Central Corticotropin-releasing Hormone System Research Articles

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.

The effect of treatment with ketoconazole on central CRH systems of depressed patients

Steroid-synthesis inhibitors are reported to reduce psychopathology in treatment-resistant depressed patients. We studied the effect of a 3-week treatment with ketoconazole on the evening plasma concentrations of cortisol, corticosteroid-binding globulin (CBG), dehydroepiandrosterone-sulfate (DHEA-S) and adrenocorticotrope hormone (ACTH) as well as morning cerebrospinal fluid (CSF) concentrations of cortisol, corticotropin-releasing hormone (CRH) and arginine-vasopressin (AVP) in six elderly treatment-resistant depressed patients. While we found plasma cortisol concentrations to be unchanged, a decline in plasma DHEA-S concentrations indicated effective steroid-synthesis inhibition. In morning CSF we found CRH concentrations that did not change. Our preliminary observations indicate that the treatment of depressed patients with the steroid-synthesis inhibitor ketoconazole does not lead to a major increase in CSF CRH secretion.

Glucocorticoid inhibition in the treatment of depression: can we think outside the endocrine hypothalamus?

Major depressive disorder affects a substantial percentage of the U.S. population, and can be highly debilitating. Selective serotonin reuptake inhibitors are commonly prescribed to treat depression, but may not be as effective for more severe or persistent depression. The authors review data concerning the effects of corticosteroid synthesis inhibitors (CSIs) in the management of depressive disorders, present a hypothesis as to their possible mechanisms of action based on recent data suggesting synergistic effects of glucocorticoids on extrahypothalamic corticotropin-releasing hormone (CRH), and consider alternative hypotheses. Published reports evaluating the efficacy of CSIs in treating depression are reviewed and presented in light of recent findings regarding actions of glucocorticoids on the central CRH system. Results from open label and double-blind studies by several groups have indicated that CSIs may be efficacious or of adjunctive value in some patients with depression, including those refractory to other agents; however, there is a need for more controlled studies. Several lines of data suggest that the mechanism of action of these agents may not be solely a function of inhibition of adrenal cortisol production. The authors propose that CSIs may be efficacious in part by reducing glucocorticoid enhancement of CRH action in neurons of the central nucleus of the amygdala and other structures outside the endocrine hypothalamus. Possible effects of systemically administered CSIs on glucocorticoid receptor regulation, neuroactive steroids, and classical monoamine systems are also discussed. We conclude that available clinical data suggest a potential role for CSIs in the management of depressive disorders, especially major depression with psychotic features.

Conditional mouse mutants highlight mechanisms of corticotropin-releasing hormone effects on stress-coping behavior

Hypersecretion of central corticotropin-releasing hormone (CRH) has been implicated in the pathophysiology of affective disorders. Both, basic and clinical studies suggested that disrupting CRH signaling through CRH type 1 receptors (CRH-R1) can ameliorate stress-related clinical conditions. To study the effects of CRH-R1 blockade upon CRH-elicited behavioral and neurochemical changes we created different mouse lines overexpressing CRH in distinct spatially restricted patterns. CRH overexpression in the entire central nervous system, but not when overexpressed in specific forebrain regions, resulted in stress-induced hypersecretion of stress hormones and increased active stress-coping behavior reflected by reduced immobility in the forced swim test and tail suspension test. These changes were related to acute effects of overexpressed CRH as they were normalized by CRH-R1 antagonist treatment and recapitulated the effect of stress-induced activation of the endogenous CRH system. Moreover, we identified enhanced noradrenergic activity as potential molecular mechanism underlying increased active stress-coping behavior observed in these animals. Thus, these transgenic mouse lines may serve as animal models for stress-elicited pathologies and treatments that target the central CRH system.

Site-specific overexpression of corticotropin-releasing hormone (CRH) in the mouse brain – modelling central CRH system hyperactivity

To gain deeper insight into the consequences of corticotropin-releasing hormone (CRH) system hyperactivity, as observed in human affective disorders including major depression, we generated a mouse model which allows the conditional CRH overexpression from the ROSA26 locus (COR). Combining the knock-in of the murine CRH cDNA into the ROSA26 locus with the Cre/loxP system enabled us to overexpress CRH in a spatially regulated fashion at different dosages. Subsequently, two different mouse lines were established where CRH overexpression was either restricted to the central nervous system (CNS, COR-Nes) or even more specifically to the anterior forebrain including structures of the limbic system (COR-Cam). Site-specific overexpression of CRH resulted in alterations within the central CRH/CRH receptor system and affected the regulation of the hypothalamic pituitary adrenocortical (HPA) axis. Furthermore, CRH overexpression resulted in significant behavioural changes in these animals compared to control mice when tested in different behavioural paradigms. The observed alterations were depending on the level and pattern of CRH overexpression.

Corticotropin-releasing hormone activates ERK1/2 MAPK in specific brain areas

Corticotropin-releasing hormone (CRH) coordinates hormonal and behavioral responses to stress. The mitogen-activated protein kinase extracellular signal-related kinase 1/2 (ERK1/2) mediates several functions in different forebrain structures and recently has been implicated in CRH signaling in cultured cells. To study in vivo CRH-mediated activation of central ERK1/2, we investigated the expression pattern of the phosphorylated ERK1/2(p-ERK1/2) in the mouse brain after intracerebroventricular CRH injections. As shown by immunohistochemistry and confocal microscopy analysis, CRH administration increased p-ERK1/2 levels specifically in the CA3 and CA1 hippocampal subfields and basolateral complex of the amygdala, both structures related to external environmental information processing and behavioral aspects of stress. Other regions such as hypothalamic nuclei and the central nucleus of the amygdala, also related to central CRH system but involved in the processing of the ascending visceral information and neuroendocrine-autonomic response to stress, did not show CRH-mediated ERK1/2 activation. To dissect the involvement of CRH receptor 1 (CRHR1) and CRHR2, we used conditional knockout mice in which Crhr1 is inactivated in the anterior forebrain and limbic structures. The conditional genetic ablation of Crhr1 inhibited the p-ERK1/2 increase, underlining the involvement of CRHR1 in the CRH-mediated activation. These findings underscore the fact that CRH activates p-ERK1/2 through CRHR1 only in selected brain regions, pointing to a specific role of this pathway in mediating behavioral adaptation to stress.

Corticotropin-releasing hormone in depression and post-traumatic stress disorder

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

Involvement of Central, but Not Placental Corticotropin Releasing Hormone (CRH) in Heat Stress Induced Immunosuppression during Pregnancy

To clarify whether corticotropin releasing hormone (CRH) and β-endorphin (βEP) system mediate maternal immunosuppression in pregnant rats exposed to heat through central or placental pathway, we examined the effects of intravenous (iv) (100 or 500 μg) or intracerebroventricular (icv) (5μg) administration of CRH receptor antagonist α-helical CRH (9–41) on splenic natural killer cell activity (NKCA) as well as βEP in blood, pituitary lobes, and placenta in pregnant rats at 15 to 16 days gestation. Two-way ANOVA revealed that heat reduced NKCA and elevated blood and pituitary βEP but did not change placental βEP. Iv administered 500 μg and icv administered α-helical CRH reversed the reduced NKCA and the elevated pituitary βEP, while iv administration of 100 μg α-helical CRH did not. The increased blood βEP was reversed by iv 100 and 500 μg α-helical CRH and icv administration. Both iv and icv administrations reduced placental βEP independent of heat exposure. Thus, the response of placental βEP to iv administration of α-helical CRH seemed to be stronger than that of pituitary βEP. These results indicate that α-helical CRH which acts on pituitary βEP antagonizes heat-induced immunosuppression during pregnancy, suggesting that immunosuppression produced by heat stress during pregnancy is mediated by the central CRH system. The placental CRH-βEP system seems unlikely to be involved in the immunosuppression. Physiologic roles of placental CRH and opioid system should be clarified by future in vitro experiments using placenta specimen including placental immunocyte.

The role of central corticoliberin in the hyperosmosis-induced secretion of neurohypophysial hormones and corticosterone in the rat

Although synthetic corticotropin-releasing hormone (CRH) is known to influence the secretion of the neurohypophysial hormones, the role of endogenous CRH in the rat brain is still unclear in this respect. Accordingly, experiments were scheduled to study the effects of intracerebroventricularly (i.c.v.) administered CRH-antiserum (AS) on the hyperosmosis-induced secretion of arginine-8-vasopressin (AVP), oxytocin (OXT) and corticosterone in Wistar male rats. A 2 μl CRH-AS injection was given, and repeated 24 h later, 30 min prior to intraperitoneal administration of hypertonic saline (HS; 2.5% NaCl, 2 ml 100 g body weight) followed by decapitation in 15 min. Plasma AVP and OXT were measured by radioimmunoassay and corticosterone by fluorimetry. HS increased the levels of AVP, OXT and corticosterone. CRH-AS did not change the plasma concentrations of these hormones in 0.9% NaCl-treated animals. CRH-AS pretreatment prevented the corticosterone-releasing action of HS, and significantly moderated the HS-induced AVP and OXT increase. These findings suggest that the central CRH system may participate in the regulation of corticosterone and neurohypophysial hormone secretion evoked by acute osmotic challenge.

ICV-CRH potently affects behavior without altering antinociceptive responding

To explore the hypothesized integrative function of corticotropin releasing hormone (CRH) in the stress response, stress-related behaviors including antinociception were studied in rats after either intracerebroventricular (ICV) or peripheral administration of CRH. The effects of low-dose (0.3 ωg) and high-dose (3.0 ωg) ICVCRH were compared to those of vehicle, employing a within- S design. The two doses yielded comparable behavioral changes suggestive of increased arousal and stress. These changes were characterized by significant increases in grooming, walking, burrowing, self-gnawing, and pica, and decreases in rearing and sleeping. None of these effects of ICVCRH were obtained with peripheral administration of the same doses. The hot-plate test of analgesia failed to show a significant effect of ICVCRH or peripherally administered CRH. A between- S experiment incorporating both the tail-flick and the hot-plate tests of analgesia compared ICVCRH (3.0 ωg) with vehicle. ICVCRH did not affect antinociceptive responding in either of these tests. In contrast, ICV morphine (10 ωg) yielded potent analgesia in both tests. Thus, with doses of ICVCRH yielding clear evidence of stress-related behavior, no evidence of analgesia was obtained. These findings question the possible role of central CRH systems in antinociceptive processes.