Central Corticotropin-releasing Hormone Research Articles

Electroacupuncture in the treatment of IBS in rats: Investigation of the mechanisms of CRH+ neurons in the paraventricular nucleus.

Electroacupuncture (EA) is well documented to treat irritable bowel syndrome (IBS). However, the mechanism of the central nervous system related to IBS and acupuncture stimulation is still not well known. In this study, a rat model of IBS was established by cold-restraint comprehensive stresses for 15 days, and it was found that the levels of corticotropin-releasing hormone (CRH), corticosterone (CORT), and adrenocorticotropic hormone (ACTH) in the peripheral serum were increased; the visceral sensitivity was enhanced; and the intestinal motility was accelerated, specifically, there was an enhancement in the discharge frequency of neurons in the paraventricular nucleus (PVN). EA treatment for 3 days, 20 min/day, alleviated the increase in the levels of CRH, CORT, and ACTH in the peripheral serum of rats, reduced the visceral sensitivity of IBS rats, and inhibited colon movement and discharge frequency of the neurons in the PVN. Additionally, EA could reduce the excitability of CRH neurons and the expression of CRHR1 and CRHR2 in PVN. At the same time, the expression of CRH, CRHR1, and CRHR2 in the peripheral colon was decreased. Taken together, EA appears to regulate intestinal functional activity through the central CRH nervous system, revealing the central regulation mechanism of EA in IBS rats, and providing a scientific research basis for the correlation among the meridians, viscera, and brain.

Electroacupuncture intervention on stress-induced cardiac autonomic imbalance in rats involves corticotropin-releasing hormone system activity.

Autonomic imbalance is a core aspect of stress response that strongly correlates to cardiovascular diseases. Enhanced activity of the central corticotropin-releasing hormone (CRH) system may result in autonomic imbalance to cause cardiovascular responses in a stress state. Electroacupuncture at PC6 acupoints has been demonstrated to prevent and treat cardiovascular diseases. In this study, we aim to demonstrate the protective role of electroacupuncture at PC6 in ameliorating cardiac autonomic imbalance and investigate the underlying mechanisms in immobilization stress rats. Four groups were subjected. Immobilization stress was applied to three groups. And the rats in two electroacupuncture-intervened groups exerted electroacupuncture at PC6 or tail respectively. Then, we performed ECG recording for heart rate variability (HRV) analysis, and rats were sacrificed after experiments for biological analysis. HRV analysis indicated that electroacupuncture at PC6 improved the enhanced low-frequency band of the power spectrum (LF), the reduced high-frequency band of the power spectrum (HF), and the enhanced LF/HF ratio caused by immobilization stress. Besides, electroacupuncture at PC6 significantly decreased phosphorylated tyrosine hydroxylase expression and increased acetylcholine esterase expression in heart of immobilization stress rats. Furthermore, electroacupuncture at PC6 significantly decreased CRH level and CRH 1 type receptor and CRH 2 type receptor (CRHR2) expressions in the rostral ventrolateral medulla (RVLM), and CRH level and CRHR2 expression in the nucleus of the solitary tract (NTS) of immobilization stress rats. Our findings suggest that electroacupuncture at PC6 can ameliorate stress-induced cardiac autonomic imbalance by modulating the CRHergic input in the RVLM and NTS.

Different oxytocin and corticotropin-releasing hormone system changes in bipolar disorder and major depressive disorder patients.

