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Cited by 103Stress Responses and CortisolNeuropeptides and Animal PhysiologyNeuroendocrine regulation and behavior

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On the role of corticotropin-releasing hormone receptors in anxiety and depression

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Reul, Johannes M. H. M., Holsboer, Florian·2002·Dialogues in Clinical Neuroscience
DOI 10.31887/dcns.2002.4.1/jreulPMC PMC3181666
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Abstract

On the basis of extensive basic and clinical studies, corticotropin-releasing hormone (CRH) and its related family members are considered to play a pivotal role in stress-related disorders, such as anxiety and depression. CRH is regarded as the principal mediator in the brain of the stress response, as it mediates neuroendocrine, autonomic, and behavioral responses to stressful challenges. Recently, this neuropeptide family has expanded due to the discovery of two new members, urocortin II (also termed stresscopin-related peptide) and urocortin III (also termed stresscopin), which are selective agonists for the CRH receptor type 2. They show a discrete neuroanatomical localization and are involved in stress-coping responses, such as anxiolysis. Here, on the basis of recent developments, we suggest that CRH, the urocortins, and their receptors form a complex system in the brain, which is recruited during both the acute and the recovery phases of the stress response.

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Figures

Figure 1. Distribution of CRHR1 and CRHR2 mRNA (A), and Ucn, Ucn II, and Ucn III mRNA (B) in a sagittal section of the rodent brain. The presented mRNA distribution is based on in situ hybridization studies.12,14,16,20-23 The drawn sagittal sections are only 2D schematic representations and, therefore, cannot be neuroanatomically exact. Abbreviations: 7, facia! nucleus; 12, hypoglossal nucleus; Amb, ambiguus nucleus; AON, anterior olfactory nucleus; AP, area postrema; APit, anterior pituitary; ARC, arcuate nucleus; Basal G, basal ganglia; BLA, basolateral amygdala; BNST, bed nucleus stria terminalis; CA1-3, fields CA1-3 of Ammon horn; CC, corpus callosum; CeA, central amygdaloid nucleus; Cereb, cerebellum; CingCx, cingulate cortex; CoA, cortical nucleus amygdala; Deep N, deep nuclei; DG, dentate gyrus; DBB, diagonal band of Broca; EW, Edinger-Westphal nucleus; FrCx, frontal cortex; IC, inferior colliculi; 10, inferior olive; IPit, intermediate lobe of the pituitary; LC, locus ceruleus; LDTg, laterodorsal tegmental nucleus; LS, lateral septum; LSO, lateral superior olive; MA, medial nucleus amygdala; MePO, median preoptic area; MS, medial septum; NTS, nucleus tractus solitarius; OB, olfactory bulb; OccCx, occipital cortex; PAG, periaqueductal gray area; ParCx, parietal cortex; PFA, perifornical area; PG, pontine gray, PPit, posterior pituitary; PPTg, pedunculopontine tegmental nucleus; PVH, paraventricular hypothalamus; R, red nucleus; RN, raphe nuclei; SC, superior colliculi; SN, substantia nigra; SON, supraoptic nucleus; SP5n: spina! trigeminal nucleus; SPO: superior paraolivary nucleus; Thai, thalamus; VMH, ventromedial hypothalamic nucleus.
