Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0848237 (acute stress)
 4,619 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Corticotropin-releasing hormone (CRH) plays a central role in the adaptation of the organism to stress. It serves as the main regulating hormone of the hypothalamic pituitary adrenal (HPA) axis, which is activated within seconds after exposure to acute stress. Furthermore, it acts as a neurotransmitter in numerous other brain regions. Globally, CRH leads to a number of metabolic, neuroendocrine and autonomic adaptations, which are vitally important for an adequate reaction to acute stress, but can lead to pathological somatic and psychological effects in chronic stress situations. The adequate functioning of CRH is a delicate equilibrium, which can be permanently disturbed by early experiences of physical or sexual abuse, leading to psychopathology in adulthood. This review discusses the physiological functions of CRH as the stress response hormone. Subsequently, the emerging data on the disruptive effects of early trauma on the CRH system are summarized. The third part is devoted to CRH and HPA axis abnormalities in major depression and other psychiatric disorders. This rapidly accumulating evidence will change our understanding of psychopathology, and might challenge the established classification of psychiatric disorders.
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PMID:Corticotropin-releasing hormone (CRH) in psychiatry: from stress to psychopathology. 1500 Mar 47

1. The characterization of corticotropin releasing factor (CRF) and, more recently, the discovery of additional CRF-related ligands, urocortin 1, urocortin 2 and urocortin 3, the cloning of two distinct CRF receptor subtypes, 1 (CRF(1)) and 2 (CRF(2)), and the development of selective CRF receptor antagonists provided new insight to unravel the mechanisms of stress. Activation of brain CRF(1) receptor signaling pathways is implicated in stress-related endocrine response and the development of anxiety-like behaviors. 2. Compelling evidence in rodents showed also that both central and peripheral injection of CRF and urocortin 1 mimic acute stress-induced colonic response (stimulation of motility, transit, defecation, mucus and watery secretion, increased ionic permeability and occurrence of diarrhea) in rodents. Central CRF enhances colorectal distention-induced visceral pain in rats. Peripheral CRF reduced pain threshold to colonic distention and increased colonic motility in humans. 3. Nonselective CRF(1)/CRF(2) antagonists and selective CRF(1) antagonists inhibit exogenous (central or peripheral) CRF- and acute stress-induced activation of colonic myenteric neurons, stimulation of colonic motor function and visceral hyperalgesia while selective CRF(2) antagonists have no effect. None of the CRF antagonists influence basal or postprandial colonic function in nonstressed animals. 4. These findings implicate CRF(1) receptors in stress-related stimulation of colonic function and hypersensitivity to colorectal distention. Targeting CRF(1)-dependent pathways may have potential benefit against stress or anxiety-/depression-related functional bowel disorders.
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PMID:CRF1 receptor signaling pathways are involved in stress-related alterations of colonic function and viscerosensitivity: implications for irritable bowel syndrome. 1510 Jan 65

The stress-related neuropeptide corticotropin-releasing factor (CRF) and the serotonin system are both critically involved in the pathophysiology of mental disorders, including anxiety and depression. To understand the potential link between them, we investigated the impact of CRF on 5-HT functions in pyramidal neurons of the prefrontal cortex (PFC), a brain region that is crucial for the control of emotion and cognition. One prominent function of serotonin in PFC is to regulate GABAergic inhibitory transmission, as indicated by a 5-HT-induced large, desensitizing (approximately 4 min) enhancement of the amplitude and frequency of spontaneous IPSCs (sIPSCs). In PFC slices exposed to CRF treatment, the regulation of sIPSCs by 5-HT was significantly prolonged (8-10 min), and this effect of CRF was blocked by treatment with the competitive CRF receptor antagonist alpha-helical CRF9-41 and with the CRF-R1-specific antagonist astressin. Inhibiting phospholipase C or protein kinase C (PKC) abolished the prolongation by CRF of the effects of 5-HT on sIPSCs. In PFC slices prepared from animals previously exposed to acute stress (forced swim or elevated platform), the regulation of sIPSCs by 5-HT was significantly prolonged, mimicking the effect of CRF treatment. The stress-induced prolongation of the effects of 5-HT on sIPSCs was diminished by alpha-helical CRF9-41 treatment, mimicked by direct activation of PKC, and reversed by short-term treatment with drugs that have anxiolytic efficacy. These results show that in response to stressful stimuli, CRF alters the serotonergic regulation of GABA transmission through a mechanism that is dependent on PKC. The interaction between CRF and 5-HT may play an important role in psychiatric disorders, in which both are highly implicated.
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PMID:Corticotropin-releasing factor and acute stress prolongs serotonergic regulation of GABA transmission in prefrontal cortical pyramidal neurons. 1516 92

