Corticotropin-releasing Factor Concentrations Research Articles

Glutamine Enhances Tight Junction Protein Expression and Modulates Corticotropin-Releasing Factor Signaling in the Jejunum of Weanling Piglets ,

Dysfunction of tight junction integrity is associated with decreased nutrient absorption and numerous gastrointestinal diseases in humans and piglets. Although l-glutamine has been reported to enhance intestinal-mucosal mass and barrier function under stressful conditions, in vivo data to support a functional role for l-glutamine on intestinal tight junction protein (TJP) expression in weanling mammals are limited. This study tested the hypothesis that glutamine regulates expression of TJPs and stress-related corticotropin-releasing factor (CRF) signaling in the jejunum of weanling piglets. Piglets were reared by sows or weaned at 21 d of age to a corn and soybean meal-based diet that was or was not supplemented with 1% l-glutamine for 7 d. Growth performance, intestinal permeability, TJP abundance, and CRF expression were examined. Weaning caused increases (P < 0.05) in intestinal permeability by 40% and in CRF concentrations by 4.7 times in association with villus atrophy (P < 0.05). Western blot analysis showed reductions (P < 0.05) in jejunal expression of occludin, claudin-1, zonula occludens (ZO) 2, and ZO-3, but no changes in the abundance of claudin-3, claudin-4, or ZO-1 in weanling piglets compared with age-matched suckling controls. Glutamine supplementation improved (P < 0.05) intestinal permeability and villus height, while reducing (P < 0.05) jejunal mRNA and protein levels for CRF and attenuating (P < 0.05) weanling-induced decreases in occludin, claudin-1, ZO-2, and ZO-3 protein abundances. Collectively, our results support an important role for l-glutamine in regulating expression of TJPs and CRF in the jejunum of weanling piglets.

Changes induced by prenatal stress in behavior and brain morphology: can they be prevented or reversed?

This chapter presents a critical analysis of the behavioral alterations reported in the offspring of women exposed to stress and/or depression during pregnancy and the neurochemical and structural changes underlying them. Among the alterations attributed to prenatal stress in humans and experimental rats of both sexes is impaired regulation of the hypothalamic-pituitary-adrenal (HPA) axis, anxiety and exaggerated fear of novelty, and decreased social interaction. Learning and attention deficits are more prevalent in boys and male rats. Fear of novelty and anxiety are associated with enlargement of the amygdala and its corticotropin-releasing factor content, and decreased socialization, with lower oxytocin activity in the amygdala. Learning deficits are associated with a decrease in neurogenesis, dendritic complexity, and spine number in the dorsal hippocampus. Fostering prenatally stressed (PS) pups onto control mothers prevents the dysregulation of the HPA axis and heightened anxiety, indicating a role for postnatal factors in their etiology. By contrast, learning impairment and decreased socialization are not affected by this fostering procedure and are therefore prenatally mediated.In spite of their widespread use in depressed pregnant women, selective serotonin reuptake inhibitor (SSRI) antidepressants do not normalize the behavior of their children. When administered during gestation to stressed rats, SSRIs do not reduce anxiety or learning deficits in their offspring. Moreover, when given to unstressed mothers, SSRIs induce anxiety in the offspring. The detrimental effect of SSRIs may result from inhibition of the serotonin transporter exposing the brain to excess amounts of 5-hydroxytryptamine (5-HT) at a critical time during fetal development.

Circadian fatigue or unrecognized restless legs syndrome? The post-polio syndrome model.

