Hypersecretion Of Corticotropin-releasing Hormone Research Articles

White hyacinth bean polysaccharide ameliorates diabetes via microbiota-gut-brain axis in type 2 diabetes mellitus rats

Gut played a potent role in onset and progression of metabolic disorders, presenting an exciting direction for diabetes prevention. Here, the anti-diabetic effects of White hyacinth bean polysaccharides (WHBP) were observed, including the reduction of blood glucose levels and improvement of intestinal impairment in type 2 diabetes mellitus (T2DM) rats. Further data concerning intestinal protection suggested that WHBP restored intestinal barrier, as evidenced by inhibition of intestinal pathological damage, up-regulation of Zonula occluden-1 expression and manipulation of the redox system in T2DM rats. Moreover, WHBP-mediated anti-diabetic effects were in parallel with the adjustment of changes in gut microbiota composition of T2DM rats. Meanwhile, hypersecretion of corticotropin-releasing hormone, adrenocorticotropic hormone, and corticosterone levels, which were critical coordinators of the hypothalamic-pituitary-adrenal (HPA) axis, were suppressed in T2DM rats exposed to WHBP, indicating that WHBP-mediated health benefits were referring to regulate brain feedback in reduction of HPA axis. Concomitantly, further suggested and expanded on gut-brain communication by data of microbial metabolites short-chain fatty acids, mediators of gut-brain interactions, were remarkably raised in cecum contents of T2DM rats subjected to WHBP. Collectively, WHBP performed anti-diabetic effects were associated with control of microbiota-gut-brain axis implicated in intestinal barrier, HPA axis, gut microbiota and their metabolites.

MON-018 Fertility Rates in Rats Characterized by Increased Hypothalamic CRH Secretion

Certain strains of rats are characterized by hyperactive Hypothalamic-Pituitary-Adrenal axis responses to stress, increased hypothalamic Corticotropin-Releasing Hormone (CRH) production and decreased fertility rates. Activation of the HPA-axis and CRH secretion has been associated with suppression of the Hypothalamic-Pituitary-Ovarian axis primarily as a result of glucocorticoids. Here we examined the hypothesis that Fischer rats have decreased fertility rates because of hypothalamic CRH hypersecretion. Antalarmin, a CRH receptor type 1 antagonist, is known to suppress adrenocorticotropin hormone secretion and other CRH receptor type 1-mediated responses. Adult female Fischer rats were injected with antalarmin or placebo, twice a day, for 16 days. Mating was evidenced by the presence of spermatozoa in the vaginal smear performed every morning. After 16 days, 20% of rats (20%) treated with placebo became pregnant and 55% rats treated with antalarmin became pregnant. We have previously reported that administration of antalarmin after the first day of pregnancy does not affect blastocyst implantation in Fischer rats. Our data suggest that antalarmin improves fertility rates in Fischer rats by antagonizing the direct antireproductive role of hypothalamic CRH.

Psychological vulnerability to stress in carriers of congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

Carriers of congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD) demonstrate increased secretion of cortisol precursors following ACTH stimulation, suggestive of impaired cortisol production and compensatory increases in hypothalamic corticotropin-releasing hormone (CRH) secretion. Both cortisol and CRH have behavioral effects, and hypothalamic CRH hypersecretion has been associated with chronic states of anxiety and depression. We performed an endocrinologic and psychological evaluation in carriers of 21-OHD and matched control subjects. We recruited 29 parents of children with classic CAH (14 males, 15 females; age (mean±SD): 41.8±5.7 yr), and hence 21-OHD carriers, and 13 normal subjects (5 males, 8 females; age: 43.8±6.1 yr). All subjects underwent a formal ovine (o) CRH stimulation test with measurement of ACTH, cortisol, 17-hydroxyprogesterone (17-OHP) and androstenedione concentrations, which was preceded by determination of 24-hour urinary free cortisol (UFC) excretion. Psychometric assessment was performed by administering the State-Anxiety (STAI 1) and Trait-Anxiety (STAI 2) Inventory, Beck Depression Inventory, Symptom Checklist-90R and Temperament and Character Inventory. Carriers of 21-OHD had significantly higher 17-OHP concentrations following oCRH stimulation and higher STAI 1 (47.6±5.6 vs. 43.3±5.4, P=0.023) scores than control subjects. Mean 24-hour UFC concentrations were positively correlated with paranoid ideation (r=0.435; P=0.023) and psychoticism (r=0.454; P=0.017). Stepwise multiple linear regression analysis revealed that the single independent predictor of STAI 1 was peak stimulated 17-OHP concentrations (β: 0.055, SE: 0.023, R2: 0.290, P=0.031). Carriers of 21-OHD may be predisposed to the development of anxiety disorders.

