On Site Link:
Norepinephrine, CRF, and Unipolar
On Site Link: Corticosteroid
Receptors and Unipolar Depression
L, Owens MJ, Plotsky PM, Nemeroff CB.
The role of corticotropin-releasing
factor in depression and anxiety disorders.
"In the present review, we describe the evidence
suggesting that CRF is hypersecreted from hypothalamic as well as from extrahypothalamic
neurons in depression, resulting in hyperactivity of the hypothalamic-pituitary-adrenal
(HPA) axis and elevations of cerebrospinal fluid (CSF) concentrations of CRF.
This increase in CRF neuronal activity is also believed to mediate certain of
the behavioral symptoms of depression involving sleep and appetite disturbances,
reduced libido, and psychomotor changes. The hyperactivity of CRF neuronal systems
appears to be a state marker for depression because HPA axis hyperactivity normalizes
following successful antidepressant treatment. Similar biochemical and behavioral
findings have been observed in adult rats and monkeys that have been subjected
to early-life stress. In contrast, clinical studies have not revealed any consistent
changes in CSF CRF concentrations in patients with anxiety disorders; however,
preclinical findings strongly implicate a role for CRF in the pathophysiology
of certain anxiety disorders, probably through its effects on central noradrenergic
systems. The findings reviewed here support the hypothesis that CRF receptor antagonists
may represent a novel class of antidepressants and/or anxiolytics." [Abstract]
Do anxiety and depression have a common pathophysiological mechanism?
Acta Psychiatr Scand Suppl 2000;(406):24-9
"OBJECTIVE: To review, examine
and propose a common mechanism for anxiety and depression based on modifications
observed in neurotransmitter systems (mainly noradrenergic and serotonergic) and
dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis. METHOD: The relevant
papers were identified by searches in Medline, Excerpta Medica, PsychLIT and other
databases. The primary reports were reviewed and classified into animal and human
data concerning: modifications of the monoamine receptors in anxiety and depression,
pathophysiology of endocrine factors in anxiety and depression, pathophysiology
of the hypothalamic-pituitary-adrenal (HPA) axis and the pathophysiology of the
HPA dysregulation in anxiety and in depression. In addition, a proposed model
of a neuroendocrine continuum for anxiety and depression, in which anxiety occurs
first during the life course and major depressive episodes occur later, was examined.
RESULTS: Based on the available literature, increased concentrations of corticotropin-releasing
factor (CRF) in the cerebrospinal fluid has been reported in both anxiety and
depression. However, release of other peptides or hormones of the HPA axis is
regulated differently in the two disorders. Anxiety is characterized by hypocortisolemia,
supersuppression after dexamethasone and increased numbers of glucocorticoid receptors,
whereas depression is characterized by hypercortisolemia, nonsuppression after
dexamethasone and decreased numbers of glucocorticoid receptors. A 'neuroendocrine
continuum' model is proposed to explain these differences. A general desensitization
of CRF receptors at pituitary, limbic (amygdala) and cortical as well as hippocampal
levels could be secondary to the loss of hippocampal inhibition resulting from
hippocampal damage linked to repeated stressing events. CONCLUSION: The proposed
hypothesis remains to be tested by examination of either the changes in receptors
and neurotransmission or the mechanisms underlying the dysregulation of endocrine
R, Griebel G, Pavone G, Stemmelin J, Le Fur G, Soubrie P.
of CRF(1) or V(1b) receptors reverses stress-induced suppression of neurogenesis
in a mouse model of depression.
Mol Psychiatry. 2003 Dec
23 [Epub ahead of print]
"Repeated exposure to stress is known to induce
structural remodelling and reduction of neurogenesis in the dentate gyrus. Corticotrophin-releasing
factor (CRF) and vasopressin (AVP) are key regulators of the stress response via
activation of CRF(1) and V(1b) receptors, respectively. The blockade of these
receptors has been proposed as an innovative approach for the treatment of affective
disorders. The present study aimed at determining whether the CRF(1) receptor
antagonist SSR125543A, the V(1b) receptor antagonist SSR149415, and the clinically
effective antidepressant fluoxetine may influence newborn cell proliferation and
differentiation in the dentate gyrus of mice subjected to the chronic mild stress
(CMS) procedure, a model of depression with predictive validity. Repeated administration
of SSR125543A (30 mg/kg i.p.), SSR149415 (30 mg/kg i.p.), and fluoxetine (10 mg/kg
i.p.) for 28 days, starting 3 weeks after the beginning of the stress procedure,
significantly reversed the reduction of cell proliferation produced by CMS, an
effect which was paralleled by a marked improvement of the physical state of the
coat of stressed mice. Moreover, mice subjected to stress exhibited a 53% reduction
of granule cell neurogenesis 30 days after the end of the 7-week stress period,
an effect which was prevented by all drug treatments. Collectively, these results
point to an important role of CRF and AVP in the regulation of dentate neurogenesis,
and suggest that CRF(1) and V(1b) receptor antagonists may affect plasticity changes
in the hippocampal formation, as do clinically effective antidepressants."
L. Brunson, Mariam Eghbal-Ahmadi, Roland Bender, Yuncai Chen, and Tallie Z. Baram
Long-term, progressive hippocampal cell loss and dysfunction induced
by early-life administration of corticotropin-releasing hormone reproduce the
effects of early-life stress
PNAS 98: 8856-8861; published
online before print as 10.1073/pnas.151224898
"Stress early in postnatal
life may result in long-term memory deficits and selective loss of hippocampal
neurons. The mechanisms involved are poorly understood, but they may involve molecules
and processes in the immature limbic system that are activated by stressful challenges.
We report that administration of corticotropin-releasing hormone (CRH), the key
limbic stress modulator, to the brains of immature rats reproduced the consequences
of early-life stress, reducing memory functions throughout life. These deficits
were associated with progressive loss of hippocampal CA3 neurons and chronic up-regulation
of hippocampal CRH expression. Importantly, they did not require the presence
of stress levels of glucocorticoids. These findings indicate a critical role for
CRH in the mechanisms underlying the long-term effects of early-life stress on
hippocampal integrity and function." [Full
Hugin-Flores ME, Steimer T, Schulz P, Vallotton
MB, Aubert ML.
Chronic corticotropin-releasing hormone and vasopressin
regulate corticosteroid receptors in rat hippocampus and anterior pituitary.
Res. 2003 Jun 27;976(2):159-70.
"Corticotropin-releasing hormone (CRH)
and vasopressin (AVP) participate in the endocrine, autonomic, immunological and
behavioral response to stress. CRH and AVP receptors are found in hippocampus
and anterior pituitary, where mineralocorticoid (MR) and glucocorticoid (GR) receptors
are abundant. We investigated the possible influence of CRH and AVP on the regulation
of MR and GR in both tissues. CRH, AVP, or their antagonists were administered
to adrenalectomized rats substituted with corticosterone, to avoid interference
with adrenal secretion. Repeated i.c.v. oCRH injections (10 microgram) for 5 days
significantly decreased MR and GR mRNA in hippocampus and MR mRNA in anterior
pituitary. AVP significantly increased both corticosteroid receptor mRNAs, as
repeated i.c.v. injections (5 microgram) for 5 days in hippocampus, and as continuous
i.c.v. infusion (10 ng/h/5 days) in anterior pituitary. The i.c.v. infusion of
5 or 10 microgram/day of the alpha-helical CRH antagonist during intermittent
restraint stress (5 days), induced a significant decrease in hippocampal MR binding.
In anterior pituitary, 5 microgram/day significantly decreased MR binding, while
10 microgram/day significantly increased GR binding. Under the same conditions
of stress, the infusion of 15 microgram/day of the vasopressin V1a/1b receptor
antagonist [dP Tyr (Me)(2)AVP] significantly increased MR and GR binding in hippocampus
and anterior pituitary; 5 microgram/day significantly decreased pituitary MR binding.
Our results show that CRH and AVP regulate MR and GR in hippocampus and anterior
pituitary. This reveals another important function of CRH and AVP, which could
be relevant to understand stress adaptation and the pathophysiology of stress-related
disorders like major depression." [Abstract]
Neuropeptides and the hypothalamic-pituitary-adrenocortical (HPA)
system: review of recent research strategies in depression.
J Biol Psychiatry 2000 Apr;1(2):105-11
"Depressed patients show a variety
of alterations in hypothalamic-pituitary-adrenocortical (HPA) system regulation
which is reflected by increased pituitary-adrenocortical hormone secretion at
baseline and a number of aberrant neuroendocrine function tests. The latter include
the combined dexamethasone (DEX) suppression/corticotropin-releasing hormone (CRH)
challenge test, in which CRH was able to override DEX induced suppression of ACTH
and cortisol secretion. Whereas the abnormal HPA activation in these patients
improved in parallel with clinical remission, persistent HPA dysregulation was
associated with an increased risk of relapse. Moreover, healthy subjects at high
genetic risk for depression also showed this phenomenon as a trait marker. In
consequence, it has been concluded that HPA alteration and development as well
as course of depression may be causally related. As evidenced from clinical and
preclinical studies, underlying mechanisms of these abnormalities involve impairment
of central corticosteroid receptor function which leads to enhanced activity of
hypothalamic neurons synthesising and releasing vasopressin and CRH. These neuropeptides
mediate not only neuroendocrine but also behavioural effects. Recent research
provided evidence that CRH can induce depression-like symptoms in animals and
that these signs are mediated through the CRH1 receptor subtype. Hence, therapeutical
application of new compounds acting more specifically on the HPA system such as
CRH1 receptor antagonists appear to be a promising approach for future treatment
options of depression. In conclusion, research in neuroendocrinology provided
new insights into the underlying pathophysiology of depression and, in consequence,
may lead to the development of new therapeutic tools." [Abstract]
SC, Owens MJ, Nemeroff CB.
Regulation of corticotropin-releasing
factor neuronal systems and hypothalamic-pituitary-adrenal axis activity by stress
and chronic antidepressant treatment.
J Pharmacol Exp Ther
"In a series of experiments, we tested the hypothesis
that chronic antidepressant drug administration reduces the synaptic availability
of corticotropin-releasing factor (CRF) through one or more effects on CRF gene
expression or peptide synthesis. We also determined whether effects of acute or
chronic stress on CRF gene expression or peptide concentration are influenced
by antidepressant drug treatment. Four-week treatment with venlafaxine, a dual
serotonin (5-HT)/norepinephrine (NE) reuptake inhibitor, and tranylcypromine,
a monoamine oxidase inhibitor, resulted in an attenuation of acute stress-induced
increases in CRF heteronuclear RNA (hnRNA) synthesis in the paraventricular nucleus
(PVN). Trends toward the same effect were observed after treatment with the 5-HT
reuptake inhibitor fluoxetine, or the NE reuptake inhibitor reboxetine. CRF mRNA
accumulation in the PVN during exposure to chronic variable stress was attenuated
by concurrent antidepressant administration. Basal CRF hnRNA and mRNA expression
were not affected by antidepressant treatment in the PVN or in other brain regions
examined. Chronic stress reduced CRF concentrations in the median eminence, but
there were no consistent effects of antidepressant drug treatment on CRF, serum
corticotropin, or corticosterone concentrations. CRF receptor expression and basal
and stress-stimulated HPA axis activity were unchanged after antidepressant administration.
These results suggest that chronic antidepressant administration diminishes the
sensitivity of CRF neurons to stress rather than alters their basal activity.
Additional studies are required to elucidate the functional consequences and mechanisms
of this interaction." [Abstract]
Heuser I, Bissette G, Dettling M, Schweiger U, Gotthardt
U, Schmider J, Lammers CH, Nemeroff CB, Holsboer F.
fluid concentrations of corticotropin-releasing hormone, vasopressin, and somatostatin
in depressed patients and healthy controls: response to amitriptyline treatment.
"The effect of amitriptyline upon hypothalamic-pituitary-adrenal
[HPA]-system-regulating neuropeptides (corticotropin-releasing hormone [CRH],
vasopressin, somatostatin) was studied in a group of depressed elderly patients
and controls. A first lumbar puncture was performed in 37 depressed in-patients.
This was followed by a 6-week medication phase with amitriptyline. Upon its completion
a second cerebrospinal fluid (CSF) sample was obtained in 18 of these 37 patients.
In 25 healthy controls a first lumbar puncture was done eleven of these individuals
agreed to take 75 mg/d amitriptyline for 6 weeks and to participate in the follow-up
CSF study. Within the group of depressed patients amitriptyline led to a significant
decrease of CSF CRH in treatment responders only (F1, 16 = 5.2; P < 0.02).
Also, in normal controls CSF CRH concentration tended to decrease with amitriptyline
treatment (t-test; P < 0.09). No effects of amitriptyline upon vasopressin
or somatostatin were observed. In normal controls (r = 0.4; P < 0.02) and in
patients (r = 0.4; P < 0.03) age correlated positively with baseline CSF somatostatin.
A trend for CSF CRH to increase with aging was found only in controls (r = 0.3;
P < 0.09); patients did not show a significant association here. Finally, CSF
neuropeptide concentration at baseline did not differ between the group of depressed
patients and healthy controls. Our study corroborates the evolving concept that
antidepressants effect various components of the HPA system with the net result
of a reduction in its activity. In addition, we found CSF CRH and CSF somatostatin
concentrations to be better reflections of age than of depression and, finally,
that during aging and during depression the HPA system changes in similar directions."
Hassan A, Chacko S, Mason D.
of the adrenocorticotrophin responses to arginine vasopressin and corticotrophin-releasing
hormone in ovine anterior pituitary cells.
"Following repeated or prolonged exposure to
either corticotrophin-releasing hormone (CRH) or arginine vasopressin (AVP), pituitary
adrenocorticotrophin (ACTH) responsiveness is reduced. This study compared the
characteristics of desensitization to CRH and AVP in perifused ovine anterior
pituitary cells. Desensitization to AVP occurred at relatively low AVP concentrations
and was both rapid and readily reversible. Treatment for 25 min with AVP at concentrations
greater than 2 nM caused significant reductions in the response to a subsequent
5 min 100 nM AVP pulse (IC(50)=6.54 nM). Significant desensitization was observed
following pretreatment with 5 nM AVP for as briefly as 5 min. Desensitization
was greater following a 10 min pretreatment, but longer exposures caused no further
increase. Resensitization was complete within 40 min following 15 min treatment
with 10 nM AVP. Continuous perifusion with 0.01 nM CRH had no effect on AVP-induced
desensitization. Treatment with 0.1 nM CRH for either 25 or 50 min caused no reduction
in the response to a subsequent 5 min stimulation with 10 nM CRH. When the pretreatment
concentration was increased to 1 nM significant desensitization was observed,
with a greater reduction in response occurring after 50 min treatment. Recovery
of responsiveness was progressive following 50 min treatment with 1 nM CRH and
was complete after 100 min. Our data show that in the sheep AVP desensitization
can occur at concentrations and durations of AVP exposure within the endogenous
ranges. This suggests that desensitization may play a key role in regulating ACTH
secretion in vivo. If, as has been suggested, CRH acts to set corticotroph gain
while AVP is the main dynamic regulator, any change in responsiveness to CRH may
significantly influence the overall control of ACTH secretion." [Abstract]
D, Skelton KH, Owens MJ, Nemeroff CB.
Are CRF receptor antagonists
Hum Psychopharmacol 2001 Jan;16(1):81-87
"Corticotropin-releasing factor (CRF) is the major regulator of the hypothalamic-pituitary-adrenal
(HPA) axis, and plays a key role in coordinating the endocrine, as well as autonomic
and behavioral responses of an organism to stress. Direct CNS administration of
CRF to laboratory animals produces an aggregate of effects that mimic the mammalian
stress response. Impeding CRF function with CNS administration of a peptidergic
CRF antagonist can block these manifestations of the stress response whether produced
by exogenous CRF or occurring naturally in response to a stressor. A role for
hypersecretion of CRF in the pathophysiology of depression is suggested by the
finding that CNS administration of CRF mirrors many of the signs and symptoms
utilized as diagnostic criteria for major depression. In addition, a large body
of clinical evidence points to excess hypothalamic secretion of CRF and an accompanying
HPA axis hyperactivity in patients with major depression. The recent development
of selective, small molecule CRF(1) receptor antagonists, which block the effects
of CRF both in vitro and in vivo, suggest that these compounds may be effective
in the treatment of affective and anxiety disorders. Early evidence indicates
that these agents possess anxiolytic and antidepressant activity in animal behavioral
AW, Nickel T, Kunzel HE, Ackl N, Sonntag A, Ising M, Holsboer F.
of the high-affinity corticotropin-releasing hormone receptor 1 antagonist R121919
in major depression: the first 20 patients treated.
Res 2000 May-Jun;34(3):171-81
"Clinical and preclinical data suggest
that unrestrained secretion of corticoctropin-releasing hormone (CRH) in the CNS
produces several signs and symptoms of depression and anxiety disorders through
continuous activation of CRH(1) receptors. This led to the development of drugs
that selectively antagonize CRH(1) receptors suppressing anxiety-like behavior
in rats and also in monkey models of anxiety. These findings led to a clinical
development program exploring the antidepressive potential of R121919, a water-soluble
pyrrolopyrimidine that binds with high affinity to human CRH(1) receptors and
is well absorbed in humans. This compound was administered to 24 patients with
a major depressive episode primarily in order to investigate whether its endocrine
mode of action compromises the stress-hormone system or whether other safety and
tolerability issues exist. The patients were enrolled in two dose-escalation panels:
one group (n=10) where the dose range increased from 5-40 mg and another group
(n=10) where the dose escalated from 40 to 80 mg within 30 days each. Four patients
dropped out because of withdrawal of consent to participate (three cases) or worsening
of depressive symptomatoloy in one case. We found that R121919 was safe and well
tolerated by the patients during the observation period. Moreover, the data suggested
that CRH(1)-receptor blockade does not impair the corticotropin and cortisol secretory
activity either at baseline or following an exogenous CRH challenge. We also observed
significant reductions in depression and anxiety scores using both, patient and
clinician ratings. These findings, along with the observed worsening of affective
symptomatology after drug discontinuation, suggests that the pharmacological principle
of CRH(1)-receptor antagonism has considerable therapeutic potential in the treatment
and the prevention of diseases where exaggerated central CRH activity is present
at baseline or following stress exposure." [Abstract]
HE, Zobel AW, Nickel T, Ackl N, Uhr M, Sonntag A, Ising M, Holsboer F.
of depression with the CRH-1-receptor antagonist R121919: endocrine changes and
J Psychiatr Res. 2003 Nov-Dec;37(6):525-33.
dysregulation of the hypothalamus-pituitary-adrenocortical (HPA) system has been
hypothesized to account for a myriad of cardinal symptoms of affective disorders.
Specifically, increased CRH signalling via CRH type 1 receptors is thought to
be an important factor in the pathogenesis of major depression and anxiety disorders.
Consequently, a number of drugs have been developed in order to target the postulated
increase in CRH/CRH 1 receptor signalling. One of these compounds, R121919, binds
with high affinity to CRH1 receptors antagonising the action of CRH. R121919 was
recently tested in an open-label study conceptualized as a safety and tolerability
study. As part of this study, a thorough endocrine evaluation and detailed clinical
laboratory analysis were assessed several times during 30 days of treatment with
two different dose regimens of R121919 (5-40 mg vs. 40-80 mg) in 24 patients with
a major depressive episode. During treatment with the experimental drug no serious
side effects were noted. In particular, there were no adverse effects or impairment
of the hypothalamic-pituitary-gonadal system, the hypothalamic-pituitary-thyroid
axis, the renin-angiotensin system, prolactin or vasopressin secretion. Furthermore,
no changes in the serum corticotropin and cortisol concentrations and in the responsivity
of corticotropin and cortisol following a CRH stimulation test were noted. No
effects of R121919 on clinical laboratory parameters including liver enzymes,
EEG and ECG were observed. These results encourage the development of other CRH-1-R
antagonists as a novel class of antidepressive drugs." [Abstract]
Mansbach RS, Brooks EN, Chen YL.
effects of CP-154,526, a selective CRF1 receptor antagonist.
Eur J Pharmacol 1997 Mar 26;323(1):21-6
"The effects of CP-154,526 (butyl-ethyl-[2,5-dimethyl-7-(2,4,6
-trimethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine), a selective corticotropin
releasing factor (CRF1) receptor antagonist, were examined in the learned helplessness
procedure, a putative model of depression with documented sensitivity to diverse
classes of antidepressant drugs. Rats were exposed to a series of inescapable
foot shocks on three consecutive days and tested in a shock-escape procedure on
the fourth day. Animals exposed to 'helplessness' training performed poorly in
the shock-escape test compared with control animals not receiving inescapable
shocks. CP-154,526 (10-32 mg/kg, intraperitoneally) dose-dependently reversed
the escape deficit when administered 60 min prior to the test session, but had
no effect on the performance of control rats not receiving prior exposure to inescapable
stress. In comparison, the tricyclic antidepressant imipramine (17.8 mg/kg) reversed
the escape deficit after repeated, but not acute, administration. These data support
evidence implicating stress systems in the pathophysiology of depression, and
suggest potential efficacy of small-molecule CRF receptor antagonists in the treatment
of affective disorders." [Abstract]
G, Simiand J, Steinberg R, Jung M, Gully D, Roger P, Geslin M, Scatton B, Maffrand
JP, Soubrie P.
thiazol-2-amine hydrochloride (SSR125543A), a potent and selective corticotrophin-releasing
factor(1) receptor antagonist. II. Characterization in rodent models of stress-related
J Pharmacol Exp Ther 2002 Apr;301(1):333-45
"The present study investigated the effects of the novel corticotrophin-releasing
factor (CRF)(1) receptor antagonist 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-
hydrochloride (SSR125543A) in a variety of rodent models of anxiety, including
conflict procedures (punished drinking and four-plate), exploration models (elevated
plus-maze and light/dark), a fear/anxiety defense test battery, and several procedures
based on stress-induced changes in physiological (isolation-induced hyperthermia
and tail pinch-induced cortical norepinephrine release) or behavioral (social
defeat-induced anxiety, maternal separation-induced vocalization) parameters.
Moreover, the effects of SSR125543A were investigated in acute (forced swimming)
and chronic (chronic mild stress; CMS) models of depression. SSR125543A and the
CRF(1) receptor antagonist antalarmin displayed limited efficacy in exploration-based
anxiety models. In contrast, both compounds produced clear-cut anxiolytic-like
activity in models involving inescapable stress, including the conflict procedures,
the social defeat-induced anxiety paradigm and the defense test battery (3-30
mg/kg i.p. or p.o.). These effects paralleled those of the anxiolytic diazepam.
In addition, SSR125543A and antalarmin antagonized stress-induced hyperthermia,
distress vocalization, and cortical norepinephrine release. In the forced swimming
test, 30 mg/kg p.o. SSR125543A and 3 to 30 mg/kg p.o. antalarmin produced clear
antidepressant-like effects. These latter results were strengthened by the findings
from the CMS, which showed that repeated administration of 10 mg/kg i.p. SSR125543A
for 30 days improved the degradation of the physical state, the reduction of body
weight gain, and anxiety produced by stress. Together, these data indicate that
SSR125543A shows good activity in acute and chronic tests of unavoidable stress
exposure, suggesting that it may have a potential in the treatment of depression
and some forms of anxiety disorders." [Abstract]
Arborelius, Lotta, Skelton, Kelly H., Thrivikraman, Karacheri
V., Plotsky, Paul M., Schulz, David W., Owens, Michael J.
Administration of the Selective Corticotropin-Releasing Factor 1 Receptor Antagonist
CP-154,526: Behavioral, Endocrine and Neurochemical Effects in the Rat
J Pharmacol Exp Ther 2000 294: 588-597
1 (CRF1) receptor antagonists may represent a novel group of drugs for the pharmacotherapy
of depression and/or anxiety disorders. We have investigated the behavioral, endocrine,
and neurochemical effects of chronic administration of a selective CRF1 receptor
antagonist, CP-154,526. After 9 to 10 days of treatment with CP-154,526 (3.2 mg/kg/day),
defensive withdrawal behavior was significantly decreased suggesting anxiolytic
activity. In animals treated for 14 days with the low dose of CP-154,526, serum
corticosterone concentrations returned to baseline levels faster after application
of an airpuff startle. Using in situ hybridization, no changes in CRF1 receptor
mRNA expression were detected in parietal cortex, basolateral amygdala, or cerebellum
after chronic treatment with CP-154,526. A dose-dependent decrease in CRF mRNA
expression was observed in the hypothalamic paraventricular nucleus (PVN) and
the Barrington's nucleus, an effect that was significant at the high but not the
low dose of CP-154,526. CP-154,526 did not alter central CRF2A receptor binding
or mRNA expression, or urocortin mRNA expression. The present findings suggest
that chronic administration of CP-154,526 produces anxiolytic-like effects but
no evidence of adrenal insufficiency. Previous postmortem studies revealed increased
CRF peptide and mRNA levels in the PVN of depressed patients, which may mediate
the hyperactivity of the hypothalamic-pituitary-adrenal axis observed in such
patients. In view of a possible use for CRF1 receptor antagonists in the treatment
of depression, the present finding that CP-154,526 decreases CRF synthesis in
the PVN is of considerable interest." [Full
Willenberg HS, Bornstein SR, Hiroi N, Path
G, Goretzki PE, Scherbaum WA, Chrousos GP.
Effects of a novel corticotropin-releasing-hormone
receptor type I antagonist on human adrenal function.
Psychiatry 2000 Mar;5(2):137-41
"Corticotropin-releasing hormone (CRH)
is the principal regulator of the hypothalamic-pituitary-adrenal (HPA) axis and
an activator of the sympathoadrenal (SA) and systemic sympathetic (SS) systems.
Mental disorders, including major depression and, more recently, Alzheimer's disease
have been associated with dysregulation of the HPA axis and the SA/SS systems.
Treatment of rats or monkeys with the novel CRH receptor type 1 (CRH-R1) antagonist
antalarmin inhibits the HPA and/or the SA/SS axes. This is the first study to
examine the potential direct effect of antalarmin on human adrenal function. Adrenocortical
and adrenomedullary cells were characterized by double-immunohistochemistry with
anti-17 alpha hydroxylase (cortical cells) and anti-chromogranin A (chromaffin
cells). Expression of CRH, ACTH, CRH type I and type II receptor mRNA were analyzed
by reverse-transcription (RT) PCR. Human adrenal cortical and/or chromaffin cells
in co-culture were incubated with CRH, antalarmin, and both CRH and antalarmin
in vitro. Exposure of these cells to corticotropin or vehicle medium served as
positive and negative controls, respectively. Cortical and chromaffin tissues
were interwoven in the human adrenals, and both in situ and in the co-culture
system the endocrine cell types were in close cellular contact. ACTH, CRH, and
CRH-R1 and CRH-R2 mRNAs were expressed in the human adrenal as determined by RT-PCR.
CRH (10-8 M) led to a moderate increase of cortisol release (145.7 +/- 20.0%)
from cortical and chromaffin adrenal cells in co-culture. This effect corresponded
to 41.8% of the maximal increase induced by ACTH (10-8 M). The action of CRH was
completely inhibited by antalarmin. CRH, ACTH, and both CRH-R1 and CRH-R2 mRNAs
are expressed in the adult human adrenal gland. CRH stimulates cortisol production
in cortical and chromaffin cell co-cultures. This effect is blocked by antalarmin,
a selective CRH-R1 receptor antagonist, suggesting that CRH-R1 receptors are involved
in an intraadrenal CRH/ACTH control system in humans." [Abstract]
J, Jahn H, Kellner M, Strohle A, Yassouridis A, Wiedemann K.
of sympathetic activity by corticotropin-releasing hormone and atrial natriuretic
Neuropeptides. 2003 Dec;37(6):362-8.
Heart rate variability represents a reliable marker to delineate the status of
autonomic nervous system (ANS) function and alterations due to stress in vivo.
Interestingly, up to now the effects of corticotropin-releasing hormone (CRH),
a key regulator of the stress hormone system, upon heart rate variability are
not sufficiently described. Hence, we attempted to investigate the ANS-effects
of a CRH bolus and the modulatory influences of atrial natriuretic peptide (ANP),
one of the most important functional antagonist of CRH actions.METHODS: 12 healthy
male volunteers were administered 100 microg CRH as bolus injection at 15:00.
Six randomly chosen subjects received 150 microg ANP dissolved in normal saline
and six subjects a normal saline infusion from 14:45 to 15:15. From 13:00 to 17:00
an ECG was recorded and mean heart rate (HR), total power (TP), very low frequency
(VLF), low frequency (LF), LF in normalized units (LF [nu]), high frequency (HF)
domains and the LF/HF-ratio in the interval from 14:00 to 16:00 were determined.RESULTS:
After administration of CRH a significant increase in HR and a fast reduction
of TP were observed, which lasted about 1 h. Based upon spectral domain analyses
the sympathetic activity after CRH administration as indicated by LF [nu] increased
by 31% (mean location) during saline. Applying ANP this increase was reduced to
19% (mean location). The VLF component, which is considered to be based in part
also on sympathetic influences, indicates comparable effect. During saline the
VLF after CRH bolus remained largely unchanged, but was reduced to 66% by ANP.
Though the vagal activity indicated by the HF component was reduced after CRH,
no significant differences emerged between both treatments. The changes of the
LF/HF-ratio were pronounced in both groups. During saline this ratio increased
by about 111%, during ANP only by 43% (mean location).CONCLUSIONS: Based upon
HRV analysis the CRH administration induced sympathotonic effects which were antagonized
by ANP. The observed vagal changes were less pronounced and need further investigation.
Further studies of autonomic effects by alterations of CRH secretion in depression
and anxiety disorder are strongly warranted." [Abstract]
PW, Calabrese JR, Kling MA, Avgerinos P, Khan I, Gallucci WT, Tomai TP, Chrousos
Abnormal ACTH and cortisol responses to ovine corticotropin
releasing factor in patients with primary affective disorder.
Prog Neuropsychopharmacol Biol Psychiatry 1986;10(1):57-65
explore hypothalamic pituitary adrenal regulation in patients with affective illness,
we administered 1 microgram/kg of synthetic ovine corticotropin releasing factor
at 2000h to 26 drug-free patients with this disorder and to 15 healthy controls.
Compared to controls, depressed patients (N = 12) showed a significant elevation
in baseline cortisol and significant reductions in the net ACTH and cortisol responses
to corticotropin releasing factor. These findings were normal in manic (N = 6)
and improved (N = 8) subjects. An additional finding was that baseline cortisol
and net ACTH and cortisol responses to CRF were negatively correlated in the entire
group of patients and controls as well as in the patients alone. These data indicate
that the reduced ACTH and cortisol responses to CRF in depression reflect normal
functioning of the pituitary corticotroph cell (i.e., that the negative feedback
effect of cortisol on ACTH secretion in depression is physiologically intact,
effectively serving as a brake on the ACTH response to exogenous CRF. Thus, the
hypercortisolism of depression may be due to a hypothalamic defect, possibly involving
hypersecretion of endogenous CRF. This possibility may be of particular interest
in light of clinical observations that depression can often be precipitated by
stress and by data in experimental animals that CRF may influence several processes
known to be altered in the overall symptom complex of depression." [Abstract]
D, Bersani G, Melia E, Magnani A, Antonozzi I, Frajese G.
factor and adrenal function in major depression.
Invest 1988 Nov;11(10):697-701
"We investigated ACTH and cortisol responses
after ovine CRF injection (1 microgram/kg one bolus) in a group of 11 drug-free
patients suffering from major depression. When compared to sex- and age-matched
normal controls, our depressed patients showed: Higher ACTH basal values (p less
than 0.002); higher cortisol basal values (p less than 0.009); blunted ACTH response
to oCRF administration (p less than 0.23); higher cortisol response to oCRF (p
less than 0.001). Our data show that in depressed patients the feed-back mechanism
is functionally intact at the pituitary level on one hand, while on the other,
a hyperresponsiveness of adrenal cortex (even to minimal stimuli) seems to be
present. Moreover, a hypersecretion of endogenous CRF in these patients seems
to be likely." [Abstract]
The role of corticotropin releasing factor in depressive illness:
a critical review.
Neurosci Biobehav Rev 1998 Sep;22(5):635-51
"Corticotropin-releasing factor (CRF) is the principal neuropeptide involved
in regulating the stress response. When centrally administered to animals it produces
somatic changes analogous to those seen in both depression and anxiety. In humans,
it is capable of reproducing the hormonal changes which are characteristically
seen in depressed patients. A literature search using Medline, Embase Psychiatry,
PsycLIT and BIDS from 1996-1997 revealed 25 studies that have examined CRF concentrations
in patients with affective disorder. The methodology of these studies varies and
they can be criticised, in particular, for failing to consider the stress response
of the lumbar puncture. Recently, post-mortem immunocytochemical techniques have
been employed to help clarify the nature of these abnormalities in depression.
On balance, evidence from CSF sampling, post-mortem findings and dynamic endocrine
studies suggests that both hypothalamic and extra-hypothalamic concentrations
of CRF are moderately elevated in a proportion of currently antidepressant treatment,
high CRF concentrations tend to normalise. The causes of increased CRF output
in depression are also unknown but may involve an integration of remote vulnerability
factors and recent stressors perhaps mediated through impaired function of glucocorticoid
receptors. Ultimately, the careful manipulation of CRF may hold therapeutic promise
for sufferers of mood disorders." [Abstract]
CB, Bissette G, Akil H, Fink M.
Neuropeptide concentrations in the
cerebrospinal fluid of depressed patients treated with electroconvulsive therapy.
Corticotrophin-releasing factor, beta-endorphin and somatostatin.
Br J Psychiatry 1991 Jan;158:59-63
"The CSF concentrations of CRF, somatostatin
and beta-endorphin were determined in nine patients who fulfilled DSM-III criteria
for major depression with psychotic features. CSF samples were obtained at baseline
in the depressed state, and again after a course of ECT. Concentrations of both
CRF and beta-endorphin decreased after ECT, while the concentration of somatostatin
increased, although the latter difference did not attain statistical significance.
The increase in CSF concentrations of CRF and beta-endorphin in depressed patients
is therefore seen to be state-dependent." [Abstract]
MJ, Bissette G, Nemeroff CB.
Acute effects of alprazolam and adinazolam
on the concentrations of corticotropin-releasing factor in the rat brain.
"Corticotropin-releasing factor (CRF) is the
major physiological regulator of the hypothalamic-pituitary-adrenal (HPA) axis.
However, considerable evidence indicates that CRF may be responsible for integrating
not only the endocrine, but the autonomic and behavioral responses of an organism
to stress as well. In addition, clinical studies indicate that CRF of both hypothalamic
and extrahypothalamic origin may be hypersecreted in major depression as well
as other psychiatric disorders. These findings, taken together, led to the hypothesis
that the efficacy of antidepressant and/or anxiolytic drugs may be related to
their actions on CRF-containing neural pathways in the central nervous system
(CNS). Therefore, alterations of CRF concentrations in 18 rat brain regions were
studied after acute administration of a tricyclic antidepressant (imipramine)
or one of two triazolobenzodiazepines (alprazolam or adinazolam) that possess
anxiolytic properties typical of benzodiazepines, as well as purported antidepressant
activity unique to these compounds. Treatment with alprazolam or adinazolam increased
hypothalamic CRF concentrations, which was associated with lower plasma ACTH concentrations.
In contrast, the concentration of CRF was markedly reduced in the locus coeruleus,
amygdala, and several cortical regions by either triazalobenzodiazepine. Acute
treatment with imipramine was without effect on CRF concentrations in any brain
region studied. Of particular interest is the finding that the two triazolobenzodiazepines
exert effects on CRF concentrations in the locus coeruleus and hypothalamus that
are opposite to CRF changes seen after stress." [Abstract]
N, Wong ML, Licinio J, Park C, Young M, Gold PW, Chrousos GP, Bornstein SR.
Expression of corticotropin releasing hormone receptors type I and type
II mRNA in suicide victims and controls.
"Corticotropin-releasing hormone (CRH) is a key neuroendocrine
factor implementing endocrine, immune and behavioral responses to stress. CRH
exerts its action through two major receptors, CRH-R1 and CRH-R2. Recently novel
non-peptidic antagonists directed against CRH-R1 or CRH-R2 have been proposed
as promising agents in the treatment of depression, anxiety and eating disorder.
However, so far the CRH-receptor system has not been widely studied in humans.
Therefore, we employed quantitative TaqMan PCR to analyze the expression and distribution
of both CRH-R1 and CRH-R2 in human brain tissue and peripheral organs. Furthermore
the expression of CRH receptors was analyzed for the first time in pituitaries
of suicide victims by in situ hybridization and quantitative PCR. Our data demonstrated
a different expression pattern in humans as compared to rodents. Both CRH-R1 and
CRH-R2 were expressed in high amounts in the brain with the strongest expression
in the pituitary. As described in rodents, however the CRH-R1 in human was the
predominant receptor in the brain (82.7 +/- 11.0%), whilst CRH-R2 was the predominant
receptor in peripheral organs (77.0 +/- 15.8%). There was a shift in the ratio
of CRH-R1/R2 in the pituitaries of suicide victims. In conclusion, both CRH-R1
and CRH-R2 are widely expressed in human tissues with a distribution substantially
different from rodents. Strong expression of both CRH-R1 and CRH-R2 in human pituitaries
suggests that particularly under stress, activation of the HPA axis can be maintained
through both receptors." [Abstract]
Z, Du L, Hrdina P, Palkovits M, Faludi G, Poulter MO, Anisman H.
in the suicide brain: mRNA expression of corticotropin-releasing hormone receptors
and GABA(A) receptor subunits in frontal cortical brain region.
Neurosci. 2004 Feb 11;24(6):1478-85.
(CRH) and GABA have been implicated in depression, and there is reason to believe
that GABA may influence CRH functioning. The levels of CRH, and mRNA for CRH-binding
protein, CRH1, and CRH2 receptors, as well as various GABA(A) receptor subunits
(alpha1, alpha2, alpha3, alpha4, alpha5, delta, and gamma2), were determined in
several frontal cortical brain regions of depressed suicide victims and nondepressed
individuals who had not died by suicide. Relative to the comparison group, CRH
levels were elevated in frontopolar and dorsomedial prefrontal cortex, but not
in the ventrolateral prefrontal cortex of suicide victims. Conversely, using quantitative
PCR analyses, it was observed that, in frontopolar cortex, mRNA for CRH1, but
not CRH2, receptors were reduced in suicide brains, possibly secondary to the
high levels of CRH activity. In addition, mRNA of the alpha1, alpha3, alpha4,
and delta receptor subunits was reduced in the frontopolar region of suicide victims.
Interestingly, a partial analysis of the GABA(A) receptor functional genome revealed
high cross-correlations between subunit expression in cortical regions of nondepressed
individuals, suggesting a high degree of coordinated gene regulation. However,
in suicide brains, this regulation was perturbed, independent of overall subunit
abundance. These findings raise the possibility that the CRH and GABA(A) receptor
subunit changes, or the disturbed coordination between these GABA(A) receptor
subunits, contribute to depression and/or suicidality or are secondary to the
illness/distress associated with it." [Abstract]
D, Lowter S, Crompton MR, Katona CL, Horton RW.
factor binding sites in cortex of depressed suicides.
(Berl) 1997 Nov;134(2):174-8
"Corticotropin-releasing factor (CRF) receptors
were measured by saturation binding in frontal and motor cortex of suicides with
a firm retrospective diagnosis of depression, and matched controls. The suicides
were divided into those who were free of antidepressant drugs, and those in whom
prescription of antidepressant drugs was clearly documented. There were no differences
in the number or affinity of CRF receptors between antidepressant-free or antidepressant-treated
suicides and matched controls in either brain region. When suicides were divided
according to violence of death, again there were no differences between violent
or non-violent suicides and controls." [Abstract]
Nemeroff CB, Owens MJ, Bissette G, Andorn AC, Stanley
Reduced corticotropin releasing factor binding sites in the
frontal cortex of suicide victims.
Arch Gen Psychiatry
"Previous studies have provided evidence that corticotropin
releasing factor (CRF) is hypersecreted in patients with major depression. This
CRF hypersecretion is believed to contribute at least in part to hyperactivity
of the hypothalamic-pituitary-adrenal axis in depressed patients. If CRF is chronically
hypersecreted in depressed patients, then, due to down-regulation, a reduced number
of CRF receptor binding sites should be present in patients with profound depressive
disorder. To test this hypothesis, we measured the number and affinity of CRF
binding sites in the frontal cortex of 26 suicide victims and 29 controls who
died of a variety of causes. There was a marked (23%) reduction in the number
of CRF binding sites in the frontal cortex of the suicide victims compared with
the controls. These data are consistent with the hypothesis that CRF is hypersecreted
in depression." [Abstract]
MJ, Nemeroff CB.
The role of corticotropin-releasing factor in the
pathophysiology of affective and anxiety disorders: laboratory and clinical studies.
Ciba Found Symp 1993;172:296-308; discussion 308-16
"The unique distribution
of corticotropin-releasing factor (CRF) and its receptors within the central nervous
system, its pre-eminent role in mediating the endocrine, behavioural, autonomic
and immunological effects of stress and its potent effects after direct administration
into the CNS all support the hypothesis that alterations in CRF neuronal systems
contribute to the pathophysiology of depression and certain anxiety disorders.
This report summarizes a series of preclinical and clinical investigations which
have sought to test the hypothesis that CRF-containing neurons show alterations
in depression and anxiety, and that drugs used to treat these disorders alter
CRF neuronal circuits. Direct injection of CRF into the locus ceruleus or nearby
parabrachial nucleus evokes an anxiogenic response. Stress increases CRF concentrations
in the locus ceruleus, whereas alprazolam, a benzodiazepine anxiolytic, decreases
the concentration of the peptide in the same area. Clinical studies reveal that
drug-free depressed patients show: (1) hyperactivity of the hypothalamo-pituitary-adrenal
axis; (2) increased CRF concentrations in the cerebrospinal fluid; (3) a blunted
release of ACTH in response to CRF; (4) a reduced density of CRF receptors in
the frontal cortex; (5) pituitary and adrenal gland hypertrophy. These findings
are all concordant with hypersecretion of CRF from hypothalamic and extrahypothalamic
CRF neurons in depression." [Abstract]
Kasckow JW, Baker D, Geracioti TD Jr.
hormone in depression and post-traumatic stress disorder.
Peptides 2001 May;22(5):845-51
"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." [Abstract]
J, Gold PW.
Role of corticotrophin releasing hormone 41 in depressive
Baillieres Clin Endocrinol Metab 1991 Mar;5(1):51-8
"CRH seems to be of fundamental importance in depressive illness. Melancholic
depressed patients, with a syndrome of hyperarousal, have increased activity of
CRH-producing neurones. Conversely, there is evidence to support the notion that
patients with atypical depression, a syndrome of hypoarousal, have decreased activity
of CRH-producing neurones. CRH-induced kindling is a possible model for the natural
history of depressive illness. Finally, effective treatments for depressive illness,
such as tricyclic antidepressants, decrease CRH production, and drugs, such as
carbamazepine, effective in preventing the recurrence of affective disorder, also
decrease CRH production. Interestingly, these drugs are not particularly effective
in the treatment of atypical depression, which seems to be related not to an activation
of CRH-producing neurones, but rather to a decrease of CRH secretion." [Abstract]
LK, Asnis GM, Rubinson E.
Biological and clinical validation of
Psychiatry Res 1996 Mar 29;60(2-3):191-8
"Depressed patients with (a) mood reactivity alone (MR group), (b) mood reactivity
plus one or more associated features (atypical depression, AD group), and (c)
patients with neither mood reactivity nor atypical depression (non-MR/AD group)
were compared on their cortisol response to 75 mg of desipramine (DMI), a relatively
selective norepinephrine reuptake inhibitor. AD patients exhibited a significantly
higher cortisol response to DMI compared with MR and non-MR/AD patients, suggesting
that atypical depression may be associated with a less impaired norepinephrine
system. MR and non-MR/AD patients did not differ, suggesting that mood reactivity
alone is not associated with the biological profile observed in atypical depression.
Results indicate that while mood reactivity may be necessary for the diagnosis
of atypical depression, the additional presence of at least one associated symptom
is required for a distinct biological profile. Our findings provide further biological
validation of the concept of atypical depression." [Abstract]
RD, Vaccarino FJ, Brown GM, Kennedy SH.
Low-dose dexamethasone challenge
in women with atypical major depression: pilot study.
Psychiatry Neurosci 2002 Jan;27(1):47-51
"OBJECTIVE: To examine if atypical
depression may be associated with hypersuppression of the hypothalamic-pituitary-adrenal
(HPA) axis. METHOD: Eight women with atypical major depression and 11 controls
with no history of psychiatric illness, matched on age and body mass index, were
challenged with low-dose dexamethasone (0.25 mg and 0.50 mg in random order and
1 week apart). Dexamethasone was self administered at 11 pm, and plasma cortisol
samples were drawn at 8 am and 3 pm on the following day. RESULTS: After the 0.50-mg
dexamethasone challenge, mean suppression of morning cortisol was significantly
greater in patients with atypical depression (91.9%, standard deviation [SD] 6.8%)
than in the controls (78.3%, SD 10.7%; p < 0.01). CONCLUSION: These preliminary
data add to the growing body of literature that suggests atypical depression,
in contrast to classic melancholia, may be associated with exaggerated negative
feedback regulation of the HPA axis." [Abstract]
L, Raison CL, Musselman DL, Lawson DH, Nemeroff CB, Miller AH.
of exaggerated HPA axis response to the initial injection of interferon-alpha
with development of depression during interferon-alpha therapy.
J Psychiatry. 2003 Jul;160(7):1342-5.
"OBJECTIVE: The authors assessed
the relationship between the hypothalamic-pituitary-adrenal (HPA) axis response
to interferon-alpha (IFN-alpha) and the development of major depression during
IFN-alpha treatment. METHOD: Adrenocorticotropic hormone (ACTH), cortisol, and
interleukin-6 (IL-6) plasma concentrations were measured in 14 patients with malignant
melanoma at regular intervals during the first 12 weeks of IFN-alpha therapy,
both immediately before and 1, 2, and 3 hours after IFN-alpha administration.
Symptom criteria for major depression were also evaluated at each visit. RESULTS:
ACTH and cortisol responses but not IL-6 responses to the initial administration
of IFN-alpha were significantly higher in the seven patients who subsequently
developed symptom criteria for major depression than in those who did not. No
differences in hormonal or cytokine responses were found between these two groups
during chronic IFN-alpha administration. CONCLUSIONS: The HPA axis response to
the acute administration of IFN-alpha reveals a vulnerability to IFN-alpha-induced
depression, possibly due to sensitization of corticotropin-releasing factor pathways."
B, Jaworska-Feil L, Tetich M, Basta-Kaim A, Kubera M, Leskiewicz M, Lason W.
of the Human Corticotropin-Releasing-Hormone Gene Promoter Activity by Antidepressant
Drugs in Neuro-2A and AtT-20 Cells.
2004 Jan 21 [Epub ahead of print]
"Major depression is frequently associated
with hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis. Clinically
effective therapy with antidepressant drugs normalizes the disturbed activity
of HPA axis, in part, by decreasing corticotropin-releasing hormone (CRH) synthesis,
but the mechanism of this action is poorly recognized. In order to find out whether
antidepressants directly affect CRH gene promoter activity, we studied their effect
on undifferentiated and differentiated Neuro-2A cells, and for comparison the
effect of the selected antidepressants on AtT-20 cells was also determined. The
cells were stably transfected with a human CRH promoter fragment (-663 to +124
bp) linked to the chloramphenicol acetyltransferase (CAT) reporter gene. The regulation
of CRH gene promoter activity is similar in Neuro-2A cells, both intact and differentiated,
and in AtT-20 cell line, and cAMP/PKA-dependent pathway plays an important role
in the stimulation of CRH gene. It was found that imipramine, amitryptyline, desipramine,
fluoxetine, and mianserin, present in the culture medium for 5 days, in a concentration-dependent
manner inhibited basal hCRH gene promoter activity in undifferentiated Neuro-2A
cells, while other drugs under study (citalopram, tianeptine, moclobemide, venlafaxine,
reboxetine, mirtazapine, and milnacipram) were inactive. In the differentiated
cells, all examined antidepressants, except moclobemide (no effect) and tianeptine
(increase), inhibited hCRH gene transcription. Moreover, in differentiated cells,
the drugs acted stronger and were effective at lower concentrations. Forskolin-induced
CAT activity was attenuated by imipramine and fluoxetine and to a lesser degree
by amitriptyline and desipramine in differentiated cells, whereas other drugs
were inactive. Moreover, imipramine and fluoxetine, but not tianeptine, showed
moderate inhibitory effect on CRH gene promoter activity also in AtT-20 cell line,
commonly used in CRH gene regulation studies. These results indicate that neuron-like
differentiated Neuro-2A cells are a better model than pituitary and intact neuroblastoma
to investigate the mechanism of psychotropic drug action. Inhibition of CRH gene
promoter activity by antidepressant drugs may be a molecular mechanism by which
these drugs inhibit the activity of HPA axis." [Abstract]
Brunson KL, Grigoriadis DE, Lorang MT, Baram TZ.
Corticotropin-releasing hormone (CRH) downregulates the function of
its receptor (CRF1) and induces CRF1 expression in hippocampal and cortical regions
of the immature rat brain.
Exp Neurol 2002 Jul;176(1):75-86
"In addition to regulating the neuroendocrine stress response, corticotropin-releasing
hormone (CRH) has been implicated in both normal and pathological behavioral and
cognitive responses to stress. CRH-expressing cells and their target neurons possessing
CRH receptors (CRF1 and CRF2) are distributed throughout the limbic system, but
little is known about the regulation of limbic CRH receptor function and expression,
including regulation by the peptide itself. Because CRH is released from limbic
neuronal terminals during stress, this regulation might play a crucial role in
the mechanisms by which stress contributes to human neuropsychiatric conditions
such as depression or posttraumatic stress disorder. Therefore, these studies
tested the hypothesis that CRH binding to CRF1 influenced the levels and mRNA
expression of this receptor in stress-associated limbic regions of immature rat.
Binding capacities and mRNA levels of both CRF1 and CRF2 were determined at several
time points after central CRH administration. CRH downregulated CRF1 binding in
frontal cortex significantly by 4 h. This transient reduction (no longer evident
at 8 h) was associated with rapid increase of CRF1 mRNA expression, persisting
for >8 h. Enhanced CRF1 expression-with a different time course-occurred also
in hippocampal CA3, but not in CA1 or amygdala, CRF2 binding and mRNA levels were
not altered by CRH administration. To address the mechanisms by which CRH regulated
CRF1, the specific contributions of ligand-receptor interactions and of the CRH-induced
neuronal stimulation were examined. Neuronal excitation without occupation of
CRF1 induced by kainic acid, resulted in no change of CRF1 binding capacity, and
in modest induction of CRF1 mRNA expression. Furthermore, blocking the neuroexcitant
effects of CRH (using pentobarbital) abolished the alterations in CRF1 binding
and expression. These results indicate that CRF1 regulation involves both occupancy
of this receptor by its ligand, as well as "downstream" cellular activation
and suggest that stress-induced perturbation of CRH-CRF1 signaling may contribute
to abnormal neuronal communication after some stressful situations." [Abstract]
Dautzenberg FM, Hauger RL.
peptide family and their receptors: yet more partners discovered.
Trends Pharmacol Sci 2002 Feb;23(2):71-7
"Abnormal signaling at corticotropin-releasing
factor CRF1 and CRF2 receptors might contribute to the pathophysiology of stress-related
disorders such as anxiety, depression and eating disorders, in addition to cardiac
and inflammatory disorders. Recently, molecular characterization of CRF1 and CRF2
receptors and the cloning of novel ligands--urocortin, stresscopin-related peptide/urocortin
II, and stresscopin/urocortin III--have revealed a far-reaching physiological
importance for the family of CRF peptides. Although the physiological roles of
the CRF2 receptor remain to be defined, the preclinical and clinical development
of specific small-molecule antagonists of the CRF1 receptor opens new avenues
for the treatment of psychiatric and neurological disorders." [Abstract]
PW, Chrousos GP.
Organization of the stress system and its dysregulation
in melancholic and atypical depression: high vs low CRH/NE states.
Mol Psychiatry 2002;7(3):254-75
"Stress precipitates depression and alters
its natural history. Major depression and the stress response share similar phenomena,
mediators and circuitries. Thus, many of the features of major depression potentially
reflect dysregulations of the stress response. The stress response itself consists
of alterations in levels of anxiety, a loss of cognitive and affective flexibility,
activation of the hypothalamic-pituitary-adrenal (HPA) axis and autonomic nervous
system, and inhibition of vegetative processes that are likely to impede survival
during a life-threatening situation (eg sleep, sexual activity, and endocrine
programs for growth and reproduction). Because depression is a heterogeneous illness,
we studied two diagnostic subtypes, melancholic and atypical depression. In melancholia,
the stress response seems hyperactive, and patients are anxious, dread the future,
lose responsiveness to the environment, have insomnia, lose their appetite, and
a diurnal variation with depression at its worst in the morning. They also have
an activated CRH system and may have diminished activities of the growth hormone
and reproductive axes. Patients with atypical depression present with a syndrome
that seems the antithesis of melancholia. They are lethargic, fatigued, hyperphagic,
hypersomnic, reactive to the environment, and show diurnal variation of depression
that is at its best in the morning. In contrast to melancholia, we have advanced
several lines of evidence of a down-regulated hypothalamic-pituitary adrenal axis
and CRH deficiency in atypical depression, and our data show us that these are
of central origin. Given the diversity of effects exerted by CRH and cortisol,
the differences in melancholic and atypical depression suggest that studies of
depression should examine each subtype separately. In the present paper, we shall
first review the mediators and circuitries of the stress system to lay the groundwork
for placing in context physiologic and structural alterations in depression that
may occur as part of stress system dysfunction." [Abstract] [Note that the authors use the atypical acronym CRH rather than the equivalent
Newport DJ, Heim C, Owens MJ, Ritchie
JC, Ramsey CH, Bonsall R, Miller AH, Nemeroff CB.
Corticotropin-Releasing Factor (CRF) and Vasopressin Concentrations Predict Pituitary
Response in the CRF Stimulation Test: A Multiple Regression Analysis.
"There is considerable evidence that stress-related
psychiatric disorders, including depression and post-traumatic stress disorder
(PTSD), are associated with hypersecretion of corticotropin-releasing factor (CRF)
within the central nervous system (CNS). One line of evidence that is consistent
with central CRF hypersecretion in these disorders is the blunted adrenocorticotropin
hormone (ACTH) response to intravenous CRF administration, likely a consequence,
at least in part, of downregulation of anterior pituitary CRF receptors. The present
study tests the hypothesis that elevated cerebrospinal fluid (CSF) concentrations
of CRF and a secondary ACTH secretagogue, arginine vasopressin (AVP), are associated
with diminished adenohypophyseal responses in a standard CRF stimulation test.
CSF concentrations of CRF and AVP, and plasma ACTH responses to the administration
of 1 &mgr;g/kg ovine CRF (oCRF) were measured in healthy adult women with
and without current major depression and/or a history of significant childhood
abuse. The primary outcome measure was ACTH area under the curve (AUC) in the
CRF stimulation test. Multiple linear regression was performed to identify the
impact of CSF CRF and AVP concentrations upon the pituitary response to CRF stimulation.
The regression model explained 56.5% of the variation in the ACTH response to
CRF stimulation. The relationship of CSF concentrations of CRF to ACTH responses
to CRF were best described by a third-order function that was inversely correlated
over most of the range of studied values. The association of ACTH response with
CSF concentration of AVP and the dose of oCRF followed second-order kinetics.
These findings support the hypothesis that central CRF hypersecretion is associated
with a blunted ACTH response to exogenously administered CRF, explaining almost
60% of the variation in the ACTH response to CRF." [Abstract]
TC, Schule C, Zwanzger P, Minov C, Holme C, Padberg F, Bidlingmaier M, Strasburger
CJ, Rupprecht R.
Evaluation of a salivary based combined dexamethasone/CRH
test in patients with major depression.
"The combined dexamethasone/corticotropin releasing
hormone (Dex/CRH) test is one of the most reliable neuroendocrine function tests
for investigation of hypothalamic-pituitary-adrenocortical (HPA) system dysregulation
in depression. Persistent high HPA system activity reflected by an enhanced cortisol
secretion during the Dex/CRH test after successful antidepressant treatment is
correlated with an enhanced risk for relapse in remitted depressives. Thus, the
Dex/CRH test might be a useful neuroendocrinological tool for treatment monitoring.
However, the performance of the test requiring multiple blood samplings renders
this test difficult for routine clinical use. Thus, a simplified test procedure
using a saliva based test without the necessity of multiple blood samplings would
be desirable.Therefore, we compared matched saliva and serum probes of Dex/CRH
tests of 73 depressed patients who underwent a total of 157 tests. Both saliva
and serum cortisol concentrations showed a significant stimulation pattern during
the test and were highly correlated. This correlation was not influenced by either
antidepressive treatment. In patients with high cortisol secretion patterns during
the Dex/CRH test there was a decrease in HPA system activity after successful
antidepressant treatment that was reflected by both the saliva and the serum Dex/CRH
test.Thus, the saliva based combined Dex/CRH test appears to be a suitable tool
for monitoring HPA system activity during the course of depressive illness. The
easier performance of the saliva Dex/CRH test in comparison to the standard test
procedure for both patients and hospital staff opens the door for routine clinical
use of the Dex/CRH test for treatment monitoring and estimation of relapse risk."
CM, Bissette G, Arato M, O'Connor L, Nemeroff CB.
factor-like immunoreactivity in depression and schizophrenia.
Am J Psychiatry 1987 Jul;144(7):873-7
"To further investigate the hypothesis
that hyperactivity of the hypothalamic-pituitary-adrenal axis in patients with
depression may be mediated by hypersecretion of corticotropin-releasing factor
(CRF), the authors measured CRF-like immunoreactivity in CSF samples from 138
neurological control, 54 depressed, and 27 nondepressed (23 schizophrenic and
four manic) subjects. The CSF CRF concentration was markedly higher (almost twofold)
in depressed patients than in control subjects and nondepressed psychiatric patients.
The concentration of CSF CRF was slightly but significantly higher in schizophrenic
patients than in control subjects. These findings provide further support for
the hypothesis that CRF hypersecretion occurs in major depression." [Abstract]
CB, Widerlov E, Bissette G, Walleus H, Karlsson I, Eklund K, Kilts CD, Loosen
PT, Vale W.
Elevated concentrations of CSF corticotropin-releasing
factor-like immunoreactivity in depressed patients.
1984 Dec 14;226(4680):1342-4
"The possibility that hypersecretion of
corticotropin-releasing factor (CRF) contributes to the hyperactivity of the hypothalamo-pituitary-adrenal
axis observed in patients with major depression was investigated by measuring
the concentration of this peptide in cerebrospinal fluid of normal healthy volunteers
and in drug-free patients with DSM-III diagnoses of major depression, schizophrenia,
or dementia. When compared to the controls and the other diagnostic groups, the
patients with major depression showed significantly increased cerebrospinal fluid
concentrations of CRF-like immunoreactivity; in 11 of the 23 depressed patients
this immunoreactivity was greater than the highest value in the normal controls.
These findings are concordant with the hypothesis that CRF hypersecretion is,
at least in part, responsible for the hyperactivity of the hypothalamo-pituitary-adrenal
axis characteristic of major depression." [Abstract]
R, Gallart JM, Castellanos JM, Galard R.
factor in depressive disorders.
Biol Psychiatry 1998 Jul
"BACKGROUND: The aim of this work was to investigate alterations
of plasma corticotropin-releasing factor (CRF) levels in depressive states. We
have also measured plasma cortisol and corticotropin (ACTH) concentrations and
examined their correlation with the peripheral CRF values. METHODS: Thirty-six
outpatients from the psychiatric department of a Barcelona hospital who were diagnosed
as having major depressive disorder (n = 26) and dysthymic depressive disorder
(n = 10) were studied. Among the major depressed patients, 10 suffered from severe
depressive disorder and 16 from mild or moderate depressive disorder. The comparison
group consisted of 17 healthy volunteers. Cortisol, ACTH, and CRF concentrations
were determined by iodine-125 radioimmunoassay; CRF measurements were performed
on C18 extracted samples. RESULTS: CRF and cortisol plasma concentrations were
significantly higher in major depression and dysthymia than in the comparison
group. The major depressed patients did not show significantly different CRF and
cortisol levels than the dysthymic. Severe major depressive disorder exhibited
significantly higher CRF plasma levels than the mild or moderate episodes. Plasma
cortisol and CRF concentrations correlated significantly. CONCLUSIONS: The results
obtained indicate that plasma CRF values are altered in depressive disorders and
suggest that these determinations could be important for understanding the pathophysiology
in affective illness." [Abstract]
S, Villafuerte S, Forsgren T, Sluijs S, Del-Favero J, Adolfsson R, Van Broeckhoven
The corticotropin-releasing hormone binding protein is associated
with major depression in a population from Northern Sweden.
Psychiatry. 2003 Nov 1;54(9):867-72.
"BACKGROUND: Recent research suggests
that central corticotropin releasing hormone hyperdrive is an important neurobiological
risk factor for developing major depression. The availability of free corticotropin
releasing hormone in the central nervous system is tightly regulated by the expression
of corticotropin releasing hormone binding protein. Therefore, the gene encoding
for corticotropin releasing hormone binding protein is a functional candidate
gene for major depression. METHODS: We present a systematic study of single nucleotide
polymorphisms in the corticotropin releasing hormone binding protein gene and
their role in the liability for major depression. Seven single nucleotide polymorphisms
were genotyped in a well-diagnosed sample of 89 patients with recurrent major
depressions and matched controls. RESULTS: Two single nucleotide polymorphisms
within the corticotropin releasing hormone binding protein gene were significantly
associated with the disease (p <.05). An expectation-maximization algorithm
estimated a specific haplotype to have a frequency of 53% in patients and 35%
in controls (p <.001). CONCLUSIONS: The corticotropin releasing hormone binding
protein gene is likely to be involved in the genetic vulnerability for major depression."
FC, Hoogendijk WJ, Stam FC, Tilders FJ, Swaab DF.
of corticotropin-releasing hormone expressing neurons in the hypothalamic paraventricular
nucleus of depressed patients.
Neuroendocrinology 1994 Oct;60(4):436-44
hypothalamo-pituitary-adrenal (HPA) axis is known to be activated in depressed
patients. Although direct evidence is lacking, this activation is hypothesized
to be due to hyperactivity of corticotropin-releasing hormone (CRH) neurons of
the hypothalamic paraventricular nucleus (PVN). Recent immunocytochemical studies
in experimental animals and in humans showed that the number of CRH-expressing
neurons correlated with the activity of these neurons. In addition, colocalization
of AVP in CRH neurons has been shown to be an index for the secretory activity.
Therefore, we estimated the total number of CRH-immunoreactive neurons and their
fraction showing colocalization with AVP in the PVN of 10 control subjects and
of 6 depressed patients who were diagnosed to be suffering from a major depression
or a bipolar disorder. The mean total number of CRH-expressing neurons of the
6 depressed patients was four times higher, and the number of CRH neurons co-expressing
AVP was almost three times higher than those in the control group. We also determined
the two activity parameters of CRH neurons in the PVN of 2 subjects with a depressive
organic mood syndrome or a depressive disorder not otherwise specified. In these
two 'non-major depressed' subjects, the activity parameters of CRH neurons were
comparable to those of control subjects. Our observations strongly support the
hypothesis that CRH neurons in the PVN are hyperactivated in major depressed patients.
This hyperactivity might be causally related to at least part of the symptomatology
of depression." [Abstract]
Austin MC, Janosky JE, Murphy HA.
corticotropin-releasing hormone immunoreactivity in monoamine-containing pontine
nuclei of depressed suicide men.
Mol Psychiatry. 2003 Mar;8(3):324-32.
number of clinical investigations and postmortem brain studies have provided evidence
that excessive corticotropin-releasing hormone (CRH) secretion and neurotransmission
is involved in the pathophysiology of depressive illness, and several studies
have suggested that the hyperactivity in CRH neurotransmission extends beyond
the hypothalamus involving several extra-hypothalamic brain regions. The present
study was designed to test the hypothesis that CRH levels are increased in specific
brainstem regions of suicide victims with a diagnosis of major depression. Frozen
tissue sections of the pons containing the locus coeruleus and caudal raphe nuclei
from 11 matched pairs of depressed suicide and control male subjects were processed
for radioimmunocytochemistry using a primary antiserum to CRH and a ()I-IgG
secondary antibody. The optical density corresponding to the level of CRH-immunoreactivity
(IR) was quantified in specific pontine regions from the film autoradiographic
images. The level of CRH-IR was increased by 30% in the locus coeruleus, 39% in
the median raphe and 45% in the caudal dorsal raphe in the depressed suicide subjects
compared to controls. No difference in CRH-IR was found in the dorsal tegmentum
or medial parabrachial nucleus between the subject groups. These findings reveal
that CRH-IR levels are specifically increased in norepinephrine- and serotonin-containing
pontine nuclei of depressed suicide men, and thus they are consistent with the
hypothesis that CRH neurotransmission is elevated in extra-hypothalamic brain
regions of depressed subjects." [Abstract]
Gaalen MM, Reul JH, Gesing A, Stenzel-Poore MP, Holsboer F, Steckler T.
overexpressing CRH show reduced responsiveness in plasma corticosterone after
a5-HT1A receptor challenge.
Genes Brain Behav. 2002 Aug;1(3):174-7.
hormone (CRH) overproduction and serotonergic dysfunction have both been implicated
in a range of psychiatric disorders, such as anxiety and depression, and several
studies have shown interactions between these two neurotransmitter systems. In
this study, we investigated the effects of CRH challenge on hypothalamo-pituitary-adrenal
(HPA) axis activity in female transgenic mice overproducing CRH. Furthermore,
the effects of mild stress on HPA axis activity and body temperature were investigated
in these mice. Pre- and post-synaptic 5-HT1A receptor function were studied by
monitoring body temperature and plasma corticosterone levels after challenge with
the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propyl-amino)-tetralin (8-OH-DPAT).
Hypothermia in response to 8-OH-DPAT treatment did not differ between transgenic
and wild type mice, indicating unaltered somatodendritic 5-HT1A autoreceptor function
in mice overproducing CRH. In wild type mice 8-OH-DPAT increased plasma corticosterone
levels, but not in transgenic animals. CRH injection, however, increased corticosterone
levels in both groups. These data suggest desensitization of post-synaptic, but
not pre-synaptic, 5-HT1A receptors in mice overproducing CRH. These findings resemble
those seen in depressed patients following 5-HT1A challenge, which is in accord
with the hypothesized role of CRH in the pathogenesis of depression." [Abstract]
G, Klimek V, Pan J, Stockmeier C, Ordway G.
of CRF in the locus coeruleus of depressed subjects.
2003 Jul;28(7):1328-35. Epub 2003 May 21.
"Research evidence that corticotropin-releasing
factor (CRF) plays a role in the pathophysiology of major depressive disorder
(MDD) has accumulated over the past 20 years. The elevation of lumbar cerebrospinal
fluid (CSF) concentrations of CRF decreased responsiveness of pituitary CRF receptors
to challenge with synthetic CRF, and increased levels of serum cortisol in MDD
subjects support the hypothesis that CRF is chronically hypersecreted in at least
the endocrine circuits of the hypothalamic-pituitary-adrenal (HPA) axis and may
also involve other CRF brain circuits mediating emotional responses and/or arousal.
One such circuit includes the excitatory CRF input to the locus coeruleus (LC),
the major source of norepinephrine in the brain. Furthermore, there are now reports
of decreased levels of CRF in lumbar CSF from MDD patients after symptom relief
from chronic treatment with antidepressant drugs or electroconvulsive therapy.
Whether this normalization reflects therapeutic effects on both endocrine- and
limbic-associated CRF circuits has not yet been effectively addressed. In this
brief report, we describe increased concentrations of CRF-like immunoreactivity
in micropunches of post-mortem LC from subjects with MDD symptoms as established
by retrospective psychiatric diagnosis compared to nondepressed subjects matched
for age and sex." [Abstract]
A, Pickar D, Linnoila M, Chrousos GP, Gold PW.
corticotropin-releasing hormone in depression: relationship to noradrenergic function.
Psychiatry Res 1987 Mar;20(3):229-37
"We investigated the neurotransmitter
regulation of corticotropin-releasing hormone (CRH). Among 21 depressed patients
cerebrospinal fluid (CSF) levels of CRH significantly correlated with urinary
outputs of norepinephrine and its major metabolites, and there were trends for
significant correlations with both CSF and plasma levels of norepinephrine. These
results suggest that CRH may be associated with the dysregulation of the norepinephrine
system that is found in [depression]." [Abstract]
RJ, Foote SL, Page ME.
The locus coeruleus as a site for integrating
corticotropin-releasing factor and noradrenergic mediation of stress responses.
Ann N Y Acad Sci 1993 Oct 29;697:173-88
"It could be predicted that the
effects of CRF neurotransmission in the LC during stress would enhance information
processing concerning the stressor or stimuli related to the stressor by LC target
neurons. One consequence of this appears to be increased arousal. Although this
may be adaptive in the response to an acute challenge, it could be predicted that
chronic CRF release in the LC would result in persistently elevated LC discharge
and norepinephrine release in targets. This could be associated with hyperarousal
and loss of selective attention as occurs in certain psychiatric diseases. Manipulation
of endogenous CRF systems may be a novel way in which to treat psychiatric diseases
characterized by these maladaptive effects." [Abstract]
AL, Valentino RJ.
Corticotropin-releasing factor neurotransmission
in locus coeruleus: a possible site of antidepressant action.
Brain Res Bull 1994;35(5-6):581-7
"Hypersecretion of corticotropin-releasing
factor (CRF), has been hypothesized to occur in depression. Because CRF may serve
as a neurotransmitter in the locus coeruleus (LC), it was proposed that CRF hypersecretion
in the LC is responsible for some characteristics of depression, and that antidepressants
act by interfering with CRF neurotransmission in the LC. To test this hypothesis,
the acute and chronic effects of four antidepressants and cocaine were characterized
on LC spontaneous and sensory-evoked discharge, LC activation by a stressor that
requires CRF release, and LC activation by exogenously administered CRF. None
of the antidepressants or cocaine altered LC activation by intracerebroventricularly
administered CRF (3.0 microgram) after chronic administration. However, chronic
administration of desmethylimipramine and mianserin inhibited LC activation by
a hypotensive stress that requires endogenous CRF release, suggesting that they
decrease CRF release in the LC. Chronic administration of sertraline and phenelzine
altered LC responses to repeated sciatic nerve stimulation in a manner opposite
to the effect produced by CRF, suggesting that these drugs may functionally antagonize
CRF actions in the LC. Cocaine did not appear to interfere with CRF actions in
the LC. In conclusion, chronic administration of antidepressants may have the
potential to interfere with CRF neurotransmission in the LC." [Abstract]
RJ, Curtis AL.
Pharmacology of locus coeruleus spontaneous and
Prog Brain Res 1991;88:249-56
"Neuroendocrine and catecholamine dysfunctions in depression may be linked
by corticotropin-releasing factor (CRF) effects on locus coeruleus (LC) neurons.
One consequence of CRF hypersecretion in depression would be persistent elevated
levels of LC discharge and diminished responses to phasic sensory stimuli. The
hypothesis that antidepressants could reverse these changes was tested by characterizing
effects of pharmacologically distinct antidepressants on LC sensory-evoked discharge,
LC activation by stress, and LC activation by CRF. The most consistent effect
of all of the antidepressants tested was a decrease in LC sensory-evoked discharge
after acute administration. However, tolerance occurs to these effects after chronic
administration. With chronic administration each of the antidepressants produced
effects which could potentially interfere with CRF function in the LC. Desmethylimipramine
and mianserin attenuated LC activation by a stressor which requires endogenous
CRF, suggesting that these antidepressants attenuate stress-elicited release of
CRF and perhaps the hypersecretion that occurs in depression. The serotonin reuptake
inhibitor, sertraline (SER), enhanced the signal-to-noise ratio of the LC sensory
response, an effect opposite to that of CRF. Thus, SER could serve as a functional
antagonist of CRF that is hypersecreted in depression. The finding that three
pharmacologically distinct antidepressants share the potential to interfere with
CRF function in the LC implies that this may be an important common mechanism
for antidepressant activity." [Abstract]
Andre L., Pavcovich, Luis A., Valentino, Rita J.
of Locus Ceruleus Sensitivity to Corticotropin-Releasing Factor by Swim Stress
J Pharmacol Exp Ther 1999 289: 1211-1219
(CRF) acts as a putative neurotransmitter in the locus ceruleus (LC) to mediate
its activation by certain stressors. In this study, we quantified LC sensitivity
to CRF 24 h after swim stress, at a time when behavioral depression that is sensitive
to antidepressants is apparent. Rats were placed in a tank with 30 cm (swim stress)
or 4 cm water and 24 h later, either behavior was monitored in a forced swim test
or LC discharge was recorded. Swim stress rats were more immobile than control
animals in the swim test. LC neurons of swim stress rats were sensitized to low
doses of CRF (0.1-0.3 µg i.c.v.) that were ineffective in control animals
and were desensitized to higher doses. Swim stress selectively altered LC sensitivity
to CRF because neither LC spontaneous discharge nor responses to other agents
(e.g., carbachol, vasoactive intestinal peptide) were altered. Finally, the mechanism
for sensitization was localized to the LC because neuronal activation by low doses
of CRF was prevented by the intracerulear administration of a CRF antagonist.
CRF dose-response curves were consistent with a two-site model with similar dissociation
constants under control conditions but divergent dissociation constants after
swim stress. The results suggest that swim stress (and perhaps other stressors)
functionally alters CRF receptors that have an impact on LC activity. Stress-induced
regulation of LC sensitivity to CRF may underlie behavioral aspects of stress-related
psychiatric disorders." [Full
Zeng J, Kitayama I, Yoshizato H, Zhang K,
Increased expression of corticotropin-releasing factor
receptor mRNA in the locus coeruleus of stress-induced rat model of depression.
Sci. 2003 Jul 18;73(9):1131-9.
"Hypersecretion of corticotropin-releasing
factor (CRF) has been hypothesized to occur in depression. To investigate CRF
receptor (CRFR) response to the increased production of CRF in chronically stressed
rats, we measured by in situ hybridization the expression of CRFR mRNA in the
locus coeruleus (LC) concomitant with measuring plasma adrenocorticotropin (ACTH).
The expression of both CRFR mRNA in the LC and the plasma level of ACTH increased
significantly in "depression-model rats" which exhibit reduced activity
following exposure to 14 days forced walking stress (FWS), but not in "spontaneous
recovery rats" whose activity was restored after the long-term stress. These
results suggest that the LC neurons continue to be stimulated by CRF, and that
the hypothalamic-pituitary-adrenal (HPA) axis is hyperfunctioning in the depression-model
C, Nemeroff CB.
The impact of early adverse experiences on brain
systems involved in the pathophysiology of anxiety and affective disorders.
Biol Psychiatry 1999 Dec 1;46(11):1509-22
"The relative contribution
of genetic and environmental factors to the development of the major psychiatric
disorders has long been debated. Recently, considerable attention has been given
to the observations that adverse experiences early in life predispose individuals
to the development of affective and anxiety disorders in adulthood. Corticotropin-releasing
factor (CRF) is the central coordinator of the endocrinologic, autonomic, immunologic,
and behavioral stress responses. When centrally administered, CRF produces many
physiologic and behavioral changes reminiscent of both acute stress and depression.
Moreover, CRF has also been implicated in the pathogenesis of a variety of anxiety
disorders, mainly through CRF neurocircuits connecting the amygdala and the locus
ceruleus. Clinical studies have provided convincing evidence for central CRF hypersecretion
in depression, and, to a lesser extent, in some anxiety disorders. Evidence mainly
from preclinical studies suggests that stress early in life results in persistent
central CRF hyperactivity and increased stress reactivity in adulthood. Thus,
genetic disposition coupled with early stress in critical phases of development
may result in a phenotype that is neurobiologically vulnerable to stress and may
lower an individual's threshold for developing depression and anxiety upon further
stress exposure. This pathophysiologic model may provide novel approaches to the
prevention and treatment of psychopathology associated with stress early in life."
C, Nemeroff CB.
The role of childhood trauma in the neurobiology
of mood and anxiety disorders: preclinical and clinical studies.
Biol Psychiatry 2001 Jun 15;49(12):1023-39
"Epidemiologic studies indicate
that children exposed to early adverse experiences are at increased risk for the
development of depression, anxiety disorders, or both. Persistent sensitization
of central nervous system (CNS) circuits as a consequence of early life stress,
which are integrally involved in the regulation of stress and emotion, may represent
the underlying biological substrate of an increased vulnerability to subsequent
stress as well as to the development of depression and anxiety. A number of preclinical
studies suggest that early life stress induces long-lived hyper(re)activity of
corticotropin-releasing factor (CRF) systems as well as alterations in other neurotransmitter
systems, resulting in increased stress responsiveness. Many of the findings from
these preclinical studies are comparable to findings in adult patients with mood
and anxiety disorders. Emerging evidence from clinical studies suggests that exposure
to early life stress is associated with neurobiological changes in children and
adults, which may underlie the increased risk of psychopathology. Current research
is focused on strategies to prevent or reverse the detrimental effects of early
life stress on the CNS. The identification of the neurobiological substrates of
early adverse experience is of paramount importance for the development of novel
treatments for children, adolescents, and adults." [Abstract]
LL, Tyrka AR, McDougle CJ, Malison RT, Owens MJ, Nemeroff CB, Price LH.
fluid corticotropin-releasing factor and perceived early-life stress in depressed
patients and healthy control subjects.
"Previous studies have reported elevated concentrations
of cerebrospinal fluid (CSF) corticotropin-releasing factor (CRF) in patients
with major depression. Elevations of CSF CRF have also been reported in adult
laboratory animals exposed to the stress of brief maternal deprivation or maternal
neglect in the neonatal or preweaning period. The present study was designed to
determine whether major depression and a history of perceived early adversity
in childhood are independently associated with elevated CSF CRF concentrations
in adults. In this case-control study, 27 medication-free adults with major depression
and 25 matched controls underwent standardized lumbar puncture for collection
of a single CSF sample at 1200. Subjects provided data about significant adverse
early-life experiences and rated their global perceived level of stress during
pre-school and preteen years on a six-point Likert scale. The mean difference
in CSF CRF between depressed patients and controls did not reach statistical significance.
In a regression model, perceived early-life stress was a significant predictor
of CSF CRF, but depression was not. Perinatal adversity and perceived adversity
in the preteen adversity years (ages 6-13 years) were both independently associated
with decreasing CSF CRF concentrations. The relationship observed between perceived
early-life stress and adult CSF CRF concentrations in this study closely parallels
recent preclinical findings. More work is needed to elucidate the critical nature
and timing of early events that may be associated with enduring neuroendocrine
changes in humans." [Abstract]
Heim C, Newport DJ, Bonsall R, Miller AH, Nemeroff
Altered pituitary-adrenal axis responses to provocative challenge
tests in adult survivors of childhood abuse.
Am J Psychiatry
"OBJECTIVE: Early adverse life events may predispose
individuals to the development of mood and anxiety disorders in adulthood, perhaps
by inducing persistent changes in corticotropin-releasing factor (CRF) neuronal
systems. The present study sought to evaluate pituitary-adrenal responses to standard
hypothalamic-pituitary-adrenal axis challenge tests in adult female survivors
of childhood abuse with and without major depressive disorder. METHOD: Plasma
ACTH and cortisol responses to the administration of 1 microg/kg ovine CRF and
plasma cortisol responses to the administration of 250 microg ACTH(1-24) were
measured in healthy women without early life stress (N=20), women with childhood
abuse without major depressive disorder (N=20), women with childhood abuse and
major depressive disorder (N=15), and women with major depression but no early
life stress (N=11). RESULTS: Abused women without major depressive disorder exhibited
greater than usual ACTH responses to CRF administration, whereas abused women
with major depressive disorder and depressed women without early life stress demonstrated
blunted ACTH responses. In the ACTH(1-24) stimulation test, abused women without
major depressive disorder exhibited lower baseline and stimulated plasma cortisol
concentrations. Abused women with comorbid depression more often suffered from
posttraumatic stress disorder and reported more recent life stress than abused
women without major depressive disorder. CONCLUSIONS: These findings suggest sensitization
of the anterior pituitary and counterregulative adaptation of the adrenal cortex
in abused women without major depressive disorder. On subsequent stress exposure,
women with a history of childhood abuse may hypersecrete CRF, resulting in down-regulation
of adenohypophyseal CRF receptors and symptoms of depression and anxiety."
DJ, Heim C, Bonsall R, Miller AH, Nemeroff CB.
responses to standard and low-dose dexamethasone suppression tests in adult survivors
of child abuse.
Biol Psychiatry. 2004 Jan 1;55(1):10-20.
Previous studies indicate that adverse childhood events are associated with persistent
changes in corticotropin-releasing factor neuronal systems. Our aim was to determine
whether altered glucocorticoid feedback mediates the neuroendocrine sequelae of
childhood trauma. METHODS: Standard and low-dose dexamethasone suppression tests
(DST) were performed in women with a history of child abuse (n=19), child abuse
and major depression (n=16), major depression and no childhood trauma (n=10),
and no history of mental illness or childhood trauma (n=19). Secondary analysis
with posttraumatic stress disorder (PTSD) as the organizing diagnosis was also
conducted. RESULTS: In the low-dose DST, depressed women with a history of abuse
exhibited greater cortisol suppression than any comparator group and greater corticotropin
suppression than healthy volunteers or nondepressed abuse survivors. There were
no differences between nondepressed abuse survivors and healthy volunteers in
the low-dose DST or between any subject groups in the standard DST. The PTSD analysis
produced similar results. CONCLUSIONS: Cortisol supersuppression is evident in
psychiatrically ill trauma survivors, but not in nondepressed abuse survivors,
indicating that enhanced glucocorticoid feedback is not an invariable consequence
of childhood trauma but is more related to the resultant psychiatric illness in
traumatized individuals." [Abstract]
Mary Ann, Joppa, Margaret, Ling, Nicholas, Foster, Alan C.
Evidence Supporting a Role for Central Corticotropin-Releasing Factor2 Receptors
in Behavioral, but not Endocrine, Response to Environmental Stress
J Pharmacol Exp Ther 2002 302: 145-152
(CRF) is one of the principle components of the stress response. The physiological
effects of CRF are mediated by two receptor subtypes, CRF1 and CRF2. Recent data
obtained with the selective CRF2 antagonist antisauvagine-30 (ASV-30) has begun
to suggest that both CRF receptor subtypes may play a role in stress-related behaviors.
Exactly how these two receptor subtypes interact to modulate the behavioral and
endocrine responses to stress is not clear, however. We have attempted to understand
the role of the CRF2 receptor in the behavioral and endocrine responses to stress
by comparing the effects of ASV-30 with the mixed CRF1/CRF2 receptor antagonist
astressin. Centrally administered ASV-30 reduced anxiety-like behavior in BALB/c
mice in three models of anxiety: marble burying [minimal effective dose (MED)
= 3 nmol], open field (MED = 3 nmol), and elevated plus maze (MED = 0.1 nmol).
ASV-30 did not change locomotor activity or the adrenocorticotropic hormone (ACTH)
response to restraint stress. The potent mixed CRF1/CRF2 antagonist astressin
not only reduced anxiety-like behavior in all three models with equivalent potency
but also blunted the ACTH response to restraint stress. Finally, the new selective
CRF2 receptor agonist urocortin-II produced a dose-dependent increase in anxiety-like
behavior in the plus maze test. Therefore, our data suggest that the CRF2 receptor
plays a role in the behavioral, but not the hypothalamic-pituitary-adrenal axis,
response to stress." [Abstract]
JH, Coverdale S, McCloskey TC, Hoffman DC, Cassella JV.
of the CRF(1) receptor antagonist, CP 154,526, in the separation-induced vocalization
anxiolytic test in rat pups.
Neuropharmacology 2000 Jun
"CRF(1) receptor antagonists have been proposed as novel
pharmacological treatments for depression, anxiety and stress disorders. The primary
goal of the present study was to evaluate the effects of the CRF(1) receptor antagonist,
CP 154,526, in the separation-induced vocalization (SIV) model of anxiety. Nine-
to 11-day-old rat pups were separated from their litter and the effects of intraperitoneally
administered test compounds on the elicited ultrasonic vocalizations were measured.
Side-effect potential was assessed using a modified inclined plane test ('time
on an inclined plane', or TIP), and using negative geotaxis. SIV was reduced by
CP 154,526 at doses that did not affect TIP or negative geotaxis, a profile like
that of the 5-HT(1A) partial agonist buspirone. The benzodiazepine anxiolytic,
diazepam, decreased SIV but also produced significant side effects at one to three-fold
higher doses. Additional pharmacological characterization of SIV demonstrated
anxiolytic-like effects of the atypical antipsychotic, clozapine, but not the
typical antipsychotic, haloperidol, and of the serotonin reuptake inhibitor, zimelidine,
but not the norepinephrine reuptake inhibitor, desipramine. In summary, the data
support the conclusion that selective CRF(1) receptor antagonists may have utility
in anxiety and stress disorders. The data further support the use of separation-induced
vocalizations for identifying mechanistically diverse compounds with anxiolytic
actions in man." [Abstract]
Novel approaches to the treatment of depression by modulating
the hypothalamic - pituitary - adrenal axis.
"Many patients with major depression show evidence
of over-activation of the hypothalamic - pituitary - adrenal axis (HPA), as evidenced
by hypercortisolism and adrenal hyperplasia. Such over-activity is associated
with increased corticotropin releasing factor (CRF) reactivity in the CSF and
blunted release of ACTH in response to CRF infusion. Recent evidence suggests
a switch from CRF to AVP regulation of the axis during depression, with depressed
patients showing enhanced response to ddAVP infusion. The HPA provides multiple
potential sites for antidepressant development. The use of glucocorticoid antagonists,
cortisol synthesis inhibitors, CRF and AVP antagonists have been suggested."
E, Bissette G, Nemeroff CB.
Monoamine metabolites, corticotropin
releasing factor and somatostatin as CSF markers in depressed patients.
J Affect Disord 1988 Mar-Apr;14(2):99-107
"CSF samples from ten healthy
volunteers and 22 patients with major depression were collected by lumbar puncture
at 9 a.m. and the content of monoamine metabolites, corticotropin releasing factor
(CRF) and somatostatin (SRIF) was analyzed. Plasma concentrations of TSH following
a TRH challenge test (200 micrograms) and plasma cortisol following dexamethasone
(1 mg; DST) were also analyzed. No relationships were observed between the CRF
or SRIF concentrations and either basal or post-dexamethasone cortisol concentrations.
Fourteen of 21 depressed patients were DST nonsuppressors using a plasma cortisol
concentration cut off point greater than or equal to 138 nmol/l. If a more conservative
cut off point was used (greater than 290 nmol/l) seven out of 21 patients revealed
a severity-related cortisol nonsuppression. No significant difference was observed
between healthy volunteers and depressed patients with regard to TSH response
to TRH. The CSF content of CRF was elevated and the content of SRIF reduced in
the depressed patients. In the healthy volunteers an inverse relationship was
observed between CSF concentrations of CRF and MHPG (r = -0.72; P = 0.019); no
relationship was observed between the concentrations of CRF and 5-HIAA or HVA.
In the depressed patients positive correlations were found between CSF concentrations
of CRF and 5-HIAA (r = 0.59; P = 0.004) and between CRF and HVA (r = 0.44; P =
0.042). These data are concordant with the view that norepinephrine and serotonin
may be involved in the regulation of CRF secretion." [Abstract]
SC, Lewine RJ, Kalin NH, Jewart RD, Risby ED, Caudle JM, Stipetic M, Turner J,
Eccard MB, Pollard WE.
activity and ventricular-to-brain ratio studies in affective illness and schizophrenia.
Neuropsychopharmacology 1992 Feb;6(2):95-100
"Some investigators have
speculated that structural brain alterations observed in some psychiatric patients
might be related to increased limbic-hypothalamic-pituitary-adrenal axis (LHPA)
activity. To explore this hypothesis, we prospectively studied 166 research volunteers
(19 patients with research diagnostic criteria (RDC) major depression, 9 patients
with RDC bipolar depression, 45 patients with RDC schizophrenia, and 94 RDC normal
controls), examining the relationship between magnetic resonance image-determined
ventricular-to-brain ratio (VBR) and indices of LHPA axis function (cerebrospinal
fluid (CSF) corticotropin-releasing factor (CRF), CSF adrenocorticotropic hormone
(ACTH), and 24-hour urinary-free cortisol secretion). We observed no significant
differences in mean VBR among the three patient groups and the normal control
volunteers. Of the indices of LHPA activity, only CSF CRF concentrations distinguished
the four subject groups, with CSF CRF being significantly elevated in the more
severely depressed major depression patients. Indices of LHPA activity were not
significantly correlated with VBR in any of the three patient groups or in the
normal volunteers. These preliminary results suggest that VBR is not highly associated
with alterations in LHPA activity, at least as determined cross-sectionally. Further
longitudinal studies with reference to diagnostic subtypes, severity, symptom
profiles, and more specific neuroanatomic regions may allow the elucidation of
possible relationships between LHPA pathology and structural brain alterations."
Sleep and the hypothalamo-pituitary-adrenocortical system.
Med Rev 2002 Apr;6(2):125-38
"The intention of this review is to summarize
the current knowledge on the bidirectional interaction between sleep EEG and the
secretion of corticotropin (ACTH) and cortisol. The administration of various
hypothalamic-pituitary- adrenocortical (HPA) hormones and their antagonists exerts
specific sleep-EEG changes in several species including humans. It is well documented
that corticotropin releasing hormone (CRH) impairs sleep and enhances vigilance.
In addition, it may promote REM sleep. Changes in the growth hormone-releasing
hormone (GHRH):CRH ratio in favour of CRH appear to contribute to shallow sleep,
elevated cortisol levels and blunted GH in depression and ageing. On the other
hand, in women GHRH appears to exert CRH-like effects on sleep. Acute cortisol
administration increases slow-wave sleep (SWS) and GH, probably due to feedback
inhibition of CRH, and inhibits REM sleep. With the mixed glucocorticoid and progesterone
receptor antagonist mifepriston sleep is disrupted. Subchronic administration
of the glucocorticoid agonist methylprednisolone desinhibited REM sleep. A synergism
of elevated CRH and cortisol activity may contribute to REM disinhibition during
depression. Also ACTH and vasopressin modulate sleep specifically but their physiological
role remains unclear. For example acute icv vasopressin enhances wakefulness in
rats, whereas its long-term administration increases SWS in the elderly. In various
studies the interaction of sleep EEG and HPA hormones has been investigated at
the baseline, after manipulation of sleep-wake behaviour and after environmental
changes. Most studies agree that the circadian pattern of cortisol is relatively
independent from sleep and environmental influences. Some data suggest a major
effect of light on cortisol secretion. Sleeping is widely associated with blunting
and awakenings are linked with increases of HPA hormones." [Abstract]
K, Kunzel H, Ising M, Schmid DA, Zobel A, Murck H, Holsboer F, Steiger A.
with the CRH1-receptor-antagonist R121919 improves sleep-EEG in patients with
J Psychiatr Res. 2004 Mar-Apr;38(2):129-36.
documented changes of sleep electroencephalogram (EEG) in patients with depression
include rapid eye movement (REM) sleep disinhibition, decreases of slow-wave-sleep
(SWS) and increase in wakefulness. Twenty-seven inpatients with major depression
were admitted subsequently to a clinical trial with the CRH(1)-receptor-antagonist
R121919 administered in two different dose escalation panels. A random subgroup
of 10 patients underwent three sleep-EEG recordings (baseline before treatment,
at the end of the first week and at the end of the fourth week of active treatment).
SWS time increased significantly compared with baseline after 1 week and after
4 weeks. The number of awakenings and REM density showed a trend toward a decrease
during the same time period. Separate evaluation of these changes for both panels
showed no significant effect at lower doses, whereas in the higher doses after
R121919 REM density decreased and SWS increased significantly between baseline
and week 4. Furthermore positive associations between HAMD scores and SWS at the
end of active treatment were found. Although these data might indicate that R121919
has a normalizing influence on the sleep EEG, the design of the study does not
allow to differentiate genuine drug effects from those of clinical improvement
and habituation to the clinical setting." [Abstract]
CL, Somes C, Seifritz E, Rivier JE.
CRF/NPY interactions: a potential
role in sleep dysregulation in depression and anxiety.
Depress Anxiety 1997;6(1):1-9
"Neuropeptide Y (NPY) has neuromodulatory
actions on multiple brain functions including endocrine, behavioral, and circadian
processes and has been implicated in the pathophysiology of both anxiety and depression.
Behavioral studies suggest that NPY is a potent anxiolytic, whereas CRF is anxiogenic,
thus it seems that a balance of these two peptides may exert important influences
on behavioral state regulation. However, little is known about how the NPY/CRF
balance affects general arousal, attention, and/or sleep states. The present study
evaluated the effects of CRF alone, and co-administered with NPY, on spontaneous
brain activity as well as on auditory processing using electrophysiological measures.
Electroencephalographic (EEG) and event-related potentials (ERPs) were obtained
in rats following intracerebroventricular administration of CRF (0.5 microgram)
and CRF (0.5 microgram)/NPY (5.0 or 15 micrograms). Auditory processing, as assessed
by ERPs, was affected most significantly in the frontal cortex where CRF produced
increases in the N1 and P3 components of the ERP, and NPY/CRF co-administration
produced significant decreases. These data are consistent with a role for CRF
in hyperarousal, and further suggest that NPY may be capable of reversing such
states. Administration of CRF also produced a significant increase in the time
to sleep onset and a decrease in the amount of time spent in non-rapid eye movement
(NREM) sleep as quantified by scoring the EEG paper records. Co-administration
of NPY with CRF reversed the effects of CRF on sleep duration and sleep onset
in a dose-dependent fashion. Spectral analysis revealed that CRF produced quantitative
changes in the EEG that were similar to what has previously been reported. CRF-induced
increases in fast frequency activity were found to be reversed by co-administration
of NPY. Taken together these data suggest that "dysregulation" of sleep
and arousal states in depression and anxiety may be consistent with an upset of
the balance between hypothalamic neuropeptide systems." [Abstract]
EM, Wheler GH, Higley JD, Loriaux DL, Suomi SJ, Doudet DJ.
corticotropin-releasing factor increases limbic glucose metabolism and has social
context-dependent behavioral effects in nonhuman primates.
Proc Natl Acad Sci U S A 2002 Nov 26;99(24):15749-54
factor (CRF) is a neuropeptide involved in integrating the behavioral, autonomic,
and hormonal responses to stress within the central nervous system. Patients suffering
from depression have abnormal activity in stress responsive brain regions and
elevated cerebrospinal fluid CRF. The DSM-IV criteria for major depressive disorder
include behavioral changes such as depressed mood, anhedonia, and psychomotor
agitationretardation. We studied the effects of 434 microg of CRF given intracerebroventricularly
over 40 min in group and individually housed monkeys to examine the role of elevated
levels of central CRF on behavior. CRF elicited a wide range of behaviors, which
fell into three broad categories: anxiety-like, depressive-like, and externally
oriented. Externally oriented behaviors decreased, and anxiety-like behaviors
increased regardless of how the animals were housed. Interestingly, increased
depressive-like behaviors were only observed when the animals were socially housed.
In a separate experiment, we examined the effects of the same dose of CRF on the
regional cerebral glucose metabolism of lightly anesthetized monkeys by using
positron emission tomography and [(18)F]fluorodeoxyglucose. CRF infusion increased
glucose metabolism in the pituitaryinfundibulum, the amygdala, and hippocampus.
These results indicate that increased central CRF tone affects primate behavior
in a context-dependent manner, and that it activates limbic and stress-responsive
regions. The fact that intracerebroventricular CRF increases depressive-like behavior
in socially housed animals and increases activity in limbic brain regions may
help explain the behavioral and metabolic alterations in humans with affective
disorders, and this model could therefore have significant value in the development
of novel antidepressant treatments." [Abstract]
RG, Flachskamm C, Zimmermann S, Wurst W, Holsboer F, Reul JM, Linthorst AC.
Corticotropin-releasing hormone receptor type 1-deficiency enhances
hippocampal serotonergic neurotransmission: an in vivo microdialysis study in
hormone plays an important role in the coordination of various responses to stress.
Previous research has implicated both corticotropin-releasing hormone and the
serotonergic system as causative factors in the development and course of stress-related
psychiatric disorders such as major depression. To delineate the role of the corticotropin-releasing
hormone receptor type 1 (CRH-R1) in the interactions between corticotropin-releasing
hormone and serotonergic neurotransmission, in vivo microdialysis was performed
in CRH-R1-deficient mice under basal (home cage) and stress (forced swimming)
conditions. Hippocampal dialysates were used to measure extracellular levels of
serotonin and its metabolite 5-hydroxyindoleacetic acid, and free corticosterone
levels to monitor the status of the hypothalamic-pituitary-adrenocortical axis.
Moreover, behavioural activity was assessed by visual observation and a scoring
paradigm.Both wild-type and heterozygous mutant mice showed a clear diurnal rhythm
in free corticosterone. Free corticosterone concentrations were, however, lower
in heterozygous mutant mice than in wild-type animals and undetectable in homozygous
CRH-R1-deficient mice. Homozygous CRH-R1-deficient mice showed enhanced hippocampal
levels of 5-hydroxyindoleacetic acid but not of serotonin during the light and
the dark phase of the diurnal cycle, which may point to an enhanced synthesis
of serotonin in the raphe-hippocampal system. Moreover, the mutation resulted
in higher behavioural activity in the home cage during the light but not during
the dark period. Forced swimming caused a rise in hippocampal serotonin followed
by a further increase after the end of the stress paradigm in all genotypes. Homozygous
and heterozygous mutant mice showed, however, a significantly amplified serotonin
response to the forced swimming as compared to wild-type control animals.We conclude
that CRH-R1-deficiency results in reduced hypothalamic-pituitary-adrenocortical
axis activity, in enhanced synthesis of serotonin during basal conditions, and
in an augmented response in extracellular levels of serotonin to stress. These
data provide further evidence for the intricate relationship between corticotropin-releasing
hormone and serotonin and the important role of the CRH-R1 herein." [Abstract]
SC, Mortas P, Owens MJ, Nemeroff CB, Moreau J.
factor concentrations in the bed nucleus of the stria terminalis of anhedonic
Eur J Pharmacol 2000 Jul 28;401(1):39-46
mild stress in rats is an antidepressant-responsive model for anhedonic symptoms
of major depression. Many patients with depression exhibit alterations in hypothalamic-pituitary-adrenal
axis activity, and corticotropin-releasing factor (CRF) neuronal function. This
study investigated the potential involvement of CRF and CRF receptors in the development
of chronic mild stress-induced anhedonia in rats. Rats were subjected to 19 days
of chronic mild stress, during which time anhedonia was periodically assessed
by determining the threshold for self-stimulation of the ventral tegmental area.
Anhedonic rats exhibited a 50% increase in CRF concentrations in the bed nucleus
of the stria terminalis compared to control rats. There were no significant changes
in hypothalamic-pituitary-adrenal axis activity, CRF or CRF(1) receptor mRNA expression,
or CRF receptor binding in the brain regions analyzed. Though preliminary, these
results are consistent with the hypothesis that chronic stress-induced modulation
of CRF function in specific brain structures such as the bed nucleus of the stria
terminalis may contribute to the pathophysiology of depression." [Abstract]
B. Müller, Rainer Landgraf, Jens Preil, Inge Sillaber, Adelheid E. Kresse,
Martin E. Keck, Stephan Zimmermann, Florian Holsboer, and Wolfgang Wurst
Activation of the Hypothalamic Vasopressinergic System in Mice Deficient for the
Corticotropin-Releasing Hormone Receptor 1 Is Dependent on Glucocorticoids
"Deficiency of CRH receptor 1 (CRHR1) severely impairs
the stress response of the hypothalamic-pituitary-adrenocortical (HPA) system
and reduces anxiety-related behavior in mice. Intriguingly, in mice deficient
for the CRHR1 (Crhr1-/-), basal plasma levels of ACTH are normal, suggesting the
presence of compensatory mechanisms for pituitary ACTH secretion. We therefore
studied the impact of the hypothalamic neuropeptides arginine vasopressin (AVP)
and oxytocin (OXT) on HPA system regulation in homozygous and heterozygous Crhr1
mutants under basal and different stress conditions. Basal plasma AVP concentrations
were significantly elevated in Crhr1-/- mice. AVP messenger RNA expression was
increased in the paraventricular nucleus of Crhr1-/- mutants together with a marked
increase in AVP-like immunoreactivity in the median eminence. Administration of
an AVP V1-receptor antagonist significantly decreased basal plasma ACTH levels
in mutant mice. After continuous treatment with corticosterone, plasma AVP levels
in homozygous Crhr1-/- mice were indistinguishable from those in wild-type littermates,
thus providing evidence that glucocorticoid deficiency is the major driving force
behind compensatory activation of the vasopressinergic system in Crhr1-/- mice.
Neither plasma OXT levels under several different conditions nor OXT messenger
RNA expression in the paraventricular nucleus were different between the genotypes.
Taken together, our data reveal a selective compensatory activation of the hypothalamic
vasopressinergic, but not the oxytocinergic system, to maintain basal ACTH secretion
and HPA system activity in Crhr1-/- mutants." [Full
Dallman MF, Pecoraro N, Akana SF, La Fleur
SE, Gomez F, Houshyar H, Bell ME, Bhatnagar S, Laugero KD, Manalo S.
stress and obesity: a new view of "comfort food".
Natl Acad Sci U S A. 2003 Sep 30;100(20):11696-701. Epub 2003 Sep 15.
effects of adrenal corticosteroids on subsequent adrenocorticotropin secretion
are complex. Acutely (within hours), glucocorticoids (GCs) directly inhibit further
activity in the hypothalamo-pituitary-adrenal axis, but the chronic actions (across
days) of these steroids on brain are directly excitatory. Chronically high concentrations
of GCs act in three ways that are functionally congruent. (i) GCs increase the
expression of corticotropin-releasing factor (CRF) mRNA in the central nucleus
of the amygdala, a critical node in the emotional brain. CRF enables recruitment
of a chronic stress-response network. (ii) GCs increase the salience of pleasurable
or compulsive activities (ingesting sucrose, fat, and drugs, or wheel-running).
This motivates ingestion of "comfort food." (iii) GCs act systemically
to increase abdominal fat depots. This allows an increased signal of abdominal
energy stores to inhibit catecholamines in the brainstem and CRF expression in
hypothalamic neurons regulating adrenocorticotropin. Chronic stress, together
with high GC concentrations, usually decreases body weight gain in rats; by contrast,
in stressed or depressed humans chronic stress induces either increased comfort
food intake and body weight gain or decreased intake and body weight loss. Comfort
food ingestion that produces abdominal obesity, decreases CRF mRNA in the hypothalamus
of rats. Depressed people who overeat have decreased cerebrospinal CRF, catecholamine
concentrations, and hypothalamo-pituitary-adrenal activity. We propose that people
eat comfort food in an attempt to reduce the activity in the chronic stress-response
network with its attendant anxiety. These mechanisms, determined in rats, may
explain some of the epidemic of obesity occurring in our society." [Abstract]
Gaalen MM, Stenzel-Poore M, Holsboer F, Steckler T.
in mice overproducing corticotropin-releasing hormone.
Brain Res. 2003 Jun 16;142(1-2):69-79.
"Data from several studies suggest
that unrestrained secretion of corticotropin-releasing hormone in the CNS produces
several signs and symptoms of depression. Recent evidence indicates that blockade
of the CRH receptor 1 reduced depression scores in depressed patients. One of
the symptoms that occur is depression is impairment in attentional processes.
Whether these impairments are due to alterations in the CRH system are so far
unknown. In order to investigate whether overproduction of CRH alters attentional
process, transgenic mice overproducing CRH were tested on an operant five choice
serial reaction time task, a task which taxes sustained and divided attention.
Mutants showed impaired autoshaping. During initial discrimination learning, transgenics
performed below wildtype level, but with extended training with long stimulus
durations, transgenic animals reached similar accuracy levels as wildtype mice.
When animals were tested at shortest stimulus duration (0.5s), a mild but significant
impairment in accurate responding emerged in transgenics. This was accompanied
by longer correct response latencies, while incorrect latencies did not differ
between groups, suggesting attentional impairment in CRH transgenics. Because
these animals have been reported to also show increased anxiety-related behaviour,
animals were treated with the anxiolytic benzodiazepine diazepam. Diazepam failed
to affect accuracy, but transgenic mice showed a stronger behavioural disinhibition.
This suggests that the attentional impairment seen in CRH overexpressors is independent
of alterations in anxiety-like behaviour. These findings may have implications
for understanding the pathophysiology of psychiatric disorders such as depression,
where it has been suggested that an overactivity of the CRH system accounts for
a variety of symptoms, including hyper-arousal and attentional impairment."