Figure 1. Distribution of CRHR1 and CRHR2 mRNA (A), and Ucn, Ucn II, and Ucn III mRNA (B) in a sagittal section of the rodent brain. The presented mRNA distribution is based on in situ hybridization studies.12,14,16,20-23 The drawn sagittal sections are only 2D schematic representations and, therefore, cannot be neuroanatomically exact. Abbreviations: 7, facia! nucleus; 12, hypoglossal nucleus; Amb, ambiguus nucleus; AON, anterior olfactory nucleus; AP, area postrema; APit, anterior pituitary; ARC, arcuate nucleus; Basal G, basal ganglia; BLA, basolateral amygdala; BNST, bed nucleus stria terminalis; CA1-3, fields CA1-3 of Ammon horn; CC, corpus callosum; CeA, central amygdaloid nucleus; Cereb, cerebellum; CingCx, cingulate cortex; CoA, cortical nucleus amygdala; Deep N, deep nuclei; DG, dentate gyrus; DBB, diagonal band of Broca; EW, Edinger-Westphal nucleus; FrCx, frontal cortex; IC, inferior colliculi; 10, inferior olive; IPit, intermediate lobe of the pituitary; LC, locus ceruleus; LDTg, laterodorsal tegmental nucleus; LS, lateral septum; LSO, lateral superior olive; MA, medial nucleus amygdala; MePO, median preoptic area; MS, medial septum; NTS, nucleus tractus solitarius; OB, olfactory bulb; OccCx, occipital cortex; PAG, periaqueductal gray area; ParCx, parietal cortex; PFA, perifornical area; PG, pontine gray, PPit, posterior pituitary; PPTg, pedunculopontine tegmental nucleus; PVH, paraventricular hypothalamus; R, red nucleus; RN, raphe nuclei; SC, superior colliculi; SN, substantia nigra; SON, supraoptic nucleus; SP5n: spina! trigeminal nucleus; SPO: superior paraolivary nucleus; Thai, thalamus; VMH, ventromedial hypothalamic nucleus.CC BY-NC-ND · PubMed Central
Figure 2. Chemical structures of several nonpeptidergic corticotropin-releasing hormone receptor type 1 (CRHR1) antagonists.
Figure 2. Chemical structures of several nonpeptidergic corticotropin-releasing hormone receptor type 1 (CRHR1) antagonists.CC BY-NC-ND · PubMed Central
Figure 3. Effect of forced swimming stress on rat hippocampal mineralocorticoid (MR) receptor levels and its consequences for MR-mediated hypothalamic-pituitary-adrenocortical (HPA) axis regulation. A. Within 24 h, forced swimming induces an increase in MR immunoreactivity in nuclei of pyramidal and granular neurons in the CA1, CA2, and CA3 fields of the Ammon horn (not shown) hippocampal pyramidal layers and dentate gyrus (DG). This effect was stressor-specific, as it was also seen after novelty stress, but not after exposure to a cold environment (not shown). B. Intracerebroventricular (ICV) pretreatment with the nonselective corticotropin-releasing hormone receptor (CRHR) antagonist D-Phe12, Nle21,38, α-Me-Leu37)-CRH12-41. (D-Phe-CRH12-41) prevented the forced swimming-induced increase in hippocampal MRs. Moreover, ICV corticotropin-releasing hormone (CRH) treatment mimics the effect of stress on hippocampal MR levels (not shown). C. As shown in an RU 28318 challenge test, the forced swimming-induced elevation in hippocampal MR levels is associated with a potentiated MR-mediated inhibition of HPA activity. RU 28318 is a selective MR antagonist and, after ICV administration and by blocking the MR, induces a release of the HPA axis from the tonic inhibitory control elicited by hippocampal MRs. The experiment was based on the idea that, when MRs are upregulated poststress, the release of HPA activity by RU 28362 would be exaggerated compared with the control, unstressed, situation. Thus, rats were stressed by forced swimming and 24 h later injected ICV with RU 28362. Trunk blood was collected 30 min postinjection. Indeed, the results show that the release of HPA activity in terms of plasma corticosterone levels was larger when rats had been stressed 24 h earlier, indicating that the stress-induced increase in hippocampal MR levels is associated with an enhanced MR-mediated tonic inhibitory control of HPA axis activity. For further details, see reference 84. Reproduced from reference 84: Gesing A, Bilang-Bleuel A, Droste SK, Linthorst ACE, Holsboer F, Reul JMHM. Psychological stress increases hippocampal mineralocorticoid receptor levels: involvement of corticotropin-releasing hormone. J Neurosci. 2001;21:4822-4829. Copyright © 2001, Society for Neuroscience.