SummaryBackgroundOxytocin (OXT) and corticotropin-releasing hormone (CRH) are both produced in hypothalamic paraventricular nucleus (PVN). Central CRH may cause depression-like symptoms, while peripheral higher OXT plasma levels were proposed to be a trait marker for bipolar disorder (BD). We aimed to investigate differential OXT and CRH expression in the PVN and their receptors in prefrontal cortex of major depressive disorder (MDD) and BD patients. In addition, we investigated mood-related changes by stimulating PVN-OXT in mice.MethodsQuantitative immunocytochemistry and in situ hybridization were performed in the PVN for OXT and CRH on 6 BD and 6 BD-controls, 9 MDD and 9 MDD-controls. mRNA expressions of their receptors (OXTR, CRHR1 and CRHR2) were determined in anterior cingulate cortex and dorsolateral prefrontal cortex (DLPFC) of 30 BD and 34 BD-controls, and 24 MDD and 12 MDD-controls. PVN of 41 OXT-cre mice was short- or long-term activated by chemogenetics, and mood-related behavior was compared with 26 controls.FindingsSignificantly increased OXT-immunoreactivity (ir), OXT-mRNA in PVN and increased OXTR-mRNA in DLPFC, together with increased ratios of OXT-ir/CRH-ir and OXTR-mRNA/CRHR-mRNA were observed in BD, at least in male BD patients, but not in MDD patients. PVN-OXT stimulation induced depression-like behaviors in male mice, and mixed depression/mania-like behaviors in female mice in a time-dependent way.InterpretationIncreased PVN-OXT and DLPFC-OXTR expression are characteristic for BD, at least for male BD patients. Stimulation of PVN-OXT neurons induced mood changes in mice, in a pattern different from BD.Funding10.13039/501100001809National Natural Science Foundation of China (81971268, 82101592).

Chapter 9 - The hypothalamus in anxiety disorders

Of all mental disorders, anxiety disorders are currently the strongest contributors to the global burden of disease, with 7.3% of the general population affected worldwide. The hypothalamus is crucial hub of a network of neural structures modulating fear conditioning and extinction and, as such, highly relevant to the pathophysiology of these conditions. Three hypothalamic systems have emerged as particularly relevant in this context. First, the oxytocin system is highly likely to be involved anxiety disorders and in particular in the cognitive and behavioral deficits pertaining to social anxiety disorder. Second, peripheral markers of the hypothalamic-pituitary-adrenal axis appear altered in patients with panic disorder and generalized anxiety disorder, which may denote aberrant functioning of their central corticotropin-releasing hormone system. Furthermore, cortisol seems to augment the effects of exposure therapy in patients with specific phobia. Third, the integrity of the hypothalamic-pituitary-thyroid axis is likely compromised in panic disorder. Further, cross-disciplinary research efforts are required to shed more light on how, exactly, these hypothalamic systems interact with the neural structures involved in fear conditioning and extinction, which should ultimately open up new avenues for the prevention and treatment of anxiety disorders.

Brain corticotropin releasing hormone and stress reactivity

The hypothalamic-pituitary-adrenocortical axis is one of the main components of stress adaptation. Corticotropin-releasing hormone (CRH) coming from the nucleus paraventricularis hypothalami (PVN) is the canonical central regulator of the axis. This CRH acts on the CRH-R1 receptors of the pituitary, and, through adrenocorticotropin, stimulates glucocorticoid release from the adrenal cortex. However, it may be synthetized in other parts of the brain as well, and may act both on CRH-R1 and CRH-R2 receptors. These areas form the central CRH network. Many of them are also stress reactive and participate in physical and psychological stress response. The central nucleus of the amygdala and bed nucleus of stria terminalis are two areas best known for their role in emotions, while hippocampus is mostly involved in glucocorticoid feedback as well as memory formation, all heavily connected to stress adaptation. Among others, the brainstem raphe nuclei get dense CRHergic innervation that, through CRH-R1 receptors, may influence the serotoninergic tone of the brain. Both stress and serotonin are strongly implicated in depression, therefore, it is not surprising that CRH-R1 antagonists were developed as therapeutic tools that extensively act on the brain CRH system. Our review suggests a general role of brain CRH network in stress adaptation which is not restricted to PVN.

Intracerebroventricularly injected nesfatin-1 activates central cyclooxygenase and lipoxygenase pathways.

Nesfatin-1 is a multifunctional neuropeptide having crucial autonomic roles. It is well known that nesfatin-1 collaborates with other central neuromodulatory systems, such as central corticotropin-releasing hormone, melanocortin, oxytocin, and cholinergic systems to show its autonomic effects. Central arachidonic acid cascade plays an important role to provide the homeostasis by exhibiting similar autonomic effects to nesfatin-1. Based on these similarities, the current study was designed to show the effects of intracerebroventricularly (ICV) injected nesfatin-1 on the hypothalamic arachidonic acid (AA) cascade. Immunochemistry and western blot approaches demonstrated that ICV administration of nesfatin-1 provokes an increase in the hypothalamic cyclooxygenase (COX) -1, -2 and lipoxygenase (LOX) protein expression. Moreover, the microdialysis study demonstrated that centrally injected nesfatin-1 increased the posterior hypothalamic extracellular AA products. In conclusion, these findings report that while nesfatin-1 is generating its autonomic effects, it also might be using central prostaglandins and leukotrienes by activating central COX and LOX pathways.

