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

Reul, Johannes M. H. M.; Holsboer, Florian

doi:10.31887/dcns.2002.4.1/jreul

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

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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CRF mediates behavioral and endocrine responses to stress and acts on CRF type 1 and CRF type 2 receptors.
“The neuropeptide corticotropin-releasing factor (CRF) mediates behavioral and endocrine responses to stress and acts on CRF type 1 (CRF1) and CRF type 2 (CRF2) receptors [168].”
From The Neurobiology of Love and Pair Bonding from Human and Animal Perspectives (2023) · cites this paper as [168]

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Background
Corticotropin Releasing Factor (CRF) Receptor Modulators: Progress and Opportunities for New Therapeutic Agents
Gilligan, P. J., Robertson, D. W., & Zaczek, R. C. (2000) · Journal of Medicinal Chemistry · doi:10.1021/jm990590f · Cited by 160 · see citing works
Glucocorticoids and depression
Steckler, T., Holsboer, F., & Reul, J. M. H. M. (1999) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1053/beem.1999.0046 · Cited by 160 · cited 1× · see citing works
“Evidence has been accumulating that disturbances in the regulatory control of the HPA axis play a pivotal role in the etiology of major depression.(66,67) Moreover, studies on depressed patients have indicated that there appears to be a close correlation between a stable remisCRH receptor types 1 and 2 in anxiety and…”
BackgroundSelf-citation
The anxiolytic effect of the CRH1 receptor antagonist R121919 depends on innate emotionality in rats
Keck, M. E., Welt, T., Wigger, A., Renner, U., Engelmann, M., Holsboer, F., & Landgraf, R. (2001) · European Journal of Neuroscience · doi:10.1046/j.0953-816x.2000.01383.x · Cited by 154 · cited 1× · see citing works
“However, it should be noted that, in many cases, the antagonists had no anxiolytic effect under nonstressed conditions in behavioral paradigms such as the light/dark box or elevated plus-maze, but did so after the animals had been preexposed to stress.(39,40,42) Thus, it seems that the antagonists need the release of…”
Background
A Cholecystokinin-Mediated Pathway to the Paraventricular Thalamus Is Recruited in Chronically Stressed Rats and Regulates Hypothalamic-Pituitary-Adrenal Function
Bhatnagar, S., Viau, V., Chu, A., Soriano, L., Meijer, O. C., & Dallman, M. F. (2000) · Journal of Neuroscience · doi:10.1523/jneurosci.20-14-05564.2000 · Cited by 152 · cited 1× · see citing works
“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 leve…”
Background
Receptor Binding, Behavioral, and Electrophysiological Profiles of Nonpeptide Corticotropin-Releasing Factor Subtype 1 Receptor Antagonists CRA1000 and CRA1001
Okuyama, S., Chaki, S., Kawashima, N., Suzuki, Y., Ogawa, S., Nakazato, A., Kumagai, T., Okubo, T., & Tomisawa, K. (1999) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(24)38220-5 · Cited by 152 · cited 1× · see citing works
“However, it should be noted that, in many cases, the antagonists had no anxiolytic effect under nonstressed conditions in behavioral paradigms such as the light/dark box or elevated plus-maze, but did so after the animals had been preexposed to stress.(39,40,42) Thus, it seems that the antagonists need the release of…”
Background
Stress‐Specific Regulation of Corticotropin Releasing Hormone Receptor Expression in the Paraventricular and Supraoptic Nuclei of the Hypothalamus in the Rat
Luo, X., Kiss, A., Makara, G. B., Lolait, S. J., & Aguilera, G. (1994) · Journal of Neuroendocrinology · doi:10.1111/j.1365-2826.1994.tb00636.x · Cited by 148 · see citing works
Expression of corticotropin releasing hormone receptors type I and type II mRNA in suicide victims and controls
Hiroi, N., Wong, M. L., Licinio, J., Park, C., Young, M., Gold, P. W., Chrousos, G. P., & Bornstein, S. R. (2001) · Molecular Psychiatry · doi:10.1038/sj.mp.4000908 · Cited by 124 · cited 1× · see citing works
“In a recent study, investigators observed in pituitaries of suicide victims a shift in the ratio of CRHR1 (less)/CRHR2 (more) mRNA levels, but it was unclear whether the victims had a history of major depressive illness.(74) Studies on the role of CRHR1 and CRHR2 in HPA regulation have mainly been performed in rodents.”
Background
Regulation of the Hypothalamic-Pituitary-Adrenocortical System in Mice Deficient for CRH Receptors 1 and 2
Preil, J., Müller, M. B., Gesing, A., Reul, J. M. H. M., Sillaber, I., van Gaalen, M. M., Landgrebe, J., Holsboer, F., Stenzel‐Poore, M. P., & Wurst, W. (2001) · Endocrinology · doi:10.1210/endo.142.11.8507 · Cited by 123 · see citing works
Molecular biology of the CRH receptors— in the mood
Dautzenberg, F. M., Kilpatrick, G. J., Hauger, R. L., & Moreau, J. (2001) · Peptides · doi:10.1016/s0196-9781(01)00388-6 · Cited by 123 · cited 1× · see citing works
“CRHR1 binds both CRH and Ucn with high affinity, whereas CRHR2 shows a clear preference for Ucn (Table I).(10,11,14,15) The next question was whether a neuropeptide that selectively binds to CRHR2 exists in mammalian brain.”
Background
Corticotropin-releasing hormone receptor (type I) antisense targeting reduces anxiety
Skutella, T., Probst, J. C., Renner, U., Holsboer, F., & Behl, C. (1998) · Neuroscience · doi:10.1016/s0306-4522(97)00682-9 · Cited by 114 · see citing works
4-(1,3-Dimethoxyprop-2-ylamino)-2,7-dimethyl-8-(2,4-dichlorophenyl)pyrazolo[1,5-a]-1,3,5-triazine: A Potent, Orally Bioavailable CRF1 Receptor Antagonist
He, L., Gilligan, P. J., Zaczek, R. C., Fitzgerald, L. W., McElroy, J., Shen, H.-S. L., Saye, J. A., Kalin, N. H., Shelton, S. E., Christ, D. D., et al. (2000) · Journal of Medicinal Chemistry · doi:10.1021/jm9904351 · Cited by 111 · see citing works
Regulation of corticotropin-releasing factor type 1 (CRF1) receptor messenger ribonucleic acid in the paraventricular nucleus of rat hypothalamus by exogenous CRF
Mansi, J. A., Rivest, S., & Drolet, G. (1996) · Endocrinology · doi:10.1210/endo.137.11.8895325 · Cited by 107 · cited 1× · see citing works
“In the PVH, only low levels of CRHR1 mRNA can be found, but levels are induced in response to stress(22,77-80) or ICV CRH administration.(81) This induction of CRHR1 mRNA may be implemented in the positive feedback action of CRH on paraventricular neurons, but the evidence needs to be further solidified.”