When Not Enough Is Too Much: The Role of Insufficient Glucocorticoid Signaling in the Pathophysiology of Stress-Related Disorders

Objective: Previous theories have emphasized the role of excessive glucocorticoid activity in the pathology of chronic stress. Nevertheless, insufficient glucocorticoid signaling (resulting from decreased hormone bioavailability or reduced hormone sensitivity) may have equally devastating effects on bodily function. Such effects may be related in part to the role of glucocorticoids in restraining activation of the immune system and other components of the stress response, including the sympathetic nervous system (SNS) and corticotropin-releasing hormone (CRH). Method: The literature on neuroendocrine function and glucocorticoid-relevant pathologies in stress-related neuropsychiatric disorders, including posttraumatic stress disorder and major depression, was reviewed. Results: Although not occurring together, both hypocortisolism and reduced responsiveness to glucocorticoids (as determined by dexamethasone challenge tests) were reliably found. Stress-related neuropsychitric disorders were also associated with immune system activation/inflammation, high SNS tone, and CRH hypersecretion, which are all consistent with insufficient glucocorticoid-mediated regulation of stress hyperresponsiveness. Finally, antidepressants, a mainstay in the treatment of stress-related disorders, were regularly associated with evidence of enhanced glucocorticoid signaling. Conclusions: Neuroendocrine data provide evidence of insufficient glucocorticoid signaling in stress-related neuropsychiatric disorders. Impaired feedback regulation of relevant stress responses, especially immune activation/inflammation, may, in turn, contribute to stress-related pathology, including alterations in behavior, insulin sensitivity, bone metabolism, and acquired immune responses. From an evolutionary perspective, reduced glucocorticoid signaling, whether achieved at the level of the hormone or its receptor, may foster immune readiness and increase arousal. Emphasis on insufficient glucocorticoid signaling in stress-related pathology encourages development of therapeutic strategies to enhance glucocorticoid signaling pathways. (Reprinted with permission from American Journal of Psychiatry 2003; 160:1554–1565)

Effects of neurosteroids on the human corticotropin-releasing hormone gene

Increased activity of hypothalamic-pituitary-adrenal (HPA) axis and hypersecretion of corticotropin-releasing hormone (CRH) are known to be important factors in pathogenesis of some stress-related diseases. Some neurosteroids exert anxiolytic and antidepressant effects probably by inhibition of HPA axis activity. The aim of our study was to find out if neurosteroids can directly affect human CRH gene transcription. The effect of allopregnanolone (ALLO), allotetrahydrodeoxycorticosterone (THDOC), pregnenolone (PGL), PGL sulfate (PGL-S), dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEA-S) on CRH expression was determined in differentiated Neuro-2A cells stably transfected with plasmid containing a fragment of human CRH promoter (-663 to+124bp) linked to the chloramphenicol acetyltransferase (CAT) reporter gene. It was found that PGL (0.3–30μΜ), ALLO (1–30μΜ) and THDOC (1–30μΜ) present in the culture medium for 5 days in the concentration-dependent manner inhibited CRH-CAT activity. These neurosteroids also inhibited forskolin-stimulated CRH gene transcription with similar potency. In contrast, PGL-S, DHEA and DHEA-S in a concentration from 0.01 to 10μΜ had no effect on basal and forskolin-stimulated CRH activity. Further experiments revealed that wortmannin (an inhibitor of phosphatidylinositol 3-kinase; PI3-K) at concentrations of 0.01 and 0.02μΜ did not change the inhibitory effect of ALLO (3μΜ) and PGL (1μΜ) on CRH gene transcription. Moreover, ALLO (3μΜ) and PGL (1μΜ) present in the culture medium for 5 days did not change the amount of active, phosphorylated form of protein kinase B (PKB, Akt) and extracellular signal-regulated kinase (ERK). The obtained results indicate that PGL, ALLO and THDOC inhibited basal and forskolin-induced CRH gene promoter activity in the differentiated Neuro-2A cells and that these effects did not depend on the activation of PI3-K/Akt and ERK-MAPK pathways.