The discussion of this research paper may represent the starting point of the debate about the influence of sleep disorders on fatigue perception. These authors observed in a small cohort of patients with paralytic poliomyelitis (PP) and post-polio syndrome (PPS) a significant circadian variation of subjective fatigue evaluated by means of a validated scale. These authors showed a progressive worsening of fatigue during afternoon in both PP and PPS (1). Polysomnographic variables did not correlate with fatigue, albeit restless legs syndrome (RLS) symptoms were not evaluated. PP is an acute poliovirus infection resulting in flaccid paralysis, due to poliovirus-induced apoptosis, and consequent central nervous system injury, which leads to paralysis. Therefore, during its clinical course an increasing and progressive fatigue may represent an integral part of PP motor symptoms. In addition, more than 90% of patients with PP develop a delayed syndrome characterized by excessive fatigue (2). PPS circadian impairment of fatigue may be more puzzling. It may be related to the presence of sleep disorders [i.e., sleep apnea, RLS, and periodic limb movements of sleep (PLMS)] previously described in PPS (3–5). Restless legs syndrome and other sleep disorders have been reported in small PPS uncontrolled cohorts or single case reports, and in selected samples complaining of fatigue and sleepiness. In addition, fatigue represents a cardinal symptom of PPS, marked by a progressive course, and able to affect significantly patient quality of life (6). Moreover, fatigue in PPS may be characterized by circadian changes, as recently showed by Viana and colleagues in a small cohort of PPS patients (1). Although, these authors did not explore clinical RLS in these PPS sample, it is intriguing to note that fatigue could resemble the circadian pattern of RLS symptoms. Therefore, RLS may represent an interesting model and a possible unifying hypothesis for fatigue in PPS similarly to other diseases both neurological (i.e., multiple sclerosis, myotonic dystrophies) and nonneurological (COPD, liver disorders) (2, 7–9). Prevalence of RLS in these disorders has been reported as higher than in the general population, but could even be underdiagnosed because of difficulties to distinguish from other symptoms such as pain or spasticity. Two different pathogenic hypotheses are interesting to highlight in this context. First, more than 90% of neurological conditions associated with RLS are linked to inflammatory mechanisms that have been supposed to play a role also in primary RLS (10, 11). On the other side, there is growing evidence that the fatigue is related to the interplay between neurotransmitters and immunological imbalance and deranged hypothalamic–pituitary–adrenal axis in states of chronic stress. In addition, fatigue affects several CNS regions and pro-inflammatory cytokines (i.e., IL1, IL-6, and TNF-alpha) that are released during systemic inflammation and are activated by reduced corticotropin releasing factor and low cortisol concentrations (2, 12). This hypothesis seems to accord with experimental data that in immune-mediated disorders, acute stress can be beneficial because rises in corticotropin releasing factor attenuate the T-helper-1 cell response. However, it is still unclear if chronic stress versus acute stress down regulates the hypothalamic– pituitary–adrenal axis, leading to persistent fatigue. This axis is underactive in patients with chronic fatigue syndrome, post-traumatic stress disorder, fibromyalgia, and also in PPS (2). In addition, it has not been clarified if the PPS denervation processes are caused by further loss of motor neurons due to normal aging or active chronic inflammatory processes as supported by the increased expression of pro-inflammatory cytokines (13). Therefore, both diseases may share a proinflammatory condition. On the other side, an alternative explanation for the supposed link between RLS and PPS should consider that the sequelae of polio, similarly to other spinal cord RLS-related diseases, may

The effect of urocortin I on the hypothalamic ACTH secretagogues and its impact on the hypothalamic-pituitary-adrenal axis

Urocortin I (UCN I) is a structural analogue of corticotropin-releasing factor (CRF), which, together with arginine-vasopressin (AVP), are the principle adrenocorticotropic hormone (ACTH) secretagogues in mammals. The aim of the present study was to investigate the effects of UCN I on the hypothalamic CRF and AVP concentration and its impact on the hypothalamic-pituitary-adrenal (HPA) axis. First, male Wistar rats were injected intracerebroventricularly (ICV) with 0.5, 1, 2 and 5μg of UCN I. After 30min hypothalamic CRF and AVP concentrations were determined by immunoassays. In parallel, the trunk blood was collected and plasma ACTH and corticosterone concentration was determined by ELISA and chemofluorescent assay, respectively. Second, rats were pretreated ICV with selective antagonists of receptors being implicated in the regulation of the HPA axis (0.1μg antalarmin for CRFR1, 1μg astressin 2B for CRFR2 or 0.1μg deamino-Pen1,Tyr2,Arg8-vasopressin for AVPR3) and treated ICV with the most effective dose of UCN I (5μg). After 30min plasma corticosterone concentration was determined by chemofluorescent assay. UCN I induced dose-dependent augmentation of the hypothalamic CRF and AVP concentration, associated with dose-dependent elevation of the plasma ACTH and corticosterone concentration. The most significant effect of UCN I on the plasma corticosterone concentration was inhibited by antalarmin, but was not influenced by astressin 2B or deamino-Pen1,Tyr2,Arg8-vasopressin. The present study demonstrates that UCN I modulates the concentration of the hypothalamic ACTH secretagogues in parallel with the concentration of the plasma ACTH and corticosterone. Our results suggest that UCN I may activate the HPA axis by stimulation of the hypothalamic CRF production, and this process is mediated by CRFR1, and not by CRFR2. UCN I may stimulate the AVP production, as well, but, based on the results with AVPR3 antagonist, this effect is not involved in the regulation of the HPA axis.