Figure 3. Effect of forced swimming stress on rat hippocampal mineralocorticoid (MR) receptor levels and its consequences for MR-mediated hypothalamic-pituitary-adrenocortical (HPA) axis regulation. A. Within 24 h, forced swimming induces an increase in MR immunoreactivity in nuclei of pyramidal and granular neurons in the CA1, CA2, and CA3 fields of the Ammon horn (not shown) hippocampal pyramidal layers and dentate gyrus (DG). This effect was stressor-specific, as it was also seen after novelty stress, but not after exposure to a cold environment (not shown). B. Intracerebroventricular (ICV) pretreatment with the nonselective corticotropin-releasing hormone receptor (CRHR) antagonist D-Phe12, Nle21,38, α-Me-Leu37)-CRH12-41. (D-Phe-CRH12-41) prevented the forced swimming-induced increase in hippocampal MRs. Moreover, ICV corticotropin-releasing hormone (CRH) treatment mimics the effect of stress on hippocampal MR levels (not shown). C. As shown in an RU 28318 challenge test, the forced swimming-induced elevation in hippocampal MR levels is associated with a potentiated MR-mediated inhibition of HPA activity. RU 28318 is a selective MR antagonist and, after ICV administration and by blocking the MR, induces a release of the HPA axis from the tonic inhibitory control elicited by hippocampal MRs. The experiment was based on the idea that, when MRs are upregulated poststress, the release of HPA activity by RU 28362 would be exaggerated compared with the control, unstressed, situation. Thus, rats were stressed by forced swimming and 24 h later injected ICV with RU 28362. Trunk blood was collected 30 min postinjection. Indeed, the results show that the release of HPA activity in terms of plasma corticosterone levels was larger when rats had been stressed 24 h earlier, indicating that the stress-induced increase in hippocampal MR levels is associated with an enhanced MR-mediated tonic inhibitory control of HPA axis activity. For further details, see reference 84. Reproduced from reference 84: Gesing A, Bilang-Bleuel A, Droste SK, Linthorst ACE, Holsboer F, Reul JMHM. Psychological stress increases hippocampal mineralocorticoid receptor levels: involvement of corticotropin-releasing hormone. J Neurosci. 2001;21:4822-4829. Copyright © 2001, Society for Neuroscience.CC BY-NC-ND · PubMed Central
Figure 4. Shift in limbic afferent control of the hypothalamic-pituitary-adrenocortical (HPA) axis and its consequences for affective states and physiological functioning. This figure presents a working hypothesis on limbic-HPA axis interactions in anxiety and depressive disorders. On the basis of established afferent and efferent regulatory interactions between the HPA axis and its limbic “partners” (the hippocampus and the amygdala), we propose a framework giving a neuropharmacological basis to the psychiatric, neurovegetative, and physiological disturbances seen in anxiety and depressive disorders. Patients suffering from major depression or pathological anxiety often show a dysregulated - mostly hyperactive - HPA axis which is associated with increased cerebrospinal fluid (CSF) levels of corticotropin-releasing hormone (CRH).30,69,70 Apart from intrinsic HPA axis disturbances at the hypothalamic, pituitary, or adrenal level, the reason for the HPA hyperactivity may well derive from defunct processes in the hippocampus and central amygdaloid nucleus (CeA) known to provide direct and indirect efferent projections to the hypothalamic paraventricular nucleus (PVH).73,89 As postulated (see text), chronic stressful life events result in a loss of capacity of CRH or CRH-related peptides to upregulate