Background
Selective Activation of the Hypothalamic Vasopressinergic System in Mice Deficient for the Corticotropin-Releasing Hormone Receptor 1 Is Dependent on Glucocorticoids1
Müller, M. B., Landgraf, R., Preil, J., Sillaber, I., Kresse, A. E., Keck, M. E., Zimmermann, S., Holsboer, F., & Wurst, W. (2000) · Endocrinology · doi:10.1210/endo.141.11.7767 · Cited by 99 · see citing works
Role of CRF receptor 1 in central CRF-induced stimulation of colonic propulsion in rats
Martı́nez, V., & Taché, Y. (2001) · Brain Research · doi:10.1016/s0006-8993(00)03277-7 · Cited by 98 · cited 1× · see citing works
“Possibly, other stress recovery processes could also be impaired by the defunct CRHR2, including HPA regulation and autonomic processes.(17,51-53,93,94)”
Background
Pituitary and Adrenocortical Responses to the Ovine Corticotropin Releasing Hormone in Depressed Patients and Healthy Volunteers
Amsterdam, J. D. (1987) · Archives of General Psychiatry · doi:10.1001/archpsyc.1987.01800210019003 · Cited by 97 · cited 1× · see citing works
“This notion originates from cerebrospinal fluid (CSF) CRH measurements, CRH binding, and CRH challenge tests.(4,85) Comparison of a variety of studies on CSF CRH measurements revealed that this was not an equivocal finding in all studies, but seemed to depend on certain factors associated with depressive illness.”
Corticotropin-releasing hormone involvement in stressor-induced alterations in sleep and in the regulation of waking
Opp, M. R. (1995) · Advances in Neuroimmunology · doi:10.1016/0960-5428(95)00004-l · Cited by 96 · cited 2× · see citing works
“Sleep disturbances are often seen after exposure to stress57,58 and are also commonly observed in major depressive disorders.59 The disturbances observed in depressed patients include a disinhibition of rapid eye movement (REM) sleep (encompassing reduced REM latency, reduced REM density, and prolonged first REM sleep…”
Background
Isolation and amino acid composition of sauvagine. An active polypeptide from methanol extracts of the skin of the South American frog Phyllomedusa sauvagei.
Montecucchi, P. C., Anastasi, A., Castiglione, R., & Erspamer, V. (1980) · PubMed · Cited by 95 · see citing works
ISOLATION AND AMINO ACID COMPOSITION OF SAUVAGINE
Montecucchi, P. C., Anastasi, A., Castiglione, R., & Erspamer, V. (1980) · International journal of peptide & protein research · doi:10.1111/j.1399-3011.1980.tb02952.x · Cited by 84 · see citing works
Corticotropin-releasing hormone receptor type 1-deficiency enhances hippocampal serotonergic neurotransmission: an in vivo microdialysis study in mutant mice
Peñalva, R. G., Flachskamm, C., Zimmermann, S., Wurst, W., Holsboer, F., Reul, J. M. H. M., & Linthorst, A. C. E. (2002) · Neuroscience · doi:10.1016/s0306-4522(01)00475-4 · Cited by 70 · cited 1× · see citing works
“CRHR1-deficient mice are unable to mount a stress-induced HPA response in terms of circulating ACTH and corticosterone, whereas baseline ACTH levels are normal and baseline corticosterone levels virtually undetectable.(32,33,75,76) Thus, CRHR1 is crucial for stress-induced HPA responsiveness, but not for the baseline…”
Background
Effect of intracerebroventricular administration of α‐helical CRH (9–41) on the sleep/waking cycle in rats under normal conditions or after subjection to an acute stressful stimulus
GONZALEZ, M. D. C., & Valatx, J. L. (1997) · Journal of Sleep Research · doi:10.1046/j.1365-2869.1997.00042.x · Cited by 66 · cited 1× · see citing works
“Moreover, pretreatment with α-helical CRH(9-41) abolished the stress-induced increases in REM sleep in rats.(58) Recently performed basic and clinical studies using R121919 have provided further insight into the role of CRHR1 in sleep/electronencephalographic (EEG) regulation and sleep disturbances in depressed patien…”
Result
Mouse models of altered CRH-binding protein expression
Seasholtz, A. F., Burrows, H. L., Karolyi, I. J., & Camper, S. A. (2001) · Peptides · doi:10.1016/s0196-9781(01)00387-4 · Cited by 65 · cited 2× · see citing works
“The complexity is further increased by the presence of a binding protein, which presumably constrains the biological activity of CRH and Ucn.(19)”
Background
Expression of Corticotropin-Releasing Hormone Type 1 Receptor in Paraventricular Nucleus after Acute Stress
Imaki, T., Katsumata, H., Miyata, M., Naruse, M., Imaki, J., & Minami, S. (2001) · Neuroendocrinology · doi:10.1159/000054646 · Cited by 64 · see citing works
The role of CRF receptor subtypes in stress-induced behavioural responses
Smagin, G. N., & Dunn, A. J. (2000) · European Journal of Pharmacology · doi:10.1016/s0014-2999(00)00553-7 · Cited by 58 · cited 1× · see citing works
“However, it should be noted that, in many cases, the antagonists had no anxiolytic effect under nonstressed conditions in behavioral paradigms such as the light/dark box or elevated plus-maze, but did so after the animals had been preexposed to stress.(39,40,42) Thus, it seems that the antagonists need the release of…”
Background
Antalarmin blockade of corticotropin releasing hormone-induced hypertension in rats
Briscoe, R. J., Cabrera, C., Baird, T. J., Rice, K. C., & Woods, J. H. (2000) · Brain Research · doi:10.1016/s0006-8993(00)02742-6 · Cited by 46 · cited 1× · see citing works
“Possibly, other stress recovery processes could also be impaired by the defunct CRHR2, including HPA regulation and autonomic processes.(17,51-53,93,94)”
Background
GABAergic organization of the cat medial geniculate body
Huang, C. L., Larue, D. T., & Winer, J. A. (1999) · The Journal of Comparative Neurology · doi:10.1002/(sici)1096-9861(19991220)415:3 · Cited by 39 · see citing works
Pain Perception following Subcutaneous Injections of Citrate-Buffered and Phosphate-Buffered Epoetin Alpha
Yu, A. W., Leung, C. B., Li, P. K. T., Lui, S., & Lai, K. N. (1998) · The International Journal of Artificial Organs · doi:10.1177/039139889802100612 · Cited by 32 · cited 1× · see citing works
“Lancel et al, unpublished data).(63) This observation points to a role of CRHR1 in stress-induced changes in sleep.”
Background
Urotensin I - a novel CRF-like peptide in Catostomus commersoni urophysis.