Involvement of orexinergic system in psychiatric and neurodegenerative disorders: A scoping review.

Orexin is a neuropeptide secreted from lateral hypothalamus and pre-frontal cortex concerned in the wakefulness and excitement. This study aimed to review the possible neurobiological effect of orexin. A diversity of search strategies was adopted and assumed which included electronic database searches of Medline and PubMed using MeSH terms, keywords, and title words during the search. Orexin plays a vital role in activation of learning, memory acquisition, and consolidation through activation of monoaminergic system, which affect cognitive flexibility and cognitive function. Orexin stimulates adrenocorticotropin and corticosteroid secretions via activation of central corticotropin-releasing hormone. Cerebrospinal fluid (CSF) and serum orexin serum levels are reduced in depression, schizophrenia, and narcolepsy. However, high orexin serum levels are revealed in drug addictions. Regarding neurodegenerative brain diseases, CSF and serum orexin serum levels are reduced Parkinson disease, Alzheimer dementia, Huntington's disease, amyotrphic lateral sclerosis, and multiple sclerosis. Orexin antagonist leads to significant reduction of sympathetic over-activity during withdrawal syndrome. As well, orexin antagonist improves sleep pattern. Orexinergic system is involved in the different psychiatric and neurological disorders; therefore, targeting of this system could be possible novel pathway in the management of these disorders. In addition, measurement of CSF and serum orexin levels might predict the relapse and withdrawal of addict patients.

Coupling corticotropin-releasing-hormone and angiotensin converting enzyme 2 dampens stress responsiveness in male mice

This study used mice to evaluate whether coupling expression of corticotropin-releasing hormone (CRH) and angiotensin converting enzyme 2 (ACE2) creates central interactions that blunt endocrine and behavioral responses to psychogenic stress. Central administration of diminazene aceturate, an ACE2 activator, had no effect on restraint-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis; however, mice that ubiquitously overexpress ACE2 had reduced plasma corticosterone (CORT) and pituitary expression of POMC mRNA. The Cre-LoxP system was used to restrict ACE2 overexpression to CRH synthesizing cells and probe whether HPA axis suppression was the result of central ACE2 and CRH interactions. Within the paraventricular nucleus of the hypothalamus (PVN), mice with ACE2 overexpression directed to CRH had a ≈2.5 fold increase in ACE2 mRNA, which co-localized with CRH mRNA. Relative to controls, mice overexpressing ACE2 in CRH cells had a decreased CORT response to restraint as well as decreased CRH mRNA in the PVN and CEA and POMC mRNA in the pituitary. Administration of ACTH similarly increased plasma CORT, indicating that the blunted HPA axis activation that accompanies ACE2 overexpression in CRH cells is centrally mediated. Anxiety-like behavior was assessed to determine whether the decreased HPA axis activation was predictive of anxiolysis. Mice with ACE2 overexpression directed to CRH cells displayed decreased anxiety-like behavior in the elevated plus maze and open field when compared to that of controls. Collectively, these results suggest that exogenous ACE2 suppresses CRH synthesis, which alters the central processing of psychogenic stress, thereby blunting HPA axis activation and attenuating anxiety-like behavior.

Role of Central and Peripheral CRH in Skin.

Hypothalamic corticotrophin-releasing hormone (CRH) has a key role in coordinating and controlling complex responses to stress, both systemically, by stimulating the expression of the pituitary POMC gene, and thus, resulting in increased production of ACTH and adrenal glucocorticoid release, and locally since CRH has been identified in several peripheral tissues. CRH seems to exert its effects through interaction with two known so far receptors, CRF1R and CRF2R. The mRNA and protein of CRH family of peptides and their receptors are expressed at several peripheral tissues including rodent and human skin. In addition to CRH, skin expresses POMC and its products, including ACTH while recent studies have shown the presence of glucocorticoids also in skin. This review aims to summarize the role of CRH in the physiology and pathophysiology of human and rodent skin. It is clear that a) locally produced CRH is involved in the inflammatory process, b) CRH has been shown to stimulate angiogenesis in vivo and chemotaxis of endothelial cells in vitro, and c) CRH mRNA and peptide have been identified in skin. Based on the above we hypothesize that CRH plays a crucial role in several inflammatory pathologies of the skin as well as in cutaneous wound healing, which are all discussed in the present review.