Congenital Adrenal Hyperplasia: Diagnosis, Evaluation, and Management

1. Zoltan Antal, MD* 2. Ping Zhou, MD† 1. *Fellow 2. †Assistant Professor, Division of Pediatric Endocrinology, Department of Pediatrics, Albert Einstein College of Medicine, Bronx, NY After completing this article, readers should be able to: 1. Describe the pathophysiology of congenital adrenal hyperplasia (CAH). 2. Characterize the signs and symptoms of CAH. 3. Describe the appropriate laboratory evaluation of CAH. 4. Know that CAH can be diagnosed prenatally. 5. Recognize adrenal insufficiency by laboratory and clinical evaluation. 6. Anticipate and plan treatment for both acute adrenal crisis and long-term therapy for a patient who has CAH. 7. Discuss the value of newborn screening for salt-losing CAH in male infants. Congenital adrenal hyperplasia (CAH) refers to a family of inherited disorders of adrenal steroidogenesis. The common functional defect in each disorder is impaired cortisol secretion, resulting in hypersecretion of corticotropin-releasing hormone (CRH) and adrenocorticotropic hormone (ACTH) and consequent hyperplasia of the adrenal glands. More than 90% of cases of CAH are caused by a defect in the enzyme 21-hydroxylase (21-hydroxylase deficiency [21OHD]). Four other enzyme deficiencies in the steroid biosynthesis pathway, along with one cholesterol transport protein defect, account for the remaining cases. Depending on the severity of the enzyme deficiency, 21OHD is defined as classic (severe form) or nonclassic (mild form). Approximately 75% of patients who have the classic form also have salt wasting due to inadequate aldosterone production, further subdividing the classification into classic simple virilizing and classic salt-wasting forms. This review highlights the diagnosis and treatment of 21OHD, with a brief discussion of the other forms of CAH. A Hispanic baby girl is born at term, has a birthweight of 3.1 kg, and has ambiguous genitalia (Fig. 1). During the first week after birth, the baby is clinically stable but demands frequent feeding. On the sixth postnatal day, serum electrolyte measurements are normal. Additional evaluation reveals female internal organs on pelvic ultrasonography and female karyotype. Newborn screening results show 17-hydroxyprogesterone (17-OHP) values of 180 and 679 ng/mL 2 and 5 days …

Conditional corticotropin-releasing hormone overexpression in the mouse forebrain enhances rapid eye movement sleep

Impaired sleep and enhanced stress hormone secretion are the hallmarks of stress-related disorders, including major depression. The central neuropeptide, corticotropin-releasing hormone (CRH), is a key hormone that regulates humoral and behavioral adaptation to stress. Its prolonged hypersecretion is believed to play a key role in the development and course of depressive symptoms, and is associated with sleep impairment. To investigate the specific effects of central CRH overexpression on sleep, we used conditional mouse mutants that overexpress CRH in the entire central nervous system (CRH-COE-Nes) or only in the forebrain, including limbic structures (CRH-COE-Cam). Compared with wild-type or control mice during baseline, both homozygous CRH-COE-Nes and -Cam mice showed constantly increased rapid eye movement (REM) sleep, whereas slightly suppressed non-REM sleep was detected only in CRH-COE-Nes mice during the light period. In response to 6-h sleep deprivation, elevated levels of REM sleep also became evident in heterozygous CRH-COE-Nes and -Cam mice during recovery, which was reversed by treatment with a CRH receptor type 1 (CRHR1) antagonist in heterozygous and homozygous CRH-COE-Nes mice. The peripheral stress hormone levels were not elevated at baseline, and even after sleep deprivation they were indistinguishable across genotypes. As the stress axis was not altered, sleep changes, in particular enhanced REM sleep, occurring in these models are most likely induced by the forebrain CRH through the activation of CRHR1. CRH hypersecretion in the forebrain seems to drive REM sleep, supporting the notion that enhanced REM sleep may serve as biomarker for clinical conditions associated with enhanced CRH secretion.