Lederis, K. P., Vale, W., Rivier, J., Kl, M., McMaster, D., Kobayashi, Y., Suess, U., & Lawrence, J. (1982) · PubMed · Cited by 32 · see citing works
CRHR1 Antagonists as Novel Treatment Strategies
Holsboer, F. (2001) · CNS Spectrums · doi:10.1017/s1092852900002133 · Cited by 30 · see citing works
Neurophysiological effects of intracerebroventricular administration of urocortin
Slawecki, C. J., Somes, C., Rivier, J. E., & Ehlers, C. L. (1999) · Peptides · doi:10.1016/s0196-9781(98)00160-0 · Cited by 27 · cited 3× · see citing works
“Recently, the effects of ICV administered urocortin on the EEG and on event-related potentials (ERPs) of awake rats was evaluated.65 It was observed that the neuropeptide enhances arousal, as determined by EEG, and modulates the speed of stimulus evaluation as measured by ERPs.65 Clearly, insight into the function of…”
BackgroundMethodInfluential
Synthesis and biological activity of fluoro-substituted pyrrolo[2,3-d]pyrimidines: The development of potential positron emission tomography imaging agents for the corticotropin-releasing hormone type 1 receptor
Hsin, L., WEBSTER, E. L., Chrousos, G. P., Gold, P. W., Eckelman, W. C., Contoreggi, C. S., & Rice, K. C. (2000) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/s0960-894x(00)00071-8 · Cited by 25 · cited 1× · see citing works
“Due to recent achievements in the development of nonpeptidergic CRHR1 ligands for single photon emission computed tomography (SPECT) and positron emission tomography (PET), in vivo monitoring of CRHR1 in the living brain may soon become possible.(49,50) In summary, there is robust evidence that CRHR1 is highly involve…”
Background
The development of a potential single photon emission computed tomography (SPECT) imaging agent for the corticotropin-releasing hormone receptor type 1
Tian, X., Hsin, L., WEBSTER, E. L., Contoreggi, C. S., Chrousos, G. P., Gold, P. W., Habib, K. E., Ayala, A. R., Eckelman, W. C., Jacobson, A. E., et al. (2001) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/s0960-894x(00)00661-2 · Cited by 19 · see citing works
Molecular cloning and characterization of the Fugu rubripes MEST/COPG2 imprinting cluster and chromosomal localization in Fugu and Tetraodon nigroviridis
Brunner, B., Grützner, F., Yaspo, M., Ropers, H., Haaf, T., & Kalscheuer, V. M. (2000) · Chromosome Research · doi:10.1023/a:1009263504671 · Cited by 15 · see citing works
Hypothalamic Peptides in Human Brain Diseases
Swaab, D. F. (1999) · Trends in Endocrinology and Metabolism · doi:10.1016/s1043-2760(99)00158-7 · Cited by 6 · see citing works
Distribution of mRNAs encoding CRF receptors in brain and pituitary of rat and mouse
Van Pett, K., Viau, V., Bittencourt, J. C., Chan, R. K. W., Li, H.-Y., Arias, C., Prins, G. S., Perrin, M., Vale, W., & Sawchenko, P. E. (2000) · The Journal of Comparative Neurology · doi:10.1002/1096-9861(20001211)428:2

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[43]Heinrichs SC. De Souza EB. Schulteis G. Lapsansky JL. Grigoriadis DE. Brain penetrance, receptor occupancy and anti-stress in vivo efficacy of a small molecule corticotropin-releasing factor 1 receptor selective antagonist. Soc Neurosci Abst. 2000 26 2149 12093593
[64]Held K. Künzel HE. Ising M. Murck H. Holsboer F. Steiger A. Sleep EEG changes among depressed patients treated with the CRHR1-antagonist NBI30775. J Psychiatr Res. in press 2001 14757326
[87]Davis M. The role of the amygdala in conditioned fear. In: Aggleton JP, ed. The Amygdala. New York, NY: Wiley-Liss; 1992 255 306
[88]Gray TS. The organization and possible function of amygdaloid corticotropin-releasing factor pathways. In: De Souza EB, Nemeroff CB, eds. Corticotropin-releasing Factor: Basic and Clinical studies of a Neuropeptide. Boca Raton, Fia: CRC Press; 1990 53 68

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The neurobiology and control of anxious states
Millan, M. J. (2003) · Progress in Neurobiology · doi:10.1016/s0301-0082(03)00087-x · Cited by 963 · see citing works
Sex differences in anxiety and depression: Role of testosterone
McHenry, J. A., Carrier, N., Hull, E. M., & Kabbaj, M. (2013) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2013.09.001 · Cited by 505 · see citing works
Pathophysiology of depression and mechanisms of treatment
Brigitta, B. (2002) · Dialogues in Clinical Neuroscience · doi:10.31887/dcns.2002.4.1/bbondy · Cited by 286 · see citing works
Pharmacological Treatment of Anxiety Disorders: The Role of the HPA Axis
Tafet, G. E., & Nemeroff, C. B. (2020) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2020.00443 · Cited by 216 · see citing works
“These steroid hormones exert their effects through binding to mineralocorticoid receptors (MRs or type I) and glucocorticoid receptors (GRs or type II), constituting a hormone-receptor complex, which in turn may interact with specific DNA sequences located in the promoter region of target genes, termed glucocorticoid…”
BackgroundInfluential
Sculpting the hippocampus from within: stress, spines, and CRH
Maras, P. M., & Baram, T. Z. (2012) · Trends in Neurosciences · doi:10.1016/j.tins.2012.01.005 · Cited by 174 · see citing works
“CRHR1 and CRHR2 differ in their distribution [37,43,44], as well as their role in mediating behavioral and endocrine responses to stress [45,46].”
Background
Oxytocin and Social Relationships: From Attachment to Bond Disruption
Bosch, O. J., & Young, L. J. (2017) · Current Topics in Behavioral Neurosciences · doi:10.1007/7854_2017_10 · Cited by 162 · see citing works
“The brain CRF system, which consists of CRF and the urocortins 1–3 as well as of CRF receptor type 1 (CRF-R1), CRF-R2, and the CRF binding protein (Reul and Holsboer 2002), is the primary regulator of the HPA axis (Vale et al. 1981; Aguilera and Liu 2012).”