Corticotropin-releasing factor (CRF) is a key mediator of the behavioral, autonomic, and endocrine responses to stress. CRF binds two receptors and a CRF-binding protein (CRF-BP), which may inactivate or modulate the actions of CRF at its receptors. The amygdala is an important anatomical substrate for CRF and contains CRF, its receptors, and CRF-BP. Few studies have examined the effects of acute stress on the regulation of amygdala CRF-BP with other CRF system genes. Therefore, we examined the time course of the effects of acute restraint stress on central (CeA) and basolateral (BLA) amygdala CRF system genes. Consistent with our previous study, acute stress increased BLA CRF-BP mRNA shortly after stress offset. Surprisingly, BLA CRF-BP mRNA remained elevated up to 21 h after the stressor. This effect was selective in the BLA as stress did not alter CeA CRF-BP mRNA, and there were no changes in CRF or CRF receptor mRNAs in either amygdala nucleus. These results suggest that alterations in BLA CRF-BP gene expression are a primary response of the BLA/CeA CRF system to acute stress. Because CRF-BP can modulate CRF action, changes in amygdala CRF-BP levels after stress exposure may affect the ability of an organism to adapt to future stressors.
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PMID:The effects of acute stress on the regulation of central and basolateral amygdala CRF-binding protein gene expression. 1553 Jun 48

The hypothalamic neuropeptides hypocretins (orexins) play a crucial role in the stability of arousal and alertness. We tested whether the hypocretinergic system is a critical component of the stress response activated by the corticotropin-releasing factor (CRF). Our results show that CRF-immunoreactive terminals make direct contact with hypocretin-expressing neurons in the lateral hypothalamus and that numerous hypocretinergic neurons express the CRF-R1/2 receptors. We also demonstrate that application of CRF to hypothalamic slices containing identified hypocretin neurons depolarizes membrane potential and increases firing rate in a subpopulation of hypocretinergic cells. CRF-induced depolarization was tetrodotoxin insensitive and was blocked by the peptidergic CRF-R1 antagonist astressin. Moreover, activation of hypocretinergic neurons in response to acute stress was severely impaired in CRF-R1 knock-out mice. Together, our data provide evidence of a direct neuroanatomical and physiological input from CRF peptidergic system onto hypocretin neurons. We propose that, after stressor stimuli, CRF stimulates the release of hypocretins and that this circuit contributes to activation and maintenance of arousal associated with the stress response.
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PMID:Interaction between the corticotropin-releasing factor system and hypocretins (orexins): a novel circuit mediating stress response. 1560 50

