Endocrine Reviews 20 (4): 460-500
Copyright © 1999 by The Endocrine Society
The Corticotropin-Release Inhibitory Factor Hypothesis: A Review of the Evidence for the Existence of Inhibitory as Well as Stimulatory Hypophysiotropic Regulation of Adrenocorticotropin Secretion and Biosynthesis1
Dennis Engler,
Eva Redei and
Ismail Kola
Laboratory of Molecular Genetics and Development (D.E., I.K),
Institute of Reproduction and Development, Monash Medical Centre,
Clayton, Victoria, Australia 3168; and The Asher Center (E.R),
Department of Psychiatry and Behavioral Sciences, Northwestern
University Medical School, Chicago, Illinois 60611
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Abstract
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- I. Introduction
- II. Hypothalamic Stimulation of ACTH Release and Biosynthesis
- A. Corticotropin-releasing factor (CRF)
- B. Arginine vasopressin (AVP)
- C. The hypothalamic CRF and AVP neurons and their connections
- D. Studies of the secretion of CRF and AVP into the hypophysial-portal
circulation
- E. Studies of the neural regulation of CRF and AVP secretion and
biosynthesis
- III. Hypothalamic Inhibition of ACTH Release and Biosynthesis
- A. Historic studies
- B. Effect of hypothalamo-pituitary disconnection in adult and fetal sheep
- C. Effects of the opiate alkaloids and opioid peptides on the HPA axis
- D. The role of the posterior pituitary in the regulation of corticotropic
function
- E. Hypothalamic ACTH release-inhibitory activity
- F. Definition of corticotropin release inhibitory factor (CRIF)
- IV. CRIF: A Consideration of Possible Candidates
- A. Somatostatin (SST)
- B. Dopamine
- C. Atrial natriuretic peptide (ANP)
- D. Prepro-TRH-(178199)
- E. Other substances
- V. Future Directions
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I. Introduction
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IT HAS been traditionally thought that the hypothalamus
only exerts a stimulatory influence upon the secretion and synthesis of
ACTH by the anterior pituitary gland and that this is mediated by
neuropeptides such as corticotropin-releasing factor (CRF), arginine
vasopressin (AVP), and oxytocin (OT), which are secreted into the
hypophysial-portal circulation (Refs. 1, 2, 3, 4, 5, 6 and Fig. 1
). However, an analysis of the effects
on the hypothalamic-pituitary-adrenal (HPA) axis of surgically
isolating the anterior pituitary from the hypothalamus suggests that
the hypothalamus may exert both inhibitory and stimulatory regulation
over ACTH secretion and POMC biosynthesis and that the inhibitory
regulation might be mediated by a currently unidentified substance that
has been named corticotropin release-inhibitory factor (CRIF) (7, 8).
In this review, we will initially summarize some of the recent
knowledge of the mechanisms by which the hypothalamus stimulates
corticotropic function and describe some of the central neural pathways
regulating the HPA axis. We will then review the historical, and more
current, literature describing the effects on the HPA axis of
surgically isolating the pituitary from the hypothalamus. We outline
several postulates that may need to be fulfilled for a substance to
qualify as a CRIF, describe studies performed to date to determine the
ACTH release-inhibitory activity of a number of possible candidates,
and finally point to possible future directions in this emerging area.

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Figure 1. A schematic representation of the current model by
which the hypothalamus is thought to regulate ACTH secretion. This
model proposes that the hypothalamus only stimulates ACTH secretion by
secreting neuropeptides such as CRF and AVP into the hypophysial-portal
circulation. ACTH then stimulates the adrenocortical production of
cortisol, which then restrains the secretion of ACTH by exerting
negative feedback effects on the anterior pituitary, hypothalamus, and
various extrahypothalamic brain sites.
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II. Hypothalamic Stimulation of ACTH Release and Biosynthesis
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A. CRF
CRF is a 41-residue peptide that was first isolated in 1981 by
Vale et al. (9) on the basis of its ability to markedly
augment the secretion of ACTH and ß-endorphin from cultured rat
anterior pituitary cells (Fig. 2
). CRF is
the most potent ACTH secretagog in the rat and in man although its
ability to stimulate ACTH secretion is potentiated severalfold by
agonists such as AVP, OT, angiotensin II, norepinephrine (NE), and
epinephrine (EPI) (10, 11, 12). However, CRF may not be the most potent
ACTH secretagog in all species as it appears to be equipotent with AVP
in the bovine species (13), and in the ovine species, AVP appears to be
even more potent than CRF (Refs. 14, 15, 16 and Fig. 3
). Moreover, in the rat, CRF is the only
hypothalamic neuropeptide known to increase POMC biosynthesis, and none
of the aforementioned ACTH secretagogs are able to potentiate this
effect of the peptide (17, 18, 19, 20, 21, 22, 23).
CRF exerts its effects on the anterior pituitary by binding to a
specific receptor that is linked to the adenylate cyclase complex. The
binding of the hormone to the corticotrope cell membrane results in
increased intracellular concentrations of cAMP, an increased influx of
extracellular Ca2+, an activation of the cAMP-dependent
protein kinase [protein kinase A (PKA)], and the phosphorylation of a
number of intracellular proteins (24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40). The brain CRF receptor is
also linked to the adenylate cyclase complex, and it is therefore
likely that a similar sequence of second messenger responses underlies
the actions of the peptide in the brain (41). The characteristics of
the CRF receptor were determined in the 1980s by studies that examined
the binding of radiolabeled CRF ligands to pituitary and brain
membranes (42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56). The anterior pituitary CRF receptor has high
affinity, its activity is modulated by divalent cations and guanyl
nucleotides, and receptor down-regulation occurs in response to
adrenalectomy, corticosterone (CS) treatment, and chronic stress. In
contrast, none of these interventions affect CRF receptor number in the
brain or intermediate pituitary. As determined by autoradiography, the
highest CRF receptor density in the primate brain is found in the pars
tuberalis of the pituitary and throughout the cerebral cortex (Ref. 51
and Fig. 4
). A very high binding density
is also found in the hippocampus and arcuate nucleus, high levels are
seen in the amygdala, and lower levels of receptor binding are also
found in a variety of other brain areas.

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Figure 4. Color-coded image of
[[125I]Tyr]oCRF autoradiographs of representative
coronal sections from rostral to caudal of monkey brain. Areas of very
high density are shown in red, and densities decrease
through yellow, green, and light
blue. Dark blue and black
correspond to nonspecific background. CC, Cingulate cortex; P, putamen;
OC, orbital cortex; C, caudate; OT, olfactory tubercle; Cl, claustrum;
TC, temporal cortex; NST, nucleus of stria terminalis; IC, insular
cortex; POA, preoptic area; AA, anterior amygdala; NPT, paraventricular
nucleus of thalamus; A, amygdala; MDT, medial dorsal thalamus; MN,
mamillary nucleus; Hi(gd), hippocampus (gyrus dentatus); SC, superior
colliculus; LPTN, lateral posterior thalamic nucleus; LGB, lateral
geniculate body; Hi, hippocampus; Cb, cerebellum; ICo, inferior
colliculus; LC, locus coeruleus; DPN, dorsal parabrachial nucleus.
[Reproduced with permission from M. A. Millan et
al.: Proc Natl Acad Sci USA 83:19211925, 1986
(51 ).]
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Two CRF receptor subtypes are encoded by distinct genes and they are
members of the calcitonin/vasoactive intestinal peptide/GHRF
subfamily of G-protein coupled receptors. The CRF-R1
receptor was the first to be cloned and characterized from a human
corticotropic adenoma, from mouse AtT20 pituitary tumor cells, and from
human and rat brain (57, 58, 59, 60). It is a 415-amino acid protein comprised
of seven membrane-spanning domains that binds rat/human CRF with high
affinity. In addition, the nonmammalian CRF-related peptides, sauvagine
and urotensin I, also bind to CRF-R1 and are nearly
equipotent with CRF in stimulating cAMP accumulation in cells
containing the expressed receptor. CRF-R1 mRNA is expressed
throughout the intermediate pituitary and in the corticotropes of the
anterior lobe (61, 62), and within the brain, its distribution conforms
well with the results of the autoradiographic studies. However, the
occurrence of sparse CRF-R1 mRNA expression in several
brain areas known to bind CRF has been observed, and this
"mismatch" may be partly due to the existence of the
CRF-R2 receptor in these sites.
The second CRF receptor to be isolated (CRF-R2) was cloned
from mouse heart and rat brain cDNA libraries (63, 64, 65, 66) and consists of
two splice variants, CRF-R2
and CRF-R2ß,
which differ at their N-terminal domain. CRF-R2
is a
411-amino acid protein cloned from the rat brain (63), whereas
CRF-R2ß is a 431-amino acid protein that was isolated
from mouse heart (64, 65, 66). CRF and the nonmammalian peptides, sauvagine
and urotensin I, all bind to CRF-R2 and stimulate adenylate
cyclase activity, and the rank order of potency of their interaction
(sauvagine > urotensin> rat/human CRF > ovine CRF) differs
markedly from their interaction with CRF-R1. The
distribution of CRF-R2 mRNA in rat brain differs from that
of CRF-R1 mRNA (67) since CRF-R1 mRNA
expression is highest in neocortical, cerebellar, and sensory relay
structures, whereas CRF-R2 mRNA expression is mainly
confined to subcortical structures and is most abundant in the lateral
septal nucleus, the ventromedial hypothalamus, and choroid plexus (Fig. 5
). In further contrast with the
CRF-R1 mRNA, the CRF-R2 mRNA is in very low
abundance within the anterior pituitary.

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Figure 5. Color-coded digitized images of CRF1
and CRF2 receptor mRNA expression in adjacent horizontal
brain sections. Regions exhibiting high levels of mRNA expression are
coded in red and orange, while the lowest
levels of expression are coded in blue. [Reproduced
with permission from D. T. Chalmers et al.:
J Neurosci 15:63406350, 1995 (67 ).]
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As noted, both CRF-R1 and CRF-R2 bind the
nonmammalian CRF-like peptides, sauvagine and urotensin-l, albeit with
different affinity. It was originally presumed that sauvagine and
urotensin-1 were CRF homologs involved in stimulating ACTH release in
amphibia and fish, respectively. However, in 1988, Okamura et
al. (68) isolated a cDNA in the teleost fish, Catostomus
commersoni, that encoded a peptide possessing 95% homology with
rat CRF and in 1992, Stenzel-Poore et al. (69) characterized
a cDNA in the frog, Xenopus laevis, which encoded a peptide
sharing 93% homology with mammalian CRFs and only 50% with sauvagine.
These findings demonstrated that sauvagine and urotensin-1 were not the
primary ACTH secretagogs in amphibia and fish and showed that at least
two members of the CRF superfamily could coexist in a single species.
Furthermore, the findings raised the possibility that a nonmammalian
CRF-like peptide might also occur in mammals. This prediction was
subsequently confirmed by the isolation of urocortin (70). In the
initial studies, urotensin-like immunoreactivity was located in the
Edinger-Westphal nucleus of the rat midbrain, and a unique cDNA was
cloned from a library encompassing this nucleus, which encoded a
precursor and a peptide that was named urocortin. The human and rat
peptides share 95% identity within the mature peptide region, and the
gene encoding the human peptide has been localized to chromosome 2
(71). In the rat brain, the most abundant immunoreactive (ir)-urocortin
perikarya are located in the supraoptic, paraventricular, and
periventricular hypothalamic nuclei, the Edinger-Westphal nucleus, the
dorsal raphe, and the dorsal and laterodorsal tegmental nuclei.
However, despite its hypothalamic distribution, no ir-urocortin has
been found in the median eminence or posterior pituitary, suggesting
that it is unlikely that the peptide is secreted into the
hypophysial-portal circulation. The distribution of ir-urocortin
overlaps with the CRF-R2 mRNA in several brain areas,
suggesting that it may mediate the functions of CRF in these sites
(72).
B. AVP
The nonapeptide AVP is also secreted into the hypophysial-portal
circulation and acts on the anterior pituitary to stimulate ACTH
release. AVP is a weak ACTH secretagog in the rat and in man, although
it appears to be as potent as CRF in the bovine species and even more
potent than CRF in the ovine species. Although CRF and AVP both
increase ACTH secretion and total ACTH content in ovine anterior
pituitary cells, AVP is clearly the more potent agonist, and these
observations gave rise to the hypothesis that both secretagogs might
increase POMC gene expression in ovine corticotropes (15). This
suggestion initially received little experimental support (73), but a
recent study by van de Pavert et al. (74) has demonstrated
that AVP, but not CRF, does increase steady-state levels of POMC mRNA
in ovine corticotropes. This finding contrasts sharply with the
situation in the rat where CRF is the only neuropeptide known to
stimulate POMC gene expression and points toward species-specific
differences in regulation of the POMC gene. The molecular basis for
these differences requires further investigation.
The pituitary AVP receptor (V1b) is clearly different from those AVP
receptors found in the liver and on vascular smooth muscle cells (V1)
or in the kidney (V2) (75, 76, 77, 78, 79, 80, 81, 82). Adrenalectomy markedly decreases AVP
binding in the pituitary, an effect that is prevented by glucocorticoid
replacement (78, 79). Moreover, Vlb receptor content is increased or
decreased by manipulations that respectively augment or reduce HPA axis
activity (83). When taken together, these findings suggest that V1b
receptor expression is positively regulated by glucocorticoids. The
nucleotide and amino acid sequences of the Vlb receptor were first
derived from a human pituitary cDNA library (84). The deduced protein
was found to contain 424 amino acid residues and 7 transmembrane
domains, and Northern blot analysis showed a single mRNA transcript
that was detectable only in the anterior pituitary. However, a
subsequent study has predicted a protein of 421 amino acids and shown
expression of 2 mRNA species in the anterior pituitary, in several
brain regions, and in a number of extrapituitary tissues (85). The
precise basis for these different findings awaits further elucidation.
The anterior pituitary AVP receptor is coupled to the
phosphatidylinositol (PI) pathway (86, 87, 88), and hormone binding
therefore stimulates PI hydrolysis and increases the production of
inositol 1,4,5-trisphosphate (IP3) and diacylglycerol
(Refs. 89, 90, 91 and Fig. 6
). The
diacylglycerol is required for the activation of protein kinase C,
which then causes the phosphorylation of a number of cellular
substrates such as the myristoylated alanine-rich C kinase substrate
(MARCKS) protein (15, 37, 92, 93, 94, 95, 96). The IP3 causes the
liberation of Ca2+ from intracellular stores and, together
with the influx of extracellular Ca2+, causes the rise in
intracellular Ca2+ that is required to mediate ACTH release
(33, 40). Since the pituitary AVP receptor is not linked to the
adenylate cyclase, it does not increase cAMP levels in this site (36, 97, 98, 99). However, it does potentiate the cAMP response to CRF, an
effect that is due to the activation of protein kinase C since it is
also mimicked by phorbol esters (36, 98, 99).

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Figure 6. A schematic representation of the subcellular
mechanisms activated by the binding of AVP to the anterior pituitary
V1b receptor. A, A unified hypothesis of the spatiotemporal aspects of
calcium signaling, based on ideas concerning calcium oscillations and
the propagation of calcium waves. A typical response begins with an
agonist (such as AVP) generating Ins(1 4 5 )P3, which then
mobilizes calcium from an Ins(1 4 5 )P3-sensitive calcium
store and also promotes the entry of external calcium to give an
initial calcium signal. In some cells, this
Ins(1 4 5 )P3-induced calcium signal can act as a
"primer" to drive a process of calcium-induced calcium release from
the Ins(1 4 5 )P3-insensitive pools to produce a spike that
might be organized in the form of a wave, thereby spreading the
signal throughout the cell. [Reproduced with permission from M.
J. Berridge and R. F. Irvine: Nature 341:197205,
1989 (86 ). © Macmillan Magazines, Ltd.]
B, Schematic representation of proposed mechanisms of protein
kinase C (PKC) activation. There are two pathways leading to the
activation of intracellular PKC from the extracellular environment: (a)
by the receptor-mediated production of diacylglycerol (DAG) via
a G protein-coupled phospholipase C; and (b) by direct pharmacological
activation with phorbol esters. Both DAG and phorbol esters [such as
phorbol 12-myristate 13-acetate (PMA)] bind to the C1 region of the
PKC-regulatory subunit that causes physical association of PKC with the
plasma membrane (translocation). DAG promotes the formation of a
PKC-phosphatidylserine (PS)-Ca2+ complex, whereas phorbol
esters cause plasma membrane insertion of the kinase and its subsequent
down-regulation. Both DAG and phorbol esters induce a conformational
change in the structure of PKC so that the inhibitory pseudosubstrate
sequence moves away from the substrate binding site. This then permits
PKC substrates to bind to the kinase and to be phosphorylated. (1 )
Receptor activation; (2 ) translocation; (3 ) down-regulation; (4 )
membrane insertion; and (5 ) substrate phosphorylation. [Reproduced
with permission from J. P. Liu: Mol Cell Endocrinol
116:129, 1996 (88 ). © Elsevier Science.]
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C. The hypothalamic CRF and AVP neurons and their connections
The CRF and AVP neurons that project to the external zone of the
median eminence are located on either side of the midline in the
paraventricular nucleus of the hypothalamus (PVH) (100-120). The rat
PVH is a complex structure that contains three dense clusters of
magnocellular neurons (anterior, medial, posterior) that project to the
posterior pituitary surrounded by a large shell of parvocellular
neurons. The parvocellular component can, in turn, be subdivided into
five parts (anterior, medial, dorsal, lateral, and periventricular),
which are interrelated with autonomic cell groups in the brainstem and
spinal cord via bidirectional pathways and with the external zone of
the median eminence (Fig. 7
).