hippocampal mineralocorticoid receptor (MR) levels (1) leading to a loosening of the tonic inhibitory influence on parvicellular neurons in the PVH.73 In depressed patients and in a variety of animal models, a reduced expression of MR has indeed been found.72,73,90 (2) Consequently, levels of CRH and coexpressed vasopressin will increase in these neurons (for a review, see references 65, 72, and 74) providing an enhanced drive on HPA activity, anterior pituitary (APit)CRH-binding receptor (CRHRI) desensitization, and adrenal hyperplasia.66,73 (3) Subsequently, the elevated circulating glucocorticoid levels will raise CRH expression in the CeA,87 (4) resulting in an enhanced stimulatory influence on the PVH. In this manner, a positive feed-forward loop develops accelerating the establishment of a state of sustained HPA hyperactivity. Importantly, regarding the activity of the efferent amygdaloid and hippocampal projections to the nucleus accumbens, (5) a shift may occur toward an augmented input from the CeA relative to that from the hippocampus. Such a shift will result in an increased emotionality likely to develop in vulnerable subjects to pathological anxiety and mood disorders. Finally, the enhanced - caudally directed - CeA activity leading to an increased sympathetic outflow in combination with the excess glucocorticoid levels can result in a variety of neurovegetative (eg, cardiovascular or gastrointestinal problems), metabolic, and immune disturbances, often seen in anxiety, mood, and psychosomatic disorders. Also, CeA- and hippocampus-associated structures are drawn such as the cortical nucleus amygdala (CoA), basolateral amygdala (BLA), and medial nucleus amygdala (MA) with regard to the CeA, and the lateral septum (LS)and media! septum (MS) with regard to the hippocampus because they participate strongly in CeA and hippocampus functioning. In addition, their own function is modulated by incoming signals via CRHR1 and/or CRHR2. The bed nucleus stria terminalis (BNST), containing both CRHR1 and CRHR2, is drawn because it is an important relay station for hippocampal output to the PVH. Thus, this model can be used as a framework to investigate in an integrative manner the anxiogenic, anxiolytic, HPA-driving, HPA-restraining, and other actions of CRH, urocortin (Ucn), Ucn II, and Ucn III. Such studies should also implement interactions of these neuropeptides with the classic neurotransmitters, which, for sake of clarity, were not depicted in the scheme, as were other, possibly participating, structures such as, for instance, the thalamic paraventricular nucleus which contains low-to-moderate CRHR1 levels.22,91 The elucidation of the interactions between the various components of this network including the CRHRs and their ligands will bring forward new pharmacotherapeutic strategies for the treatment of anxiety and depressive disorders. Note: The green boxes comprise primary elements (ie, brain regions and parts of the HPA axis) of the system of limbic-HPA axis interactions. The orange ovals represent the different categories of pathological disturbances resulting (as indicated by the pointing hands) from aberrant functioning of certain elements of the network. The localization in certain elements (eg, brain regions, APit, adrenal gland) of CRHR1 is indicated in red, CRHR2 in blue, whereas other important components such as CRH, adrenocorticotropic hormone (ACTH), glucocorticoids, and MR, are indicated in dark green. With (1) to (5) the sequence of the progressive disturbances are denoted (see main text of legend). CRHR1i: CRHR1 mRNA inducible by stress or CRH (see text).