Effect of tribulus terrestris saponins on behavior and neuroendocrine in chronic mild stress depression rats

ObjectiveTo observe the effect of tribulus terrestris saponins (TTS) on behavior and neuroendocrine of chronic mild stress (CMS) depression rats. MethodsThirtymaleSprague-Dawleyratswererandomly allocated to six groups: vehicle group, CMS group, CMS + fluoxetine group and CMS + TTS of low-dosage (0.375 g/kg), medium-dosage (0.75 g/kg) and high-dosage (2.25 g/kg) groups. All rats except the vehicle group singly housed and exposed an unpredicted sequence of mild stressors. The behavior of rats was detected by open-field test (OFT) and sucrose preference test (SPT). The concentration of corticotropin-releasing factor (CRF) and adrenocorticotropic hormone (ACTH) in serum of the rats were detected by radioimmunoassay. The concentration of cortisol (CORT) in serum was detected by enzyme immunoassay. ResultsCMS procedure not only significantly decreased the scores of crossing, rears and grooming in OFT and the sucrose preference in SPT (all P< 0.01), but also markedly increased serum CRH and CORT levels (both P<0.05). Treatment with TTS (0.75 and 2.25 g/kg) could significantly prevent all of these abnormalities induced by CMS (P<0.05, P< 0.01). ConclusionCMS can affect rat behavior and neuroendocrine and cause depression. TTS has the antagonism on CMS and produce antidepressive effects.

Impact of chondroitin sulfate treatment on immunoregulatory neuropeptides levels in OA patients synovitis

Purpose: Osteoarthritis (OA) is the most prevalent joint disease, characterized by synovial inflammation, cartilage destruction and subchondral bone sclerosis. Synovitis has been described to be an important process in OA progression, where several immune mediators, such as immunoregulatory neuropeptides, play an important role. The vasoactive intestinal peptide (VIP) and the corticotropin-releasing factor (CRF)/urocortins (UCNs) family are neuropeptides expressed in central and peripheral tissues, including immune cells, that modulate the expression of inflammatory and extracellular matrix remodelling mediators. VIP has previously shown a plethora of beneficial effects, both in inflammatory disorder animal models and in human OA, being a potential therapeutic agent. Besides, it has shown that high VIP levels are correlated with a decrease of the OA severity progress. In addition, CRF and Urocortin1 (UCN1) are secreted to the OA joint microenvironment exerting an autocrine and paracrine immuno/inflammatory regulation. Chondroitin sulfate (CS) is a Symptomatic Slow Action Drug for Osteoarthritis (SYSADOA) described to improve the symptoms of OA disease. The NIH-funded GAIT study demonstrated that CS is an effective drug in reducing OA patients’ synovitis. The aim of this study was to compare the effect of CS vs. paracetamol on synovitis in OA patients, and to evaluate their impact on VIP, CRF and UCN1 concentrations. Methods: 71 OA patients with synovitis (synovial hypertrophy+effusion≥4mm) were treated with CS (Condrosan®, CS Bio-ActiveTM, Bioibérica S.A., Barcelona, Spain) (800mg/day) or paracetamol (4g/day) for 6 months. Patients were followed-up until month 9 to evaluate the CS carry-over effect. In each visit (0, 6 and 9 months) synovitis was evaluated by sonography and plasma and synovial fluid were collected for the quantification of VIP, CRF and UCN1 by EIA (Enzyme Immunoassay). Once the clinical data have been collected, CS treated patients were subdivided into two groups, as responding and non-responding to treatment. A responding patient was defined by a sinovitis reduction at 6 months greater than 20% from basal value. Time-course analysis study was performed by a Wilcoxon two-related samples test. The comparation between responding and non-responding patients was analyzed by a Mann-Whitney U test. P values less than or equal to 0.05 were considered significant. Results: The analysis of the results obtained showed that CS but not paracetamol reduces effectively the synovitis observed in OA patients. The improvement remained after 3 months treatment cessation. Synovial fluid presents a progressive decrease neuropeptides levels along the CS treatment, reaching significancy VIP reduction at 9 months. This tendency is more pronounced when only the responding patients are analyzed. In contrast no tendency was observed with the paracetamol group, showing a lonely significant decrease of UCN1 at 6 months. The neuropeptides levels in plasma did not show significant differences neither in the chondroitin treated patients nor in the responding group. However, the paracetamol grup present a progressive increment of CRF/UCN levels being significant the UCN1 increase at 9 months. When comparing the basal levels of the neuropeptides between responding and non-responding CS groups, we observed that patients with high level of neuropeptides before CS treatment, demonstrated a positive response to the treatment. Conclusions: These results indicate that CS but not paracetamol effectively reduces synovitis, even after leaving the CS treatment. This improvement lead to a decreased VIP level in synovial fluid, probably because of a fall of the mediators that regulates its expression. Neuropeptides levels could represent an important biomarker to distinguish which patients are responder to CS, since high level of them in synovial fluid at the onset of treatment are correlated with a positive response to CS treatment.