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Figure 7. A schematic diagram to show the major cell groups
of the paraventricular nucleus of the hypothalamus in the rat, as
viewed from above. The three parts of the magnocellular division are
shown in stipple,and are embedded in the parvocellular
division, which consists of five parts. The abbreviations are as
follows: am, anterior magnocellular; ap, anterior parvocellular; dp,
dorsal parvocellular; lp, lateral parvocellular; mm, medial
magnocellular; mp, medial parvocellular; pm, posterior magnocellular;
pv, periventricular. [Reproduced with permission from L. W.
Swanson et al.: J Comp Neurol
196:271285, 1981 (129 ). © Wiley-Liss, Inc., a division of John Wiley
& Sons, Inc.]
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The rat brain contains about 2,000 CRF-stained perikarya distributed
throughout all 8 parts of the PVH, and most of these cells are found in
the parvocellular division (111). The medial, periventricular, and
medial lateral parts of the parvocellular division contain about half
of the total number of CRF-stained neurons, and these areas are known
to send massive projections to the external zone of the median
eminence. In addition, about 15% of the total CRF-stained population
is found in those areas of the magnocellular division that
predominantly contain oxytocinergic cells. In addition to the PVH,
CRF-stained cells are also found in the basal hypothalamus,
telencephalon, and brainstem, and these areas are involved in the
functioning of the autonomic nervous system. Finally, CRF-stained cells
are found scattered throughout the cerebral cortex and, in this region,
they are concentrated in layers II and III (Fig. 8
).

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Figure 8. A schematic illustration of the major CRF-stained
cell groups (black dots) and fiber systems in the rat
brain. Most of the immunoreactive cells and fibers appear to be
associated with systems that regulate the output of the pituitary and
the autonomic nervous system, and with cortical interneurons. Most of
the longer central fibers course either ventrally through the medial
forebrain bundle and its caudal extension in the reticular formation,
or dorsally through a periventricular system in the thalamus and
brainstem central gray. The direction of fibers in these systems is
unclear because they appear to interconnect regions that contain
CRF-stained cell bodies. Thus, for example, three adjacent CRF-stained
cell groups, the laterodorsal tegmental nucleus (LDT), locus ceruleus
(LC), and parabrachial nucleus (PB), lie in the dorsal pons. However,
it is uncertain which of these cell groups contributes to each of the
pathways shown, and which of them receives inputs from the same
pathways. Abbreviations: HIP, hippocampus; SEPT, septal region; BST,
bed nucleus of the stria terminalis; SI, substantia innominata; CeA,
central nucleus of the amygdala; PVH, paraventricular hypothalamic
nucleus; MPO, medial preoptic area; ME, median eminence; PP, posterior
pituitary; LHA, lateral hypothalamic area; MID THAL, midline thalamic
nuclei; POR, perioculomotor nucleus; CG, central gray; DR, dorsal
raphe; MR, median raphe; LDT, laterodorsal tegmental nucleus; LC, locus
ceruleus; PB, parabrachial nucleus; MVN, medial vestibular nucleus;
DVC, dorsal vagal complex; A1, A5, noradrenergic cell groups; ac,
anterior commissure; cc, corpus callosum; st, stria terminalis; mfb,
medial forebrain bundle. [Reproduced with permission from L. W.
Swanson et al.: Neuroendocrinology
36:165186, 1983 (111 ). © Karger, Basel.]
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The CRF neurons in the parvocellular division of the PVH may be further
subdivided into two populations that are distinguished by the
colocalization of the AVP precursor (pro-AVP)-derived peptides AVP, the
vasopressin-neurophysin (NP), or the pro-AVP C-terminal
glycopeptide (121, 122). The CRF+/AVP+
and CRF+/AVP- subpopulations are similarly
distributed in the rostral and caudal regions of the PVH but
differently distributed in the region midway between the rostral and
caudal ends of the nucleus. In the normal rat, almost half of the
CRF-positive axon terminals in the external zone of the median eminence
stain intensely for AVP and NP, and both CRF and the pro-AVP-derived
peptides are found within the same neurosecretory vesicles. However,
the majority (>90%) of the pro-AVP-deficient neurons and virtually
all the CRF-positive structures in the median eminence stain intensely
for AVP, NP, or glycopeptide in the adrenalectomized rat. These
findings indicate that the normal circulating level of glucocorticoid
is sufficient to inhibit pro-AVP gene expression in the
CRF+/AVP- neurons but not in the
CRF+/AVP+ cells and are consistent with the
hypothesis that modulation of the CRF:AVP molar ratio in the
hypophysial-portal circulation could be partly mediated by differential
regulation of the two CRF neuronal subpopulations in the PVH.
The PVH is also connected with a number of brain regions, and prominent
among these are the forebrain, the limbic system, and the brainstem.
For example, the parvocellular part of the PVH receives moderately
dense projections arising from all areas of the hypothalamus (except
the supraoptic nucleus, the medial and lateral mamillary nuclei, and
the magnocellular preoptic nucleus), from the subfornical organ, and
the bed nucleus of the stria terminalis, but the magnocellular division
of the PVH receives relatively few inputs from these structures (123).
Although a large amount of physiological and functional evidence
indicates that several parts of the limbic system (septum, amygdala,
and hippocampal formation) may regulate the activity of the PVH,
detailed autoradiographic studies have failed to detect direct
projections from any of these areas to the PVH or the supraoptic
nucleus (124, 125, 126). Rather, these structures may give rise to
pathways that end in cell groups lying immediately adjacent to the PVH.
The only exception to this statement is the projection from the ventral
subiculum, which may interact directly with the PVH by means of a relay
in the bed nucleus of the stria terminalis (127). As noted, the PVH is
densely innervated by aminergic and peptidergic axon terminals that
arise from cell bodies located in brainstem nuclei. The aminergic
terminals contain NE, EPI, dopamine (DA), and serotonin and, to
date, the noradrenergic and adrenergic projections have been subjected
to the most detailed analysis (128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139).
The noradrenergic input to the PVH arises almost exclusively from three
interrelated cell groups in the brainstem, namely the A2 region in the
nucleus of the tractus solitarius (NTS), the A1 region in the
ventrolateral medulla, and the A6 area in the locus ceruleus (Fig. 9
). The projections from the A1 region
are almost entirely directed toward the magnocellular division and
terminate preferentially on vasopressinergic cell bodies. The fibers
originating from the A2 region are primarily distributed throughout the
parvocellular division and are most dense in the dorsal medial part, a
region known to contain a large population of CRF-immunoreactive
neurons. The projections arising from the A6 area are almost entirely
distributed to the parvocellular PVH, and their most prominent input is
localized to the periventricular zone, an area known to contain DA-,
somatostatin (SST)-, and TRH-staining neurons (138). When taken
together, these findings suggest that the A1, A2, and A6 noradrenergic
cell groups may each regulate the activity of anatomically and
functionally distinct groups of neurosecretory neurons.

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Figure 9. Schematic drawing of a sagittal section through
the rat brain to indicate the dominant biochemical makeup and
distribution of catecholaminergic and NPY-immunoreactive inputs from
the brainstem to the PVH. Adrenergic (E) projections arise from the C1,
C2, and C3 regions, are distributed overwhelmingly to the parvicellular
(pc) division of the nucleus, and generally stain positive for NPY
immunoreactivity. Noradrenergic (NE) projections from the locus
coeruleus and A2 cell groups are also distributed primarily to the
parvicellular division, but are, for the most part, NPY negative. A
heterogeneous input arises from the A1 region and is distributed to
both the parvicellular division and preferentially to those parts of
the magnocellular division in which vasopressinergic neurons (V)
predominate over oxytocinergic ones (o). One component appears also to
contain NPY immunoreactivity, whereas a second one does not.
[Reproduced with permission from P. E. Sawchenko et
al.: J Comp Neurol 24:138153, 1985 (149 ).
© Wiley-Liss, Inc., a division of John Wiley & Sons, Inc.]
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The ascending adrenergic projections to the PVH are also derived from
three discrete brainstem cell groups, namely the C1 group (in the
rostral ventrolateral medulla), the C2 group (in the rostromedial part
of the nucleus of the tractus solitarius), and the C3 group (in the
medial longitudinal fasciculus and nucleus prepositus hypoglossi).
However, in contrast to the highly differentiated noradrenergic
projection to the PVH, the projections from each of the adrenergic cell
groups are very similarly distributed within the PVH and, in each case,
the most dense innervation is seen in the dorsal medial parvocellular
part, a region that is rich in CRF-staining neurons. These findings
suggest that the C1, C2, and C3 adrenergic cell groups may each
influence similar groups of parvicellular neurosecretory and/or
autonomic neurons in the PVH (139).
As stated above, the PVH is also innervated by peptidergic axon
terminals, and those that stain for neuropeptide Y (NPY) appear
particularly prominent (140, 141). NPY-stained perikarya and axon
terminals are widely distributed within the brain, and the PVH and
hypothalamic arcuate nucleus, respectively, contain the highest density
of NPY-stained axon terminals and perikarya within the brain
(142, 143, 144, 145, 146). NPY is extensively colocalized within brainstem adrenergic
neurons that project to the PVH, while its expression in noradrenergic
neurons appears limited to a subpopulation of cells in the A1 group
(147, 148, 149, 150, 151). NPY-stained projections are most dense in the anterior and
medial parvocellular parts of the PVH, and these areas are known to
contain CRF- and TRH-stained neurons (Fig. 10
). Furthermore, the ultrastructural
demonstration of direct synaptic contacts between NPY-stained axon
terminals and CRF-stained perikarya in the PVH provides the anatomical
basis for considering NPY a potentially important regulator of the HPA
axis (152).

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Figure 10. Darkfield photomicrographs of avidin-biotin
immunoperoxidase preparations to show the distribution of
fibers and varicosities stained for
phenylethanolamine-N-methyltransferase (PNMT),
dopamine-ß-hydroxylase (DBH), and neuropeptide Y (NPY)
immunoreactivity at a similar level through the paraventricular nucleus
(PVH; the third ventricle is at the extreme left of each micrograph).
At this midcaudal level, basic similarities and differences in the
distribution and density of each input may be appreciated, although in
these thicker (3035 µM) sections, details of the
distributions cannot necessarily be inferred. Note that the
distribution of PNMT-stained elements is largely limited to a discrete
part of the parvicellular division of the nucleus; few are seen in the
magnocellular division. The DBH-stained projection encompasses and
exceeds that localized with anti-PNMT, providing a prominent input to
the magnocellular division, which is located at the right-hand margin
of the nucleus at this level. The NPY-stained input encompasses and
exceeds the distribution and density provided by DBH-immunoreactive
inputs, providing perhaps the most prominent chemically specified input
to the PVH yet described. [Reproduced from P. E. Sawchenko
et al.: J Comp Neurol
241:138153,1985 (149 ). © Wiley-Liss, Inc., a division of John Wiley
& Sons, Inc.]
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D. Studies of the secretion of CRF and AVP into the
hypophysial-portal circulation
The studies of Porter and Jones (153) represent one of the
earliest efforts to detect the presence of ACTH-releasing activity in
hypophysial-portal plasma. These authors demonstrated that the
intravenous injection of canine hypophysial-portal vessel plasma into
the hydrocortisone-inhibited, intact rat caused ACTH release, as judged
by the adrenal ascorbic acid depletion assay. The effect was not
observed in animals injected with canine carotid artery plasma,
suggesting "that venous blood from the hypothalamico-hypophyseal
portal vessels contains a substance(s) which accelerates the release of
ACTH and that this substance(s) is not present or is present in much
less concentration in the blood from the carotid artery." The
response was also abolished by hypophysectomy, indicating that the
anterior pituitary is required for the effect to be seen.
In the 1980s and l990s, in vivo studies were performed in
the rat, the sheep, and the horse, which demonstrated that CRF, AVP,
and OT were secreted into the hypophysial-portal circulation
(154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186). The first studies to appear were performed in the
anesthetized rat (154, 155, 156, 157, 158), and when they are compared with those
subsequently performed in the conscious sheep and horse, it is apparent
that the stress of the anesthesia, and perhaps the surgical procedure
itself, elevated the baseline levels of these peptides. Nevertheless,
the studies in the rat demonstrated that maneuvers such as chemical
adrenalectomy, volume depletion, nitroprusside-induced hypotension,
insulin-induced hypoglycemia, the intracerebroventricular
administration of NE, and transection of the fornix all increased CRF
concentrations in portal blood (157, 158, 161, 162, 163, 166, 173, 174).
Furthermore, manipulations such as exposure to glucocorticoid-negative
feedback, the surgical or chemical destruction of the hypothalamic
noradrenergic input, and surgical lesions of the PVN all decreased the
basal or stress-induced increments in CRF concentrations in portal
plasma (155, 160, 168, 176, 177, 178).
These experimental manipulations were also found to exert effects on
the levels of AVP and OT in portal plasma. Volume depletion,
hypoglycemia, and fornix transection increased portal AVP and OT
concentrations (157, 158, 174), nitroprusside-induced hypotension did
not alter either of their levels (177), and chemical adrenalectomy had
no discernible effect on OT (161). In contrast, the exposure to
glucocorticoids also decreased portal levels of AVP and OT (176, 177),
but destruction of the hypothalamic noradrenergic input or the PVN
itself had no effect on portal AVP concentrations (168, 176). These
findings have given rise to the concept that a substantial proportion
of the AVP in portal plasma may be of magnocellular origin (176).
Finally, recent studies in the rat employing the technique of
microdialysis have shown that emotional stress may also increase the
release of AVP into the PVH (187). However, it appears that AVP, when
released into the PVH, exerts an inhibitory, rather than a stimulatory,
effect on the HPA axis. Although the mechanisms by which this
inhibitory effect is mediated were not elucidated, the findings
indicate that the same neuropeptide may exert opposite effects on the
HPA axis at the level of the PVH and anterior pituitary gland.
In the late 1980s, several studies appeared in which portal CRF and AVP
concentrations were measured in conscious, unanesthetized animals (159, 167, 169, 170, 171, 175, 185). In our studies, ovine pituitary portal blood
was collected by the technique developed by Clarke and Cummins (188).
This method allowed portal blood to be collected in the conscious
animal at 5- to 10-min intervals and thereby permitted the first
evaluation of the normal ultradian secretion of the hypothalamic
releasing factors and their responses to stressful stimuli. These
studies, and those of Caraty et al. (169, 175) performed in
conscious rams, demonstrated that CRF and AVP were secreted in a
pulsatile manner, that the two peptides were secreted synchronously or
asynchronously, that their basal concentrations were generally less
than 100 pg/ml, and that their basal secretory patterns differed in
each individual animal (Fig. 11
). They
also showed that volume depletion, a fear-associated audiovisual
stimulus, or insulin-induced hypoglycemia all increased CRF and AVP
levels in portal plasma and generally increased the AVP:CRF molar
ratio. Since fear-associated audiovisual stimuli initially activate the
auditory and visual cortices, respectively, and subsequently activate
the limbic system whereas hypoglycemia primarily activates several
subcortical brain areas, these findings showed that the CRF and AVP
neurons within the PVN may be activated by different neural inputs.
When sheep were treated with dexamethasone, the basal levels of CRF,
ACTH, and cortisol were decreased, the pituitary-adrenal response to an
audiovisual stimulus was inhibited, and the HPA response to
hypoglycemia was attenuated (171).
The studies in the horse measured CRF and AVP in the pituitary venous
effluent via a catheter that was introduced through the facial vein
(189), but since the tip of the catheter lay below the anterior
pituitary, the concentrations of CRF and AVP measured may be up to
10-fold lower than those actually present in the portal blood (159, 167, 172, 181, 183, 184). However, a high degree of concordance was
found between AVP and ACTH pulses, and the overall conclusions of these
studies were remarkably in accord with those derived from the studies
in the rat and sheep.
E. Studies of the neural regulation of CRF and AVP secretion and
biosynthesis
1. The central noradrenergic and adrenergic pathways. The
early studies of Krieger and Krieger (190) that were performed in the
conscious cat suggested that centrally administered catecholamines
activated the pituitary-adrenal axis. However, throughout the 1970s and
early 1980s, it was generally accepted that central NE inhibited ACTH
release, and this view was based on experiments by Ganong and
co-workers (191, 192) that were performed in the anesthetized dog .
However, in the late 1980s and early 1990s, studies in conscious
animals (rat, sheep) and in man appeared that strongly supported the
view that central catecholamines stimulate the pituitary-adrenal axis
(193, 194, 195, 196, 197, 198, 199, 200, 201, 202). The diametrically opposed findings of Ganong et
al. (191, 192) may be due to the use of anesthesia and are
reconciled with all these studies when one considers that anesthesia
may cause a single, centrally administered agonist to exert opposite
effects on brainstem NE release and/or biosynthesis (203).
Our studies in the conscious sheep were initiated to determine how
insulin-induced hypoglycemia might stimulate CRF and AVP secretion into
the hypophysial-portal circulation. The PVH does not appear to contain
glucose-sensitive neurons, but the NTS, the lateral hypothalamic area,
and the ventromedial hypothalamus do contain neurons that respond to
changes in glucose concentration by altering their firing rates
(204, 205, 206). Therefore, the effect of hypoglycemia on CRF and AVP
release is likely to be secondary to a primary activation of one or
more of these glucose-sensitive sites. The experiments were based on
the finding that hypoglycemia increases the hypothalamic turnover of NE
(207), and the anatomic relationships that exist between the PVH and
the brainstem catecholaminergic and peptidergic cell groups. It was
hypothesized that the effect of hypoglycemia on neuronal activity in
the NTS might increase NE synthesis within the nucleus or within the Al
and A6 areas, since all three regions are interconnected (131). This
conceptual framework would explain the increased hypothalamic turnover
of NE during hypoglycemia and would also predict that NE, and possibly
EPI, might stimulate the release of CRF and/or AVP.
When NE or EPI was injected into the lateral cerebral ventricle of the
conscious sheep, an acute and sustained increase in ACTH and cortisol
secretion was observed, and NE appeared to be the more potent agonist
(202). The finding that NE and EPI released only very modest amounts of
ACTH from cultured anterior pituitary cells suggested that both amines
were mainly acting on suprahypophysial brain sites to increase CRF and
AVP release. This prediction was tested by determining the effects of
intracerebroventricular (icv) NE on the secretion of CRF and AVP into
the hypophysial-portal circulation of the conscious sheep (Ref. 185
and Fig. 12
). The icv injection of 50
µg NE acutely increased CRF and AVP concentrations in portal plasma
and activated the pituitary-adrenal axis. In addition, NE caused
sustained hypersecretion of CRF and AVP even though plasma cortisol
levels were greatly elevated. This observation suggested that
activation of the central noradrenergic system might override the
normal glucocorticoid negative feedback on those areas of the brain
concerned with regulation of the HPA axis. This concept of "acquired
glucocorticoid resistance" has been recently addressed by De Kloet
et al. (208), and the following subcellular mechanisms may
underly this phenomenon.