GH response to intravenous clonidine challenge correlates with history of childhood trauma in personality disorder

BackgroundChildhood trauma is a risk factor for personality disorder. We have previously shown that childhood trauma is associated with increased central corticotrophin-releasing hormone concentration in adults with personality disorder. In the brain, the release of corticotrophin-releasing hormone can be stimulated by noradrenergic neuronal activity, raising the possibility that childhood trauma may affect the hypothalamic-pituitary adrenal (HPA) axis by altering brain noradrenergic function. In this study, we sought to test the hypothesis that childhood trauma is associated with blunted growth hormone response to the α-2 adrenergic autoreceptor agonist clonidine. MethodsAll subjects provided written informed consent. Twenty personality disordered and twenty healthy controls (without personality disorder or Axis I psychopathology) underwent challenge with clonidine, while plasma Growth Hormone (GH) concentration was monitored by intravenous catheter. On a different study session, subjects completed the Childhood Trauma Questionnaire and underwent diagnostic interviews. ResultsContrary to our a priori hypothesis, childhood trauma was associated with enhanced GH response to clonidine. This positive relationship was present in the group of 40 subjects and in the subgroup 20 personality disordered subjects, but was not detected in the healthy control subjects when analyzed separately. The presence of personality disorder was unrelated to the magnitude of GH response. DiscussionChildhood trauma is positively correlated with GH response to clonidine challenge in adults with personality disorder. Enhanced rather that blunted GH response differentiates childhood trauma from previously identified negative predictors of GH response, such as anxiety or mood disorder.

Effect of a high-fat–high-fructose diet, stress and cinnamon on central expression of genes related to immune system, hypothalamic–pituitary–adrenocortical axis function and cerebral plasticity in rats

The intake of a high-fat/high-fructose (HF/HFr) diet is described to be deleterious to cognitive performances, possibly via the induction of inflammatory factors. An excess of glucocorticoids is also known to exert negative effects on cerebral plasticity. In the present study, we assessed the effects of an unbalanced diet on circulating and central markers of inflammation and glucocorticoid activity, as well as their reversal by dietary cinnamon (CN) supplementation. A group of male Wistar rats were subjected to an immune challenge with acute lipopolysaccharide under a HF/HFr or a standard diet. Another group of Wistar rats were fed either a HF/HFr or a control diet for 12 weeks, with or without CN supplementation, and with or without restraint stress (Str) application before being killed. We evaluated the effects of such regimens on inflammation parameters in the periphery and brain and on the expression of actors of brain plasticity. To assess hypothalamic-pituitary-adrenocortical axis activity, we measured the plasma concentrations of corticosterone and the expression of central corticotrophin-releasing hormone, mineralocorticoid receptor, glucocorticoid receptor and 11β-hydroxysteroid dehydrogenase. We found that the HF/HFr diet induced the expression of cytokines in the brain, but only after an immune challenge. Furthermore, we observed the negative effects of Str on the plasma concentrations of corticosterone and neuroplasticity markers in rats fed the control diet but not in those fed the HF/HFr diet. Additionally, we found that CN supplementation exerted beneficial effects under the control diet, but that its effects were blunted or even reversed under the HF/HFr diet. CN supplementation could be beneficial under a standard diet. [corrected].