S62-03 Alcoholism and depression: Recent results on the mutual interaction between alcohol use, stress-axis dysfunction, and affective disorders

Alcohol intake is known to modulate plasma concentrations of neuroendocrine peptides. However, recent results suggest that the endocrine system may not only respond passively to alcohol intake, but that -vice versa- it also actively modulates alcohol intake behaviour. The most coherent body of data concerns the hypothalamo-pituitary-adrenocortical (HPA) axis, with low corticotropin releasing hormone (CRH) being associated with more intense craving and increased probability of relapse after acute detoxification. It is important to bear in mind that dysregulation of the HPA system, as observed in alcohol dependence, is also a feature of anxiety and depression, two conditions which are frequently linked with alcohol dependence and have been reported to be associated with a poor prognosis. In depression, increased secretion of CRH seems to be one crucial mechanism. It has been found as a marker of depressive symptoms, which normalises when depression is successfully treated. Hypersecretion of CRH is associated with a general hyperactivity of the HPA system, notably elevated plasma levels of ACTH and cortisol, a blunted cortisol stress response and a blunted dexamethasone suppression test. In any case, HPA dysregulation, alcohol dependence, and depression are closely interrelated. Exactly which component of this triad is the driving force behind the various neuroendocrine correlates of drinking behaviour is currently unclear, and will need to be elucidated by future research. This will allow for an enlightened choice of potentially therapeutic agents for the treatment of co-morbid anxiety, depression, and alcohol dependence, acting primarily on the HPA system.

Cushing's Syndrome Due to Ectopic CRH Secretion by Adrenal Pheochromocytoma Accompanied by Renal Infarction

Ectopic production of corticotropin-releasing hormone (CRH) by a pheochromocytoma is an infrequent cause of Cushing's syndrome. We report the case of a 43-year-old man with Cushing's syndrome due to a CRH-producing adrenal pheochromocytoma. The patient had clinical and biochemical evidence of hypercortisolism in conjunction with high ACTH levels and non-suppressible serum cortisol levels on low-dose and high-dose dexamethasone suppression testing. In addition to these clinical features of one month's duration, the patient developed symptoms of pheochromocytoma including headache, hypertension that was resistant to conventional therapy and excessive sweating. Biochemical testing confirmed elevated 24-hour urinary catecholamines and metabolites. Abdominal CT revealed a 4.5 x 4 x 3.5 cm mass in the left adrenal gland. He underwent elective left adrenalectomy. Light microscopic and immunochemical studies revealed a pheochromocytoma that contained immunoreactive CRH and was negative for ACTH. Plasma ACTH and dexamethasone supression tests normalized after surgery. This is an unusual case of a CRH-secreting pheochromocytoma. This was complicated by renal infarction, illustrating further the complexity of Cushing's syndrome in a patient with pheochromocytoma caused by CRH hypersecretion.

