings in adult patients with mood and anxiety disorders. Emerging evidence from clinical studies suggests that exposure to early life stress is associated with neurobiological changes in children and adults, which may underlie the increased risk of psychopathology. Current research is focused on strategies to prevent or reverse the detrimental effects of early life stress on the CNS. The identification of the neurobiological substrates of early adverse experience is of paramount importance for the development of novel treatments for children, adolescents, and adults." [Abstract]

Carpenter LL, Tyrka AR, McDougle CJ, Malison RT, Owens MJ, Nemeroff CB, Price LH.
Cerebrospinal fluid corticotropin-releasing factor and perceived early-life stress in depressed patients and healthy control subjects.
Neuropsychopharmacology. 2004 Apr;29(4):777-84.
"Previous studies have reported elevated concentrations of cerebrospinal fluid (CSF) corticotropin-releasing factor (CRF) in patients with major depression. Elevations of CSF CRF have also been reported in adult laboratory animals exposed to the stress of brief maternal deprivation or maternal neglect in the neonatal or preweaning period. The present study was designed to determine whether major depression and a history of perceived early adversity in childhood are independently associated with elevated CSF CRF concentrations in adults. In this case-control study, 27 medication-free adults with major depression and 25 matched controls underwent standardized lumbar puncture for collection of a single CSF sample at 1200. Subjects provided data about significant adverse early-life experiences and rated their global perceived level of stress during pre-school and preteen years on a six-point Likert scale. The mean difference in CSF CRF between depressed patients and controls did not reach statistical significance. In a regression model, perceived early-life stress was a significant predictor of CSF CRF, but depression was not. Perinatal adversity and perceived adversity in the preteen adversity years (ages 6-13 years) were both independently associated with decreasing CSF CRF concentrations. The relationship observed between perceived early-life stress and adult CSF CRF concentrations in this study closely parallels recent preclinical findings. More work is needed to elucidate the critical nature and timing of early events that may be associated with enduring neuroendocrine changes in humans." [Abstract]

Heim C, Newport DJ, Bonsall R, Miller AH, Nemeroff CB.
Altered pituitary-adrenal axis responses to provocative challenge tests in adult survivors of childhood abuse.
Am J Psychiatry 2001 Apr;158(4):575-81
"OBJECTIVE: Early adverse life events may predispose individuals to the development of mood and anxiety disorders in adulthood, perhaps by inducing persistent changes in corticotropin-releasing factor (CRF) neuronal systems. The present study sought to evaluate pituitary-adrenal responses to standard hypothalamic-pituitary-adrenal axis challenge tests in adult female survivors of childhood abuse with and without major depressive disorder. METHOD: Plasma ACTH and cortisol responses to the administration of 1 microg/kg ovine CRF and plasma cortisol responses to the administration of 250 microg ACTH(1-24) were measured in healthy women without early life stress (N=20), women with childhood abuse without major depressive disorder (N=20), women with childhood abuse and major depressive disorder (N=15), and women with major depression but no early life stress (N=11). RESULTS: Abused women without major depressive disorder exhibited greater than usual ACTH responses to CRF administration, whereas abused women with major depressive disorder and depressed women without early life stress demonstrated blunted ACTH responses. In the ACTH(1-24) stimulation test, abused women without major depressive disorder exhibited lower baseline and stimulated plasma cortisol concentrations. Abused women with comorbid depression more often suffered from posttraumatic stress disorder and reported more recent life stress than abused women without major depressive disorder. CONCLUSIONS: These findings suggest sensitization of the anterior pituitary and counterregulative adaptation of the adrenal cortex in abused women without major depressive disorder. On subsequent stress exposure, women with a history of childhood abuse may hypersecrete CRF, resulting in down-regulation of adenohypophyseal CRF receptors and symptoms of depression and anxiety." [Abstract]

