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

“The cause for the aberrant—in most cases, hyperactive—HPA axis is presumably a hyperactive central CRH system (for review, see references 24, 30, and 69 to 71) and defunct brain and pituitary corticosteroid receptor systems.(66,72,73) Although it was more than a decade ago that a reduced CRH receptor density was found…”

“They can be distinguished in two types of glucocorticoid-binding receptors: the mineralocorticoid receptor (MR or type I) and the glucocorticoid receptor (GR or type II).(83) MRs are mainly localized in the hippocampus, whereas GRs have a widespread distribution in the CNS.”

“CRH is highly implicated in the regulation of anxietyrelated behavior and is thought to play a pivotal role in anxiety and depressive disorders.(24,30,31) Several lines of evidence point to the participation of CRHR1 in the effects of CRH.”

“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.”

“In contrast to CRH and Ucn, neither Ucn II nor Ucn III bind to CRHBP.14 The murine Ucn II (mUcn II) gene encodes a 112–amino acid (aa) precursor containing a putative 38-aa mature peptide at the C terminus.16 Amino acid sequences in the coding region of mUcn II show 76%, 47%, 34%, and 42% homology with human urocortin…”

“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.”

“Second, CRHR1-deficient mice show decreased anxiety-related behavior.(32,33) Third, transgenic mice overexpressing CRH show increased anxiety-related behavior(34) (van Gaalen et al, unpublished data).”

“The murine Ucn II (mUcn II) gene encodes a 112–amino acid (aa) precursor containing a putative 38-aa mature peptide at the C terminus.(16) Amino acid sequences in the coding region of mUcn II show 76%, 47%, 34%, and 42% homology with human urocortin-related peptide (URP [GenBank accession No.”

“It is clear from these data that there is an array of changes in the HPA axis of CRHR2 mutant mice that may explain the different hormonal responses: (i) hypersensitivity of the corticotrophs to hypothalamic secretagogues; (ii) higher glucocorticoid levels cause ACTH levels to fall earlier due to higher negative feedb…”

“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.”

“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 (…”

“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 ad…”

“It is clear from these data that there is an array of changes in the HPA axis of CRHR2 mutant mice that may explain the different hormonal responses: (i) hypersensitivity of the corticotrophs to hypothalamic secretagogues; (ii) higher glucocorticoid levels cause ACTH levels to fall earlier due to higher negative feedb…”

“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…”

“However, as pointed out by Bittencourt and Sawchenko,(21) a puzzling issue remains that neuronal activation (in terms of Fos expression) is found in nuclei known to be pertinent for eliciting the stress response (eg, the central nucleus of the amygdala, paraventricular nucleus, nucleus tractus solitarius (NTS), ventro…”

“hormones.(86) Thus, those depressed patients who hypersecrete glucocorticoids—at least in part due to defunct hippocampal inhibition of HPA activity (see above and Figure 4)— also have increased CRH synthesis in the central amygdaloid nucleus.”

“also observed 30 min after a 60-min immobilization trial, which was prevented by intraseptal, but not intradorsohippocampal, administration of antisauvagine-30 before the stress procedure.(55) Thus, acutely CRHR2-mediated signaling in the iLS results in anxiogenesis.”

“sion of the clinical symptomatology and a normalization of HPA regulation.(68) The cause for the aberrant—in most cases, hyperactive—HPA axis is presumably a hyperactive central CRH system (for review, see references 24, 30, and 69 to 71) and defunct brain and pituitary corticosteroid receptor systems.”

“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.”

“CRH is highly implicated in the regulation of anxietyrelated behavior and is thought to play a pivotal role in anxiety and depressive disorders.(24,30,31) Several lines of evidence point to the participation of CRHR1 in the effects of CRH.”

“Beside the CRH receptors, corticosteroid receptors are also key elements in the regulation of the HPA axis.(72,73) They can be distinguished in two types of glucocorticoid-binding receptors: the mineralocorticoid receptor (MR or type I) and the glucocorticoid receptor (GR or type II).”

“Furthermore, we have postulated that, given the eminent role of the CRH-MR pathway in maintaining control of HPA axis activity poststress, in patients suffering from a stressrelated disorder, such as major depression, HPA hyperactivity may have developed due to desensitization of MR-inducibility by CRH or CRH-like neu…”

“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 ad…”

“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 ad…”

“Moreover, basic research studies have presented evidence that elevated central CRH levels are involved in the etiology of stress-related physiological and behavioral disorders.(6) In pharmacology, however, the discovery of two types of CRH-binding receptors (CRHR1 and CRHR2) and a nonreceptor CRH-binding protein (CRHB…”

“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…”

“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…”

“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…”

“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…”

“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.”

“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.”

“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.”

“Possibly, other stress recovery processes could also be impaired by the defunct CRHR2, including HPA regulation and autonomic processes.(17,51-53,93,94)”

“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.”

“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…”

“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…”

“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…”

“The complexity is further increased by the presence of a binding protein, which presumably constrains the biological activity of CRH and Ucn.(19)”

“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…”

“Possibly, other stress recovery processes could also be impaired by the defunct CRHR2, including HPA regulation and autonomic processes.(17,51-53,93,94)”

“Lancel et al, unpublished data).(63) This observation points to a role of CRHR1 in stress-induced changes in sleep.”

“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…”

“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…”

“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…”

“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].”