Identification of molecules potentially involved in mediating the in vivo actions of the corticotropin-releasing hormone receptor 1 antagonist, NBI30775 (R121919)

The neuropeptide corticotropin-releasing hormone (CRH) plays a central role in the regulation of the hypothalamo-pituitary-adrenocortical (HPA) axis. The view that CRH hypersecretion underlies anxiety and mood disorders was recently supported by preclinical and clinical data obtained after application of the CRH receptor (CRH-R1) antagonist NBI30775 (R121919). Despite its therapeutic efficacy, there is only little information about its mechanisms of action on cellular and molecular targets. To identify some of the intracellular substrates mediating the actions of NBI30775 after its acute administration in a stress-independent animal model. Of the different doses of NBI30775 tested (0.5, 1, 5 and 30 mg/kg), the 1-mg/kg dose proved behaviorally active insofar that it reduced anxiety-like behavior in mice under basal conditions. Subsequent analysis of brain tissues revealed NBI30775-induced increases in the nuclear translocation of glucocorticoid receptors (GR) and BAG-1, an upregulation of mRNA transcripts encoding GR, mineralocorticoid receptors (MR) and CRH-R1, and a suppression of the DNA-binding activity of the transcription factor AP-1. These changes were significant at a dose of 1 mg/kg of NBI30775. NBI30775 reduces levels of anxiety in mice (under basal conditions) with a steep dose-response curve. Molecules such as GR, MR, BAG-1 and AP-1 have been identified as some of the drug's intracellular targets; interestingly, changes in these molecules have also been seen in response to conventional antidepressants, showing that structurally and mechanistically unrelated anxiolytic and antidepressant drugs can influence common downstream pathways.

When not enough is too much: the role of insufficient glucocorticoid signaling in the pathophysiology of stress-related disorders.

Previous theories have emphasized the role of excessive glucocorticoid activity in the pathology of chronic stress. Nevertheless, insufficient glucocorticoid signaling (resulting from decreased hormone bioavailability or reduced hormone sensitivity) may have equally devastating effects on bodily function. Such effects may be related in part to the role of glucocorticoids in restraining activation of the immune system and other components of the stress response, including the sympathetic nervous system (SNS) and corticotropin-releasing hormone (CRH). The literature on neuroendocrine function and glucocorticoid-relevant pathologies in stress-related neuropsychiatric disorders, including posttraumatic stress disorder and major depression, was reviewed. Although not occurring together, both hypocortisolism and reduced responsiveness to glucocorticoids (as determined by dexamethasone challenge tests) were reliably found. Stress-related neuropsychiatric disorders were also associated with immune system activation/inflammation, high SNS tone, and CRH hypersecretion, which are all consistent with insufficient glucocorticoid-mediated regulation of stress hyperresponsiveness. Finally, antidepressants, a mainstay in the treatment of stress-related disorders, were regularly associated with evidence of enhanced glucocorticoid signaling. Neuroendocrine data provide evidence of insufficient glucocorticoid signaling in stress-related neuropsychiatric disorders. Impaired feedback regulation of relevant stress responses, especially immune activation/inflammation, may, in turn, contribute to stress-related pathology, including alterations in behavior, insulin sensitivity, bone metabolism, and acquired immune responses. From an evolutionary perspective, reduced glucocorticoid signaling, whether achieved at the level of the hormone or its receptor, may foster immune readiness and increase arousal. Emphasis on insufficient glucocorticoid signaling in stress-related pathology encourages development of therapeutic strategies to enhance glucocorticoid signaling pathways.

The CRH1 receptor antagonist R121919 attenuates stress-elicited sleep disturbances in rats, particularly in those with high innate anxiety

Excessive corticotropin-releasing hormone (CRH) secretion in limbic and prefrontal brain areas has been postulated to underly stress-related clinical conditions. Studies in mice with deleted or pharmacologically compromized CRH type 1 receptors (CRH-R1) point to a key role of the CRH/CRH-R1 signaling cascade as a potential drug target. Therefore, we compared the effect of a selective high affinity CRH-R1 antagonist (R121919) on sleep–wake behavior in two rat lines selectively bred for either high or low innate anxiety. We found that the subcutaneous injection of the solvent of R121919, a citrate buffer solution, transiently increased circulating levels of the stress hormones ACTH and corticosterone and reduced sleep, especially in high-anxiety animals. When R121919 was added to the solvent, hormone levels and sleep patterns returned to baseline and were indistinguishable between the rat lines. This finding is in accord with previous observations from a clinical trial in depressed patients and studies in rats with high innate anxiety that suggested major effects of CRH-R1 antagonism in the presence of a pathological (i.e. CRH hypersecretion) condition only.