Newport DJ, Heim C, Bonsall R, Miller AH, Nemeroff CB.
Pituitary-adrenal responses to standard and low-dose dexamethasone suppression tests in adult survivors of child abuse.
Biol Psychiatry. 2004 Jan 1;55(1):10-20.
"BACKGROUND: Previous studies indicate that adverse childhood events are associated with persistent changes in corticotropin-releasing factor neuronal systems. Our aim was to determine whether altered glucocorticoid feedback mediates the neuroendocrine sequelae of childhood trauma. METHODS: Standard and low-dose dexamethasone suppression tests (DST) were performed in women with a history of child abuse (n=19), child abuse and major depression (n=16), major depression and no childhood trauma (n=10), and no history of mental illness or childhood trauma (n=19). Secondary analysis with posttraumatic stress disorder (PTSD) as the organizing diagnosis was also conducted. RESULTS: In the low-dose DST, depressed women with a history of abuse exhibited greater cortisol suppression than any comparator group and greater corticotropin suppression than healthy volunteers or nondepressed abuse survivors. There were no differences between nondepressed abuse survivors and healthy volunteers in the low-dose DST or between any subject groups in the standard DST. The PTSD analysis produced similar results. CONCLUSIONS: Cortisol supersuppression is evident in psychiatrically ill trauma survivors, but not in nondepressed abuse survivors, indicating that enhanced glucocorticoid feedback is not an invariable consequence of childhood trauma but is more related to the resultant psychiatric illness in traumatized individuals." [Abstract]

Pelleymounter, Mary Ann, Joppa, Margaret, Ling, Nicholas, Foster, Alan C.
Pharmacological Evidence Supporting a Role for Central Corticotropin-Releasing Factor2 Receptors in Behavioral, but not Endocrine, Response to Environmental Stress
J Pharmacol Exp Ther 2002 302: 145-152
"Corticotropin-releasing factor (CRF) is one of the principle components of the stress response. The physiological effects of CRF are mediated by two receptor subtypes, CRF1 and CRF2. Recent data obtained with the selective CRF2 antagonist antisauvagine-30 (ASV-30) has begun to suggest that both CRF receptor subtypes may play a role in stress-related behaviors. Exactly how these two receptor subtypes interact to modulate the behavioral and endocrine responses to stress is not clear, however. We have attempted to understand the role of the CRF2 receptor in the behavioral and endocrine responses to stress by comparing the effects of ASV-30 with the mixed CRF1/CRF2 receptor antagonist astressin. Centrally administered ASV-30 reduced anxiety-like behavior in BALB/c mice in three models of anxiety: marble burying [minimal effective dose (MED) = 3 nmol], open field (MED = 3 nmol), and elevated plus maze (MED = 0.1 nmol). ASV-30 did not change locomotor activity or the adrenocorticotropic hormone (ACTH) response to restraint stress. The potent mixed CRF1/CRF2 antagonist astressin not only reduced anxiety-like behavior in all three models with equivalent potency but also blunted the ACTH response to restraint stress. Finally, the new selective CRF2 receptor agonist urocortin-II produced a dose-dependent increase in anxiety-like behavior in the plus maze test. Therefore, our data suggest that the CRF2 receptor plays a role in the behavioral, but not the hypothalamic-pituitary-adrenal axis, response to stress." [Abstract]

Kehne JH, Coverdale S, McCloskey TC, Hoffman DC, Cassella JV.
Effects of the CRF(1) receptor antagonist, CP 154,526, in the separation-induced vocalization anxiolytic test in rat pups.
Neuropharmacology 2000 Jun 8;39(8):1357-67
"CRF(1) receptor antagonists have been proposed as novel pharmacological treatments for depression, anxiety and stress disorders. The primary goal of the present study was to evaluate the effects of the CRF(1) receptor antagonist, CP 154,526, in the separation-induced vocalization (SIV) model of anxiety. Nine- to 11-day-old rat pups were separated from their litter and the effects of intraperitoneally administered test compounds on the elicited ultrasonic vocalizations were measured. Side-effect potential was assessed using a modified inclined plane test ('time on an inclined plane', or TIP), and using negative geotaxis. SIV was reduced by CP 154,526 at doses that did not affect TIP or negative geotaxis, a profile like that of the 5-HT(1A) partial agonist buspirone. The benzodiazepine anxiolytic, diazepam, decreased SIV but also produced significant side effects at one to three-fold higher doses. Additional pharmacological characterization of SIV demonstrated anxiolytic-like effects of the atypical antipsychotic, clozapine, but not the typical antipsychotic, haloperidol, and of the serotonin reuptake inhibitor, zimelidine, but not the norepinephrine reuptake inhibitor, desipramine. In summary, the data support the conclusion that selective CRF(1) receptor antagonists may have utility in anxiety and stress disorders. The data further support the use of separation-induced vocalizations for identifying mechanistically diverse compounds with anxiolytic actions in man." [Abstract]