Altered colonic function and microbiota profile in a mouse model of chronic depression

Background Depression often coexists with the irritable bowel syndrome (IBS) which is characterized by alterations in gut function. There is emerging evidence that the microbial composition (microbiota) of the gut is altered in IBS, but the basis for this is poorly understood. The aim of this study was to determine whether the induction of chronic depression results in changes in the colonic function and in its microbial community, and to explore underlying mechanisms.Methods Bilateral olfactory bulbectomy (OBx) was used to induce depression-like behavior in mice. Colonic function was assessed by measuring muscle contractility, pellet excretion, c-fos activity, and serotonin levels. Microbiota profiles were obtained using denaturing gradient gel electrophoresis (DGGE). The hypothalamic-pituitary axis (HPA) was assessed by the hypothalamic expression of corticotropin-releasing hormone (CRH). In separate studies, mice without OBx received CRH via intracerebroventricular (ICV) infusion for 4 weeks prior to assessing colonic function and microbiota profiles.Key Results Olfactory bulbectomy mice demonstrated chronic depression- and anxiety-like behaviors associated with elevated central CRH expression and increases in c-Fos activity, serotonin levels, and motility in the colon. These changes were accompanied by an altered intestinal microbial profile. Central CRH administration produced similar changes in behavior and motility and altered the microbiota profile in the colon.Conclusions & Inferences The induction of chronic depression alters motor activity and the microbial profile in the colon likely via activation of the HPA. These findings provide a basis for linking the behavioral and gastrointestinal manifestations of IBS.

Effects of Gold Thioglucose Treatment on Central Corticotrophin‐Releasing Hormone Systems in Mice

Systemic administration of gold thioglucose (GTG) causes a hypothalamic lesion that extends from the ventral part of the ventromedial hypothalamus (VMH) to the dorsal part of the arcuate nucleus (ARC), resulting in hyperphagia and obesity in mice. In the present study, we used in situ hybridisation histochemistry to explore the effects of GTG on the central corticotrophin-releasing hormone (CRH) system, which regulates feeding and energy homeostasis. Type 2 CRH receptor (CRHR-2) mRNA expression decreased by 40% at 8 weeks in the VMH and by 40-60% at 2 and 8 weeks in the ARC after GTG injection. By contrast, CRHR-2 mRNA expression in the hypothalamic paraventricular nucleus (PVN) and lateral septum was unchanged. Urocortin (Ucn) 3 mRNA expression in the perifornical area and medial amygdala decreased, whereas CRH mRNA expression in the PVN increased at 2 and 8 weeks after GTG injection. Ucn 1 mRNA expression in the Edingher-Westphal nucleus and Ucn 2 mRNA expression in the PVN were unchanged. Because Ucn 3 is an anorexigenic and a possible endogenous ligand for VMH CRHR-2, our results suggest that decreased Ucn 3 expression and decreased VMH CRHR-2 expression contribute, in part, to GTG-induced hyperphagia and obesity. To determine whether VMH CRHR-2 mediates the anorexigenic effects of Ucn 3, Ucn 3 was administered i.c.v. and food intake was measured 8 weeks after GTG treatment. Ucn 3 decreased cumulative food intake on days 4-7 after surgery compared to i.c.v. administration of vehicle in control mice. By contrast, the anorexigenic effects of i.c.v. Ucn 3 were abolished in GTG-treated mice. Taken together, our results indicate that the Ucn 3 pathway, which innervates the VMH, is involved in appetite regulation via CRHR-2. It remains to be determined whether CRHR-2 in the ARC has additional roles in appetite regulation by Ucn 3.

An integrated map of corticotropin‐releasing hormone signaling pathway

An integrated map of corticotropin‐releasing hormone signaling pathway

Feeding response following central administration of chicken vasoactive intestinal peptide in chicks

Vasoactive intestinal peptide (VIP) is expressed in central nervous systems and peripheral tissues across lower and higher vertebrates and is involved in many physiological functions. One of these functions is appetite regulation; however the mechanisms mediating this response are poorly understood. Therefore, the purpose of this study was to investigate central mechanisms of VIP induction of satiety using chicks as models. Intracerebroventricular (ICV) injection of VIP (0.1 and 0.5nmol) significantly decreased food intake under both ad libitum and food deprivation conditions and chicken VIP (cVIP) was more potent than mammalian VIP. The mechanisms involved with the VIP-induced anorexigenic effect were investigated by studying the involvement of the central corticotrophin-releasing hormone (CRH) systems. ICV injection of cVIP caused increased plasma corticosterone concentration and decreased diencephalic mRNA expression of CRH, CRH receptor-2 (CRH-R2) and urocortin 3 (UCN-3, which has high affinity for CRH-R2). This simultaneous decrease in the expression of ligands and their receptor, with the increase in plasma corticosterone concentration suggests that the anorexigenic effect of cVIP might be related to CRH systems. The cVIP-induced anorexigenic effect was partly attenuated by co-injection of astressin, a CRH-R2 antagonist, supporting this thesis. The present study demonstrated that VIP inhibits feeding behavior via CRH systems in the brain of chicks.