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Figure 12. The effect of an icv injection of 50 µg
norepinephrine on plasma CRF, AVP, ACTH, and cortisol in three ewes.
The arrow ( ) depicts the time of injection.
[Reproduced with permission from J.-P. Liu et al.:
J Clin Invest 93:14391450, 1994 (185 ). © The
American Society for Clinical Investigation.]
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First, activation of hypothalamic adrenergic receptors by icv NE might
stimulate CRF (and AVP) biosynthesis to such a degree that the
glucocorticoid-inhibitory effect on CRF (and AVP) gene expression is
overridden. The suggestion that the central noradrenergic pathways
might stimulate CRF biosynthesis in vivo is supported by the
observations that microinjection of NE into the rat PVH increases CRF
mRNA expression in the nucleus (209) and that unilateral hemisection of
the brainstem between the locus ceruleus and NTS reduces both the basal
and stress-induced rise in CRF mRNA expression in the ipsilateral PVH
(210, 211). Second, chronic activation of the central catecholaminergic
pathways by repeated immobilization of the rat also attenuates
glucocorticoid-negative feedback by decreasing type 2 glucocorticoid
receptor (GR) mRNA in the PVH and hippocampus (212). The immobilization
causes hypercortisolemia, which may in turn mediate the effect on GR
gene expression since it is not observed in adrenalectomized animals
bearing implanted cortisol pellets.
The activation of the cAMP/protein kinase A pathway and the
cAMP-regulatory element binding protein (CREB) may constitute one of
the intracellular mechanisms that mediates the effect of NE on CRF
biosynthesis. The cAMP-regulatory element (CRE), generally represented
by the palindromic motif 5'-TGACGTCA-3', binds a number of
transcription factors including CREB, an intranuclear PKA substrate
protein that is phosphorylated upon activation of the cAMP-PKA pathway
(213, 214, 215, 216, 217). The CRE is also present in the rat, ovine, and human CRF
genes (218, 219, 223, 224) and is likely to be physiologically
important since activation of the cAMP-PKA pathway increases CRF mRNA
levels in vitro (220, 221, 222), and mutation of the CRE site
completely abolishes this effect (224). Moreover, the cAMP-PKA pathway
is also important in stimulating CRF gene expression in vivo
since 8-bromo-cAMP, when microinjected into the PVH, increases CRF
mRNA in the hypothalamus, increases POMC mRNA in the anterior
pituitary, and increases plasma ACTH concentrations (225). Furthermore,
the increase in CRF mRNA that occurs as a consequence of
insulin-induced hypoglycemia can be attenuated by the prior injection
into the PVN of a CREB antisense oligonucleotide. Since insulin-induced
hypoglycemia also increases NE turnover in the hypothalamus, these
findings point toward a major role for CREB in mediating the
stimulatory effect of the ascending catecholaminergic pathways on CRF
gene expression.
2. Neuropeptide Y. A number of studies have assessed the role
of Neuropeptide Y in the regulation of the HPA axis (185, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235).
This 36-residue peptide is widely distributed within the brain, and it
exerts its effects by acting on five receptor subtypes (designated
Y1-Y5) (236, 237). The cDNAs encoding all except the Y3 receptor have
been isolated (238, 239, 240, 241, 242, 243, 244), each one is expressed in the brain, and the
Y2 and Y5 receptor mRNAs seem restricted to this site (240, 244). NPY
mimics the action of icv NE on the pituitary-adrenal axis when
injected into the cerebral ventricles of the rat, dog, and sheep, and
the studies in the conscious sheep indicate that the effect is mediated
at one or more suprahypophysial sites since NPY increases the release
of CRF and AVP into the hypophysial-portal circulation, but does not
increase the release of ACTH from cultured ovine anterior pituitary
cells (185). Like NE, NPY also stimulates CRF biosynthesis since icv
NPY increases CRF mRNA in the rat hypothalamus (233). Although these
effects of NPY on CRF are likely to be mediated by binding of the
peptide to NPY receptors in the PVH, the exact NPY receptor subtype
responsible for this action is currently unclear. Moreover, the finding
that a broad range of NPY-related peptides increase plasma ACTH when
administered icv raises the possibility that multiple NPY receptor
subtypes are involved in mediating this effect (245).
3. CRF. Recent studies suggest that CRF may also exert an
ultrashort positive feedback regulation on its own biosynthesis within
the PVN (246). When injected icv in the rat, CRF initially increases
the PVN expression of the immediate-early genes c-fos and
NGFI-B and subsequently increases CRF mRNA in the nucleus. Since
these effects are markedly attenuated by the prior icv injection of the
CRF antagonist,
-helical CRF(9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41), they are likely to be mediated
by binding of the peptide to specific CRF receptors located either on
CRF neurons within the PVN or in other brain areas. The brainstem
catecholaminergic neurons could represent an alternative site of CRF
binding since the peptide could be transported to these neurons by the
cerebrospinal fluid after icv injection and since icv CRF has been
shown to increase c-fos expression in the A1 and C1 cell
groups. The activated brainstem catecholaminergic cell groups could
then signal to the PVH and other brain areas by means of the ascending
catecholaminergic pathways to increase neuronal c-fos
expression in these sites.
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III. Hypothalamic Inhibition of ACTH Release and Biosynthesis
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A. Historic studies
Although the vast bulk of the studies related to the HPA axis can
be adequately explained by assuming the hypothalamus only exerts a
stimulatory influence upon ACTH release and biosynthesis, an analysis
of the early studies employing pituitary stalk section and other
ablative surgical procedures suggests that hypothalamic stimulation of
ACTH secretion may not completely explain all of the experimental
evidence. The earliest studies showed that pituitary stalk section in
the rat and the dog failed to prevent the adrenal hypertrophy that
occurs as a consequence of cold exposure (247, 248, 250). The surgery
also failed to prevent the adrenal depletion of ascorbic acid in
response to unilateral adrenalectomy in the rat (249), failed to
prevent cold-induced adrenal cholesterol depletion in the guinea pig
(251), and reduced, or abolished, the rabbits lymphopenic response to
restraint and cold exposure while exerting little effect on this
animals response to subcutaneous EPI or laparotomy (252). In 1954,
Keller et al. (253) sectioned the pituitary stalk and
destroyed the ventral hypothalamus in the dog and noted that the
procedure resulted in a chronic decrease in insulin tolerance, but did
not prevent the animals from withstanding further surgery such as a
unilateral adrenalectomy or pancreatectomy. Furthermore, the adrenal
gland weights (mg/kg body weight) and adrenal cholesterol contents
(mg/kg body weight) were also increased by the hypothalamectomy (Fig. 13
). In most instances, the
hypothalamectomy also caused an acute eosinopenia, and a drastic
eosinopenia was elicited by further surgery. The authors concluded that
their experiments "add crucial support to the conclusion drawn by
others that excitation of the adenohypophysis is not dependent upon
direct hypothalamic humoral or neurogenic influence," but the
findings could also be interpreted as providing support for the idea
that pituitary stalk section removed a dominant inhibitory influence
over ACTH secretion.

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Figure 13. Adrenal data for four groups of animals: a) 10
dogs having hypophysectomies of varying magnitude (insulin dosages they
were able to tolerate ranged from 1/40 to 1/10 U/kg of body weight, the
mean being 1/20 U; b) 7 normal dogs which were terminated
without being duressed previously in any way; c) 9 normal dogs which
were terminated at varying time intervals after a major surgical
procedure (in most instances a pancreatectomy); and d) 8 ventral
hypothalamectomized dogs which were either terminated during some sort
of duress or were found dead. Open bars represent
individual animals; the crossed bars represent the group
averages. Although there was considerable variability surrounding this
datavarying size dogs and the difficulty in quantitating the
magnitude of any particular duressed statethe data graphed clearly
demonstrate a) the absence of adrenal atrophy and b) a normal range in
cholesterol content of these animals. The suspicion of a tendency to
adrenal hypertrophy (on the basis of gross inspection) in the
hypothalamectomized dog is also verified by the composite data.
[Reproduced with permission from A. D. Keller et
al.: Am J Physiol 179:514, 1954 (253 ).]
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In the 1960s, Egdahl (254, 255, 256) performed a large number of experiments
in dogs bearing surgically isolated pituitaries. In animals in which
the brain above the inferior colliculus was removed, the basal adrenal
venous 17-hydroxycorticosteroid output was increased, and this
secretion was augmented further by stimuli such as burning the hind
leg, laparotomy, and constriction of the inferior vena cava (Figs. 14
, 15
, and 16
). From these studies, Egdahl
derived two conclusions: first, "higher areas of the brain tonically
inhibit lower areas which produce and release ACTH-releasing
neurohumors in the dog"; second, "an area which produces an
ACTH-releasing neurohumor is located in the hindbrain. This hindbrain
factor (HBF) acts through the systemic blood stream to effect ACTH
release from the pituitary, or possibly, in the intact animal to
stimulate release of the hypothalamic ACTH-releasing neurohumor"
(254). To test the second hypothesis, Egdahl removed the brain to the
level of the pons, removed the entire spinal cord, and subjected the
animals to bilateral nephrectomy or total abdominal evisceration.
However, none of these procedures prevented the elevation in basal
adrenal venous 17-hydroxysteroid secretion. These findings led Egdahl
to speculate as follows: "On the other hand, if it is suggested that
there is an inhibitory neurohumor as well as an excitatory one
which has been removed by the brain removal procedure, then the
spontaneous activity of the pituitary has been unmasked. The
hypothesis which is proposed in this paper suggests that the excitatory
and inhibitory neurohumoral areas are localised in the
diencephalon-mesencephalon and are controlled by impulses coming from
both the spinal cord and cerebral cortex" (256). This quotation is
likely to be the first, and clearest, enunciation of the possible
existence of both stimulatory and inhibitory hypothalamic factors
involved in the regulation of ACTH release.

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Figure 14. The effect of brain removal on adrenal venous
corticosteroid output in the dog. Resting level of corticosteroid
output in this animal ranged from 2.2 to 5 g/min. Burns on five
different occasions resulted in sharp increases in corticosteroid
output. The increase in output following burning was comparable to that
obtained following exogenous ACTH. [Reproduced with permission from
R. H. Egdahl: Endocrinology 66:200216, 1960
(254 ). © The Endocrine Society.]
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Figure 15. Dog C-2 (total brain removal, total spinal cord
removal with isolated pituitary). Fourteen hours after this operation
adrenal cortical hypersecretion was still present. [Reproduced with
permission from R. H. Egdahl: Endocrinology
71:926935, 1962 (256 ). © The Endocrine Society.]
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Figure 16. B-303 (isolated pituitary with brain removal to
pons and bilateral nephrectomy). The kidneys are not essential to the
increased pituitary adrenal activity observed in dogs with isolated
pituitaries. [Reproduced with permission from R. H. Egdahl:
Endocrinology 71:926935, 1962 (256 ). © The Endocrine
Society.]
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In the mid-1960s, Halász and co-workers (257, 258, 259) analyzed the
effects of partial and total deafferentation of the medial basal
hypothalamus (MBH) on pituitary-adrenal function in the rat (Fig. 17
). One to 4 weeks after the surgical
interruption of all the neural afferents to the MBH, plasma CS levels
in the morning and afternoon were significantly increased, and the
normal CS diurnal rhythm was abolished (Fig. 18
). Surgical stress further increased
plasma CS in these animals, and compensatory adrenal hypertrophy
developed after unilateral adrenalectomy. In contrast, interruption of
the lateral, dorsal, and posterior connections of the MBH did not raise
plasma CS levels and did not alter the normal CS diurnal rhythm (258).
A diurnal variation in pituitary ACTH content was also observed in
sham-operated rats, the values being relatively high in the morning and
low in the afternoon (259). Complete deafferentation of the MBH
markedly increased pituitary ACTH levels and abolished the ACTH diurnal
rhythm, but interruption of the dorsal, lateral, and posterior
connections of the MBH did not affect adenohypophysial ACTH content and
did not alter its diurnal rhythm. From these findings, Halász and
co-workers concluded that complete deafferentation of the MBH increased
both the secretion and synthesis of ACTH.