Brain‐derived neurotrophic factor, corticotropin‐releasing factor, and hypothalamic neuronal histamine interact to regulate feeding behavior

Brain-derived neurotrophic factor (BDNF), corticotropin-releasing factor (CRF), and hypothalamic neuronal histamine are anorexigenic substances within the hypothalamus. This study examined the interactions among BDNF, CRF, and histamine during the regulation of feeding behavior in rodents. Food intake was measured after treatment with BDNF, α-fluoromethyl histidine (FMH; a specific suicide inhibitor of histidine decarboxylase that depletes hypothalamic neuronal histamine), or CRF antagonist. We measured food intake in wild-type mice and mice with targeted disruption of the histamine H1 receptor (H1KO mice) after central BDNF infusion. Furthermore, we investigated CRF content and histamine turnover in the hypothalamus after BDNF treatment, and conversely, BDNF content in the hypothalamus after histamine treatment. We used immunohistochemical staining for histamine H1 receptors (H1-R) in BDNF neurons. BDNF-induced feeding suppression was partially attenuated in rats pre-treated with FMH or a CRF antagonist, and in H1KO mice. BDNF treatment increased CRF content and histamine turnover in the hypothalamus. Histamine increased BDNF content in the hypothalamus. Immunohistochemical analysis revealed that H1-Rs were expressed on BDNF neurons in the ventromedial nucleus of the hypothalamus. These results indicate that CRF and hypothalamic neuronal histamine mediate the suppressive effects of BDNF on feeding behavior and body weight.

De amygdala, een schakelstation voor het aan- en uitzetten van pijn: de rol van limbisch corticotropin-releasing factor bij neuropathische pijn

Corticotropin-releasing factor (CRF) plays a prominent role in mood disorders like anxiety and depression. Upon experimentally-induced neuropathy, it is up-regulated in limbic structures such as the amygdala. This review discusses the literature on the role of CRF in pain processing and highlights the amygdala as key center in pain control. Not only has CRF analgesic effects following local and systemic administration, but more recently also hyperalgesic effects were shown upon endogenous amygdalar CRF increase or by blocking the CRF type 1 receptor (CRFR1). We here postulate a central mechanism for pain control with the amygdala as critical brain component in turning the sensation of pain on and off. Upon painful stimuli, CRFR1 in the amygdala is activated by CRF and induces hyperalgesia. The activated CRFR1 is then internalized (pain initiation) to trigger the translocation of the cytoplasmic CRFR2 to the plasma membrane. This CRFR2 can be recruited by either high (pharmacological) concentrations of CRF or by endogenous CRFR2 ligands, such as urocortins, which leads to analgesia (pain termination). Redistribution of the CRF receptors to their initial locations and activity states completes the on-off switching. We propose that in neuropathic pain, this mechanism is dysregulated, which leads to a state of permanent hyperalgesia, and we present an integrative (patho)physiological model for the way disturbed CRF receptor signaling in the amygdala could initiate neuropathic pain.