Early‐life stress‐induced anxiety‐related behavior in adult mice partially requires forebrain corticotropin‐releasing hormone receptor 1

Early-life stress may lead to persistent changes in central corticotropin-releasing hormone (CRH) and the CRH receptor 1 (CRHR1) system that modulates anxiety-related behavior. However, it remains unknown whether CRH-CRHR1 signaling is involved in early-life stress-induced anxiety-related behavior in adult animals. In the present study, we used conditional forebrain CRHR1 knockout (CRHR1-CKO) mice and examined the potential role of forebrain CRHR1 in the anxiogenic effects of early-life stress. As adults, wild-type mice that received unstable maternal care during the first postnatal week showed reduced body weight gain and increased anxiety levels in the open field test, which were prevented in stressed CRHR1-CKO mice. In the light-dark box test, control CRHR1-CKO mice were less anxious, but early-life stress increased anxiety levels in both wild-type and CRHR1-CKO mice. In the elevated plus maze test, early-life stress had only subtle effects on anxiety-related behavior. Moreover, early-life stress did not alter the basal home cage activity and gene expression levels of key hypothalamic-pituitary-adrenal axis regulators in adult wild-type and CRHR1-CKO mice, but enhanced neuroendocrine reactivity to acute immobilization stress in CRHR1-CKO mice. Our findings highlight the importance of forebrain CRHR1 in modulating some of the anxiogenic effects of early-life stress, and suggest that other neural circuits are also involved in the programming effects of early-life stress on anxiety-related behavior.

Assessing Behavioural Effects of Chronic HPA Axis Activation Using Conditional CRH-Overexpressing Mice

The corticotropin-releasing hormone (CRH) and its cognate receptors have been implicated in the pathophysiology of stress-related disorders. Hypersecretion of central CRH and elevated glucocorticoid levels, as a consequence of impaired feedback control, have been shown to accompany mood and anxiety disorders. However, a clear discrimination of direct effects of centrally hypersecreted CRH from those resulting from HPA axis activation has been difficult. Applying a conditional strategy, we have generated two conditional CRH-overexpressing mouse lines: CRH-COE ( Del ) mice overexpress CRH throughout the body, while CRH-COE ( APit ) mice selectively overexpress CRH in the anterior and intermediate lobe of the pituitary. Both mouse lines show increased basal plasma corticosterone levels and consequently develop signs of Cushing's syndrome. However, while mice ubiquitously overexpressing CRH exhibited increased anxiety-related behaviour, overexpression of CRH in the pituitary did not produce alterations in emotional behaviour. These results suggest that chronic hypercorticosteroidism alone is not sufficient to alter anxiety-related behaviour but rather that central CRH hyperdrive on its own or in combination with elevated glucocorticoids is responsible for the increase in anxiety-related behaviour. In conclusion, the generated mouse lines represent valuable animal models to study the consequences of chronic CRH overproduction and HPA axis activation.

Brain Melanocortin Receptors are Involved In CRH-Mediated HPA Axis Activity And Thermogenesis