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Figure 17. a, d, And g, schematic sagittal drawings of the
hypothalamo-pituitary complex to demonstrate the different
deafferentations of the medial basal hypothalamus. b, e, and h, The
knife cuts as seen from the base of the brain. Heavy
line indicates the cut; broken lines with arrow
indicate the level of the histological sections presented in c.f. - c,
f, i. Microphotographs of rat hypothalamus showing the knife cut
(arrows). c, Complete deafferentation (coronal section);
f, incomplete deafferentation (coronal section); g, frontal cut
(horizontal section) (x25). Abbreviations: AC, anterior commissure;
AL, anterior lobe of pituitary; ARC, arcuate nucleus; ME, median
eminence; MM, medial mamillary nucleus: OC, optic chiasm; ON, optic
nerve; PED, cerebral peduncle; PL, posterior lobe of pituitary; PV,
paraventricular nucleus; SC, suprachiasmatic nucleus; V, third
ventricle; VM, ventromedial nucleus. [Reproduced with permission from
B. Halász et al.:
Neuroendocrinology 2:4355, 1967 (258 ). © Karger,
Basel.]
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Figure 18. Upper, Diurnal variation in plasma
corticosterone levels. Lower left, Pituitary-adrenal
response to stress. Lower right, Adrenal compensatory
hypertrophy in animals with partial or total deafferentation of the
medial basal hypothalamus. S, Sham operated; CD, complete
deafferentation; ID, incomplete deafferentation; FC, frontal cut. The
drawings at the top of this figure show, in schematic
sagittal section, the type of deafferentation (heavy
line) in the groups below. AM, Rats sacrificed in the morning;
PM, sacrificed in the afternoon. Adrenal compensatory hypertrophy: I,
weight of the adrenal removed first; II, weight of the second adrenal
30 days later. [Reproduced with permission from B. Halász
et al.: Neuroendocrinology 2:4355, 1967
(258 ). © Karger, Basel.]
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In the 1960s and 1970s, several groups analyzed the effects of
hypothalamo-pituitary disconnection or pituitary stalk section on
endocrine function in the monkey (260, 261, 262, 263, 264, 265, 266). Kendall and Roth (260)
removed the forebrain or sectioned the pituitary stalk and noted that
adrenal venous 11-hydroxysteroid secretion remained unaltered for
up to 8 h after the surgery, and their observations corroborated
Egdahls findings. Knobil and co-workers (261, 262, 263) studied the
effects of an anterior or complete disconnection of the MBH and noted
that anterior disconnection of the MBH did not alter the cortisol
diurnal rhythm in most animals and had little effect on plasma cortisol
concentrations. In contrast, complete MBH disconnection severely
attenuated, or abolished, the normal cortisol diurnal rhythm and
lowered plasma cortisol concentrations. Ferin and co-workers (264, 265, 266)
studied the effect of sectioning the pituitary stalk and noted that
effective surgery caused an acute and chronic rise in serum PRL levels,
abolished the normal cortisol rhythm, lowered the morning cortisol
levels to the afternoon range seen in intact animals, and markedly
attenuated the cortisol response to hypoglycemia. However, a
morphological analysis of the pituitary revealed that the surgery
caused a variable amount of necrosis (545%) of the pars distalis in
most animals. Taken together, the findings in the primate partly concur
with those obtained in the dog, the rat, and the sheep, and the
discrepancies might be due in part to the anterior pituitary necrosis
produced by pituitary stalk section.
B. Effect of hypothalamo-pituitary disconnection in adult and fetal
sheep
The hypothalamo-pituitary disconnection (HPD) procedure was first
described by Clarke et al. (267), and it essentially removes
the hypothalamic-releasing and release-inhibiting factors from the
hypophysial-portal circulation and severs the innervation to the
intermediate and posterior pituitary lobes. However, in contrast to
stalk section, which often compromises the blood supply to the anterior
pituitary and causes infarction of the gland, HPD preserves the blood
supply to the adenohypophysis. The procedure causes no apparent
histological alteration of the anterior lobe, but results in marked
hypertrophy of the intermediate lobe and atrophy of the posterior
pituitary.
As expected, the lack of GnRH in the hypophysial-portal circulation in
the HPD animal caused a gradual decline in plasma LH and FSH
concentrations, and they became undetectable 1 week after the procedure
(267). By analogy with the hypothalamic-pituitary-gonadal axis, if the
hypothalamus merely stimulated ACTH release, the absence of CRF and AVP
in the hypophysial-portal circulation of HPD-treated animals would also
be expected to reduce plasma ACTH and cortisol concentrations to
subnormal, or undetectable, levels and abolish their response to
stress. However, in 1986, Clarke et al. (268) noted that
basal ACTH,
-MSH, ß-endorphin, and cortisol levels were
significantly elevated in those animals subjected to HPD and concluded
that the ovine pituitary could function in the absence of hypothalamic
influence. In 1988, Engler et al. (269) confirmed the effect
of HPD on the basal levels of these POMC peptides and demonstrated that
HPD virtually abolished their rise in response to an audiovisual
stimulus and insulin-induced hypoglycemia, indicating that CRF and AVP
are essential to mount an adequate pituitary-adrenal response to stress
(Fig. 19
). In addition, these authors
also noted that the direction in which plasma ACTH and cortisol levels
changed after HPD was identical to that of PRL, since
hyperprolactinemia is also a consequence of pituitary isolation in the
sheep, the rat, and the monkey (263, 270, 271, 272, 273). The hypothalamus both
stimulates and inhibits PRL secretion and synthesis, and the dominant
inhibitory regulation is mediated by DA, whereas the stimulatory input
is mediated by neuropeptides such as TRH, vasoactive intestinal
peptide, OT, and the newly discovered PRL-releasing peptide (271, 272, 274, 275, 276, 277). Since the hyperprolactinemia that follows stalk section is
thought to be due to withdrawal of the major inhibitory factor DA (271, 274), it was argued that the increased ACTH secretion by the isolated
anterior pituitary might also be due to withdrawal of the corticotropes
from the influence of a hypothalamic factor that inhibits ACTH
secretion. It was suggested this substance be named corticotropin
release inhibitory factor (CRIF) since neither of the two best
characterized inhibitory substances in portal plasma, namely SST and
DA, seemed to possess the criteria required of such a substance (see
below).
The POMC peptide ultradian rhythm also persists after HPD, indicating
that the ovine pituitary possesses an intrinsic ability to secrete
these peptides in a pulsatile fashion (278). However, as judged by
measurement of pulse amplitude and interpulse interval, the
POMC-peptide rhythm in the HPD-treated animal differs from that in the
intact animal, indicating that the POMC-peptide ultradian rhythm in the
intact animal is the net result of an intrinsic pituitary oscillator
that is being continually modified by the hypothalamus (Fig. 20
). Similar conclusions have been made
by Carnes and co-workers (279, 280), who noted that CRF
immunoneutralization in the rat abolished high amplitude-low frequency
ACTH pulses but did not affect the appearance of low amplitude-high
frequency fluctuations (279). In addition, these authors also noted
that pulsatile ACTH secretion persisted in the PVN-lesioned animal
(280).
In addition to raising the basal plasma levels of ACTH and cortisol,
HPD also increases the POMC mRNA level in the ovine anterior pituitary
(281). These findings strongly suggest that the hypothalamus also
exerts a tonic inhibitory influence over POMC gene expression (Fig. 21
), although it is currently unknown
whether this regulation is exerted at the level of mRNA transcription
or translation.

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Figure 21. The effect of hypothalamopituitary disconnection
(HPD) and dexamethasone on sheep anterior pituitary POMC mRNA levels.
Hybridization of 32P-labeled human POMC DNA to a Northern
blot of 25 µg anterior pituitary total RNA from control (lanes 13),
dexamethasone-treated (lanes 46), ovariectomized (OVX)-HPD (lanes
79), and OVX-HPD dexamethasone-treated (lanes 1012) sheep.
[Reproduced with permission from J. E. Mercer et
al.: Neuroendocrinology 50:280285, 1989 (281 ).
© Karger, Basel.]
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The findings in the adult sheep have also been extended to the ovine
fetus (282, 283, 284, 285, 286, 287). When the fetal sheep is subjected to HPD at 108112
days of gestation, essentially similar histological alterations to the
pituitary are produced as occur in the adult animal, and gestation is
prolonged by 8 days. HPD also increases basal plasma ACTH
concentrations in the ovine fetus, but it does not elevate basal plasma
cortisol levels. In these studies, plasma ACTH was measured by a RIA
that also detects high molecular weight (MW) forms of ACTH. Since high
MW ACTH-containing peptides circulate in the fetus and since the ACTH
precursor peptides, POMC and pro-ACTH, inhibit the ability of
ACTH(1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39) to release cortisol from fetal adrenocortical cells, the
finding of a normal plasma cortisol in the presence of a raised plasma
ACTH may be due to the secretion of an ACTH with reduced bioactivity by
the ovine fetal pituitary. Alternatively, it is possible that the
reduced pulsatile secretion of ACTH after the HPD may reduce the
responsiveness of the fetal adrenal cortex to ACTH. These caveats
aside, the findings do provide experimental support for the
observations made in the adult animal.
C. Effects of the opiate alkaloids and opioid peptides on the HPA
axis
An analysis of the in vivo and in
vitro effects of opiate agonists and antagonists also provides
indirect evidence for the participation of hypothalamic factors in
addition to CRF and AVP in regulating the pituitary-adrenal axis
(288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319).
The opiate alkaloids and opioid peptides suppress the pituitary-adrenal
axis in man since morphine, ß-endorphin, and the met-enkephalin
analog DAMME decrease basal plasma cortisol levels (290, 291, 300, 302, 303, 304), and morphine and DAMME also attenuate the ACTH and cortisol
responses to CRF (305, 311, 312). These effects are likely to be
mediated at a suprahypophysial site since morphine does not affect the
release of ACTH from cultured rat anterior pituitary cells (305, 314).
Conversely, the opiate receptor antagonist naloxone elevates basal
plasma ACTH and cortisol levels, but the effect is only observed when
high doses are used, suggesting that its effects are mediated by
naloxone-insensitive
-opiate receptors (292, 294, 295, 298, 300, 302, 307, 312, 318).
Studies in the rat suggest that the opiates act on distinct receptors
to exert both inhibitory and stimulatory effects on the
pituitary-adrenal axis, although their stimulatory effect is seen only
in the unanesthetized animal (288, 289, 296, 297, 299, 301, 306, 313, 315). For example, the opiate antagonist naloxone and the
-receptor
agonist MR 2034 increase basal pituitary-adrenal activity in the rat,
and these effects are abolished by a CRF antiserum. These findings
suggest that the endogenous opiates restrain CRF release by acting on
-opiate receptors. This conclusion is also supported by in
vitro studies showing that naloxone increases basal CRF release or
reverses the ß-endorphin-induced suppression of CRF release from
incubated or perifused rat hypothalami (309, 317). By contrast, the
µ-receptor agonist morphine also increases pituitary-adrenal activity
in the rat, but this effect seems not to be mediated by increased CRF
release since it is not affected by a CRF antiserum (313). This
conclusion is further supported by in vitro studies that
show that opiates decrease both the basal and stimulated release of CRF
from cultured or perifused rat hypothalami (309, 314). Taken together,
the stimulatory effects of morphine on the rat HPA axis could be
explained by postulating that the opiate acts on µ-receptors to
inhibit the release of both CRF and a CRIF (317).
The effects of the opiates on the release of CRF and AVP into the
hypophysial-portal circulation have been assessed in the anesthetized
rat and in the conscious horse (308, 310, 319). When injected into the
cerebral ventricles of the rat, ß-endorphin and dynorphin inhibit the
basal and hypotension-induced stimulation of CRF release into the
hypophysial-portal circulation, whereas naltrexone increases both the
spontaneous and stimulated CRF secretion (308). In addition, the
intravenous administration of morphine also decreases the release of
AVP into rat hypophysial-portal plasma (310). These findings provide
direct evidence that the opiates restrain the release of both CRF and
AVP into the hypophysial-portal circulation and suggest that their
ability to stimulate the HPA axis must involve mechanisms that are
independent of CRF and AVP. The effect of naloxone on the secretion of
CRF and AVP in the conscious horse has been studied in detail by
Alexander and Irvine (319). The administration of high doses of
naloxone increases plasma ACTH and cortisol in the horse and also
augments the CRF and AVP secretion rates. In contrast, low doses of
naloxone also raise plasma ACTH and cortisol but do not alter the CRF
and AVP secretion rates (Fig. 22
).
These findings demonstrate that endogenous opiates also inhibit the
equine HPA axis, and the effects of low-dose naloxone provide further
reason for speculating that endogenous opioids might also modulate the
secretion of a CRIF.

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Figure 22. Pituitary venous concentrations of CRH ( ),
ACTH (solid line), and AVP in two mares given
naloxone, at a low dose rate (0.2 mg/kg iv bolus at the
arrow). A, Mare 9; B, mare 10. [Reproduced with
permission from S. L. Alexander and C. H. G. Irvine:
Endocrinology 136:51395147, 1995 (319 ). © The
Endocrine Society.]
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In summary, the endogenous opioids tonically inhibit the HPA axis in
all species studied. Their actions are mediated at one or more
suprahypophysial sites, they reduce the hypophysial-portal release of
CRF and AVP, and their actions also point toward the existence of a
CRIF.
D. The role of the posterior pituitary in the regulation of
corticotropic function
It is theoretically possible that the anterior pituitary could be
regulated by factors secreted from nerve terminals located in both the
external zone of the median eminence and the posterior pituitary
because the blood supply to the adenohypophysis is derived from both
the long portal vessels that originate in the median eminence and the
short portal vessels that originate from the infundibular process of
the posterior pituitary (320, 321).
The studies of Saffran and Schally (322) were among the first to point
toward a role for the posterior pituitary in the regulation of ACTH
secretion. When rat anterior pituitary tissue was only incubated with
the posterior lobe, the release of ACTH was unaltered. However, in the
presence of either arterenol, sphingosine, or hypothalamic tissue, the
posterior lobe tissue caused the release of a large amount of ACTH. In
1957, McCann (323) injected a variety of agents into rats with
transient or chronic diabetes insipidus caused by acute or chronic
bilateral hypothalamic lesions. The clearest results were obtained in
rats with transient diabetes insipidus and, in these animals,
intravenous Pitressin (Parke-Davis, Morris Plains, NJ) caused
reproducible ACTH release as judged by the adrenal ascorbic acid
depletion assay. The results led McCann to propose that "the evidence
obtained in vivo supports the hypothesis that ADH may be the
neuro-humor responsible for eliciting ACTH discharge."
The removal of the neurointermediate lobe (NIL) in the rat also alters
the function of the HPA axis (324, 325, 326, 327). For example, Arimura
et al. (325) demonstrated that removal of the NIL markedly
decreased, or abolished, the ACTH responses to repeated footshock,
laparotomy, and the intraperitoneal (ip) or intravenous injection of
lysine vasopressin, but basal ACTH concentrations and the ACTH response
to ip histamine remained unaffected by the procedure. More recently,
Fagin et al. (327) showed that similar surgery increased the
mean 24-h CS level, attenuated the pituitary-adrenal response to an
auditory stimulus, but did not affect the pituitary-adrenal responses
to hemorrhage or insulin-induced hypoglycemia. The data regarding the
effect of posterior lobectomy on the ovine HPA axis are much more
limited and do not include measurements of plasma cortisol (328).
Nevertheless, the procedure appears not to affect basal ACTH
concentrations or the ACTH responses to an audiovisual stress, to
serotonin, or to insulin-induced hypoglycemia. These findings suggest
that the posterior lobe may be of little, if any, importance in
regulating ACTH release from the ovine anterior pituitary and imply
that any putative hypothalamic CRIF would need to be secreted into the
long portal vessels by nerve terminals in the median eminence to
regulate ovine corticotropic function.
E. Hypothalamic ACTH release-inhibitory activity
A number of in vitro studies have also suggested that
hypothalamic extract contains ACTH release-inhibitory activity, but the
precise nature of this activity currently remains uncertain (329, 330, 331, 332).
In an effort to define the CRF activity in rat stalk median eminence
(SME), Gillies et al. (330) subjected rat SME extract to
Sephadex G-50 and BioGel P2 column chromatography and noted that
certain fractions eluting on the BioGel P2 column (at 5763 ml)
possessed some ACTH release-inhibitory activity. However, further
purification of this activity was not undertaken.
In 1983, Rédei and Endröczi (331) postulated the existence
of a corticotropin-inhibiting factor by drawing an analogy with
the hypothalamic regulation of PRL and GH secretion. In their initial
studies, porcine hypothalamic tissue was purified by Sephadex G-25
column chromatography, preparative TLC, and two-dimensional TLC. These
procedures isolated an "inhibitory factor" with a molecular weight
that was larger than
-aminobutyric acid, methionine
enkephalin, and TRH, but smaller than that of SST. When a purified
preparation of this "inhibitory factor" (in an amount equivalent to
0.31 hypothalamic extract as starting material) was administered
intravenously to rats 1 min after their exposure to 10 electric shocks,
plasma CS concentrations at 20 min were significantly lower than those
in saline-injected animals, but were not significantly different from
the control group at 40 min. Moreover, when the inhibitory factor was
added to medium perfusing hypothalamic tissue slices, anterior
pituitary fragments, or adrenal cortex quarters, it inhibited the
effect of CRF at the pituitary level.
In 1989, Redei and Evans (332) reported further studies in which bovine
hypothalamic extract was purified by reversed phase and Sephadex G-50
column chromatography. Those fractions that inhibited the release of
ACTH from dispersed rat anterior pituitary cells were again purified by
reversed phase HPLC (RP-HPLC), the purification-bioassay step was
repeated three times, and the final purified material was eluted as a
single peak that retained 37% of the ACTH release-inhibitory activity.
The purified "inhibitor" caused a concentration-dependent
inhibition of basal ACTH secretion from dispersed rat anterior
pituitary cells, although the highest concentration (1:400 dilution of
purified factor from 200 g bovine hypothalamic starting
material) only decreased ACTH release by approximately 48%. When the
cells were incubated with 0.110 nM CRF and a 1:1750
dilution of inhibitor, the response to CRF did not differ from control
incubations, but when the cells were preincubated (60 min) with the
inhibitor, the ACTH response to 10 nM CRF was consistently
reduced by up to 45%. When the inhibitor was injected intravenously
into rats 5 min before or 1 min after their exposure to an inescapable
footshock, plasma CS levels were significantly lower than those in the
control group at 20 min. Finally, when the inhibitor was injected
intravenously into freely moving, chronically cannulated rats, basal
plasma ACTH concentrations were significantly suppressed at 40 min when
compared with saline-injected animals.
These series of studies represent the most comprehensive performed to
date with a partially purified hypothalamic "inhibitory factor,"
but the lack of protein sequence of the starting material precludes
definitive judgment of their physiological significance.
F. Definition of CRIF
From the foregoing review, we suggest that a substance would need
to fulfill the following postulates to qualify as a bona fide CRIF
(Table 1
).
First, we postulate that CRIF acts on normal corticotropic cells
in vivo and in vitro to attenuate basal ACTH
secretion and the CRF- and/or AVP-induced increases in ACTH release.
Second, we postulate that CRIF also inhibits POMC gene expression by an
effect on gene transcription and/or translation.
Third, we postulate that blockade of CRIF activity would increase basal
ACTH secretion and may potentiate the release of ACTH caused by
physiological stimuli.
Fourth, we postulate that CRIF will be present in nerve terminals of
the external zone of the median eminence and will be found in
hypophysial-portal blood in sufficient concentration to inhibit ACTH
secretion.
Fifth, we postulate that CRIF binds to a specific receptor on the
anterior pituitary. It is not essential that the receptor possess a
specific structure, but it could be linked to one or more G proteins
and possess seven transmembrane domains since all the anterior
pituitary receptors identified to date possess these characteristics
(57, 58, 59, 60, 63, 64, 65, 66, 84, 85, 277, 333, 334, 335, 336, 357).
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IV. CRIF: A Consideration of Possible Candidates
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In this section, we summarize the activities of several well
characterized substances on the HPA axis and discuss whether they do,
or do not, satisfy these postulates.
A. SST
A large number of studies have been performed over the last 20 yr
to delineate the neuroendocrinology of SST and to assess its effects on
the HPA axis (337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358). The two naturally occurring SST peptides,
SST-14 and SST-28, are derived from the posttranslational processing of
the prohormone prosomatostatin (pro-SST) in neurons and endocrine
cells, and SST-like immunoreactivity has been demonstrated throughout
the central nervous system, the gastrointestinal tract, and the
pancreatic islet D cells. Within the hypothalamus, SST-containing
perikarya are located in the periventricular nucleus, in the
parvocellular PVH, the anterior hypothalamic nucleus, the perifornical
region, and the lateral hypothalamus, and the most dense aggregation of
hypothalamic fibers and terminals is seen in the external zone of the
median eminence (341), from where the peptide is secreted into the
hypophysial-portal circulation (339, 340, 348, 354). The actions of SST
are mediated by five distinct receptor subtypes (SSTR15), which are
coupled to the adenylyl cyclase, to K+ and Ca2+
ion channels, and to a protein tyrosine phosphatase (355, 356, 357, 358).
The in vivo studies in normal human subjects have shown that
SST does not affect basal ACTH levels or the ACTH response to CRF,
suggesting that it does not normally act at the pituitary level to
regulate corticotrope function (350, 352). However, SST does decrease
basal ACTH secretion in patients with Addisons disease (337), and it
also attenuates the POMC peptide and cortisol response to
insulin-induced hypoglycemia, presumably by acting at a
suprahypophysial site to attenuate CRF secretion (350).
The in vitro studies have clearly shown that the effects of
SST on ACTH secretion are critically dependent upon the use of normal
or neoplastic pituitary tissue and on the presence or absence of
glucocorticoids in the incubation medium (338, 342, 343, 344, 345, 346, 347, 349, 351, 352). The clonal GH3 and AtT-20 pituitary cell lines have
been used to study the subcellular mechanisms of action of SST on the
anterior pituitary and to characterize its effects on ACTH secretion
(342, 343, 344, 345, 346, 349). The AtT-20 mouse pituitary tumor cell line responds to
SST since it expresses those mRNAs encoding three of the four
SST-14-selective receptors, namely SSTR 1, 2, and 4, as well as the
mRNA encoding the SST-28-selective receptor SSTR5 (356). SST markedly
attenuates the ability of CRF, isoproterenol, vasoactive intestinal
peptide, forskolin, and cholera toxin to stimulate cAMP formation in
AtT-20 cells (343) and also decreases the
[Ca2+]i in both GH3 and AtT-20
cells by reducing the voltage-dependent Ca2+ current (344, 349). In addition, SST (10-10 to 10-7
M) inhibits basal ACTH release from AtT-20 cells (343) and
the ACTH response to CRF, 50 mM KCl, and hypothalamic
extract (342, 343).
However, studies employing normal rat anterior pituitary cells,
fragments, or halves have shown that 10-12 to
10-6 M SST has no effect on basal ACTH
secretion (338, 345, 346, 347, 353). However, Voigt et al. (338)
first showed that SST (10-11 to 10-5
M) could attenuate the ACTH response to rat stalk median
eminence extract or 100 nM AVP in pituitary cells derived
from adrenalectomized animals, thereby suggesting that the inhibitory
effect requires the absence of glucocorticoids. This finding was
confirmed by Lamberts et al. (353), who showed that SST
could only inhibit the ACTH response to CRF when normal rat anterior
pituitary cells were cultured in glucocorticoid-free medium or were
preincubated with the glucocorticoid receptor antagonist RU 38486 (Fig. 23
).