Background
Extra-adrenal glucocorticoid biosynthesis: implications for autoimmune and inflammatory disorders
Slominski, R. M., Tuckey, R. C., Manna, P. R., Jetten, A. M., Postlethwaite, A., Raman, C., & Slominski, A. T. (2020) · Genes & Immunity · doi:10.1038/s41435-020-0096-6 · Cited by 155 · see citing works
Stress, Definitions, Mechanisms, and Effects Outlined
Fink, G. (2016) · Elsevier eBooks · doi:10.1016/b978-0-12-800951-2.00001-7 · Cited by 137 · see citing works
Sex, social status and physiological stress in primates: the importance of social and glucocorticoid dynamics
Cavigelli, S. A., & Caruso, M. J. (2015) · Philosophical Transactions of the Royal Society B: Biological Sciences · doi:10.1098/rstb.2014.0103 · Cited by 112 · see citing works
Neuropeptide Regulation of Signaling and Behavior in the BNST
Kash, T. L., Pleil, K. E., Marcinkiewcz, C. A., Lowery‐Gionta, E. G., Crowley, N. A., Mazzone, C. M., Sugam, J. A., Hardaway, J. A., & McElligott, Z. A. (2014) · Molecules and Cells · doi:10.14348/molcells.2015.2261 · Cited by 105 · see citing works
“CRF binds to CRF-1 and CRF-2 receptors (CRF-1Rs and CRF-2Rs), which are G-protein coupled receptors (GPCRs) acting through a Gs-cAMP-PKA signaling mechanism (Arzt and Holsboer, 2006; Blank et al., 2003; Dautenberg and Hauger, 2002; Reul and Holsboer, 2002).”
Background
The role of GPCRs in neurodegenerative diseases: avenues for therapeutic intervention
Huang, Y., Todd, N., & Thathiah, A. (2017) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2017.02.001 · Cited by 99 · see citing works
Prefrontal Cortex Corticotropin-Releasing Factor Receptor 1 Conveys Acute Stress-Induced Executive Dysfunction
Uribe-Mariño, A., Gassen, N. C., Wiesbeck, M. F., Balsevich, G., Santarelli, S., Solfrank, B., Dournes, C., Fries, G. R., Masana, M., Labermeier, C., et al. (2016) · Biological Psychiatry · doi:10.1016/j.biopsych.2016.03.2106 · Cited by 90 · see citing works
Neuroendocrine, neuroinflammatory and pathological outcomes of chronic stress: A story of microglial remodeling
Picard, K., St‐Pierre, M., Vecchiarelli, H. A., Bordeleau, M., & Tremblay, M. (2021) · Neurochemistry International · doi:10.1016/j.neuint.2021.104987 · Cited by 77 · see citing works
Long-lasting effects of prenatal stress on HPA axis and inflammation: A systematic review and multilevel meta-analysis in rodent studies
Creutzberg, K. C., Sanson, A., Viola, T. W., Marchisella, F., Begni, V., Grassi‐Oliveira, R., & Riva, M. A. (2021) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2021.04.032 · Cited by 65 · see citing works
Neural and endocrine mechanisms underlying stress-induced suppression of pulsatile LH secretion
McCosh, R. B., Breen, K. M., & Kauffman, A. S. (2019) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2019.110579 · Cited by 65 · see citing works
“This disparity could reflect compensatory changes in whole-body knock-out animals during development, actions of the other CRHR1 agonist urocortin 1, or species differences.”
BackgroundInfluential
Reduced brain corticotropin‐releasing factor receptor activation is required for adequate maternal care and maternal aggression in lactating rats
Klampfl, S. M., Neumann, I. D., & Bosch, O. J. (2013) · European Journal of Neuroscience · doi:10.1111/ejn.12274 · Cited by 63 · see citing works
Hypoactivation of CRF Receptors, Predominantly Type 2, in the Medial-Posterior BNST Is Vital for Adequate Maternal Behavior in Lactating Rats
Klampfl, S. M., Brunton, P. J., Bayerl, D. S., & Bosch, O. J. (2014) · Journal of Neuroscience · doi:10.1523/jneurosci.4220-13.2014 · Cited by 63 · see citing works
The Lateral Hypothalamus: An Uncharted Territory for Processing Peripheral Neurogenic Inflammation
Fakhoury, M., Salman, I., Najjar, W., Merhej, G., & Lawand, N. (2020) · Frontiers in Neuroscience · doi:10.3389/fnins.2020.00101 · Cited by 60 · see citing works
“Activation of the HPA axis occurs through the corticotropin releasing hormone (CRH), which binds to CRH1 and CRH2 receptors, whose activation regulate several behavioral and physiological processes including anxiety and sleep (Reul and Holsboer, 2002).”
Background
Tet3 ablation in adult brain neurons increases anxiety-like behavior and regulates cognitive function in mice
Antunes, C., Silva, J. D. D., Guerra‐Gomes, S., Alves, N. D., Ferreira, F., Loureiro‐Campos, E., Branco, M. R., Sousa, N., Reik, W., Pinto, L., et al. (2020) · Molecular Psychiatry · doi:10.1038/s41380-020-0695-7 · Cited by 60 · see citing works
“Regarding HPA axis, we confirmed by qRT-PCR the downregulation of corticotropin releasing hormone receptor type 2 (Crhr2), involved in stress-related disorders, such as anxiety and depression [36] (Fig.”
The Neurobiology of Love and Pair Bonding from Human and Animal Perspectives
Blumenthal, S. A., & Young, L. J. (2023) · Biology · doi:10.3390/biology12060844 · Cited by 59 · see citing works
Maternal stress and the MPOA: Activation of CRF receptor 1 impairs maternal behavior and triggers local oxytocin release in lactating rats
Klampfl, S. M., Schramm, M. M., Gaßner, B. M., Hübner, K., Seasholtz, A. F., Brunton, P. J., Bayerl, D. S., & Bosch, O. J. (2018) · Neuropharmacology · doi:10.1016/j.neuropharm.2018.02.019 · Cited by 57 · see citing works
“The CRF system consists of four ligands, CRF (protein: CRF, gene: Crh) and the urocortins 1e3, which bind with different affinities to the two CRF receptors (protein: CRFR, gene: Crhr): CRFR1 and CRFR2 (Reul and Holsboer, 2002a).”
Mom doesn’t care: When increased brain CRF system activity leads to maternal neglect in rodents
Klampfl, S. M., & Bosch, O. J. (2019) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2019.01.001 · Cited by 51 · see citing works
Role of Corticotropin Releasing Factor in the Neuroimmune Mechanisms of Depression: Examination of Current Pharmaceutical and Herbal Therapies
Jiang, Y., Peng, T., Gaur, U., Silva, M., Little, P. J., Chen, Z., Qiu, W., Zhang, Y., & Zheng, W. (2019) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2019.00290 · Cited by 53 · see citing works
Post-stroke depression: epigenetic and epitranscriptomic modifications and their interplay with gut microbiota
Jeong, S., Chokkalla, A. K., Davis, C. K., & Vemuganti, R. (2023) · Molecular Psychiatry · doi:10.1038/s41380-023-02099-8 · Cited by 49 · see citing works
“In addition, Tet3 deletion in mice led to neonatal lethality, and conditional Tet3 deletion increased anxiety-like behavior with downregulation of corticotropin-releasing hormone receptor type 2, involved in stress-related disorders (Table 1) [67 – 69].”