Vasopressin (AVP) and corticotropin-releasing factor (CRF) are key mediators in the organism's neuro-adaptive response to stress. Through pituitary and central vasopressin V(1b) receptors, AVP participates in the control of the hypothalamic-pituitary-adrenal axis (HPA) and is involved in various emotional processes. SSR149415 is the first selective, orally active vasopressin V(1b) receptor antagonist yet described. It is a competitive antagonist with nanomolar affinity for animal and human V(1b) receptors and displays a highly selective profile with regard to a large number of receptors or enzymes. In vitro, SSR149415 potently antagonizes functional cellular events associated with V(1b) receptor activation by AVP, such as intracellular Ca(2+) increase or proliferation in various cell systems. Pharmacological studies, performed by measuring ACTH secretion induced by various stimulants such as hormones (AVP or AVP + CRF) or physical stress (restraint or forced swimming stress and dehydration) in conscious rats or mice, confirm the antagonist profile of SSR149415 and its efficacy in normalizing ACTH secretion in vivo. SSR149415 is active by the oral route, at doses from 3 mg/kg, it potentiates CRF effect and displays a long-lasting oral effect in the different models. At 10 mg/kg p.o. its duration of action is longer than 4 h. This molecule also decreases anxiety and exerts marked antidepressant-like activity in several predictive animal models. The anxiolytic effects of SSR149415 have been demonstrated in various Generalized Anxiety Disorders (GAD) models (four-plate, punished drinking, elevated plus-maze, light dark, mouse defense test battery, fear-potentiated startle and social interaction tests). It is as effective as the benzodiazepine diazepam in the acute stress exposure test. SSR149415 has similar efficacy to the reference antidepressant drug, fluoxetine, in acute (forced-swimming) and chronic (chronic mild stress and subordination stress) situations in rodents. SSR149415 also reduces offensive aggression in the resident-intruder model in mice and hamsters. Depending on the model, the minimal effective doses are in the range of 1-10 mg/kg i.p. or 3-10 mg/kg p.o. SSR149415 is devoid of adverse effects on motor activity, sedation, memory or cognitive functions and produces no tachyphylaxis when administered repeatedly. It is well-tolerated in animals and humans and exhibits an adequate ADME profile. Thus, SSR149415 is a new dual anxiolytic/antidepressant compound, which appears to be free of the known side effects of classical anxiolytic/antidepressant drugs. Clinical trials are in progress, they will hopefully demonstrate its therapeutical potential for treating stress-related disorders.
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PMID:An overview of SSR149415, a selective nonpeptide vasopressin V(1b) receptor antagonist for the treatment of stress-related disorders. 1586 52

We used captive European starlings (Sturnus vulgaris) to test whether corticosterone responses differed in birds held under normal laboratory conditions or conditions of chronic stress. Surprisingly, both basal corticosterone concentrations and corticosterone responses to acute stress were significantly reduced when birds were chronically stressed. To determine the mechanism underlying this reduced response, animals under both conditions were injected with lactated Ringer's solution (control), adrenocorticotropin (ACTH), arginine vasotocin (AVT), or dexamethasone (DEX). ACTH increased corticosterone concentrations above stress-induced levels in both cases, although maximum responses were lower in chronically stressed birds. AVT did not augment the corticosterone response under nonchronically stressed conditions, but it did under chronically stressed conditions. DEX reduced maximal corticosterone concentrations in both cases. Neither ovine nor rat corticotropin-releasing factor (CRF) altered normal stress responses. These data indicate that changes in responsiveness of the hypothalamic-pituitary-adrenal axis to ACTH and AVT serve to downregulate corticosterone responses during chronic stress. Furthermore, these data lead to the following hypothesis: ACTH output from the pituitary limits maximum corticosterone concentrations under normal conditions, but reduced AVT release from the hypothalamus regulates lower corticosterone concentrations under chronic stress conditions.
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PMID:Exposure to chronic stress downregulates corticosterone responses to acute stressors. 1588 58

Major depressive disorder (MDD) is characterized by a dysregulation of the stress response system. A corticotropin-releasing factor (CRF) hyperdrive is a consistent and well-documented finding. CRF-binding protein (CRF-BP) may play a role in the pathogenesis of MDD. CRF-BP reduces the availability of CRF by binding free CRF and inhibits CRF function at the pituitary level. Moreover, CRF-BP expression increases in the pituitary and amygdala in response to acute stress, providing an additional feedback mechanism to maintain the homeostasis of the stress response. There are different regulatory elements of the expression of CRF-BP gene that are implicated in the pathophysiology of MDD, including CRF, glucocorticoids, cytokines and estrogens. A specific haplotype within the CRF-BP gene has been associated with MDD, but confirmation of this finding is necessary. Currently, the possible role of CRF-BP in the pathophysiology of conditions that have been associated with a hypofunction of the CRF system and immune dysfunctions is unclear. Implications of the function of CRF-BP for therapeutic strategies in MDD are being discussed. An important advantage of ligands that target CRF-BP is that concentrations of free CRF can be altered without acting directly on the transmission of CRF through its receptor.
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PMID:Corticotropin-releasing factor-binding protein, stress and major depression. 1599 2