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Figure 23. Effect of somatotropin release-inhibiting hormone
(SRIH) on CRH-stimulated (0.1 nM) ACTH release by
normal female rat pituitary cells. Upper panel
(control), the cells were incubated for 2 days in MEM + 10% FCS and
then cultured for 2 days in MEM alone; middle panel, the
cells were incubated in MEM + 100 nM RU 38486; lower
panel, the cells were cultured in MEM + 5 nM
dexamethasone. [Reproduced with permission from S. W. Lamberts
et al.: Neuroendocrinology 50:4450,
1989 (353 ). © Karger, Basel.]
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When considered in their entirety, these results suggest that SST
cannot be considered to be a physiological CRIF.
B. Dopamine
The catecholamine dopamine (DA) is the most important
PRL-inhibiting hormone, although several studies have suggested that it
may also regulate corticotropic function, and for this reason it is
considered in this review (359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375). The anterior, intermediate, and
posterior pituitary lobes are regulated by three groups of
tuberohypophysial DA neurons: one group is located in the rostral
arcuate nucleus and innervates the pars intermedia; a second group of
cells that lies immediately caudal to the first group innervates the
posterior lobe; and a third group of arcuato-infundibular neurons
innervates the external layer of the median eminence and the pituitary
stalk (359). DA is secreted into the hypophysial-portal circulation
(360, 361, 364, 366, 374), binds to adenohypophysial D2 DA receptors
(362, 365, 371), and inhibits the secretion and synthesis of PRL by
mechanisms that include a reduction in cAMP accumulation and
phosphatidylinositol turnover (332, 367, 372, 373, 375).
The in vivo studies in man indicate that the dopaminergic
agonist bromocriptine can lower ACTH concentrations
in some patients with Cushings disease and Nelsons syndrome (363, 369), and the in vitro studies have shown that DA
(10-7 M) can decrease the release of ACTH from
cultured human corticotropic adenoma cells (Ref. 370 and Fig. 24
). However, these findings are more
likely due to the aberrant expression of DA receptors by neoplastic
corticotropes since DA does not regulate the release of ACTH from
normal corticotropic cells (Ref. 370 and Fig. 25
) and for this reason is unlikely to
be a physiological CRIF.

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Figure 24. Effect of dopamine (DA) alone or in combination
with haloperidol on ACTH secretion by cultured corticotroph adenoma
cells obtained from patients with Nelsons syndrome (patients 14)
and a patient with Cushings disease (patient 5). In one adenoma
tissue (no. 4), experiments were repeated on day 5 and on day 13 in
culture to ascertain whether the response was reproducible. A minimum
of four replicates was used for each variable. Results are expressed as
the percentage of change in secretion relative to a preincubation in
medium alone. For comparison, the mean values in the control incubation
were designated as 100%. Results are the mean ± SEM.
*, P < 0.05; **, P < 0.01.
[Reproduced with permission from M. Ishibashi and T. Yamaji:
J Clin Invest 68:10181027, 1981 (370 ). © The
American Society for Clinical Investigation.]
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Figure 25. Effect of cyproheptadine, dopamine, TRH,
hydrocortisone, and lysine vasopressin on ACTH secretion by cultured
normal human corticotrophs obtained from a patient at the time of
hypophysectomy for the palliation of metastatic breast cancer. A
minimum of four replicates was used for each variable. Results are
expressed as the percentage of change in secretion relative to a
preincubation in medium alone. For comparison, the mean value in the
control incubation was designated as 100%. Results are the mean
± SEM. **, P < 0.01. [Reproduced
with permission from M. Ishibashi and T. Yamaji: J Clin
Invest 68:10181027, 1981 (370 ). © The American Society for
Clinical Investigation.]
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C. Atrial natriuretic peptide (ANP)
In the early 1980s, de Bold and co-workers (376, 377) demonstrated
that an intravenous injection of rat cardiac atrial extract caused a
rapid diuresis and increased the renal excretion of sodium, chloride,
and potassium in the rat. The authors concluded that the extract
contained a powerful inhibitor of renal tubular NaCl reabsorption and
subsequently demonstrated that the activity was due to a novel
28-residue cardiac hormone that was termed atrial natriuretic factor
(ANF) or atrial natriuretic peptide [ANP or ANP(1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28)] (378). Since
those original observations, many aspects of the physiology of ANP have
been elucidated, and its role as a possible modulator of the HPA axis
has been explored (379, 380, 381, 382, 383, 384, 385, 386, 387, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408, 409, 410, 411, 412, 413, 414, 415, 416). In the rat and in man, ANP(1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28) (or
-ANP) is located at the C-terminal end of a larger precursor
molecule (379, 380, 381, 382). Although the rat and human prohormones are subject
to different forms of proteolytic cleavage in cardiac tissue (383, 384), the major secreted form of ANP that enters the rat and human
systemic circulation is ANP(1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28) or
-ANP (388, 389, 390, 391).
Although ANP was originally identified in the heart, ir-ANP has also
been demonstrated in neurons and nerve terminals in the brain (386, 387, 393). However, in contrast to the cardiac atrium, the predominant
molecular forms of ANP in the brain are ANP(4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28) and ANP(5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28)
(392). Although the ir-ANP in hypothalamic neurons is comprised solely
of ANP(4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28), the neuron secretes ANP(5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28), thereby implying that it
processes ANP(4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28) to ANP(5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28) before secretion (403). Within the
hypothalamus, the most abundant collection of ir-ANP perikarya is
located in the periventricular area that extends caudally from the
anteroventral tip of the third ventricle to the mamillary region. At a
more caudal level, the periventricular neurons invade the
suprachiasmatic nucleus, the arcuate nucleus, and the paraventricular
nucleus (PVH). These findings indicate that ir-ANP neurons are present
in hypothalamic nuclei that are known to project to the median eminence
and to other brain areas. The majority of ir-ANP fibers in the
hypothalamus are associated with the wall of the third ventricle, but
large populations of fibers also innervate the PVH, the dorsomedial,
arcuate, and ventromedial nuclei, and the external zone of the median
eminence.
The findings of ir-ANP in some hypothalamic neurons that project to the
median eminence and of ir-ANP in nerve terminals in the external zone
of the median eminence suggest that ANP could be secreted into the
hypophysial-portal circulation (Fig. 26
). This suggestion is supported by
the finding that rat hypophysial-portal plasma contains ir-ANP in
concentrations that are 2.5- to 4.5-fold higher than those found in the
systemic circulation (402, 407) and that the predominant molecular
species of ANP is ANP(5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28) (414). The peptide could bind the ANP
receptor(s) that are present on the anterior pituitary (385) since the
adenohypophysis contains two forms of the ANP receptor, both
ANP(1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28) and ANP(5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28) demonstrate a similar potency in receptor
binding, and both cause a dose-dependent accumulation of cyclic GMP in
the anterior pituitary (399). Although ir-ANP is found in
tuberoinfundibular neurons and ANP(5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28) is present in portal plasma,
despite the finding of ANP receptors on the anterior pituitary and the
ability of ANP to stimulate the accumulation of cyclic GMP in the
anterior pituitary, the available evidence indicates that these events
are not coupled to the secretion of any anterior pituitary hormone.

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Figure 26. Atriopeptin (APir) staining in the median
eminence (ME) and arcuate nucleus (ARC). This photomicrograph of a
coronal section stained with the immunofluorescent technique shows
dense clusters of APir varicosities in the external lamina of the
median eminence. A few fibers can be seen traversing the internal
lamina. At top are APir neurons in the ventral part of the arcuate
nuclues. Scale bar, 50 µm. [Reproduced with permission from D.
G. Standaert et al.: J Comp Neurol
253:315341, 1986 (393 ). © Wiley-Liss, Inc., a division of John Wiley
& Sons, Inc.]
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The first studies to assess the effect of ANP on the pituitary-adrenal
axis were performed in vitro and were followed by those
performed in vivo (394, 395, 396, 397, 398, 400, 401, 404, 405, 406, 408, 409, 410, 411, 412, 413, 415, 416). Shibasaki et al. (394) first reported that rat
ANP(4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28) caused a concentration-dependent suppression of basal ACTH
release from normal rat anterior pituitary cells, that the maximal
effect occurred at 10-9 M, and that this
concentration also attenuated the ACTH response to CRF. Heisler
et al. (396) examined the effect of ANP(8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33) in AtT-20
cells and showed that the peptide had no effect on basal or
CRF-stimulated adenylate cyclase activity, that it did not affect basal
or CRF-stimulated cAMP formation, but that it increased cyclic GMP
synthesis. Despite these effects on cGMP, ANP(8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33) had no effect on
basal, CRF-, or forskolin-induced stimulation of ACTH release. Tan
et al. (413) confirmed that <10-6
M ANP(1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28) had no effect on ir-ß-endorphin release from
AtT-20 cells, but found that 10-6 M ANP(1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28)
modestly (15%) suppressed ir-ß-endorphin release and decreased cAMP
concentrations, but markedly reduced POMC mRNA abundance (
60%).
Hashimoto et al. (397) showed that an unspecified ANP
(1100 ng/ml) had no effect on basal ACTH release from normal rat
anterior pituitary cells and that 11000 ng/ml affected neither CRF-
nor AVP-induced ACTH release. Abou-Samra et al. (398) also
demonstrated that 10-7 M rANP(5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28)
stimulated cGMP synthesis in normal rat anterior pituitary cells, but
that it had no effect on either basal ACTH release or on CRF-induced
ACTH secretion. Mulligan et al. (415) perifused equine
anterior pituitary cells with a continuous background of CRF and
cortisol and intermittent pulses of AVP using concentrations designed
to replicate those found in equine pituitary venous effluent. However,
despite this faithful mimicry of the in vivo situation,
these authors were unable to demonstrate any effect of ANP on basal or
AVP-induced ACTH release. Most recently, Bowman et al. (416)
reported that 10 nM rat ANP(1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28) exerted no effect on
CRF-, AVP-, or CRF- and AVP-stimulated ß-endorphin release from
perifused ovine or rat anterior pituitary cells. Moreover, the nitric
oxide donors molsidomine and NaNO2 were also without effect
on CRF- and AVP-stimulated ß-endorphin release from the ovine cells.
Thus, the weight of the in vitro evidence suggests that ANP
may regulate POMC peptide secretion and synthesis in the AtT-20 cell
line, but it does not appear to do so when normal anterior pituitary
cells are used.
The in vivo studies have been performed in the rat and in
man and have also yielded diverse findings. Kovåcs and Antoni (404)
showed that ANP(5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28), when given in an amount sufficient to cause
transient hypotension, significantly reduced CRF/AVP-induced ACTH
release in intact rats while a higher dose, which produced persistent
hypotension, prolonged the CRF/AVP-induced ACTH response.
Although the higher dose also caused sustained hypotension in
PVN-lesioned animals, it markedly decreased the ACTH response to
CRF/AVP (Fig. 27
). These findings
suggested that ANP may act as a potent inhibitor of stimulated ACTH
release, but its ability to cause hypotension may also increase the
secretion of ACTH-releasing factors in the intact animal, thereby
masking its inhibitory effect on ACTH release. Several studies have
used in vivo immunoneutralization to assess the effect of
ANP on the pituitary-adrenal axis. In this regard, Fink et
al. (406, 409) have used both the Wistar and Brattleboro rat, the
latter strain being deficient in AVP and demonstrating a significantly
diminished response to stress. In the Wistar rat, the systemic
administration of an ovine anti-ANP serum increased basal ACTH and CS
levels but did not potentiate the pituitary-adrenal response to an
ether stress. In contrast, ether stress failed to increase
pituitary-adrenal activity in the Brattleboro rat, but the stimulus
was effective in those animals pretreated with an anti-ANP serum.
Antoni et al. (410) showed that the intracarotid injection
of a rabbit anti-ANP serum in the Wistar rat augmented the ACTH and CS
responses to intraperitoneal NaCl but had no effect on baseline
pituitary-adrenal activity. Taken together, these findings have
suggested that a complete ACTH response to stress may require
activation of an hypothalamic stimulatory mechanism that is mediated by
CRF and AVP and suppression of an inhibitory hypothalamic mechanism
that may involve ANP.