Dinan T.
Novel approaches to the treatment of depression by modulating the hypothalamic - pituitary - adrenal axis.
Hum Psychopharmacol 2001 Jan;16(1):89-93
"Many patients with major depression show evidence of over-activation of the hypothalamic - pituitary - adrenal axis (HPA), as evidenced by hypercortisolism and adrenal hyperplasia. Such over-activity is associated with increased corticotropin releasing factor (CRF) reactivity in the CSF and blunted release of ACTH in response to CRF infusion. Recent evidence suggests a switch from CRF to AVP regulation of the axis during depression, with depressed patients showing enhanced response to ddAVP infusion. The HPA provides multiple potential sites for antidepressant development. The use of glucocorticoid antagonists, cortisol synthesis inhibitors, CRF and AVP antagonists have been suggested." [Abstract]

Widerlov E, Bissette G, Nemeroff CB.
Monoamine metabolites, corticotropin releasing factor and somatostatin as CSF markers in depressed patients.
J Affect Disord 1988 Mar-Apr;14(2):99-107
"CSF samples from ten healthy volunteers and 22 patients with major depression were collected by lumbar puncture at 9 a.m. and the content of monoamine metabolites, corticotropin releasing factor (CRF) and somatostatin (SRIF) was analyzed. Plasma concentrations of TSH following a TRH challenge test (200 micrograms) and plasma cortisol following dexamethasone (1 mg; DST) were also analyzed. No relationships were observed between the CRF or SRIF concentrations and either basal or post-dexamethasone cortisol concentrations. Fourteen of 21 depressed patients were DST nonsuppressors using a plasma cortisol concentration cut off point greater than or equal to 138 nmol/l. If a more conservative cut off point was used (greater than 290 nmol/l) seven out of 21 patients revealed a severity-related cortisol nonsuppression. No significant difference was observed between healthy volunteers and depressed patients with regard to TSH response to TRH. The CSF content of CRF was elevated and the content of SRIF reduced in the depressed patients. In the healthy volunteers an inverse relationship was observed between CSF concentrations of CRF and MHPG (r = -0.72; P = 0.019); no relationship was observed between the concentrations of CRF and 5-HIAA or HVA. In the depressed patients positive correlations were found between CSF concentrations of CRF and 5-HIAA (r = 0.59; P = 0.004) and between CRF and HVA (r = 0.44; P = 0.042). These data are concordant with the view that norepinephrine and serotonin may be involved in the regulation of CRF secretion." [Abstract]

Risch SC, Lewine RJ, Kalin NH, Jewart RD, Risby ED, Caudle JM, Stipetic M, Turner J, Eccard MB, Pollard WE.
Limbic-hypothalamic-pituitary-adrenal axis activity and ventricular-to-brain ratio studies in affective illness and schizophrenia.
Neuropsychopharmacology 1992 Feb;6(2):95-100
"Some investigators have speculated that structural brain alterations observed in some psychiatric patients might be related to increased limbic-hypothalamic-pituitary-adrenal axis (LHPA) activity. To explore this hypothesis, we prospectively studied 166 research volunteers (19 patients with research diagnostic criteria (RDC) major depression, 9 patients with RDC bipolar depression, 45 patients with RDC schizophrenia, and 94 RDC normal controls), examining the relationship between magnetic resonance image-determined ventricular-to-brain ratio (VBR) and indices of LHPA axis function (cerebrospinal fluid (CSF) corticotropin-releasing factor (CRF), CSF adrenocorticotropic hormone (ACTH), and 24-hour urinary-free cortisol secretion). We observed no significant differences in mean VBR among the three patient groups and the normal control volunteers. Of the indices of LHPA activity, only CSF CRF concentrations distinguished the four subject groups, with CSF CRF being significantly elevated in the more severely depressed major depression patients. Indices of LHPA activity were not significantly correlated with VBR in any of the three patient groups or in the normal volunteers. These preliminary results suggest that VBR is not highly associated with alterations in LHPA activity, at least as determined cross-sectionally. Further longitudinal studies with reference to diagnostic subtypes, severity, symptom profiles, and more specific neuroanatomic regions may allow the elucidation of possible relationships between LHPA pathology and structural brain alterations." [Abstract]