HPA axis dysregulation in mice overexpressing corticotropin releasing hormone

Background: Hypersecretion of corticotropin-releasing hormone (CRH) in the brain has been implicated in stress-related human pathologies. We developed a transgenic mouse line overexpressing CRH (CRH-OE) exclusively in neural tissues to assess the effect of long-term CRH overproduction on regulation of the hypothalamic-pituitary-adrenal (HPA) axis. Methods: Male transgenic CRH-OE 2122 mice on a C57BL/6J background were used. Littermate wildtype mice served as control animals. Basal plasma corticotropin and corticosterone concentrations were measured, and adrenal gland weight was determined. A dexamethasone suppression test measured the effects of long-term CRH hypersecretion on negative feedback control. Additionally, we measured plasma corticosterone concentrations in reaction to stress. Results: CRH-OE 2122 mice showed elevated basal plasma corticosterone concentrations, hypertrophy of the adrenal gland, and dexamethasone nonsuppression. Basal plasma ACTH concentrations of wildtype and CRH-OE 2122 mice did not differ significantly. In reaction to stress, CRH-OE 2122 mice showed a normal corticosterone response. Conclusions: The HPA axis abnormalities observed in CRH-OE 2122 mice suggest that long-term hypersecretion of CRH in the brain can be a main cause of HPA axis dysregulation. The alterations in HPA axis regulation are reminiscent of changes reported in major depressive disorder. As such, these CRH -OE 2122 mice may model the neuroendocrine changes observed in major depressive disorder.

Decreased corticotropin-releasing hormone (CRH) concentrations in the cerebrospinal fluid of eucortisolemic suicide attempters

Several lines of evidence suggest a dysregulation of the adrenocortical (HPA) system with hypersecretion of CRH is associated with suicidal behavior. However, controversial results have emerged from the determination of corticotropin-releasing hormone (CRH) concentrations in the lumbar cerbrospinal fluid (CSF) of suicide attempters probably due to methodological differences. We simultaneously measured CRH concentrations in the CSF and in the plasma of 41 psychiatric in-patients with different diagnoses (affective disorder, schizophrenia, personality disorders, adjustment disoder, substance abuse) and eight neurological control subjects. We also measured plasma cortisol concentrations because data from animal experiments suggest that cortisol may influence CSF CRH concentrations. The major finding was that patients who attempted suicide prior to admission had significantly lower CSF CRH concentrations than psychiatric patients without suicidal behavior. CRH concentrations were significantly higher in the CSF than in plasma in both, psychiatric patients and neurological control subjects. There was no significant difference between suicide attempters and patients with acute suicidal ideations. The latter group showed a trend towards lower CSF CRH concentrations compared with the neurological control subjects. Patients with affective disorder alone as well as patients with multiple diagnoses, but not schizophrenic patients, showed significantly lower CSF CRH concentrations than neurological control subjects. Plasma CRH and plasma cortisol concentrations did not differ among diagnostic groups or between suicide attempters vs. non-attempters. Further studies with more homogenous samples, drug-free patients and with simultaneous assessment of various parameters of the HPA system are warranted.

Immunoneutralization of Endogenous Corticotropin Releasing Hormone (CRH) Blocks the Suppression of Luteinizing Hormone (LH) Secretion Induced by Adrenalectomy and Restraint Stress.

Corticotropin releasing-hormone (CRH) is recognized as modulating luteinizing hormone releasing hormone (LH-RH) secretion at the medial preoptic area (MPOA), but the physiological significance of the effects of endogenous CRH on LH-RH secretion at the median eminence (ME) is not clear. To clarify the effects of CRH at ME, we used two animal models (adrenalectomized and restraint stressed rats) for hypersecretion of CRH and examined the effects of iv administration of CRH antiserum on LH secretion. Adrenalectomy for 2 weeks clearly increased plasma concentrations of ACTH and decreased plasma concentrations of LH in adult male rats. The iv injection of CRH antiserum attenuated the increased levels of plasma ACTH and restored the suppressed levels of plasma LH in adrenalectomized rats. In response to restraint stress, plasma concentrations of ACTH and PRL were increased and plasma concentrations of LH were decreased in adult male rats. The iv injection of CRH antiserum blocked the suppression of LH secretion induced by stress, but it did not have any effects on PRL secretion. These results suggest that immunoneutralization of endogenous CRH at the ME increases LH secretion probably mediated by LH-RH release and ME is probably one of the action sites of CRH on LH-RH secretion in addition to MPOA.