Narrow band ultraviolet B irradiations cause alteration in interleukin-31 serum level in psoriatic patients

Scientific communications indicate the disturbed expression of neuropeptides in the skin and serum in psoriasis vulgaris (PsV) patients. Narrow-band ultraviolet radiation (NB-UVB) is one of the systemic therapies of PsV. The aim of the study was to evaluate the influence of NB-UVB therapy on substance P (SP), calcitonin gene-related peptide (CGRP), brain-derived neurotrophic factor (BDNF), corticotropin-releasing factor (CRF) and interleukin-31 (IL-31) serum concentrations in PsV patients. 59 psoriatic patients with mean PASI (psoriasis area and severity index) 14.3 were treated with NB-UVB (20 exposures). The control group consisted of 50 healthy subjects, whose age and sex matched. In all patients, serum concentration of BDNF, CRF, IL-31 substance P and CGRP was analyzed by ELISA before the treatment and in psoriatic group the analysis was also done after 10 and 20 irradiations. In patients there was found a significantly higher concentration of IL-31 (215.3 vs. 748.6 ng/ml; p < 0.0001), SP (25.7 vs. 67.2 pg/ml; p < 0.01), CGRP (31.4 vs. 44.15 pg/ml; p < 0.01) and a lower concentration of CRF (0.89 vs. 0.426 ng/ml; p < 0.0001) and BDNF (16.39 vs. 14.15 ng/ml; p = 0.1216) in comparison with the controls. 20 NB-UVB exposures caused a significant decrease in IL-31 level (748.6 vs. 631.7 ng/ml; p < 0.0001). The NB-UVB therapy had no major effect on neuropeptides serum levels regardless of a number of irradiations. On the basis of our study it can be suggested that IL-31 is involved in pathogenesis of psoriasis and the NB-UVB therapy causes alterations in its level.

Central Administration of Aminoprocalcitonin Inhibits Food Intake and Stimulates the Hypothalamic‐Pituitary‐Adrenal Axis in Rats via the Corticotrophin‐Releasing Factor System

Aminoprocalcitonin (N-PCT), a neuroendocrine peptide derived from procalcitonin, reduces food intake and body weight when administered centrally in rats. We have recently shown that N-PCT is expressed in brain areas known to be involved in energy homeostasis, including the paraventricular nucleus (PVN) of the hypothalamus, which contains a prominent population of corticotrophin-releasing factor (CRF)-synthesising neurones. CRF plays a pivotal role in the regulation of the hypothalamic-pituitary adrenal (HPA) axis and food intake. However, little is known about functional interactions of N-PCT and CRF. In the present study, we found endogenous N-PCT protein in the rat PVN. We also showed N-PCT immunoreactivity in PVN co-localised with NeuN, a neuronal marker, or glial fibrillary acidic protein, an astrocyte marker. Double staining immunohistochemistry revealed that N-PCT co-localised with CRF in parvocellular neurones of the PVN. Intracerebroventricular N-PCT administration increased CRF mRNA and content in the hypothalamus, suggesting that N-PCT stimulates the HPA axis and suppresses food intake and body weight via CRF-dependent pathways. In keeping with this, i.c.v. co-injection of D-Phe-CRF(12-41), a CRF receptor antagonist, significantly attenuated N-PCT-induced reduction in food intake and body weight in a dose-dependent manner. Furthermore, i.c.v. administration of N-PCT increased plasma adrenocorticotrophic hormone and corticosterone concentrations and induced the expression of Fos protein, a marker of neuronal activity, in parvocellular CRF neurones. These data collectively support the hypothesis that N-PCT inhibits food intake and body weight and stimulates the HPA axis via CRF-mediated pathways.

Experimental neuropathy increases limbic forebrain CRF

Neuropathic pain is often accompanied by stress, anxiety and depression. Although there is evidence for involvement of corticotropin-releasing factor (CRF), the detailed neuronal basis of these pain-related mood alterations is unknown. This study shows that peripheral mononeuropathy was accompanied by changes in limbic forebrain CRF, but did not lead to changes in the functioning of the hypothalamo-pituitary-adrenal axis and the midbrain Edinger-Westphal centrally projecting (EWcp) neuron population, which play main roles in the organism's response to acute pain. Twenty-four days after chronic constriction injury (CCI) of the rat sciatic nerve, the oval bed nucleus of the stria terminalis (BSTov) contained substantially more Crf mRNA as did the central amygdala (CeA), which, in addition, possessed more CRF. In contrast, Crf mRNA and CRF contents of the hypothalamic paraventricular nucleus (PVN) were unaffected by CCI. Similarly, EWcp neurons, producing the CRF family member urocortin 1 (Ucn1) and constitutively activated by various stressors including acute pain, did not show an effect of CCI on Ucn1 mRNA or Ucn1. Also, the immediate early gene products cFos and deltaFosB in the EWcp were unaffected by CCI. These results indicate that neuropathic pain does not act via the HPA-axis or the EWcp, but includes a main role of Crf in the limbic system, which is in clear contrast to stressors like acute and chronic pain, which primarily act on the PVN and the EWcp.