The endocrine stress response is pivotal in vertebrate physiology. The stress hormone cortisol-the end product of the endocrine stress axis-(re-)directs energy flows for optimal performance under conditions where homeostasis may be or become at risk. Key players in the continuous adaptation process are corticotropin-releasing factor (CRF) from the hypothalamic nucleus preopticus (NPO), pituitary adrenocorticotropic hormone (ACTH) and cortisol produced by the interrenal cells in the headkidney (adrenal equivalent of fish). CRF is a member of a large family of related peptides that signals through CRF-receptor subtypes specific for central and peripheral actions of the peptide. CRF is "chaperoned" by a unique and phylogenetically very well-conserved binding protein (CRFBP); the functions of the CRFBP can only be speculated on so far, but its mRNA and protein abundance are important indicators of the central CRF-system activity, and indeed its mRNA levels are altered by restraint stress. Moreover, the unique structure and size of the CRFBP provide good tools in phylogenetic studies, that date the CRF-system to at least one billion years old. Pro-opiomelanocortin is produced and processed to ACTH and endorphin in the hypothalamic NPO and pituitary pars distalis ACTH-cells, to MSH and acetylated endorphins in the pituitary pars intermedia MSH-cells. ACTH is the prime corticotrope in acute stress conditions. In carp, MSH, considered a mild corticotrope in chronic stress responses in other fish, lacks corticotropic effects (in line with the absence of the melanocortin-5 receptor in headkidney); yet, an unknown corticotropic signal substance in the pars intermedia of carp awaits elucidation. Interesting observations were made on the CRF control of pituitary cells. CRF stimulates ACTH-cells, but only when these cells experience a mild dopaminergic block. Endorphin, produced in the NPO and transported via axons to the pituitary gland in vivo, reverses the stimulatory CRF action on MSH-cells to a differential inhibition of N-acetyl beta-endorphin release in vitro (MSH release is not affected). We speculate that the consistently observed elevation of plasma MSH during chronic stress may exert central actions related to feeding and leptin regulated processes. A BOLD-fMRI study revealed the functional anatomy of the stress response at work in a paradigm, where carp were exposed to a sudden water temperature drop. In carp (and other fish), the endocrine stress axis is already operational in very early life stages, viz., around hatching and comprises hypothalamic, pituitary, and interrenal signaling to adjust the physiology of the hatchling to its dynamically changing environment. Understanding of stress during early life stages is critical as the consequent rises in cortisol may have long lasting effects on survival and fish quality.
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PMID:CRF and stress in fish. 1640 2

Social isolation of rats both reduces the cerebrocortical and plasma concentrations of 3a-hydroxy-5a-pregnan-20-one (3a,5a-TH PROG) and 3a,5a-tetrahydrodeoxycorticosterone and potentiates the positive effects of acute stress and ethanol on the concentrations of these neuroactive steroids. We now show that social isolation decreased the plasma level of adrenocorticotropin (ACTH), moreover, intracerebroventricular administration of corticotropin releasing factor (CRF) induced a marked increase in the plasma corticosterone level in both isolated and group-housed rats, but this effect was significantly greater in the isolated rats (+121%) than in the group-housed rats (+86%). In addition, in isolated rats, a low dose of dexamethasone had no effect on the plasma corticosterone concentration, whereas, a high dose significantly reduced it; both doses of dexamethasone reduced plasma corticosterone in group-housed rats. Furthermore, the corticosterone level after injection of dexamethasone at the high dose was significantly greater in the isolated animals than in the group-housed rats. These results suggest that social isolation increased sensitivity of the pituitary to CRF and impaired negative feedback regulation of the hypothalamic-pituitary-adrenal (HPA) axis.
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PMID:Social isolation-induced changes in the hypothalamic-pituitary-adrenal axis in the rat. 1642 14


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