Steiger A.
Sleep and the hypothalamo-pituitary-adrenocortical system.
Sleep Med Rev 2002 Apr;6(2):125-38
"The intention of this review is to summarize the current knowledge on the bidirectional interaction between sleep EEG and the secretion of corticotropin (ACTH) and cortisol. The administration of various hypothalamic-pituitary- adrenocortical (HPA) hormones and their antagonists exerts specific sleep-EEG changes in several species including humans. It is well documented that corticotropin releasing hormone (CRH) impairs sleep and enhances vigilance. In addition, it may promote REM sleep. Changes in the growth hormone-releasing hormone (GHRH):CRH ratio in favour of CRH appear to contribute to shallow sleep, elevated cortisol levels and blunted GH in depression and ageing. On the other hand, in women GHRH appears to exert CRH-like effects on sleep. Acute cortisol administration increases slow-wave sleep (SWS) and GH, probably due to feedback inhibition of CRH, and inhibits REM sleep. With the mixed glucocorticoid and progesterone receptor antagonist mifepriston sleep is disrupted. Subchronic administration of the glucocorticoid agonist methylprednisolone desinhibited REM sleep. A synergism of elevated CRH and cortisol activity may contribute to REM disinhibition during depression. Also ACTH and vasopressin modulate sleep specifically but their physiological role remains unclear. For example acute icv vasopressin enhances wakefulness in rats, whereas its long-term administration increases SWS in the elderly. In various studies the interaction of sleep EEG and HPA hormones has been investigated at the baseline, after manipulation of sleep-wake behaviour and after environmental changes. Most studies agree that the circadian pattern of cortisol is relatively independent from sleep and environmental influences. Some data suggest a major effect of light on cortisol secretion. Sleeping is widely associated with blunting and awakenings are linked with increases of HPA hormones." [Abstract]

Held K, Kunzel H, Ising M, Schmid DA, Zobel A, Murck H, Holsboer F, Steiger A.
Treatment with the CRH1-receptor-antagonist R121919 improves sleep-EEG in patients with depression.
J Psychiatr Res. 2004 Mar-Apr;38(2):129-36.
"Well documented changes of sleep electroencephalogram (EEG) in patients with depression include rapid eye movement (REM) sleep disinhibition, decreases of slow-wave-sleep (SWS) and increase in wakefulness. Twenty-seven inpatients with major depression were admitted subsequently to a clinical trial with the CRH(1)-receptor-antagonist R121919 administered in two different dose escalation panels. A random subgroup of 10 patients underwent three sleep-EEG recordings (baseline before treatment, at the end of the first week and at the end of the fourth week of active treatment). SWS time increased significantly compared with baseline after 1 week and after 4 weeks. The number of awakenings and REM density showed a trend toward a decrease during the same time period. Separate evaluation of these changes for both panels showed no significant effect at lower doses, whereas in the higher doses after R121919 REM density decreased and SWS increased significantly between baseline and week 4. Furthermore positive associations between HAMD scores and SWS at the end of active treatment were found. Although these data might indicate that R121919 has a normalizing influence on the sleep EEG, the design of the study does not allow to differentiate genuine drug effects from those of clinical improvement and habituation to the clinical setting." [Abstract]