The amygdala, a relay station for switching on and off pain

Neuropathic pain is strongly associated with mood disorders like anxiety and depression. Corticotropin-releasing factor (CRF) plays a prominent role in these disorders as it is up-regulated in limbic structures such as the amygdala, upon experimentally induced neuropathy. This review discusses recent literature on the role of CRF in pain processing and highlights the amygdala as a potential hot spot in supraspinal descending pain control. Many studies have demonstrated analgesic effects of CRF following local and systemic administration, but more recently also hyperalgesic effects were shown upon endogenous amygdalar CRF increase or by blocking the CRF type 1 receptor (CRFR1). On the basis of the reviewed literature, we postulate a central mechanism for pain control in which the amygdala plays a critical role by switching on and off chronic pain. In this mechanism, upon pain stimuli, CRFR1 in the amygdala is activated by CRF to induce hyperalgesia. When the activated CRFR1 is internalized (pain initiation), it triggers the translocation of the cytoplasmic CRF type 2 receptor (CRFR2) to the plasma membrane. Here, CRFR2 can be recruited by either high (pharmacological) concentrations of CRF or by endogenous CRFR2 ligands, the urocortins, leading to analgesia (pain termination). This on-off switching of pain is completed by redistribution of the CRF receptors to their initial activity state. We furthermore propose that in neuropathic pain, this mechanism is dysregulated and causes a state of permanent hyperalgesia, and present an integrative (patho)physiological model for the way disturbed CRF receptor signalling in the amygdala could initiate neuropathic pain.

CRF treatment induces a readjustment in glucosensing capacity in the hypothalamus and hindbrain of rainbow trout

Stress conditions induced in rainbow trout a readjustment in the glucosensing response of the hypothalamus and hindbrain such that those sensors did not respond properly to changes in glucose levels, as demonstrated in previous studies. To evaluate the hypothesis that corticotropin-releasing factor (CRF) could be involved in that response, we have incubated the hypothalamus and hindbrain of rainbow trout at different glucose concentrations in the presence of different concentrations of CRF. Under those conditions, we evaluated whether parameters related to glucosensing [the levels of glucose, glycogen and glucose 6-phosphate, the activities of glucokinase (GK), glycogen synthase (GSase) and pyruvate kinase (PK), and mRNA abundance of transcripts for GK, Glut2, Kir.6-like and sulfonylurea receptor (SUR)-like] are modified in the presence of CRF in a way comparable to that observed under stress conditions. We obtained evidence allowing us to suggest that CRF could be involved in the interaction between stress and glucosensing as CRF treatment of the hypothalamus and hindbrain in vitro induced a readjustment in glucosensing parameters similar to that previously observed under stress conditions in vivo. We had also previously demonstrated that stress elicits alterations in food intake in parallel with the readjustment of glucosensing systems. Here, we provide evidence that the mRNA abundance of several of the neuropeptides involved in the regulation of food intake, such as neuropeptide Y (NPY) or cocaine and amphetamine-regulated transcript (CART), is affected by CRF treatment, in such a way that their expression does not respond to changes in glucose levels in the same way as controls, allowing us to suggest that the food intake response that is integrated by changes in those peptides and known to be reduced by stress could be also mediated by CRF action in glucosensing areas.