Preclinical evidence implicating corticotropin‐releasing factor signaling in ethanol consumption and neuroadaptation
Phillips, T. J., Reed, C. L., & Pastor, R. (2015) · Genes Brain & Behavior · doi:10.1111/gbb.12189 · Cited by 46 · see citing works
Neuropeptides encoded by nlp-49 modulate locomotion, arousal and egg-laying behaviours in Caenorhabditis elegans via the receptor SEB-3
Chew, Y. L., Grundy, L. J., Brown, A. E., Beets, I., & Schafer, W. R. (2018) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.2017.0368 · Cited by 41 · see citing works
Changes Induced by Prenatal Stress in Behavior and Brain Morphology: Can They Be Prevented or Reversed?
Weinstock, M. (2014) · Advances in neurobiology · doi:10.1007/978-1-4939-1372-5_1 · Cited by 37 · see citing works
“This has been attributed to the increased action of corticotropin-releasing factor (CRF; Keck 2006; Reul and Holsboer 2002).”
Gene expression in cord blood links genetic risk for neurodevelopmental disorders with maternal psychological distress and adverse childhood outcomes
Breen, M. S., Wingo, A. P., Koen, N., Donald, K. A., Nicol, M., Zar, H. J., Ressler, K. J., Buxbaum, J. D., & Stein, D. J. (2018) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2018.05.016 · Cited by 35 · see citing works
“, 2005) and numerous neuropeptides (Reul and Holsboer, 2002) (e.”
Deciphering the Contributions of CRH Receptors in the Brain and Pituitary to Stress-Induced Inhibition of the Reproductive Axis
Raftogianni, A., Roth, L. C., García‐González, D., Bus, T., Kühne, C., Monyer, H., Spergel, D. J., Deussing, J. M., & Grinevich, V. (2018) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2018.00305 · Cited by 36 · see citing works
CRF-R1 activation in the anterior-dorsal BNST induces maternal neglect in lactating rats via an HPA axis-independent central mechanism
Klampfl, S. M., Brunton, P. J., Bayerl, D. S., & Bosch, O. J. (2015) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2015.11.015 · Cited by 32 · see citing works
Resource scarcity but not maternal separation provokes unpredictable maternal care sequences in mice and both upregulate Crh-associated gene expression in the amygdala
Demaestri, C., Gallo, M. E., Mazenod, E., Hong, A. T., Arora, H., Short, A. K., Stern, H. S., Baram, T. Z., & Bath, K. G. (2022) · Neurobiology of Stress · doi:10.1016/j.ynstr.2022.100484 · Cited by 33 · see citing works
Sex differences in neuroplasticity- and stress-related gene expression and protein levels in the rat hippocampus following oxycodone conditioned place preference
Randesi, M., Contoreggi, N. H., Zhou, Y., Rubin, B. R., Bellamy, J. R., Yu, F., Gray, J. D., McEwen, B. S., Milner, T. A., & Kreek, M. J. (2019) · Neuroscience · doi:10.1016/j.neuroscience.2019.04.047 · Cited by 31 · see citing works
“Crhr1 and Crhr2 mRNA show distinct but overlapping distributions in the brain (Reul and Holsboer, 2002).”
Background
Genetic Variants in the Genes of the Stress Hormone Signalling Pathway and Depressive Symptoms during and after Pregnancy
Schneider, M. O., Engel, A., Fasching, P. A., Häberle, L., Binder, E. B., Voigt, F., Grimm, J., Faschingbauer, F., Eichler, A., Dammer, U., et al. (2014) · BioMed Research International · doi:10.1155/2014/469278 · Cited by 29 · see citing works
Distribution of corticotropin-releasing factor receptor 1 in the developing mouse forebrain: A novel sex difference revealed in the rostral periventricular hypothalamus
Rosinger, Z. J., Jacobskind, J. S., Park, S. G., Justice, N. J., & Zuloaga, D. G. (2017) · Neuroscience · doi:10.1016/j.neuroscience.2017.08.016 · Cited by 29 · see citing works
“CRFR2 deletion leads to increased anxiety-like behaviors; it may be that CRFR2 is partially necessary for inhibition of stress-related responses (Kishimoto et al., 2000; Reul and Holsboer, 2002).”
Background
Depression and the Glutamate/GABA-Glutamine Cycle
Mamelak, M. (2024) · Current Neuropharmacology · doi:10.2174/1570159x22666240815120244 · Cited by 29 · see citing works
Pharmacogenomic assessment of herbal drugs in affective disorders
Sahoo, S., & Brijesh, S. (2018) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2018.10.135 · Cited by 29 · see citing works
Fluoride exposure causes behavioral, molecular and physiological changes in adult zebrafish (Danio rerio) and their offspring
Karaman, M., Toraman, E., Sulukan, E., Baran, A., Bolat, İ., Yıldırım, S., Kankaynar, M., Ghosigharehagaji, A., Budak, H., & Ceyhun, S. B. (2022) · Environmental Toxicology and Pharmacology · doi:10.1016/j.etap.2022.104044 · Cited by 26 · see citing works
The behavioral and molecular evaluation of effects of social instability stress as a model of stress-related disorders in adult female rats
Nowacka-Chmielewska, M. M., Liśkiewicz, D., Barski, J. J., Obuchowicz, E., & Małecki, A. (2017) · Stress · doi:10.1080/10253890.2017.1376185 · Cited by 26 · see citing works
Short-term sleep fragmentation enhances anxiety-related behavior: The role of hormonal alterations
Grubač, Ž., Šutulović, N., Ademovič, A., Velimirović, M., Rašić-Marković, A., Μacut, D., Petronijević, N., Stanojlović, O. P., & Hrnčić, D. (2019) · PLoS ONE · doi:10.1371/journal.pone.0218920 · Cited by 24 · see citing works
Mitochondrial stress-induced GFRAL signaling controls diurnal food intake and anxiety-like behavior
Gil, C. I., Coull, B. M., Jonas, W., Lippert, R. N., Klaus, S., & Ost, M. (2022) · Life Science Alliance · doi:10.26508/lsa.202201495 · Cited by 25 · see citing works
“Given the involvement of CRH in the control of the stress response and anxiety-like behavior (Reul & Holsboer, 2002), we aimed to further characterize behavioral implications of GFRAL-dependent increased hypo-thalamic CRH in TG mice.”
Assessing the Role of Cortisol in Anxiety, Major Depression, and Neuroticism: A Mendelian Randomization Study Using SERPINA6/SERPINA1 Variants
Chan, I. I., & Wu, A. M. S. (2024) · Biological Psychiatry Global Open Science · doi:10.1016/j.bpsgos.2024.100294 · Cited by 27 · see citing works
“Depletion of CRF1 signaling in mice led to reduced symptoms related to anxiety and depression (67), and elevated cortisol was observed in patients with comorbid major depression and anxiety, but not in patients with major depression alone (68).”