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Figure 27. The effect of atriopeptin on plasma ACTH in
conscious paraventricular nucleus-lesioned male rats injected at time
zero with 1 pmol CRF and 10 pmol AVP (CRF/AVP) iv. Atriopeptin was
given intravenously as a bolus injection (arrow)
followed by a continuous infusion at a rate of 0.005 ml/min
(striped bar). Control animals received
saline. Data are means ± SEM. *,
P < 0.05 when compared with saline-treated
controls at the same time point by U test.
Inset, Plasma ACTH expressed as the average increase
over baseline during a period of 30 min after the injection of CRF/AVP.
Data are means ± SEM. *, P <
0.05 by U test. [Reproduced with permission from K. J.
Kovåcs and F. A. Antoni: Endocrinology
127:30033008, 1990 (404 ). © The Endocrine Society.]
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Ur et al. (408) infused healthy male volunteers with
ANP(1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28), raised the systemic plasma ANP level to 29.6 pmol/liter,
and showed that this did not affect the normal ACTH and cortisol
circadian rhythm or the pituitary-adrenal response to CRF. However,
Kellner et al. (411) infused healthy males with
ANP(1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28) at a 7-fold greater rate (
0.07 µg/kg/min) and
showed that it significantly attenuated the ACTH response to CRF
(100 µg iv bolus). Finally, Wittert et al. (412) raised
plasma ANP concentrations 4- to 5-fold in normal male volunteers and
demonstrated that the pituitary-adrenal response to hypoglycemia
remained unaffected, although plasma AVP and angiotensin II levels were
significantly reduced.
Taken together, the studies with ANP represent the most compelling
evidence to date that a neuropeptide may inhibit ACTH release. However,
the inability of ANP to consistently decrease basal, or stimulated,
ACTH release from normal anterior pituitary cells and its inability to
consistently affect the HPA axis in man suggest that ANP may not be the
CRIF but it may be a subsidiary modulator of the HPA axis.
D. Prepro-TRH-(178199)
The hypothalamic tripeptide TRH was identified in 1970 by its
ability to stimulate the release of TSH (417, 418) but was subsequently
found to be widely distributed within the central nervous system and in
extraneural tissues (419, 420, 421, 422, 423). Within the hypothalamus, the largest
concentration of TRH-stained perikarya is found in the anterior and
medial parvocellular subdivisions of the paraventricular hypothalamus,
while the highest concentration of TRH-stained fibers is found in the
external zone of the median eminence from where the peptide is secreted
into the hypophysial-portal circulation (Fig. 28
and Ref. 424). The rat TRH
prohormone (pro-TRH) is a 29,247-Da protein that contains five copies
of the TRH progenitor sequence Gln-His-Pro-Gly and additional cleavage
sites, which result in the generation of non-TRH peptides (426, 429, 433, 434). In contrast to TRH, which is located in both neuronal
perikarya and axon terminals, pro-TRH is largely confined to neuronal
cell bodies (425, 427, 435), suggesting that it is rapidly processed
within the cell soma and does not undergo significant axoplasmic
transport. Moreover, ir-pro-TRH is also found in areas of the brain
that contain undetectable amounts of ir-TRH, suggesting that in these
sites pro-TRH undergoes alternative modes of posttranslational
processing that result in the generation of non-TRH peptides
(428, 429, 430, 431).

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Figure 28. Coronal sections through the paraventricular
nucleus demonstrating the location of ir-TRH in the anterior
parvocellular subdivision (A; PVNa), the medial (B;
PVNm) and periventricular (P) subdivisions, and the caudal
portion of the PVNm (C). In panel B, note the
peroxidase-positive cell bodies that appear to be within the ependymal
cell wall (open arrows) and the medially directed
neuronal processes (closed arrows) toward the third
ventricle (III). The high power photomicrograph in the
inset depicts an immunoreactive periventricular neuron
with extension of a process (small arrow) within the
ependymal lining. Clusters of peroxidase-positive neurons are also
present in a perifornical distribution (arrows in A and
B). D, Extinction of immunoreactive staining after absorption of the
antiserum with excess synthetic TRH. Original magnification: AC,
x156; D, x98; inset, x390. F, Fornix;
PVNl, magnocellular division of the paraventricular
nucleus. [Reproduced with permission from R. M. Lechan and
I. M. D. Jackson: Endocrinology 111:5565,
1982 (424 ). © The Endocrine Society.]
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To date, two prepro-TRH-derived peptides, prepro-TRH-(160169) (Ps4)
and prepro-TRH-(178199) (Ps5) have been found in the rat olfactory
lobe, hypothalamus, and spinal cord (433). The findings that the rat
anterior pituitary contains specific Ps4 binding sites, that
depolarizing concentrations of KCl release both Ps4 and TRH from rat
median eminence slices, and that Ps4 markedly potentiates the ability
of TRH to release TSH from anterior pituitary fragments suggest a
possible physiological role for Ps4 as a modulator of the
pituitary-thyroid axis (434). Prepro-TRH-(178199)-positive cell
bodies are concentrated in the parvocellular division of the PVH and to
a lesser extent in the ventromedial, dorsomedial, and hypothalamic
periventricular nuclei (432, 433), and Ps5-stained fibers have been
observed in the external zone of the median eminence and other brain
areas (Fig. 29
). Like Ps4, Ps5 can also
be released from perifused hypothalamic slices, suggesting that it
could subserve a neurotransmitter role at this site (436). The
possibility that a non-TRH peptide such as prepro-TRH(178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199) might
function as a physiological CRIF has been explored by Redei et
al. (437, 438), and the rationale for undertaking these studies
was derived from a review of the pituitary-thyroid and
pituitary-adrenal responses to stress and on an interpretation of the
hormonal and serological findings in patients with isolated ACTH
deficiency.

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Figure 29. Immunocytochemical detection of
prepro-TRH-(178199) in rat hypothalamus and median eminence.
Cryostat-cut sections (8 µm) were first incubated with rabbit
antiserum to synthetic Ps5 (dilution of 1:200) and then with goat
anti-rabbit -globulins conjugated to fluorescein isothiocyanate. A,
Section through the median eminence (ME). Magnification x425. B,
Section through the paraventricular nucleus of the hypothalamus from a
colchicine-treated rat. Immunostaining was detected in numerous cell
bodies of the pars parvocellularis of the paraventricular nucleus
(PVN). Immunoabsorption of the antiserum with 1 µM Ps5
completely prevented staining. III, Third ventricle. Magnification,
x106. [Reproduced with permission from M. Bulant et
al.: J Biol Chem 263:1718917196, 1988
(Ref. 433).]
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A number of early studies showed that emotionally and physically
stressful stimuli could simultaneously augment adrenal glucocorticoid
secretion and depress thyroid function in the rabbit and guinea pig
(439, 440, 441). The decreased thyroid activity was also seen in
adrenalectomized, steroid-replaced animals, suggesting that it was not
simply due to the increased glucocorticoid secretion. The nutritional
stress of starvation also causes a discordant increase in
pituitary-adrenal activity and decrease in pituitary-thyroid activity,
and these events may represent a neuroendocrine response to the
fasting-induced reductions in serum insulin and leptin (442, 443).
However, the decreased pituitary-thyroid activity of starvation is also
sustained by the increased glucocorticoid secretion since exogenous
glucocorticoid administration decreases pro-TRH synthesis, reduces TRH
secretion into hypophysial-portal blood, and decreases TSH synthesis
(444). Since starvation reduces the hypothalamic content of pro-TRH
mRNA, decreases the content of TRH and prepro-TRH(160, 161, 162, 163, 164, 165, 166, 167, 168, 169) in the PVN,
and reduces the release of both these peptides into the
hypophysial-portal blood, the findings raise the possibility that
fasting, and other stressful stimuli, might also reduce the secretion
into the portal circulation of other non-TRH peptides such as
prepro-TRH(178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199).
Isolated ACTH deficiency is a condition in which plasma ACTH
concentrations are either low or undetectable and plasma cortisol
levels are subnormal (445, 446). In most patients, an autoimmune
destruction of the corticotropes is suggested by the findings of
lymphocytic infiltration of the anterior pituitary, the presence of
antipituitary antibodies in serum, an onset of the condition in the
postpartum period, and an association with autoimmune thyroid disease
and other autoimmune endocrinopathies. However, the apparent absence of
pituitary autoimmunity and the lack of antithyroid antibodies in the
serum of some patients with raised TSH concentrations led Redei
et al. to propose that primary hypothalamic dysfunction
might underlie the disorder in these cases. It was proposed that the
elevated TSH level in antibody-negative cases was due to hypersecretion
of TRH and that the low ACTH level was due to concomitant
hypersecretion of a non-TRH peptide that possessed CRIF activity.
However, this hypothesis is open to debate since hypothalamic
neuropeptide secretion cannot be determined in man, and the apparent
absence of serum antibodies may not entirely exclude an autoimmune
pathogenesis.
Nevertheless, to test the hypothesis that the TRH prohormone may
contain an ACTH release-inhibiting moiety, mouse AtT-20 pituitary tumor
cells were transiently transfected with increasing concentrations of
rat prepro-TRH cDNA. A progressive decline in basal and CRF-stimulated
ACTH secretion and POMC mRNA levels was observed, and a similar effect
on POMC mRNA levels was also seen when the cells were stably
transfected with the prepro-TRH cDNA (437). To determine which part of
the pro-TRH molecule might possess the CRIF activity, Redei et
al. (438) transfected AtT-20 cells with a prepro-TRH cDNA
construct lacking the sequence encoding amino acids 119229. This
resulted in the loss of ACTH releasing-inhibiting activity, suggesting
that a peptide contained within this region was responsible for the
inhibitory activity. When AtT-20 cells were incubated with either
10-9 to 10-6 M TRH or the TRH
progenitor peptide, prepro-TRH-(115151), -(160169), or -(208220),
ACTH secretion remained unaltered. However, 10-8 to
10-6 M prepro-TRH-(178199) inhibited both
basal and CRF-stimulated ACTH release, and similar results were
observed when rat anterior pituitary cells were used (Fig. 30
). These findings, however, have not
been confirmed by Nicholson and Orth (Ref. 447 and Fig. 31
). These investigators employed
cultured rat anterior pituitary cells and demonstrated that neither an
acute, nor a prolonged (24 h), exposure of the cells to 500
nM, or graded concentrations, of prepro-TRH-(178199) was
able to affect the basal or CRF-induced ACTH release.
More recently, McGivern et al. (448) have shown that
intravenous prepro-TRH(178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199) could attenuate the rise in
plasma ACTH and cortisol that occurs in response to restraint or
footshock stress (Fig. 32
). In
addition, the stress-induced rise in PRL was also diminished, but the
decline in serum TSH was unaffected by the peptide. However, as
physiological immunoneutralization studies have not yet been reported,
the role of prepro-TRH(178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199) in the regulation of the
pituitary-adrenal axis currently remains an open question.

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Figure 32. ACTH, corticosterone, PRL, and TSH secretion in
response to 5-min restraint stress. Data are mean and SEM
of five to six animals per treatment. The animals were restrained
between 1100 and 1300 h. Prepro-TRH178199 (100 or 200 µg/kg)
was infused in the home cage through the indwelling atrial cannula 5
min before restraint. After restraint the cannula was connected
immediately with an extender tubing for serial bleeding, and the
animals were subsequently returned to the home cage. *,P < 0.05 from both doses of prepro-TRH178199.
[Reproduced with permission from R. F. McGivern et
al.: J Neurosci 17:48864894, 1997
(448 ).]
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E. Other substances
The inhibins and activins are dimeric peptides that were isolated
from ovarian follicular fluid on the basis of their ability to inhibit
or stimulate FSH secretion (449, 450, 451, 452, 453, 454, 455, 456, 457, 458), but their subunits and mRNAs
have also been found in extragonadal tissues including the pituitary
and brain (459). Inhibin ß-positive neurons are located in the
nucleus of the tractus solitarius and project to the oxytocinergic
cells in the magnocellular division of the paraventricular hypothalamus
(460). Although centrally administered activin increases CRF and ACTH
secretion in the anesthetized rat (180), activin inhibits POMC mRNA
production in the AtT-20 corticotropic tumor cell line, providing yet
another example of negative peptidergic regulation of the POMC gene
(461). However, activin has not been detected in the hypophysial-portal
circulation in concentrations greater than those in the systemic
circulation, suggesting that it is not secreted by the hypothalamus and
is therefore unlikely to be a physiological CRIF.
Finally, there are neuropeptides in the external zone of the median
eminence that may not be secreted into the hypophysial-portal
circulation. For example, neuropeptide Y, substance P, and galanin have
been demonstrated in the ovine median eminence, but their
concentrations in portal plasma are not greater than those in systemic
plasma (462). Moreover, portal plasma concentrations of neurokinin A,
peptide histidine isoleucine, neurotensin, and cholecystokinin were
either undetectable or not greater than those in jugular plasma,
thereby excluding these known neuropeptides as potential
releasing or release-inhibiting factors in the ovine species.
 |
V. Future Directions
|
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DA and SST are the two best characterized inhibitory factors in
the hypophysial-portal circulation, and their analogs are now in use in
clinical medicine. For example, the SST analogs, octreotide and
lanreotide, are used as the primary therapy, or as an adjunct to
surgery, in the management of gastrointestinal tumors that cause watery
diarrhea and in patients with GH- and TSH-secreting pituitary tumors.
Moreover, the dopaminergic agonist drugs bromocriptine,
pergolide, and cabergoline are usually the
treatment of choice in patients with PRL-secreting microadenomas and
macroadenomas and are also used to treat Parkinsons disease. By
analogy, it is conceivable that a peptidic or nonpeptidic analog with
ACTH release-inhibiting activity might also be of use in the treatment
of patients with pituitary ACTH-secreting adenomas that cause
Cushings disease.
In contrast, an analog with the capacity to antagonize the action of a
naturally occurring CRIF, and to thereby raise plasma cortisol
concentrations, might also be therapeutically useful in patients with
autoimmune or rheumatic diseases. This statement is based on studies in
animals and man which indicate that a hyporesponsive HPA axis may
increase susceptibility to diseases such as experimental allergic
encephalomyelitis, autoimmune thyroiditis, and rheumatoid arthritis.
Moreover, such an analog might also be of benefit in reversing the
hypercortisolemia that occurs in some psychiatric disorders (anorexia
nervosa, endogenous depression), in neurodegenerative diseases
(Alzheimers disease), and in normal aging. However, these hypotheses
can only be tested if a substance, or substances, is isolated that
fulfill(s) the proposed criteria of a CRIF (Fig. 33
).