Corticotropin-releasing factor and urocortin I activate CREB through functionally selective Gβγ signaling in hippocampal pyramidal neurons

Stress is a perceived perturbation in the environment of the organism that affects numerous extrahypothalamic brain regions including the hippocampus, a limbic structure critical for learning, spatial memory and the regulation of stress hormones. Though many effects of stress on the hippocampus are mediated via local glucocorticoid action, there is now ample evidence for the contributions of the stress peptides corticotropin-releasing factor (CRF) and urocortin I (UCN). Thus, understanding the intracellular signaling pathways activated by stress peptides is required to fully understand the mechanisms by which stress influences the hippocampus. Here we elucidate molecular mechanisms by which CRF and UCN induce phosphorylation of the activity-dependent transcription factor CREB, a molecule critical for numerous forms of neuronal plasticity. We report that nanomolar concentrations of both CRF and UCN lead to a rapid, CRF receptor 1 (CRFR1)- and Gβγ-dependent increase in CREB phosphorylation in rat hippocampal pyramidal neurons. Interestingly, CRF- and UCN-induced signaling pathways diverge downstream of Gβγ, with UCN, but not CRF, signaling to CREB via a MEK/MAPK-dependent pathway. These data suggest novel molecular mechanisms by which stress can directly impact hippocampal neurons, as well as highlight an emerging role for Gβγ signaling in mediating the effects of stress peptides in extrahypothalamic stress-responsive brain regions.

Acute ether stress differentially affects corticotropin-releasing factor and urocortin 1 in the Brattleboro rat

Arginine-vasopressin (AVP), corticotropin-releasing factor (CRF) and urocortin 1 (Ucn1) play a role in the stress response. The CRF-producing paraventricular nucleus of the hypothalamus (PVN), oval bed nucleus of the stria terminalis (BSTov) and central amygdala (CeA), and the Ucn1-expressing non-preganglionic Edinger-Westphal nucleus (npEW) all possess AVP receptors. We hypothesized that AVP is involved in the response of these four brain centers to acute physiological (ether) stress. To test this hypothesis, we studied AVP-deficient Brattleboro (BB) rats using quantitative immunocytochemistry. First, we showed that non-stressed wild-type (WT) and BB rats did not differ from each other in Fos contents, indicating similar (immediate early) gene expression activity, but that in BB rats CRF contents were lower in the PVN and higher in the CeA. Second, we found that stress induced Fos response in the PVN, CeA and npEW with strengths different for each center, but similar for BB and WT rats. Finally, no effects of stress on CRF and Ucn1 contents were seen in the WT rat brain, but in BB rats stress increased CRF contents in the PVN, and the CeA revealed more CRF in stressed BB than in WT rats. On the basis of these results we propose that during acute stress AVP interacts with, especially, the PVN and the CeA, to change their rates of biosynthesis and/or release of CRF.

Corticotropin-Releasing Factor, Interleukin-6, Brain-Derived Neurotrophic Factor, Insulin-Like Growth Factor-1, and Substance P in the Cerebrospinal Fluid of Civilians With Posttraumatic Stress Disorder Before and After Treatment With Paroxetine

Posttraumatic stress disorder (PTSD) is associated with altered concentrations of stress-related neurohormones, neurotrophins, and neuropeptides in plasma and serum; however, few studies have examined central alterations of these measures in individuals with PTSD. Furthermore, no study to date has evaluated the effects of successful antidepressant treatment on cerebrospinal fluid (CSF) abnormalities in PTSD. Sixteen medication-free outpatients with chronic PTSD (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria) due to physical and/or sexual abuse or motor vehicle accidents (mean ± SD age = 36 ± 11.4 years, 12 women) and 11 nontraumatized healthy subjects (mean ± SD age = 35.3 ± 13.1 years, 7 women) underwent a lumbar puncture for collection of CSF. Seven PTSD patients had a repeat lumbar puncture 12 weeks later, after successful treatment of PTSD with paroxetine. CSF was analyzed for corticotropin-releasing factor (CRF), interleukin-6 (IL-6), brain-derived neurotrophic factor (BDNF), insulin-like growth factor-1 (IGF-1), and substance P concentrations. The study was conducted between January 2003 and August 2004. Compared to nontraumatized healthy controls, patients with chronic PTSD had similar pretreatment concentrations of CSF CRF, IL-6, BDNF, IGF-1, and substance P. Posttreatment CSF measures did not change significantly in patients whose symptoms remitted with paroxetine. Chronic, moderate PTSD due to civilian trauma, without psychotic symptoms and without significant rates of comorbid depression, alcohol dependence, or substance dependence, is not associated with abnormalities in CSF CRF, IL-6, BDNF, IGF-1, or substance P levels. Despite substantial reduction in PTSD symptoms, antidepressant treatment does not alter normal central concentrations of these neurochemicals, with the possible exception of substance P.