Ehlers CL, Somes C, Seifritz E, Rivier JE.
CRF/NPY interactions: a potential role in sleep dysregulation in depression and anxiety.
Depress Anxiety 1997;6(1):1-9
"Neuropeptide Y (NPY) has neuromodulatory actions on multiple brain functions including endocrine, behavioral, and circadian processes and has been implicated in the pathophysiology of both anxiety and depression. Behavioral studies suggest that NPY is a potent anxiolytic, whereas CRF is anxiogenic, thus it seems that a balance of these two peptides may exert important influences on behavioral state regulation. However, little is known about how the NPY/CRF balance affects general arousal, attention, and/or sleep states. The present study evaluated the effects of CRF alone, and co-administered with NPY, on spontaneous brain activity as well as on auditory processing using electrophysiological measures. Electroencephalographic (EEG) and event-related potentials (ERPs) were obtained in rats following intracerebroventricular administration of CRF (0.5 microgram) and CRF (0.5 microgram)/NPY (5.0 or 15 micrograms). Auditory processing, as assessed by ERPs, was affected most significantly in the frontal cortex where CRF produced increases in the N1 and P3 components of the ERP, and NPY/CRF co-administration produced significant decreases. These data are consistent with a role for CRF in hyperarousal, and further suggest that NPY may be capable of reversing such states. Administration of CRF also produced a significant increase in the time to sleep onset and a decrease in the amount of time spent in non-rapid eye movement (NREM) sleep as quantified by scoring the EEG paper records. Co-administration of NPY with CRF reversed the effects of CRF on sleep duration and sleep onset in a dose-dependent fashion. Spectral analysis revealed that CRF produced quantitative changes in the EEG that were similar to what has previously been reported. CRF-induced increases in fast frequency activity were found to be reversed by co-administration of NPY. Taken together these data suggest that "dysregulation" of sleep and arousal states in depression and anxiety may be consistent with an upset of the balance between hypothalamic neuropeptide systems." [Abstract]

Strome EM, Wheler GH, Higley JD, Loriaux DL, Suomi SJ, Doudet DJ.
Intracerebroventricular corticotropin-releasing factor increases limbic glucose metabolism and has social context-dependent behavioral effects in nonhuman primates.
Proc Natl Acad Sci U S A 2002 Nov 26;99(24):15749-54
"Corticotropin-releasing factor (CRF) is a neuropeptide involved in integrating the behavioral, autonomic, and hormonal responses to stress within the central nervous system. Patients suffering from depression have abnormal activity in stress responsive brain regions and elevated cerebrospinal fluid CRF. The DSM-IV criteria for major depressive disorder include behavioral changes such as depressed mood, anhedonia, and psychomotor agitationretardation. We studied the effects of 434 microg of CRF given intracerebroventricularly over 40 min in group and individually housed monkeys to examine the role of elevated levels of central CRF on behavior. CRF elicited a wide range of behaviors, which fell into three broad categories: anxiety-like, depressive-like, and externally oriented. Externally oriented behaviors decreased, and anxiety-like behaviors increased regardless of how the animals were housed. Interestingly, increased depressive-like behaviors were only observed when the animals were socially housed. In a separate experiment, we examined the effects of the same dose of CRF on the regional cerebral glucose metabolism of lightly anesthetized monkeys by using positron emission tomography and [(18)F]fluorodeoxyglucose. CRF infusion increased glucose metabolism in the pituitaryinfundibulum, the amygdala, and hippocampus. These results indicate that increased central CRF tone affects primate behavior in a context-dependent manner, and that it activates limbic and stress-responsive regions. The fact that intracerebroventricular CRF increases depressive-like behavior in socially housed animals and increases activity in limbic brain regions may help explain the behavioral and metabolic alterations in humans with affective disorders, and this model could therefore have significant value in the development of novel antidepressant treatments." [Abstract]

Penalva RG, Flachskamm C, Zimmermann S, Wurst W, Holsboer F, Reul JM, Linthorst AC.
Corticotropin-releasing hormone receptor type 1-deficiency enhances hippocampal serotonergic neurotransmission: an in vivo microdialysis study in mutant mice.
Neuroscience 2002;109(2):253-66
"Corticotropin-releasing hormone plays an important role in the coordination of various responses to stress. Previous research has implicated both corticotropin-releasing hormone and the serotonergic system as causative factors in the development and course of stress-related psychiatric disorders such as major depression. To delineate the role of the corticotropin-releasing hormone receptor type 1 (CRH-R1) in the interactions between corticotropin-releasing hormone and serotonergic neurotransmission, in vivo microdialysis was performed in CRH-R1-deficient mice under basal (home cage) and stress (forced swimming) conditions. Hippocampal dialysates were used to measure extracellular levels of serotonin and its metabolite 5-hydroxyindoleacetic acid, and free corticosterone levels to monitor the status of the hypothalamic-pituitary-adrenocortical axis. Moreover, behavioural activity was assessed by visual observation and a scoring paradigm.Both wild-type and heterozygous mutant mice showed a clear diurnal rhythm in free corticosterone. Free corticosterone concentrations were, however, lower in heterozygous mutant mice than in wild-type animals and undetectable in homozygous CRH-R1-deficient mice. Homozygous CRH-R1-deficient mice showed enhanced hippocampal levels of 5-hydroxyindoleacetic acid but not of serotonin during the light and the dark phase of the diurnal cycle, which may point to an enhanced synthesis of serotonin in the raphe-hippocampal system. Moreover, the mutation resulted in higher behavioural activity in the home cage during the light but not during the dark period. Forced swimming caused a rise in hippocampal serotonin followed by a further increase after the end of the stress paradigm in all genotypes. Homozygous and heterozygous mutant mice showed, however, a significantly amplified serotonin response to the forced swimming as compared to wild-type control animals.We conclude that CRH-R1-deficiency results in reduced hypothalamic-pituitary-adrenocortical axis activity, in enhanced synthesis of serotonin during basal conditions, and in an augmented response in extracellular levels of serotonin to stress. These data provide further evidence for the intricate relationship between corticotropin-releasing hormone and serotonin and the important role of the CRH-R1 herein." [Abstract]

Stout SC, Mortas P, Owens MJ, Nemeroff CB, Moreau J.
Increased corticotropin-releasing factor concentrations in the bed nucleus of the stria terminalis of anhedonic rats.
Eur J Pharmacol 2000 Jul 28;401(1):39-46
"Chronic mild stress in rats is an antidepressant-responsive model for anhedonic symptoms of major depression. Many patients with depression exhibit alterations in hypothalamic-pituitary-adrenal axis activity, and corticotropin-releasing factor (CRF) neuronal function. This study investigated the potential involvement of CRF and CRF receptors in the development of chronic mild stress-induced anhedonia in rats. Rats were subjected to 19 days of chronic mild stress, during which time anhedonia was periodically assessed by determining the threshold for self-stimulation of the ventral tegmental area. Anhedonic rats exhibited a 50% increase in CRF concentrations in the bed nucleus of the stria terminalis compared to control rats. There were no significant changes in hypothalamic-pituitary-adrenal axis activity, CRF or CRF(1) receptor mRNA expression, or CRF receptor binding in the brain regions analyzed. Though preliminary, these results are consistent with the hypothesis that chronic stress-induced modulation of CRF function in specific brain structures such as the bed nucleus of the stria terminalis may contribute to the pathophysiology of depression." [Abstract]

Marianne B. Müller, Rainer Landgraf, Jens Preil, Inge Sillaber, Adelheid E. Kresse, Martin E. Keck, Stephan Zimmermann, Florian Holsboer, and Wolfgang Wurst
Selective Activation of the Hypothalamic Vasopressinergic System in Mice Deficient for the Corticotropin-Releasing Hormone Receptor 1 Is Dependent on Glucocorticoids
Endocrinology 141: 4262-4269
"Deficiency of CRH receptor 1 (CRHR1) severely impairs the stress response of the hypothalamic-pituitary-adrenocortical (HPA) system and reduces anxiety-related behavior in mice. Intriguingly, in mice deficient for the CRHR1 (Crhr1-/-), basal plasma levels of ACTH are normal, suggesting the presence of compensatory mechanisms for pituitary ACTH secretion. We therefore studied the impact of the hypothalamic neuropeptides arginine vasopressin (AVP) and oxytocin (OXT) on HPA system regulation in homozygous and heterozygous Crhr1 mutants under basal and different stress conditions. Basal plasma AVP concentrations were significantly elevated in Crhr1-/- mice. AVP messenger RNA expression was increased in the paraventricular nucleus of Crhr1-/- mutants together with a marked increase in AVP-like immunoreactivity in the median eminence. Administration of an AVP V1-receptor antagonist significantly decreased basal plasma ACTH levels in mutant mice. After continuous treatment with corticosterone, plasma AVP levels in homozygous Crhr1-/- mice were indistinguishable from those in wild-type littermates, thus providing evidence that glucocorticoid deficiency is the major driving force behind compensatory activation of the vasopressinergic system in Crhr1-/- mice. Neither plasma OXT levels under several different conditions nor OXT messenger RNA expression in the paraventricular nucleus were different between the genotypes. Taken together, our data reveal a selective compensatory activation of the hypothalamic vasopressinergic, but not the oxytocinergic system, to maintain basal ACTH secretion and HPA system activity in Crhr1-/- mutants." [Full Text]