Altered neuroimmunoendocrine communication during a condition of chronically increased brain corticotropin-releasing hormone drive.

Presently, it is clear that the brain, immune system, and endocrine system build a complex network of interactions at various levels. Inflammation, which may be regarded as a stressful challenge, initiates apart from immunological, autonomic, and neuroendocrine responses also profound behavioral (e.g., immobility, social disinterest) changes. Key mediators herein are corticotropin-releasing hormone (CRH) and cytokines, such as interleukin-1 beta (IL-1 beta). Currently, the behavioral changes, collectively termed sickness behavior, are thought to be adaptive responses to support the body's efforts to fight the infection. Using in vivo microdialysis and biotelemetry in freely moving animals, we have studied the monoaminergic circuits in the brain implicated in the regulation of physiological and behavioral responses to a peripheral inflammatory challenge (see also chapter of Linthorst and Reul in this volume). To expand our insight into the relationship between hypersecretion of CRH and physiological and behavioral abnormalities associated with stress-related disorders, a series of experiments was conducted with long-term centrally CRH-infused rats. These rats showed reduced body weight gain, decreased food intake, elevated plasma ACTH and corticosterone levels, thymus involution and immunosuppression, but, paradoxically, enhanced IL-1 beta mRNA expression in spleen macrophages. After a peripheral endotoxic challenge on the seventh day of treatment, the CRH-infused rats produced aberrant (i.e., blunted and/or delayed) HPA axis, fever, behavioral, and hippocampal serotonergic responses. However, endotoxin-induced plasma IL-1 and IL-6 bioactivities were significantly enhanced in these animals. The data show that chronically elevated central CRH levels as occurring during chronic stress result in defective central nervous system and immune system responses to an acute (inflammatory) challenge. These observations provide evidence that chronic CRH hypersecretion is an important factor in the etiology of stress-related disorders.

Low cerebrospinal fluid corticotropin-releasing hormone concentrations in eucortisolemic depression

Hypersecretion of corticotropin-releasing hormone (CRH) and resulting hypercortisolism have been implicated in the pathogenesis of major depression. To test this CRH hypersecretion hypothesis, cerebrospinal fluid (CSF) was continuously withdrawn from 11:00 AM to 5:00 PM via an indwelling subarachnoid catheter (placed at 8:00 AM), and immunoreactive CRH concentrations were determined at 10-min intervals in 10 depressed patients, the majority of whom exhibited at least one "atypical" symptom, and in 15 normal volunteers. CSF CRH was low, plasma adrenocorticotropin (ACTH) tended to be low, and plasma cortisol was normal in the depressed patients. Also, tobacco smokers had lower CSF CRH than nonsmokers. CRH increased acutely in response to lumbar puncture, had a brief half-life, showed rapid variability in concentration over time, and displayed a diurnal concentration rhythm that was preserved in fasting individuals and in most depressed patients. CSF CRH did not correlate with plasma ACTH or cortisol; this and its rapidly fluctuating levels suggest a primarily extrahypothalamic origin of lumbar CSF CRH.