Figure 4. Shift in limbic afferent control of the hypothalamic-pituitary-adrenocortical (HPA) axis and its consequences for affective states and physiological functioning. This figure presents a working hypothesis on limbic-HPA axis interactions in anxiety and depressive disorders. On the basis of established afferent and efferent regulatory interactions between the HPA axis and its limbic “partners” (the hippocampus and the amygdala), we propose a framework giving a neuropharmacological basis to the psychiatric, neurovegetative, and physiological disturbances seen in anxiety and depressive disorders. Patients suffering from major depression or pathological anxiety often show a dysregulated - mostly hyperactive - HPA axis which is associated with increased cerebrospinal fluid (CSF) levels of corticotropin-releasing hormone (CRH).30,69,70 Apart from intrinsic HPA axis disturbances at the hypothalamic, pituitary, or adrenal level, the reason for the HPA hyperactivity may well derive from defunct processes in the hippocampus and central amygdaloid nucleus (CeA) known to provide direct and indirect efferent projections to the hypothalamic paraventricular nucleus (PVH).73,89 As postulated (see text), chronic stressful life events result in a loss of capacity of CRH or CRH-related peptides to upregulate hippocampal mineralocorticoid receptor (MR) levels (1) leading to a loosening of the tonic inhibitory influence on parvicellular neurons in the PVH.73 In depressed patients and in a variety of animal models, a reduced expression of MR has indeed been found.72,73,90 (2) Consequently, levels of CRH and coexpressed vasopressin will increase in these neurons (for a review, see references 65, 72, and 74) providing an enhanced drive on HPA activity, anterior pituitary (APit)CRH-binding receptor (CRHRI) desensitization, and adrenal hyperplasia.66,73 (3) Subsequently, the elevated circulating glucocorticoid levels will raise CRH expression in the CeA,87 (4) resulting in an enhanced stimulatory influence on the PVH. In this manner, a positive feed-forward loop develops accelerating the establishment of a state of sustained HPA hyperactivity. Importantly, regarding the activity of the efferent amygdaloid and hippocampal projections to the nucleus accumbens, (5) a shift may occur toward an augmented input from the CeA relative to that from the hippocampus. Such a shift will result in an increased emotionality likely to develop in vulnerable subjects to pathological anxiety and mood disorders. Finally, the enhanced - caudally directed - CeA activity leading to an increased sympathetic outflow in combination with the excess glucocorticoid levels can result in a variety of neurovegetative (eg, cardiovascular or gastrointestinal problems), metabolic, and immune disturbances, often seen in anxiety, mood, and psychosomatic disorders. Also, CeA- and hippocampus-associated structures are drawn such as the cortical nucleus amygdala (CoA), basolateral amygdala (BLA), and medial nucleus amygdala (MA) with regard to the CeA, and the lateral septum (LS)and media! septum (MS) with regard to the hippocampus because they participate strongly in CeA and hippocampus functioning. In addition, their own function is modulated by incoming signals via CRHR1 and/or CRHR2. The bed nucleus stria terminalis (BNST), containing both CRHR1 and CRHR2, is drawn because it is an important relay station for hippocampal output to the PVH. Thus, this model can be used as a framework to investigate in an integrative manner the anxiogenic, anxiolytic, HPA-driving, HPA-restraining, and other actions of CRH, urocortin (Ucn), Ucn II, and Ucn III. Such studies should also implement interactions of these neuropeptides with the classic neurotransmitters, which, for sake of clarity, were not depicted in the scheme, as were other, possibly participating, structures such as, for instance, the thalamic paraventricular nucleus which contains low-to-moderate CRHR1 levels.22,91 The elucidation of the interactions between the various components of this network including the CRHRs and their ligands will bring forward new pharmacotherapeutic strategies for the treatment of anxiety and depressive disorders. Note: The green boxes comprise primary elements (ie, brain regions and parts of the HPA axis) of the system of limbic-HPA axis interactions. The orange ovals represent the different categories of pathological disturbances resulting (as indicated by the pointing hands) from aberrant functioning of certain elements of the network. The localization in certain elements (eg, brain regions, APit, adrenal gland) of CRHR1 is indicated in red, CRHR2 in blue, whereas other important components such as CRH, adrenocorticotropic hormone (ACTH), glucocorticoids, and MR, are indicated in dark green. With (1) to (5) the sequence of the progressive disturbances are denoted (see main text of legend). CRHR1i: CRHR1 mRNA inducible by stress or CRH (see text).CC BY-NC-ND · PubMed Central
Figure 5. Changes in the self-rating Beck Depression Inventory (BDI; left) and the 21-item Hamilton Depression Rating Scale (HAMD; right) during and after treatment with the nonpeptidergic CRHRI antagonist R121919 (formerly called NBI-30775) and the selective serotonin reuptake inhibitor (SSRI) paroxetine. During the screening period, all psychoactive medication was stopped for a minimum of 5 days. Patients were enrolled in two dose escalation panels. In panel 1, the dose range increased from 5 to 40 mg (open diamonds), whereas, in panel 2, the dose range increased from 40 to 80 mg (closed circles). The increases took place within 30 days. The panel 2 treatment regimen resulted in a response rate (ie, 50% reduction of the initial severity of depression) equivalent to that found in paroxetine-treated patients (open squares; historical data for patients matched according to age, gender, and severity of depression; patients had been treated with 20 to 40 mg paroxetine under clinical drug study conditions). In both panels, HAMD and BDI rating scales worsened after discontinuation of R121919. Data are means ± standard error of the mean. Reproduced from reference 92: Zobel AW, Nickel T, Kunzel HE, et al. Effects of the high-affinity corticotropin-releasing hormone receptor I antagonist R121919 in major depression: the first 20 patients treated. J Psychiatr Res. 2000;34:171-181. Copyright © 2000, Elsevier Science.