Dallman MF, Pecoraro N, Akana SF, La Fleur SE, Gomez F, Houshyar H, Bell ME, Bhatnagar S, Laugero KD, Manalo S.
Chronic stress and obesity: a new view of "comfort food".
Proc Natl Acad Sci U S A. 2003 Sep 30;100(20):11696-701. Epub 2003 Sep 15.
"The effects of adrenal corticosteroids on subsequent adrenocorticotropin secretion are complex. Acutely (within hours), glucocorticoids (GCs) directly inhibit further activity in the hypothalamo-pituitary-adrenal axis, but the chronic actions (across days) of these steroids on brain are directly excitatory. Chronically high concentrations of GCs act in three ways that are functionally congruent. (i) GCs increase the expression of corticotropin-releasing factor (CRF) mRNA in the central nucleus of the amygdala, a critical node in the emotional brain. CRF enables recruitment of a chronic stress-response network. (ii) GCs increase the salience of pleasurable or compulsive activities (ingesting sucrose, fat, and drugs, or wheel-running). This motivates ingestion of "comfort food." (iii) GCs act systemically to increase abdominal fat depots. This allows an increased signal of abdominal energy stores to inhibit catecholamines in the brainstem and CRF expression in hypothalamic neurons regulating adrenocorticotropin. Chronic stress, together with high GC concentrations, usually decreases body weight gain in rats; by contrast, in stressed or depressed humans chronic stress induces either increased comfort food intake and body weight gain or decreased intake and body weight loss. Comfort food ingestion that produces abdominal obesity, decreases CRF mRNA in the hypothalamus of rats. Depressed people who overeat have decreased cerebrospinal CRF, catecholamine concentrations, and hypothalamo-pituitary-adrenal activity. We propose that people eat comfort food in an attempt to reduce the activity in the chronic stress-response network with its attendant anxiety. These mechanisms, determined in rats, may explain some of the epidemic of obesity occurring in our society." [Abstract]

van Gaalen MM, Stenzel-Poore M, Holsboer F, Steckler T.
Reduced attention in mice overproducing corticotropin-releasing hormone.
Behav Brain Res. 2003 Jun 16;142(1-2):69-79.
"Data from several studies suggest that unrestrained secretion of corticotropin-releasing hormone in the CNS produces several signs and symptoms of depression. Recent evidence indicates that blockade of the CRH receptor 1 reduced depression scores in depressed patients. One of the symptoms that occur is depression is impairment in attentional processes. Whether these impairments are due to alterations in the CRH system are so far unknown. In order to investigate whether overproduction of CRH alters attentional process, transgenic mice overproducing CRH were tested on an operant five choice serial reaction time task, a task which taxes sustained and divided attention. Mutants showed impaired autoshaping. During initial discrimination learning, transgenics performed below wildtype level, but with extended training with long stimulus durations, transgenic animals reached similar accuracy levels as wildtype mice. When animals were tested at shortest stimulus duration (0.5s), a mild but significant impairment in accurate responding emerged in transgenics. This was accompanied by longer correct response latencies, while incorrect latencies did not differ between groups, suggesting attentional impairment in CRH transgenics. Because these animals have been reported to also show increased anxiety-related behaviour, animals were treated with the anxiolytic benzodiazepine diazepam. Diazepam failed to affect accuracy, but transgenic mice showed a stronger behavioural disinhibition. This suggests that the attentional impairment seen in CRH overexpressors is independent of alterations in anxiety-like behaviour. These findings may have implications for understanding the pathophysiology of psychiatric disorders such as depression, where it has been suggested that an overactivity of the CRH system accounts for a variety of symptoms, including hyper-arousal and attentional impairment." [Abstract]