Recent studies indicate that corticotropin-releasing hormone (CRH) acts down-stream from brain melanocortin receptors (MC-Rs), however, much older evidence actually suggested the opposite. To reconcile this, rats were chroni- cally infused centrally with the MC-R antagonist SHU9119 (0.5 nmol/day) over 14 days. Acute central CRH administra- tion (0.5 μg) caused temporal anorexia, which was not impaired by SHU9119 treatment relative to controls. SHU9119 treatment, however, did attenuate CRH-induced plasma ACTH and thermogenic responses. Since SHU9119 pair-fed rats showed generally similar effects as SHU9119-treated ad libitum feeding rats, the modulation of ACTH and thermogenic responses are not secondary to increased body weight by SHU9119 treatment. Central pre-treatment with the glucocorti- coid receptor agonist dexamethasone (10 μg) before CRH demonstrated that the inhibitory effect of SHU9119 treatment on the CRH-induced ACTH response was not attributed to increased glucocorticoid feedback. Peripheral dexamethasone pre-treatment (25 μg/kg rat), on the other hand, more potently suppressed CRH-induced corticosterone responses in SHU9119-treated rats. This effect is explained by sensitization of the adrenal cortex to glucocorticoid feedback as a result of SHU9119 treatment. We conclude that MC-Rs act down-stream from CRH to facilitate CRH-induced HPA axis activa- tion and thermogenesis, but not down-stream from CRH to facilitate anorexia.

Effect of oxytocin, prolactin-releasing peptide, or corticotropin-releasing hormone on feeding behavior in steers

As a preliminary step to elucidate the involvement of central neurotransmitters in the dip in voluntary feed intake during the perinatal period in cows, we investigated the effect of intracerebroventricular (ICV) administration of oxytocin, prolactin-releasing peptide (PrRP), or corticotropin-releasing hormone (CRH), the central functions of all of which undergo drastic changes during the perinatal period, on feed intake in steers. Thirty minutes before the onset of feeding, the treatment solution was injected into the third ventricle through an implanted cannula, and feeding-related behaviors were observed for 1 h after the onset of feeding. Neither ICV oxytocin (5 and 50 μg) nor PrRP (2 and 20 nmol) reduced feed intake ( n = 6). Twenty nanomoles of bovine CRH noticeably inhibited feeding behavior compared with vehicle treatment ( n = 5, p < 0.05). Fifty micrograms of oxytocin reduced latency to the first water access after feeding onset ( p < 0.1), which may be because of the stimulation of arginine vasopressin V1b receptor by the high dose of oxytocin. We conclude that CRH inhibits feeding behavior by its central action in this species, although this could also be an indirect effect due to the increased expression of abnormal behaviors caused by CRH. Central administration of neither oxytocin nor PrRP reduced feed intake in steers. Although the effects of sex steroids need to be examined, it appears that increased activity of oxytocin, and possibly PrRP, during the perinatal period does not contribute to the dip in voluntary feed intake in this species. On the other hand, it makes sense that suppressed central CRH activity during the perinatal period should act in the direction of maintaining or even increasing food intake to aid a steady supply of energy to the fetus or offspring. We thus speculate that CRH is not a prime candidate involved in the dip in voluntary feed intake during the perinatal period in cows.

The neuroendocrinology of childhood trauma in personality disorder

Childhood trauma has been associated with elevated central corticotropin releasing hormone (CRH) drive in adults meeting general DSM-IV criteria for personality disorder. It is not clear how this may be related to pituitary or adrenal responsiveness in personality disorder. It was hypothesized that high levels of childhood trauma would be associated with blunted cortisol and adrenocorticotropin releasing hormone (ACTH) response to the combined dexamethasone(DEX)/CRH test in adults meeting general DSM-IV criteria for personality disorder. 24 healthy, medication free adults with personality disorder (N=16) and a group of healthy controls (N=8) underwent semi-structured diagnostic interviews and completed the Childhood Trauma Questionnaire (CTQ). Across two separate study sessions separated by at least a week, cerebrospinal fluid (CSF) was sampled by lumbar puncture for measurement of CRH concentration (N=17), and peripheral blood cortisol and ACTH levels were measured after challenge with DEX/CRH (N=24). As hypothesized, high CTQ score was associated with a blunted cortisol and ACTH response to DEX/CRH challenge. Indices of cortisol and ACTH response (peak level and area under the curve (AUC)) to DEX/CRH were in turn significantly negatively correlated with CSF CRH concentration. Childhood trauma in adults with personality disorder is associated with blunted cortisol and ACTH secretion following DEX/CRH challenge. These effects are independent of depression or posttraumatic stress disorder. Previous work would suggest that blunted pituitary-adrenal response is related to elevated central CRH drive. Corroborating this, CSF CRH levels were significantly and negatively correlated with peak level and AUC of both cortisol and ACTH.