Background
Down, But Not Out: Partial Elimination of Androgen Receptors in the Male Mouse Brain Does Not Affect Androgenic Regulation of Anxiety or HPA Activity
Chen, C. V., Brummet, J. L., Jordan, C. L., & Breedlove, S. M. (2015) · Endocrinology · doi:10.1210/en.2015-1417 · Cited by 21 · see citing works
Human fear acquisition deficits in relation to genetic variants of the corticotropin‐releasing hormone receptor 1 and the serotonin transporter — revisited
Heitland, I., Groenink, L., van Gool, J. M. G., Domschke, K., Reif, A., & Baas, J. M. P. (2015) · Genes Brain & Behavior · doi:10.1111/gbb.12276 · Cited by 21 · see citing works
“A multitude of potential underlying mechanisms for this interplay have been described (recently: Fox & Lowry 2013); see also (Homberg & Contet 2009; Reul & Holsboer 2002; Valentino et al. 2010) for reviews).”
Brain CRF-binding protein modulates aspects of maternal behavior under stressful conditions and supports a hypo-anxious state in lactating rats
Klampfl, S. M., Schramm, M. M., Stinnett, G. S., Bayerl, D. S., Seasholtz, A. F., & Bosch, O. J. (2016) · Hormones and Behavior · doi:10.1016/j.yhbeh.2016.06.009 · Cited by 18 · see citing works
When mothers neglect their offspring: an activated CRF system in the BNST is detrimental for maternal behavior
Klampfl, S. M., & Bosch, O. J. (2018) · Archives of Women s Mental Health · doi:10.1007/s00737-018-0897-z · Cited by 19 · see citing works
“The CRF system plays a key role in a diversity of behaviors accompanying stress, anxiety, and depression and in their underlying physiology (Bale and Vale 2004; Koob andHeinrichs 1999; Reul and Holsboer 2002).”
Background
Effects of dorsal periaqueductal gray CRF1- and CRF2-receptor stimulation in animal models of panic
Sergio, T. D. O., Spiacci, A., & Zangrossi, H. (2014) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2014.07.026 · Cited by 18 · see citing works
Cortisol as a Target for Treating Mental Disorders: A Promising Avenue for Therapy
Patel, V. K., Vaishnaw, A., Shirbhate, E., Kore, R., Singh, V. P., Veerasamy, R., & Rajak, H. (2023) · Mini-Reviews in Medicinal Chemistry · doi:10.2174/0113895575262104230928042150 · Cited by 18 · see citing works
Corticotropin-Releasing Hormone Receptor Type 1 (CRHR1) Clustering with MAGUKs Is Mediated via Its C-Terminal PDZ Binding Motif
Bender, J. G., Engeholm, M., Ederer, M. S., Breu, J., Møller, T. C., Michalakis, S., Raskó, T., Wanker, E. E., Biel, M., Martinez, K. L., et al. (2015) · PLoS ONE · doi:10.1371/journal.pone.0136768 · Cited by 18 · see citing works
“The corticotropin-releasing hormone receptor type 1 (CRHR1) is an important regulator of neuroendocrine, behavioral, and autonomic response to stress [1].”
Background
Murine splenic B cells express corticotropin-releasing hormone receptor 2 that affect their viability during a stress response
Harlé, G., Kaminski, S., Dubayle, D., Frippiat, J., & Ropars, A. (2018) · Scientific Reports · doi:10.1038/s41598-017-18401-y · Cited by 17 · see citing works
“CRH is known for having a greater affinity for CRHR1 than for CRHR2 (Kd of 3 nM and 10–40 nM, respectively) 37 .”
Association and Genetic Expression between Genes Involved in HPA Axis and Suicide Behavior: A Systematic Review
Hernández‐Díaz, Y., Mendoza, A. D. G., González‐Castro, T. B., Tovilla‐Zárate, C. A., Juárez‐Rojop, I. E., López‐Narváez, M. L., & Nicolini, H. (2021) · Genes · doi:10.3390/genes12101608 · Cited by 19 · see citing works
“CRHR1 plays a critical role in the acute phase of stress-induced HPA response and CRHR2 is involved in the recovery phase [12,13].”
Background
Age-related changes in central effects of corticotropin-releasing factor (CRF) suggest a role for this mediator in aging anorexia and cachexia
Tenk, J., Rostás, I., Füredi, N., Mikó, A., Solymár, M., Soós, S., Gaszner, B., Feller, D., Székely, M., Pétervári, E., et al. (2017) · GeroScience · doi:10.1007/s11357-017-9962-1 · Cited by 16 · see citing works
Comparative Efficacy of Animal Depression Models and Antidepressant Treatment: A Systematic Review and Meta-Analysis
Ratajczak, P., Martyński, J., Zięba, J. K., Świło, K., Kopciuch, D., Paczkowska, A., Zaprutko, T., & Kus, K. (2024) · Pharmaceutics · doi:10.3390/pharmaceutics16091144 · Cited by 16 · see citing works
Allergic rhinitis increases the risk of incident panic disorder among young individuals: A nationwide population-based cohort study in Taiwan
Hsieh, M.-T., Liang, S. H., Yang, Y., Kuo, T., Lin, T., Wang, T., Chen, V. C., & Wu, M.-H. (2019) · Journal of Affective Disorders · doi:10.1016/j.jad.2019.04.037 · Cited by 15 · see citing works
The effects of alcohol on anxiety-like, depression-like, and social behavior immediately and a day after binge drinking
Simon, B., Thury, A. Á., Török, L., Földesi, I., Csabafi, K., & Bagosi, Z. (2023) · Alcohol · doi:10.1016/j.alcohol.2023.05.004 · Cited by 14 · see citing works
Bipolar mania and epilepsy pathophysiology and treatment may converge in purine metabolism: A new perspective on available evidence
Daniels, S. D., & Boison, D. (2023) · Neuropharmacology · doi:10.1016/j.neuropharm.2023.109756 · Cited by 15 · see citing works
Metabolic underpinnings of cancer-related fatigue
Zhang, X., & Perry, R. J. (2024) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00378.2023 · Cited by 17 · see citing works
The Irritable Bowel Syndrome: How Stress Can Affect the Amygdala Activity and the Brain-Gut Axis
Bonaz, B. L., Sonia Pellissier, A., Sinniger, V., Clarençon, D., Peinnequin, A., & Canini, F. (2012) · InTech eBooks · doi:10.5772/52066 · Cited by 11 · see citing works
Effects of denial of reward through maternal contact in the neonatal period on adult hypothalamic–pituitary–adrenal axis function in the rat
Diamantopoulou, A., Raftogianni, A., Stamatakis, A., Oitzl, M. S., & Stylianopoulou, F. (2012) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2012.09.007 · Cited by 12 · see citing works
“The direct and indirect projections of the hippocampus and the CeA to the PVN suggest that stress response and related emotionality behaviors are regulated by such an interplay and the abundance of CRH-R1 in these regions may as well act, at least partially, as such a mediator (Reul and Holsboer, 2002).”