Figure 5. Changes in the self-rating Beck Depression Inventory (BDI; left) and the 21-item Hamilton Depression Rating Scale (HAMD; right) during and after treatment with the nonpeptidergic CRHRI antagonist R121919 (formerly called NBI-30775) and the selective serotonin reuptake inhibitor (SSRI) paroxetine. During the screening period, all psychoactive medication was stopped for a minimum of 5 days. Patients were enrolled in two dose escalation panels. In panel 1, the dose range increased from 5 to 40 mg (open diamonds), whereas, in panel 2, the dose range increased from 40 to 80 mg (closed circles). The increases took place within 30 days. The panel 2 treatment regimen resulted in a response rate (ie, 50% reduction of the initial severity of depression) equivalent to that found in paroxetine-treated patients (open squares; historical data for patients matched according to age, gender, and severity of depression; patients had been treated with 20 to 40 mg paroxetine under clinical drug study conditions). In both panels, HAMD and BDI rating scales worsened after discontinuation of R121919. Data are means ± standard error of the mean. Reproduced from reference 92: Zobel AW, Nickel T, Kunzel HE, et al. Effects of the high-affinity corticotropin-releasing hormone receptor I antagonist R121919 in major depression: the first 20 patients treated. J Psychiatr Res. 2000;34:171-181. Copyright © 2000, Elsevier Science.CC BY-NC-ND · PubMed Central

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Research works printed but not linked: 11

  1. Holsboer F., 1984, N Engl J Med., 311, 1127
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Metadata

Authors
Reul, J. M. H. M., & Holsboer, F.
Affiliations
Max Planck Institute of Psychiatry (DE)
Corresponding author
Reul, Johannes M. H. M.
ORCID
Reul, Johannes M. H. M.
Venue
Dialogues in Clinical Neuroscience
Publisher
Informa UK Limited
Published
2002-03-31
Volume
4
Issue
1
Pages
31-46
ISSN
  • 1294-8322 (ISSN-L)
  • 1958-5969
DOI
10.31887/dcns.2002.4.1/jreul
PMC
PMC3181666
OpenAlex
W4294249858
Cited by
103
References
85
Citations by year
2026: 3 · 2025: 8 · 2024: 16 · 2023: 8 · 2022: 5 · 2021: 8 · 2020: 5 · 2019: 9 · 2018: 8 · 2017: 6 · 2016: 4 · 2015: 7 · 2014: 5 · 2013: 3 · 2012: 6
FWCI
0.28
Type
journal article
Language
en
Open access
Licence
Locations
  • Dialogues in Clinical Neuroscience (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Bristol Research (University of Bristol) (publishedVersion)
  • PubMed
Topics
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Neuroendocrine regulation and behavior
Keywords
corticotropin-releasing factor, CRH receptors, urocortin II, stress response, anxiety, depression, stress coping, anxiolysis, neuroendocrine stress response, neuropeptides

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