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Figure 33. A conceptual model of the way the hypothalamus
may regulate ACTH secretion. This is a model that is based on the
studies summarized in this review, and it postulates that the
hypothalamus may both stimulate and inhibit ACTH secretion. Moreover,
it suggests that the hypothalamic inhibition of ACTH release is
mediated by the secretion of a single CRIF. However, it is possible
that several substances could cooperate to mediate the inhibition by
acting in an analogous fashion to the stimulatory interaction of CRF
and AVP.
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Acknowledgments
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We are indebted to Dr. Seymour Reichlin for continued critical
reading of the manuscript and to Ms. Carole Sheppard for secretarial
assistance.
 |
Footnotes
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Address reprint requests to: Dennis Engler, M.D., Laboratory of Molecular Genetics and Development, Institute of Reproduction and Development, Monash Medical Centre, 246 Clayton Road, Clayton, Victoria, Australia 3168.
1 The studies from the authors laboratories were supported by the
National Health & Medical Research Council of Australia and the
National Institutes of Health, USA. 
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References
|
|---|
-
Antoni FA 1986 Hypothalamic control of
adrenocorticotropin secretion: advances since the discovery of
41-residue corticotropin-releasing factor. Endocr Rev 7:351378[Abstract/Free Full Text]
-
Plotsky PM 1991 Pathways to the secretion of
adrenocorticotropin: a view from the portal. J Neuroendocrinol 3:19
-
Harbuz MS, Lightman SL 1992 Stress and the
hypothalamic-pituitary-adrenal axis: acute, chronic and immunological
activation. J Endocrinol 134:327339[Abstract/Free Full Text]
-
Antoni FA 1993 Vasopressinergic control of
pituitary adrenocorticotropin secretion comes of age. Front
Neuroendocrinol 14:76122[CrossRef][Medline]
-
Dallman MF 1993 Stress update. Adaptation of the
hypothalamic-pituitary-adrenal axis to chronic stress. Trends
Endocrinol Metab 4:6269
-
Romero LM, Sapolsky RM 1996 Patterns of ACTH
secretagog secretion in response to psychological stimuli. J
Neuroendocrinol 8:243258[CrossRef][Medline]
-
Engler D 1993 Evidence that the hypothalamus
exerts both stimulatory and inhibitory influences over
adrenocorticotropin secretion and biosynthesis in the sheep. Regul Pept 45:171182[CrossRef][Medline]
-
Engler D, Liu J-P, Clarke IJ, Funder JW 1994 Corticotropin-release inhibitory factor. Evidence for dual stimulatory
and inhibitory hypothalamic regulation over adrenocorticotropin
secretion and biosynthesis. Trends Endocrinol Metab 5:272283[CrossRef][Medline]
-
Vale W, Spiess J, Rivier C, Rivier J 1981 Characterization of a 41-residue ovine hypothalamic peptide that
stimulates the secretion of corticotropin and ß-endorphin. Science 213:13941397[Free Full Text]
-
Baird A, Wehrenberg WB, Shibasaki T, Benoit R,
Chong-Li Z, Esch F, Ling N 1982 Ovine corticotropin-releasing
factor stimulates the concomitant secretion of corticotropin,
ß-lipotropin, ß-endorphin and
-melanotropin by the bovine
adenohypophysis in vitro. Biochem Biophys Res Commun 108:959964[CrossRef][Medline]
-
Gillies GE, Linton EA, Lowry PJ 1982 Corticotropin releasing activity of the new CRF is potentiated several
times by vasopressin. Nature 299:355357[CrossRef][Medline]
-
Vale W, Vaughan J, Smith M, Yamamoto G, Rivier J,
Rivier C 1983 Effect of synthetic ovine corticotropin-releasing
factor, glucocorticoids, catecholamines, neurohypophyseal peptides, and
other substances on cultured corticotropic cells. Endocrinology 113:11211131[Abstract/Free Full Text]
-
Schwartz J, Vale W 1988 Dissociation of the
adrenocorticotropin secretory responses to corticotropin-releasing
factor (CRF) and vasopressin or oxytocin by using a specific cytotoxic
analog of CRF. Endocrinology 122:16951700[Abstract/Free Full Text]
-
Familari M, Smith AI, Smith R, Funder JW 1989 Arginine vasopressin is a much more potent stimulus to ACTH release
from ovine anterior pituitary cells than ovine corticotropin-releasing
factor. I. In vitro studies. Neuroendocrinology 50:152157[CrossRef][Medline]
-
Liu J-P, Robinson PJ, Funder JW, Engler D 1990 The biosynthesis and secretion of adrenocorticotropin by the ovine
anterior pituitary is predominantly regulated by arginine vasopressin
(AVP). Evidence that protein kinase C mediates the action of AVP.
J Biol Chem 265:1413614142[Abstract/Free Full Text]
-
Kemppainen RJ, Clark TP, Sartin JL, Zerbe CA 1993 Hypothalamic peptide regulation of ACTH secretion from sheep pituitary.
Am J Physiol 265:R840R845
-
Bruhn TO, Sutton RE, Rivier CL, Vale WW 1984 Corticotropin-releasing factor regulates proopiomelanocortin messenger
ribonucleic acid levels in vivo. Neuroendocrinology 39:170175[Medline]
-
Höllt V, Haarmann I 1984 Corticotropin-releasing factor differentially regulates
pro-opiomelanocortin messenger ribonucleic acid levels in anterior as
compared to intermediate pituitary lobes of rats. Biochem Biophys Res
Commun 124:407415[CrossRef][Medline]
-
Loeffler JP, Kley N, Pittius CW, Höllt V 1985 Corticotropin releasing factor and forskolin increase
proopiomelanocortin messenger RNA levels in rat anterior and
intermediate cells in vitro. Neurosci Lett 62:383387[CrossRef][Medline]
-
Gagner J-P, Drouin J 1985 Opposite regulation of
pro-opiomelanocortin gene transcription by glucocorticoids and CRH. Mol
Cell Endocrinol 40:2532[CrossRef][Medline]
-
Simard J, Labrie F, Gossard F 1986 Regulation of
growth hormone mRNA levels by cyclic AMP in rat anterior pituitary
cells in culture. DNA 5:263270[Medline]
-
Eberwine JH, Jonassen JA, Evinger MJQ, Roberts JL 1987 Complex transcriptional regulation by glucocorticoids and
corticotropin-releasing hormone of proopiomelanocortin gene expression
in rat pituitary cultures. DNA 6:483492[Medline]
-
Suda T, Tozawa F, Yamada M, Ushiyama T, Tomori N,
Sumitomo T, Nakagami Y, Demura H, Shizume K 1988 Effects of
corticotropin-releasing hormone and dexamethasone on
proopiomelanocortin messenger RNA level in human corticotroph adenoma
cells in vitro. J Clin Invest 82:110114
-
Labrie F, Veilleux R, Lefevre R, Coy DH, Sueiras-Diaz
J, Schally AV 1982 Corticotropin-releasing factor stimulates
accumulation of adenosine 3',5'-monophosphate in rat pituitary
corticotrophs. Science 216:10071008[Abstract/Free Full Text]
-
Aguilera G, Harwood JP, Wilson JX, Morell J, Brown JH,
Catt KJ 1983 Mechanisms of action of corticotropin-releasing
factor and other regulators of corticotropin release in rat pituitary
cells. J Biol Chem 258:80398045[Abstract/Free Full Text]
-
Litvin Y, PasMantier R, Fleischer N, Erlichman J 1984 Hormonal activation of the cAMP-dependent protein kinases in AtT20
cells. Preferential activation of protein kinase I by corticotropin
releasing factor, isoproterenol, and forskolin. J Biol Chem 259:1029610302[Abstract/Free Full Text]
-
Murakami K, Hashimoto K, Ota Z 1985 Calmodulin
inhibitors decrease the CRF-and AVP-induced ACTH release in
vitro: interaction of calcium-calmodulin and the cyclic AMP
system. Neuroendocrinology 41:712[Medline]
-
Dave JR, Eiden LE, Lozovsky D, Waschek JA, Eskay
RL 1987 Calcium-independent and calcium-dependent mechanisms
regulate corticotropin-releasing factor-stimulated proopiomelanocortin
peptide secretion and messenger ribonucleic acid production.
Endocrinology 120:305310[Abstract/Free Full Text]
-
Guild S, Reisine T 1987 Molecular mechanisms of
corticotropin-releasing factor stimulation of calcium mobilization and
adrenocorticotropin release from anterior pituitary tumor cells. J
Pharmacol Exp Ther 241:125130[Abstract/Free Full Text]
-
Childs GV, Marchetti C, Brown AM 1987 Involvement
of sodium channels and two types of calcium channels in the regulation
of adrenocorticotropin release. Endocrinology 120:20592069[Abstract/Free Full Text]
-
Marchetti C, Childs GV, Brown AM 1987 Membrane
currents of identified isolated rat corticotropes and gonadotropes.
Am J Physiol 252:E340E346
-
Abou-Samra AB, Catt KJ, Aguilera G 1987 Calcium-dependent control of corticotropin release in rat anterior
pituitary cell cultures. Endocrinology 121:965971[Abstract/Free Full Text]
-
Leong DA 1988 A complex mechanism of facilitation
in pituitary ACTH cells: recent single-cell studies. J Exp Biol 139:151168[Abstract/Free Full Text]
-
Won JGS, Orth DN 1990 Roles of intracellular and
extracellular calcium in the kinetic profile of adrenocorticotropin
secretion by perifused rat anterior pituitary cells. I.
Corticotropin-releasing factor stimulation. Endocrinology 126:849857[Abstract/Free Full Text]
-
Guérineau N, Corcuff J-B, Tabarin A, Mollard
P 1991 Spontaneous and corticotropin-releasing factor-induced
cytosolic calcium transients in corticotropes. Endocrinology 129:409420[Abstract/Free Full Text]
-
Liu J-P, Robinson PJ, Funder JW, Engler D 1994 A
comparative study of the role of adenylate cyclase in the release of
adrenocorticotropin from the ovine and rat anterior pituitary. Mol Cell
Endocrinol 101:173181[CrossRef][Medline]
-
Liu J-P 1994 Studies of the mechanisms of action
of corticotropin-releasing factor (CRF) and arginine vasopressin (AVP)
in the ovine anterior pituitary: evidence that CRF and AVP stimulate
protein phosphorylation and dephosphorylation. Mol Cell Endocrinol 106:5766[CrossRef][Medline]
-
Kuryshev YA, Childs GC, Ritchie AK 1996 Corticotropin-releasing hormone stimulation of Ca2+ entry
in corticotropes is partially dependent on protein kinase A.
Endocrinology 136:39253935[Abstract]
-
Kuryshev YA, Childs GV, Ritchie AK 1996 Corticotropin-releasing hormone stimulates Ca2+ entry
through L- and P-type Ca2+ channels in rat corticotropes.
Endocrinology 137:22692277[Abstract]
-
Katoh K, Chen C, Liu J-P, Engler D 1999 Studies
of the mechanisms by which corticotropin-releasing factor and arginine
vasopressin increase intracellular calcium and adrenocorticotropin
secretion in ovine anterior pituitary cells. Mol Cell Endocrinol, in
press
-
Chen FM, Bilezikjian LM, Perrin MH, Rivier J, Vale
W 1986 Corticotropin releasing factor receptor-mediated
stimulation of adenylate cyclase activity in the rat brain. Brain Res 38:4957[CrossRef]
-
Wynn PC, Aguilera G, Morell J, Catt KJ 1983 Properties and regulation of high-affinity pituitary receptors for
corticotropin-releasing factor. Biochem Biophys Res Commun 110:602608[CrossRef][Medline]
-
Wynn PC, Hauger RL, Holmes MC, Millan MA, Catt KJ,
Aguilera G 1984 Brain and pituitary receptors for
corticotropin-releasing factor: localization and differential
regulation after adrenalectomy. Peptides 5:10771084[CrossRef][Medline]
-
De Souza EB, Perrin MH, Rivier J, Vale WW, Kuhar
MJ 1984 Corticotropin-releasing factor receptors in rat pituitary
gland: autoradiographic localization. Brain Res 296:202207[CrossRef][Medline]
-
De Souza EB, Perrin MH, Insel TR, Rivier J, Vale WW,
Kuhar MJ 1984 Corticotropin-releasing factor receptors in rat
forebrain: autoradiographic identification. Science 224:14491451[Abstract/Free Full Text]
-
De Souza EB, Insel TR, Perrin MH, Rivier J, Vale WW,
Kuhar MJ 1985 Corticotropin-releasing factor receptors are widely
distributed within the rat central nervous system: an autoradiographic
study. J Neurosci 5:31893203[Abstract]
-
De Souza EB, Perrin MH, Whitehouse PJ, Rivier J, Vale
W, Kuhar MJ 1985 Corticotropin-releasing factor receptors in human
pituitary gland: autoradiographic localization. Neuroendocrinology 40:419422[Medline]
-
Wynn PC, Harwood JP, Catt KJ, Aguilera G 1985 Regulation of corticotropin-releasing factor (CRF) receptors in the rat
pituitary gland: effects of adrenalectomy on CRF receptors and
corticotroph responses. Endocrinology 116:16531659[Abstract/Free Full Text]
-
De Souza EB, Insel TR, Perrin MH, Rivier J, Vale WW,
Kuhar MJ 1985 Differential regulation of corticotropin-releasing
factor receptors in anterior and intermediate lobes of pituitary and in
brain following adrenalectomy in rats. Neurosci Lett 56:121128[CrossRef][Medline]
-
Perrin MH, Haas Y, Rivier JE, Vale WW 1986 Corticotropin-releasing factor binding to the anterior pituitary
receptor is modulated by divalent cations and guanyl nucleotides.
Endocrinology 118:11711179[Abstract/Free Full Text]
-
Millan MA, Jacobowitz DM, Hauger RL, Catt KJ, Aguilera
G 1986 Distribution of corticotropin-releasing factor receptors in
primate brain. Proc Natl Acad Sci USA 83:19211925[Abstract/Free Full Text]
-
Millan MA, Abou Samra A-B, Wynn PC, Catt KJ, Aguilera
G 1987 Receptors and actions of corticotropin-releasing hormone in
the primate pituitary gland. Endocrinology 64:10361041
-
De Souza EB 1987 Corticotropin-releasing factor
receptors in the rat central nervous system: characterization and
regional distribution. J Neurosci 7:88100[Abstract]
-
Hauger RL, Millan MA, Catt KJ, Aguilera G 1987 Differential regulation of brain and pituitary corticotropin-releasing
factor receptors by corticosterone. Endocrinology 120:15271533[Abstract/Free Full Text]
-
Kapcala LP, De Souza EB 1988 Characterization of
corticotropin-releasing factor receptors in dissociated brain cell
cultures. Brain Res 456:159167[CrossRef][Medline]
-
Hauger RL, Lorang M, Irwin M, Aguilera G 1990 CRF
receptor regulation and sensitization of ACTH responses to acute ether
stress during chronic intermittent immobilization stress. Brain Res 532:3440[CrossRef][Medline]
-
Chen R, Lewis KA, Perrin MH, Vale WW 1993 Expression cloning of a human corticotropin-releasing factor receptor.
Proc Natl Acad Sci USA 90:89678971[Abstract/Free Full Text]
-
Vita N, Laurent P, Lefort S, Chalon P, Lelias JM,
Kaghad M, LeFur G, Caput D, Ferrara P 1993 Primary structure and
functional expression of mouse pituitary and human brain corticotrophin
releasing factor receptors. FEBS Lett 335:15[CrossRef][Medline]
-
Perrin MH, Donaldson CJ, Chen R, Lewis KA, Vale
WW 1993 Cloning and functional expression of a rat brain
corticotropin releasing factor (CRF) receptor. Endocrinology 133:30583161[Abstract/Free Full Text]
-
Chang C-P, Pearse RV II, OConnell S, Rosenfeld
MG 1993 Identification of a seven transmembrane helix receptor for
corticotropin-releasing factor and sauvagine in mammalian brain. Neuron 11:11871195[CrossRef][Medline]
-
Potter E, Sutton S, Donaldson C, Chen R, Perrin M,
Lewis K, Sawchenko PE, Vale W 1994 Distribution of
corticotropin-releasing factor receptor mRNA expression in the rat
brain and pituitary. Proc Natl Acad Sci USA 91:87778781[Abstract/Free Full Text]
-
Wong M-L, Licinio J, Pasternak KI, Gold PW 1994 Localization of corticotropin-releasing hormone (CRH) receptor mRNA in
adult rat brain by in situ hybridization histochemistry.
Endocrinology 135:22752278[Abstract]
-
Lovenberg TW, Liaw CW, Grigoriadis DE, Clevenger W,
Chalmers DT, De Souza EB, Oltersdorf T 1995 Cloning and
characterization of a functionally distinct corticotropin-releasing
factor receptor subtype from rat brain. Proc Natl Acad Sci USA 92:836840[Abstract/Free Full Text]
-
Kishimoto T, Pearse II RV, Lin CR, Rosenfeld MG 1995 A sauvagine/corticotropin-releasing factor receptor expressed in
heart and skeletal muscle. Proc Natl Acad Sci USA 92:11081112[Abstract/Free Full Text]
-
Perrin MH, Donaldson C, Chen R, Blount A, Berggren T,
Bilezikjian L, Sawchenko PE, Vale W 1995 Identification of a
second corticotropin-releasing factor receptor gene and
characterization of a cDNA expressed in heart. Proc Natl Acad Sci USA 92:29692973[Abstract/Free Full Text]
-
Stenzel P, Kesterson R, Yeung W, Cone RD, Rittenberg
MB, Stenzel-Poore MP 1995 Identification of a novel murine
receptor for corticotropin-releasing hormone expressed in the heart.
Mol Endocrinol 9:637645[Abstract/Free Full Text]
-
Chalmers DT, Lovenberg TW, De Souza EB 1995 Localization of novel corticotropin-releasing factor receptor
(CRF2) mRNA expression to specific subcortical nuclei in