Background
Gamma-Aminobutyric Acid Involvement in Depressive Illness
Anisman, H., Merali, Z., & Poulter, M. O. (2012) · Frontiers in neuroscience · doi:10.1201/b12215-5 · Cited by 11 · see citing works
A role of noradrenergic receptors in anxiolytic-like effect of high CRF in the rat frontal cortex
Śmiałowska, M., Zieba, B. A., & Domin, H. (2021) · Neuropeptides · doi:10.1016/j.npep.2021.102162 · Cited by 11 · see citing works
- Gamma-Aminobutyric Acid Involvement in Depressive Illness: Interactions with Corticotropin-Releasing Hormone and Serotonin
Dwivedi, Y. (2012) · CRC Press eBooks · doi:10.1201/b12215-10 · Cited by 11 · see citing works
Sex/Gender Differences in Depression and Anxiety Disorders
Park, H. Y. (2024) · Springer eBooks · doi:10.1007/978-981-97-0130-8_21 · Cited by 10 · see citing works
Pharmacogenetics of antidepressants and mood stabilizers
Serretti, A., Gibiino, S., & Olgiati, P. (2012) · Handbook of clinical neurology · doi:10.1016/b978-0-444-52002-9.00043-7 · Cited by 10 · see citing works
Wildfire-related smoke inhalation worsens cardiovascular risk in sleep disrupted rats
Martin, W. K., Schladweiler, M. C. J., Oshiro, W. M., Smoot, J. L., Fisher, A., Williams, W. C., Valdez, M. C., Miller, C. N., Jackson, T. W., Freeborn, D., et al. (2023) · Frontiers in Environmental Health · doi:10.3389/fenvh.2023.1166918 · Cited by 9 · see citing works
“A single sleep disruption and FA exposure increased hypothalamic expression of key hormonal receptors including Crhr2 and Nr3c2, which mediate stress and salt and water balance (63, 64), potentially indicating activation of the hypothalamicpituitary-adrenal stress axis (65–67), although circulating markers of these pr…”
Background
Exploring the transformative impact of traditional Chinese medicine on depression: Insights from animal models
Yang, Y., Chen, Y.-K., & Xie, M. (2024) · World Journal of Psychiatry · doi:10.5498/wjp.v14.i5.607 · Cited by 8 · see citing works
Neural oscillations in the infralimbic cortex after electrical stimulation of the amygdala. Relevance to acute stress processing
Luque‐García, A., Teruel‐Martí, V., Martínez‐Bellver, S., Adell, A., Cervera‐Ferri, A., & Martínez‐Ricós, J. (2018) · The Journal of Comparative Neurology · doi:10.1002/cne.24416 · Cited by 8 · see citing works
“…that mediate emotional behaviors, and are commonly related to alterations in the hypothalamic–pituitary–adrenal (HPA) axis, corticotropin-releasing factor signaling and consequent glucocorticoid secretion (Nemeroff, 1988; Arborelius, Owens, Plotsky, & Nemeroff, 1999; Reul & Holsboer, 2002).”
Background
A randomized controlled clinical trial of prazosin for alcohol use disorder in active duty soldiers: Predictive effects of elevated cardiovascular parameters
Raskind, M. A., Williams, T., Holmes, H. A., Hart, K. L., Crews, L., Poupore, E. L., Thomas, R. G., Darnell, J., Daniels, C., Goke, K., et al. (2023) · Alcoholism Clinical and Experimental Research · doi:10.1111/acer.14989 · Cited by 7 · see citing works
Glucocorticoid-induced depression – the role of the dopaminergic system and microRNAs
Skórzewska, A. (2021) · Postępy Psychiatrii i Neurologii · doi:10.5114/ppn.2021.110791 · Cited by 7 · see citing works
“GR receptors play an important role in response to a stress factor when the concentration of GCs is high [2, 9].”
Background
Urocortin stimulates ERK1/2 phosphorylation and proliferation but reduces ATP production of MCF7 breast cancer cells
Balogh, B., Vecsernyés, M., Veres-Székely, A., Berta, G., Stayer‐Harci, A., Tarjányi, O., & Sétáló, G. (2022) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2022.111610 · Cited by 7 · see citing works
“UCNs are central regulators of food uptake and stress-coping (Reul and Holsboer, 2002), while being overweight and overstressed are both known risk factors in human tumorigenesis, including the development of breast cancer.”
Background
TOB is an effector of the hippocampus-mediated acute stress response
Youssef, M., Hamada, H. T., Lai, S., Kiyama, Y., El‐Tabbal, M., Kiyonari, H., Nakano, K., Kühn, B., & Yamamoto, T. S. (2022) · Translational Psychiatry · doi:10.1038/s41398-022-02078-7 · Cited by 7 · see citing works
“Crhr2 is activated by Urocotins I, II (stresscopin-related peptide), and III (stresscopin), which belong to the corticotrophin-releasing factor (CRF)-related peptides [83].”
Background
Response of CRH system in brain and gill of marine medaka to seawater acidification
Chen, H., Feng, Y., Cui, J., & Wang, X. (2024) · Fish Physiology and Biochemistry · doi:10.1007/s10695-024-01332-7 · Cited by 6 · see citing works
“Crh acts through Crhr1 or Crhr2 with different distributions and physiological functions (Flik et al. 2006; Reul and Holsboer 2002).”
Acute central effects of corticotropin-releasing factor (CRF) on energy balance: Effects of age and gender
Tenk, J., Rostás, I., Füredi, N., Mikó, A., Soós, S., Solymár, M., Gaszner, B., Székely, M., Pétervári, E., & Balaskó, M. (2016) · Peptides · doi:10.1016/j.peptides.2016.09.005 · Cited by 5 · see citing works
A brain-driven neural circuit contributes to tissue regeneration in joint cartilage
Huo, K., Ma, X., Xue, Y., Zhao, L., Wang, F., Wang, G., You, Y., Jiang, W., Wang, R., Li, Y., et al. (2026) · Annals of the Rheumatic Diseases · doi:10.1016/j.ard.2025.12.004 · Cited by 4 · see citing works
Brain monoamine changes modulate the corticotropin-releasing hormone receptor 1-mediated behavioural response to acute thermal stress in zebrafish larvae
Rajeswari, J. J., Gilbert, G. N. Y., Khalid, E., & Vijayan, M. M. (2025) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2025.112494 · Cited by 4 · see citing works
Effect of photoperiod on the anxiety of zebrafish
Zhang, Y., Tao, H., Shen, Y.-J., Chen, Q.-L., & Liu, Z. (2024) · Environmental Biology of Fishes · doi:10.1007/s10641-024-01645-9 · Cited by 4 · see citing works
“Corticotro-pin-releasing hormone (CRH), a neuropeptide, plays a critical role in stress-related behaviors such as anxiety, arousal, motor function, learning, and memory (Reul and Holsboer 2002; Xin et al. 2020; Faught and Vijayan 2022).”
Comparative Study of CRH Microinjections into PVN and CeA Nuclei on Food Intake, Ghrelin, Leptin, and Glucose Levels in Acute Stressed Rats
Radahmadi, M., Izadi, M. S., Rayatpour, A., & Ghasemi, M. (2021) · Basic and Clinical Neuroscience Journal · doi:10.32598/bcn.12.1.2346.1 · Cited by 4 · see citing works
“145 CRH neuropeptide family) mRNA in the paraventricular nucleus and amygdala that are involved in stress-coping responses related to CRH (Reul & Holsboer, 2002).”
Background
Advances in Neurobiology
Schmidt, B. L., Santos, M. J., Cariaga-Martínez, A. E., Hill, L., Barloese, M. C. J., & Hall, Z. J. (2017) · Cited by 4 · see citing works
Unraveling the molecular basis of cannabidiolic acid methyl Ester's anti-depressive effects in a rat model of treatment-resistant depression
Hen-Shoval, D., Indig-Naimer, T., Moshe, L., Kogan, N. M., Zaidan, H., Gaisler‐Salomon, I., Okun, E., Mechoulam, R., Shoval, G., Zalsman, G., et al. (2024) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2024.04.033 · Cited by 3 · see citing works
5,7,3′,4′,5′‐Pentamethoxyflavone, a Flavonoid Monomer Extracted From Murraya paniculata (L.) Jack, Alleviates Anxiety Through the A2AR /Gephyrin/ GABRA2 Pathway
Ma, W., Sui, D., Sun, W., Yu, P., Li, Y., Guo, M., Wang, H., Zhang, X., Yu, X., Fu, W., et al. (2024) · Phytotherapy Research · doi:10.1002/ptr.8327 · Cited by 2 · see citing works
“The pathogenesis of anxiety disorders is linked to the hyper-activity of the HPA axis (Reul and Holsboer 2002).”
Sex differences in resilience at puberty depend upon divergent effects of a stress steroid at α4βδ GABAA receptors
Kenney, L. A., Tekin, M., de Leon, D. M., Marshall, S., & Smith, S. S. (2025) · Brain Research · doi:10.1016/j.brainres.2025.149874
Fight, Flight or Freeze: Fear as a neglected driver of decisions in markets, medicine, society and ecology
Upadhyay, R. K., Barman, D., & Bhardwaj, K. (2026) · Nonlinear Dynamics · doi:10.1007/s11071-026-12223-2 · Cited by 2 · see citing works
Molecular basis of urostyle development in frogs: genes and gene regulation underlying an evolutionary novelty
Senevirathne, G., & Shubin, N. H. (2024) · Open Biology · doi:10.1098/rsob.240111
“I and VIM.2 [40,41]), extracellular matrix organizing and connective tissue-strengthening (e.g. COL9A1 , COL8A1 and CHAD [42,43]) and stress regulation ( CRCH.1 [44]).”
Background
The role of the CRF-urocortin system in stress resilience
Henckens, M. J. A. G., Deussing, J. M., & Chen, A. (2019) · Elsevier eBooks · doi:10.1016/b978-0-12-813983-7.00016-1 · Cited by 1 · see citing works
Validation of Enhancer Regions in Primary Human Neural Progenitor Cells using Capture STARR-seqPreprint
Gaynor-Gillett, S. C., Cheng, L., Shi, M., Liu, J. J., Wang, G., Spector, M., Flaherty, M., Wall, M., Hwang, A., Gu, M., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.03.14.585066 · Cited by 1 · see citing works
A Mechanistic Model for the HPA Axis Cortisol Paradox in PTSDPreprint
Danan, D., Grosskopf, Y., Hayut, Y., Toledano, Y., Doenyas‐Barak, K., Mayo, A., & Alon, U. S. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.10.13.681561 · Cited by 1 · see citing works
The Corticotropin-Releasing Factor system in lactating rats: implications in the regulation of maternal behavior with special focus on the BNST
Klampfl, S. M. (2015) · University of Regensburg Publication Server (University of Regensburg) · doi:10.5283/epub.31369
Effects of Early, Elevated Prenatal Testosterone on the HPA Axis and Hormone Responsiveness in Mice
Wilson, H. A. (2019) · The Atrium (University of Guelph)
The role of the selective CRF receptor agonists and antagonists in nicotine addiction
Búzás, A. (2019) · doi:10.14232/phd.10217
Potential Interactions Between Environmental and Psychoneurobiological Factors in the Interface Between Stress and Depression: A Road Map to Resilience
Tafet, G. E., & Feder, D. J. (2021) · Springer eBooks · doi:10.1007/978-3-030-61721-9_28
Molecular Basis of Urostyle Development: Genes and Gene Regulation Underlying an Evolutionary NoveltyPreprint
Senevirathne, G., & Shubin, N. H. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.10.04.462674
Estudio de interacción entre genes del eje hipotálamo-hipófisis-adrenal y el trauma en la infancia en el intento suicida
Sanabrais‐Jiménez, M. A. (2020) · doi:10.24275/uami.8g84mm39n
A REVIEW ON THERAPEUTIC UTILITY OF CRF1 RECEPTOR
(2024) · International Journal of Biology Pharmacy and Allied Sciences · doi:10.31032/ijbpas/2024/13.4.7970
ANALYSIS OF MODERN CONCEPTS OF NEURODEGENERATIVE PROPERTIES OF DEPRESSION
Yasenyavskaya, A. L., Tsibizova, A., & Самотруева, М. А. (2023) · Molekulyarnaya Meditsina (Molecular medicine) · doi:10.29296/24999490-2023-04-05
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“…CRH is synthesized and released from the PVN of the hypothalamus, and, after reaching the median eminence, it stimulates the secretion of adrenocorticotrophic hormone (ACTH) in the anterior pituitary, which in turn stimulates the secretion of corticosteroids in the adrenal cortex [125].”

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: diamond
doi.org
Licence: cc-by-nc-nd
creativecommons.org/licenses/by-nc-nd/3.0/ (vor)
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
Social Sciences › Psychology › Social Psychology › 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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On the role of corticotropin-releasing hormone receptors in anxiety and depression

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