Early-life stress, corticotropin-releasing factor, and serotonin transporter gene: A pilot study

Recent studies have indicated a gene-by-environment interaction between serotonin transporter gene (5-HTTLPR) polymorphism and childhood abuse on depressive symptoms. In addition, persistent elevation of cerebrospinal fluid (CSF) corticotropin-releasing factor (CRF) concentrations following early-life adversity has been posited to underlie the subsequent development of major depression. This pilot study tested the hypothesis that elevations of juvenile CSF CRF concentrations are, in part, determined by an interaction between polymorphisms of the 5-HTTLPR and early-life stress. Nine juvenile male bonnet macaques (Macaca radiata) had been raised under variable foraging demand (VFD) conditions, a nonhuman primate model of early-life stress, whereas nine subjects were normatively raised under LFD (low foraging demand) conditions. Genotyping revealed that four (44.4%) of the VFD-reared monkeys possessed at least one "s" allele whereas five VFD monkeys were of the l/l genotype. Of the nine LFD subjects, two (22%) had the s/l genotype and seven had the l/l genotype. A "juvenile" CSF sample was obtained at approximately 3 years of age. CSF CRF concentrations were elevated specifically in the VFD "s/s" and "s/l" allele group in comparison to each of the remaining three groups, indicating a gene-by-environment (G×E) interaction.

Dopamine receptor mechanisms mediate corticotropin‐releasing factor‐induced long‐term potentiation in the rat amygdala following cocaine withdrawal

Corticotropin-releasing factor (CRF) in the amygdala is involved in stress responses. Moreover, dopaminergic neurotransmission in the brain reward system including the amygdala plays a significant role in the pathology of cocaine addiction. The present study analysed CRF-induced synaptic plasticity, its pharmacological sensitivity and interactions with the dopamine (DA) system in the basolateral to lateral capsula central amygdala (lcCeA) pathway after a 2-week withdrawal from repeated cocaine administration. A physiologically relevant CRF concentration (25 nm) induced long-term potentiation (LTP) that was enhanced after cocaine withdrawal. In saline-treated rats, CRF-induced LTP was mediated through N-methyl-d-aspartate (NMDA) receptors, L-type voltage-gated calcium channels (L-VGCCs) and CRF(1) receptors. However, in cocaine-withdrawn animals, activation of CRF(1) and CRF(2) receptors was found to enhance LTP. This enhanced CRF-induced LTP after cocaine withdrawal was mediated through endogenous activation of both D1- and D2-like receptors. Furthermore, expression of the D1 receptor (D1R) but not the D2R, D3R, D4R or D5R was significantly increased after cocaine withdrawal. CRF(1) but not CRF(2) protein expression was increased, suggesting that elevated levels of these proteins contributed to the enhancement of CRF-induced LTP during cocaine withdrawal. CRF interactions with the DA system in the amygdala may represent a fundamental neurochemical and cellular mechanism linking stress to cocaine-induced neuronal plasticity.

Hypothalamic—Pituitary— Adrenal Axis Dysregulation in Women With Irritable Bowel Syndrome in Response to Acute Physical Stress

Irritable bowel syndrome (IBS) supports the concept of a dysregulated hypothalamic-pituitary-adrenal (HPA) axis. This study investigates the neuroendocrine and psychological responses to the acute physical stress of a lumbar puncture (LP) in women with diarrhea-predominant IBS by assessing central and peripheral HPA activity and affective measures. Blood samples have been collected at baseline and immediately post- and 1 hr following LP from 13 women with IBS and 13 controls. Plasma adrenocorticotropic hormone (ACTH), cortisol, epinephrine, and norepinephrine levels are analyzed. A single measure of cerebrospinal fluid (CSF) concentrations of corticotropin-releasing factor (CRF(CSF)) and norepinephrine(CSF) is noted. Affective assessments are used to rate anxiety and depression with the Hospital Anxiety and Depression Scale (HADS) and acute mood state is rated using the Stress Symptom Rating questionnaire (stress, anxiety, anger, arousal). The women with IBS display blunted ACTH and cortisol responses to the LP along with a profile of affective responsiveness suggestive of chronic psychosocial stress, although no CRF(CSF) differences between groups are observed.

17. Pregnancy-related stress influences maternal corticotropin-releasing factor and estriol concentrations affecting birth outcome

17. Pregnancy-related stress influences maternal corticotropin-releasing factor and estriol concentrations affecting birth outcome