rat brain: comparison with CRF1 receptor mRNA expression.
J Neurosci 15:63406350[Abstract/Free Full Text]
-
Okamura Y, Morley SD, Burzio LO, Zwiers H, Lederis K,
Richter D 1988 Cloning and sequence analysis of cDNA for
corticotropin-releasing factor precursor from the teleost fish
Catostomus commersoni. Proc Natl Acad Sci USA 85:84398443[Abstract/Free Full Text]
-
Stenzel-Poore MP, Heldwein KA, Stenzel P, Lee S, Vale
WW 1992 Characterization of the genomic corticotropin-releasing
factor (CRF) gene from Xenopus laevis: two members of the
CRF family exist in amphibians. Mol Endocrinol 6:17161724[Abstract/Free Full Text]
-
Vaughan J, Donaldson C, Bittencourt J, Perrin MH,
Lewis K, Sutton S, Chan R, Turnbull AV, Lovejoy D, Rivier C, Rivier J,
Sawchenko PE, Vale W 1995 Urocortin, a mammalian neuropeptide
related to fish urotensin I and to corticotropin-releasing factor.
Nature 378:287292[CrossRef][Medline]
-
Donaldson CJ, Sutton SW, Perrin MH, Corrigan AZ, Lewis
KA, Rivier JE, Vaughan JM, Vale WW 1996 Cloning and
characterization of human urocortin. Endocrinology 137:21672170[Abstract]
-
Kozicz T, Yanaihara H, Arimura A 1998 Distribution of urocortin-like immunoreactivity in the central nervous
system of the rat. J Comp Neurol 391:110[CrossRef][Medline]
-
Levin N, Wallace C, Bengani N, Blum M, Farnworth P,
Smith AI, Roberts JL 1990 Ovine anterior pituitary
proopiomelanocortin gene expression is not increased by ACTH
secretagogues in vitro. Endocrinology 132:16921700[Abstract/Free Full Text]
-
van de Pavert SA, Clarke IJ, Rao A, Vrana KE, Schwartz
J 1997 Effects of vasopressin and elimination of
corticotropin-releasing hormone-target cells on pro-opiomelanocortin
mRNA and adrenocorticotropin secretion in ovine anterior pituitary
cells. J Endocrinol 154:139147[Abstract/Free Full Text]
-
Antoni FA 1981 Novel ligand specificity of
pituitary vasopressin receptors in the rat. Neuroendocrinology 39:186188
-
Antoni F, Holmes MC, Makara GB, Kártesi M,
Lászlo FA 1984 Evidence that the effects of
arginine-8-vasopressin (AVP) on pituitary corticotropin (ACTH) release
are mediated by a novel type of receptor. Peptides 5:519522[CrossRef][Medline]
-
Gaillard RC, Schoenenberg P, Favrod-Coune CA, Muller
AF, Marie J, Bockaert J, Jard S 1984 Properties of rat anterior
pituitary vasopressin receptors: relation to adenylate cyclase and the
effect of corticotropin-releasing factor. Proc Natl Acad Sci USA 81:29072911[Abstract/Free Full Text]
-
Koch B, Lutz-Bucher B 1985 Specific receptors for
vasopressin in the pituitary gland: evidence for down-regulation and
desensitization to adrenocorticotropin-releasing factors. Endocrinology 116:671676[Abstract/Free Full Text]
-
Antoni FA, Holmes MC, Kiss JZ 1985 Pituitary
binding of vasopressin is altered by experimental manipulations of the
hypothalamic-pituitary-adrenocortical axis in normal as well as
homozygous (di/di) Brattleboro rats. Endocrinology 117:12931299[Abstract/Free Full Text]
-
Baertschi AJ, Friedli M 1985 A novel type of
vasopressin receptor on anterior pituitary corticotrophs? Endocrinology 116:499502[Abstract/Free Full Text]
-
Jard S, Gaillard RC, Guillon G, Marie J, Schoenenberg
P, Muller AF, Manning M, Sawyer WH 1986 Vasopressin antagonists
allow demonstration of a novel type of vasopressin receptor in the rat
adenohypophysis. Mol Pharmacol 30:171177[Abstract]
-
Shen PJ, Clarke IJ, Canny BJ, Funder JW, Smith AI 1990 Arginine vasopressin and corticotropin releasing factor: binding
to ovine anterior pituitary membranes. Endocrinology 127:20852089[Abstract/Free Full Text]
-
Aguilera G, Pham Q, Rabadan-Diehl C 1994 Regulation of pituitary vasopressin receptors during chronic stress:
relationship with corticotroph responsiveness. J Neuroendocrinol 6:299304[CrossRef][Medline]
-
Sugimoto T, Saito M, Mochizuki S, Watanabe Y,
Hashimoto S, Kawashima H 1994 Molecular cloning and functional
expression of a cDNA encoding the human V1b vasopressin
receptor. J Biol Chem 269:2708827092[Abstract/Free Full Text]
-
Lolait SJ, OCarroll A-M, Mahan LC, Felder CC, Button
DC, Young III WS, Mezey E, Brownstein MJ 1995 Extrapituitary
expression of the rat V1b vasopressin receptor gene. Proc Natl Acad Sci
USA 92:67836787[Abstract/Free Full Text]
-
Berridge MJ, Irvine RF 1989 Inositol phosphates
and cell signalling. Nature 341:197205[CrossRef][Medline]
-
Nishizuka Y 1992 Intracellular signalling by
hydrolysis of phospholipids and activation of protein kinase C. Science 258:607614[Abstract/Free Full Text]
-
Liu J-P 1996 Protein kinase C and its substrates.
Mol Cell Endocrinol 116:129[CrossRef][Medline]
-
Raymond V, Leung PCK, Veilleux R, Labrie F 1985 Vasopressin rapidly stimulates phosphatidic acid-phosphatidylinositol
turnover in rat anterior pituitary cells. FEBS Lett 182:196200[CrossRef][Medline]
-
Todd K, Lightman SL 1987 Vasopressin activation
of phosphatidylinositol metabolism in rat anterior pituitary in
vitro and its modification by changes in the
hypothalamo-pituitary-adrenal axis. Neuroendocrinology 45:212218[Medline]
-
Bilezikjian LM, Blount AL, Vale WW 1987 The
cellular actions of vasopressin on corticotrophs of the anterior
pituitary: resistance to glucocorticoid action. Mol Endocrinol 1:451458[Abstract/Free Full Text]
-
Bilezikjian LM, Woodgett JR, Hunter T, Vale WW 1987 Phorbol ester-induced down-regulation of protein kinase C
abolishes vasopressin-mediated responses in rat anterior pituitary
cells. Mol Endocrinol 1:555560[Abstract/Free Full Text]
-
Carvallo P, Aguilera G 1989 Protein kinase C
mediates the effect of vasopressin in pituitary corticotrophs. Mol
Endocrinol 3:19351943[Abstract/Free Full Text]
-
Oki Y, Nicholson WE, Orth DN 1990 Role of protein
kinase-C in the adrenocorticotropin secretory response to arginine
vasopressin (AVP) and the synergistic response to AVP and corticotropin
releasing factor by perifused rat anterior pituitary cells.
Endocrinology 127:350357[Abstract/Free Full Text]
-
Liu J-P, Engler D, Funder JW, Robinson PJ 1992 Evidence that the stimulation by arginine vasopressin (AVP) of the
release of adrenocorticotropin (ACTH) from the ovine anterior pituitary
involves the activation of protein kinase C. Mol Cell Endocrinol 87:3547[CrossRef][Medline]
-
Liu J-P, Engler D, Funder JW, Robinson PJ 1994 Arginine vasopressin (AVP) causes the reversible phosphorylation of the
myristoylated alanine rich C kinase substrate (MARCKS) protein in the
ovine anterior pituitary. Evidence that MARCKS phosphorylation is
associated with adrenocorticotropin (ACTH) secretion. Mol Cell
Endocrinol 105:217226[CrossRef][Medline]
-
Giguere V, Labrie F 1982 Vasopressin potentiates
cyclic AMP accumulation and ACTH release induced by
corticotropin-releasing factor (CRF) in rat anterior pituitary cells in
culture. Endocrinology 111:17521754[Abstract/Free Full Text]
-
Cronin MJ, Zysk JR, Baertschi AJ 1986 Protein
kinase C potentiates corticotropin releasing factor stimulated cyclic
AMP in pituitary. Peptides 7:935938[CrossRef][Medline]
-
Abou-Samra A-B, Harwood JP, Manganiello VC, Catt KJ,
Aguilera G 1987 Phorbol 12-myristate 13-acetate and
vasopressin potentiate the effect of corticotropin-releasing factor on
cyclic AMP production in rat anterior pituitary cells. J Biol Chem 262:11291136[Abstract/Free Full Text]
-
Armstrong WE, Warach S, Hatton GI, McNeill TH 1980 Subnuclei in the rat hypothalamic paraventricular nucleus: a
cytoarchitectural, horseradish peroxidase and immunocytochemical
analysis. Neuroscience 5:19311958[CrossRef][Medline]
-
Swanson LW, Kuypers HGJM 1980 The paraventricular
nucleus of the hypothalamus: cytoarchitectonic subdivisions and
organization of projections to the pituitary, dorsal vagal complex, and
spinal cord as demonstrated by retrograde fluorescence double-labeling
methods. J Comp Neurol 194:555570[CrossRef][Medline]
-
Swanson LW, Sawchenko PE 1980 Paraventricular
nucleus: a site for the integration of neuroendocrine and autonomic
mechanisms. Neuroendocrinology 31:410417[Medline]
-
van den Pol AN 1982 The magnocellular and
parvocellular paraventricular nucleus of rat: intrinsic organization.
J Comp Neurol 206:317345[CrossRef][Medline]
-
Swanson LW, Sawchenko PE 1983 Hypothalamic
integration: organization of the paraventricular and supraoptic nuclei.
Annu Rev Neurosci 6:269324[CrossRef][Medline]
-
Kiss JZ, Martos J, Palkovits M 1991 Hypothalamic
paraventricular nucleus: a quantitative analysis of cytoarchitectonic
subdivisions in the rat. J Comp Neurol 313:563573[CrossRef][Medline]
-
Olschowka JA, ODonohue TL, Mueller GP, Jacobowitz
DM 1982 The distribution of corticotropin releasing factor-like
immunoreactive neurons in the rat brain. Peptides 3:9951015[CrossRef][Medline]
-
Merchenthaler I, Vigh S, Petrusz P, Schally AV 1982 Immunocytochemical localization of corticotropin-releasing factor
(CRF) in the rat brain. Am J Anat 165:385396[CrossRef][Medline]
-
Paull WK, Schöler J, Arimura A, Meyers CA, Chang
JK, Chang D, Shimizu M 1982 Immunocytochemical localization of CRF
in the ovine hypothalamus. Peptides 1:183191
-
Bugnon C, Fellmann D, Gouget A, Cardot J 1982 Corticoliberin in rat brain: immunocytochemical identification and
localization of a novel neuroglandular system. Neurosci Lett 30:2530[CrossRef][Medline]
-
Bloom FE, Battenberg ELF, Rivier J, Vale W 1982 Corticotropin releasing factor (CRF): immunoreactive neurones and
fibers in rat hypothalamus. Regul Pept 4:4348[CrossRef][Medline]
-
Swanson LW, Sawchenko PE, Rivier J, Vale WW 1983 Organization of ovine corticotropin-releasing factor immunoreactive
cells and fibers in the rat brain: an immunohistochemical study.
Neuroendocrinology 36:165186[Medline]
-
Kolodziejczyk E, Baertschi AJ, Tramu G 1983 Corticoliberin-immunoreactive cell bodies localised in two distinct
areas of the sheep hypothalamus. Neuroscience 9:261270[CrossRef][Medline]
-
Antoni FA, Palkovits M, Makara GB, Linton EA, Lowry PJ,
Kiss JZ 1983 Immunoreactive corticotropin-releasing hormone in the
hypothalamoinfundibular tract. Neuroendocrinology 36:415423[CrossRef][Medline]
-
Roth KA, Weber E, Barchas JD, Chang D, Chang J-K 1983 Immunoreactive dynorphin-(18) and corticotropin-releasing factor
in subpopulation of hypothalamic neurons. Science 219:189191[Abstract/Free Full Text]
-
Mouri T, Suda T, Sasano N, Andoh N, Takei Y, Takase M,
Sasaki A, Murakami O, Yoshinaga K 1984 Immunocytochemical
identification of CRF in the human hypothalamus. Tohoku J Exp Med 142:423426[Medline]
-
Papadopoulos GC, Karamanlidis AN, Michaloudi H,
Dinopoulos A, Antonopoulos J, Parnavelas JG 1985 The coexistence
of oxytocin and corticotropin-releasing factor in the hypothalamus: an
immunocytochemical study in the rat, sheep and hedgehog. Neurosci Lett 62:213218[CrossRef][Medline]
-
Sakanaka M, Shibasaki T, Lederis K 1987 Corticotropin releasing factor-like immunoreactivity in the rat brain
as revealed by a modified cobalt-glucose oxidase-diaminobenzidine
method. J Comp Neurol 260:256298[CrossRef][Medline]
-
Levidiotis M, Oldfield B, Wintour EM 1987 Corticotropin-releasing factor and arginine vasopressin fibre
projections to the median eminence of fetal sheep. Neuroendocrinology 46:453456[Medline]
-
Alonso G, Siaud P, Assenmacher I 1988 Immunocytochemical ultrastructural study of hypothalamic neurons
containing corticotropin-releasing factor in normal and
adrenalectomized rats. Neuroscience 24:553565[CrossRef][Medline]
-
Kawano H, Daikoku S, Shibasaki T 1988 CRF-containing neuron systems in the rat hypothalamus: retrograde
tracing and immunohistochemical studies. J Comp Neurol 272:260268[CrossRef][Medline]
-
Whitnall MH, Mezey E, Gainer H 1985 Co-localization of corticotropin-releasing factor and vasopressin in
median eminence neurosecretory vesicles. Nature 317:248250[CrossRef][Medline]
-
Whitnall MH 1988 Distributions of pro-vasopressin
expressing and pro-vasopressin deficient CRH neurons in the
paraventricular hypothalamic nucleus of colchicine-treated normal and
adrenalectomized rats. J Comp Neurol 275:1328[CrossRef][Medline]
-
Sawchenko PE, Swanson LW 1983 The organization of
forebrain afferents to the paraventricular and supraoptic nuclei of the
rat. J Comp Neurol 218:121144[CrossRef][Medline]
-
Swanson LW, Cowan WM 1977 An autoradiographic
study of the organization of the efferent connections of the
hippocampal formation in the rat. J Comp Neurol 172:4984[CrossRef][Medline]
-
Swanson LW, Cowan WM 1979 The connections of the
septal region in the rat. J Comp Neurol 186:521565
-
Krettek JE, Price JL 1978 Amygdaloid projections
to subcortical structures within the basal forebrain and the brainstem
in the rat and cat. J Comp Neurol 178:255280[CrossRef][Medline]
-
Cullinan WE, Herman JP, Watson SJ 1993 Ventral
subicular interaction with the hypothalamic paraventricular nucleus:
evidence for a relay in the bed nucleus of the stria terminalis. J
Comp Neurol 332:129[CrossRef][Medline]
-
Swanson LW, Hartman BK 1975 The central adrenergic
system. An immunofluorescence study of the location of cell bodies and
their efferent connections in the rat utilizing
dopamine-ß-hydroxylase as a marker. J Comp Neurol 163:467506[CrossRef][Medline]
-
Swanson LW, Sawchenko PE, Bérod A, Hartman BK,
Helle KB, Vanorden DE 1981 An immunohistochemical study of the
organization of catecholaminergic cells and terminal fields in the
paraventricular and supraoptic nuclei of the hypothalamus. J Comp
Neurol 196:271285[CrossRef][Medline]
-
Sawchenko PE, Swanson LW 1981 Central
noradrenergic pathways for the integration of hypothalamic
neuroendocrine and autonomic responses. Science 214:685687[Abstract/Free Full Text]
-
Sawchenko PE, Swanson LW 1982 The organization of
noradrenergic pathways from the brainstem to the paraventricular and
supraoptic nuclei in the rat. Brain Res Rev 4:275325
-
Sawchenko PE, Swanson LW, Steinbusch HWM, Verhofstad
AAJ 1983 The distribution of cells of origin of serotonergic
inputs to the paraventricular and supraoptic nuclei of the rat. Brain
Res 277:355360[CrossRef][Medline]
-
Buijs RM, Geffard M, Pool CW, Hoorneman MD 1984 The dopaminergic innervation of the supraoptic and paraventricular
nucleus. A light and electron microscopical study. Brain Res 323:6572[CrossRef][Medline]
-
Silverman A-J, Oldfield B, Hou-Yu A, Zimmerman EA 1985 The noradrenergic innervation of vasopressin neurons in the
paraventricular nucleus of the hypothalamus: an ultrastructural study
using radioautography and immunocytochemistry. Brain Res 325:215229[CrossRef][Medline]
-
Liposits Zs Phelix C, Paull WK 1986 Electron
microscopic analysis of tyrosine hydroxylase, dopamine-ß-hydroxylase
and phenylethanolamine-N-methyltransferase immunoreactive
innervation of the hypothalamic paraventricular nucleus in the rat.
Histochemistry 84:105120[CrossRef][Medline]
-
Tucker DC, Saper CB, Ruggiero DA, Reis DJ 1987 Organization of central adrenergic pathways. I. Relationships of
ventrolateral medullary projections to the hypothalamus and spinal
cord. J Comp Neurol 259:591603[CrossRef][Medline]
-
Kitazawa S, Shioda S, Nakai Y 1987 Catecholaminergic innervation of neurons containing
corticotropin-releasing factor in the paraventricular nucleus of the
rat hypothalamus. Acta Anat (Basel) 129:337343[Medline]
-
Cunningham Jr ET, Sawchenko PE 1988 Anatomical
specificity of noradrenergic inputs to the paraventricular and
supraoptic nuclei of the rat hypothalamus. J Comp Neurol 274:6076[CrossRef][Medline]
-
Cunningham Jr ET, Bohn MC, Sawchenko PE 1990 Organization of adrenergic inputs to the paraventricular and supraoptic
nuclei of the hypothalamus in the rat. J Comp Neurol 292:651667[CrossRef][Medline]
-
Tatemoto K, Carlquist M, Mutt V 1982 Neuropeptide
Y a novel brain peptide with structural similarities to peptide YY
and pancreatic polypeptide. Nature 296:659660[CrossRef][Medline]
-
Tatemoto K 1982 Neuropeptide Y: complete amino
acid sequence of the brain peptide. Proc Natl Acad Sci USA 79:54855489[Abstract/Free Full Text]
-
Adrian TE, Allen JM, Bloom SR, