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Stress Neurobiology and Corticotropin-Releasing Factor: Page 2 of 4

Stress Neurobiology and Corticotropin-Releasing Factor: Page 2 of 4

In response to stress, this neural circuit becomes
activated, thereby releasing CRF from median
eminence nerve terminals into the hypothalamohypophyseal
portal system, where it activates CRF
receptors on corticotrophs in the anterior pituitary
to promote the synthesis of pro-opiomelanocortin
and the release of its major posttranslation products,
ACTH and .-endorphin. ACTH, released from
the anterior pituitary, stimulates the production and
release of cortisol from the adrenal cortex. These
same hypothalamic CRF neurons also project to the
spinal cord16 and brainstem nuclei,17 including the
locus caeruleus (LC), the major noradrenergic
nucleus in the brain.18

Shortly after the isolation and characterization
of CRF, a standardized intravenous CRF stimulation
test was developed to assess HPA axis activity.
In this paradigm, CRF is administered intravenously
(usually at a dose of 1 µg/kg or a fixed
dose of 100 µg) and the ACTH and cortisol responses
are measured at 30-minute intervals over a 2- to
3-hour period.19 Numerous studies have now documented
a blunted ACTH and ß-endorphin response
to exogenously administered ovine CRF or human
CRF in depressed patients compared with nondepressed
persons; the cortisol response in depressed
patients and nondepressed control subjects did not
consistently differ.20-24

It has been hypothesized that the attenuated
ACTH response to CRF is due to chronic hypersecretion
of CRF from nerve terminals in the median
eminence,which results in down-regulation of CRF
receptors in the anterior pituitary, and/or to chronic
hypercortisolemia and its associated negative feedback.
CRF receptor down-regulation results in a
reduced responsivity of the anterior pituitary to
CRF, as repeatedly demonstrated in laboratory
animals.25-29
Two CRF receptor subtypes, CRF1 and CRF2,
with distinct anatomic localization and receptor pharmacology,
have been identified in rats and
humans.11,14,15 Both receptors are G-protein coupled
receptors (GPCRs) and are positively coupled to
adenylyl cyclase via the protein Gs. The CRF1 receptor
is predominantly expressed in the pituitary, cerebellum,
and neocortex in the rat.30 Considerable
evidence from laboratory animal studies has shown
that CRF1 receptors may specifically mediate some
of the anxiogenic-like behaviors observed after
administration of CRF.31-34

In agreement with these findings, mice with
targeted knockouts of the CRF1 receptor were found
to have an impaired stress response.35 The CRF1
receptor knockout mice were less anxious than their
wild-type litter mates when tested in the elevated
plus maze, a paradigm commonly used to assess
anxiety-like behavior. In addition, data in these transgenic
mice showed a significant reduction in stressinduced
release of ACTH and corticosterone.

CRF2 receptor knockout mice have also been
generated.36,37 Deletion of the CRF2 receptor gene
during development provided an ambiguous profile,
showing increased anxiety in some but not all anxiety
tasks36,37: in males, but not females37; in males
and females36; or not at all.38 Thus these studies
suggest CRF2 receptor blockade may lead to states
of increased anxiety, although it is likely that both
the environment and the genetic background on
which the knockouts were bred significantly contribute
to the behavioral phenotype of these animals.

Research using selective CRF2 receptor agonists
and antagonists has been even more inconsistent.
Several studies have used the selective CRF2 receptor
antagonist antisauvagine-30 (ASV-30),39 which
has been reported to be between 100- and 1000-
fold selective for the CRF2 receptor, depending on
whether the radiolabeled ligand is sauvagine39 or
ASV-30,40 respectively. Intraseptal administration of
ASV-30 was shown to reduce anxious behavior
induced by immobilization stress in the plus maze
task or by previous association with foot shock in
mice.41 These behavioral data were corroborated in
rats, where intracerebroventricular ASV-30 reduced
anxious behavior in the plus maze, defensive withdrawal,
and a conditioned anxiety paradigm.32,42

Selective agonists at the CRF2 receptor have also
been discovered. The peptides urocortin II and urocortin
III are structurally and ancestrally related to
CRF but show between 100- and 1000-fold selectivity
at the CRF2 receptor versus the CRF1 receptor.43,44
Urocortin III has been shown to mildly suppress
locomotion and has an anxiolytic-like profile in
mice.45 However, another study from the same group
demonstrated that urocortin II was inactive in the
mice in the plus maze after acute administration but
increased their exploratory behavior in the plus maze
4 hours later. Thus, compounds reported to be both
selective agonists and antagonists at the CRF2 receptor
have shown anxiolytic-like effects, making
the exact role of this receptor in modulating stress-induced
behaviors ambiguous.

Extrahypothalamic CRF
circuits and depression

Although initially investigated for its role as one of
the key modulators of the HPA axis, further research
has revealed that CRF controls not only the neuroendocrine
but also the autonomic, immune, and behavioral
responses to stress in mammals. Results from
both clinical studies and a rich body of literature
conducted primarily in rodents and lower primates
has highlighted the importance of extrahypothalamic
CRF neurons.12,46,47 In rodents, primates, and
humans, CRF and its receptors have been heterogeneously
localized in a variety of regions, including
the amygdala, thalamus, hippocampus, and prefrontal
cortex, among others.48-51 These brain regions
are important in regulating many aspects of the mammalian
stress response and affect.

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