Long-Term Intracerebroventricular Infusion of Corticotropin-Releasing Hormone Alters Neuroendocrine, Neurochemical, Autonomic, Behavioral, and Cytokine Responses to a Systemic Inflammatory Challenge

Corticotropin-releasing hormone (CRH) was infused intracerebroventricularly into rats for 7 d via a miniosmotic pump (1 microg . microl-1 . hr-1). Body temperature and locomotor activity were recorded during the treatment using biotelemetry, whereas hippocampal serotonergic neurotransmission and free corticosterone levels were monitored using in vivo microdialysis on day 7 of CRH treatment. During the microdialysis experiment, behavioral activity was scored by assessing the time during which rats were active (locomotion, grooming, eating, drinking). Continuous intracerebroventricular infusion of CRH produced a transient increase in body temperature and locomotion. Moreover, intracerebroventricularly CRH-treated rats showed elevated free corticosterone levels with no apparent diurnal rhythm. Intraperitoneal administration of bacterial endotoxin -lipopolysaccharide (LPS); 100 microg/kg body weight- on day 7 of CRH/vehicle treatment produced a marked fever response in control animals, which was significantly blunted in intracerebroventricularly CRH-treated rats. Although free corticosterone levels reached similar peak concentrations in both intracerebroventricularly vehicle- and CRH-infused groups after LPS, this response was delayed significantly by approximately 1 hr in the intracerebroventricularly CRH-treated animals. Microdialysis experiments showed no changes in basal extracellular levels of serotonin and 5-hydroxyindoleacetic acid in intracerebroventricularly CRH-infused animals. Injection of LPS in intracerebroventricularly CRH-treated rats produced a blunted 5-HT response and a delayed onset of behavioral inhibition and other signs of sickness behavior. Assessment of the endotoxin-induced cytokine responses showed significantly enhanced plasma interleukin-1 (IL-1) and IL-6 bioactivities in the intracerebroventricularly CRH-infused animals 3 hr after injection of LPS, whereas tumor necrosis factor bioactivity responses were not different. Our data demonstrate that chronically elevated brain CRH levels produce marked changes in basal (largely CRH regulated) physiological and behavioral processes accompanied by aberrant responses to an acute challenge. The present study provides evidence that chronic CRH hypersecretion is an important factor in the etiology of stress-related disorders.

In vivo and in vitro characterization of antalarmin, a nonpeptide corticotropin-releasing hormone (CRH) receptor antagonist: suppression of pituitary ACTH release and peripheral inflammation.

Corticotropin-releasing hormone (CRH) secreted from the hypothalamus is the major regulator of pituitary ACTH release and consequent glucocorticoid secretion. CRH secreted in the periphery also acts as a proinflammatory modulator. CRH receptors (CRH-R1, R2alpha, R2beta) exhibit a specific tissue distribution. Antalarmin, a novel pyrrolopyrimidine compound, displaced 12SI-oCRH binding in rat pituitary, frontal cortex and cerebellum, but not heart, consistent with antagonism at the CRHR1 receptor. In vivo antalarmnin (20 mg/kg body wt.) significantly inhibited CRH-stimulated ACTH release and carageenin-induced subcutaneous inflammation in rats. Antalarmin, or its analogs, hold therapeutic promise in disorders with putative CRH hypersecretion, such as melancholic depression and inflammatory disorders.

Corticotropin, Cortisol and β‐endorphin responses to the human corticotropin‐releasing hormone during melancholia and after unilateral electroconvulsive therapy

Previous research in neuroendocrinology has evidenced that hyperactivity of the hypothalamic-pituitary-adrenal axis (HPA) depends on hypersecretion of corticotropin-releasing hormone (CRH). The aim of this study was to investigate the activity of HPA before and after recovery in depressed patients treated with electroconvulsive therapy (ECT). An h-CRH-stimulation test was performed on 2 occasions with examination of the HPA axis before ECT treatment during episodes of major depressive disorders with melancholia, and during the recovery phase after treatment. The results showed that patients during depression had significantly higher plasma levels of cortisol at 15 and 30 min after h-CRH-administration than after recovery. Depressed patients had significantly higher plasma levels of beta-endorphin 30 min after h-CRH-stimulation. The results are in agreement with previous studies, which have shown hypercortisolemia during depression. A possible hypersecretion of CRH may explain the effect on cortisol and beta-endorphin. No significant differences were found between cumulative responses of corticotropin, cortisol and beta-endorphin, calculated as the areas under the concentration curves.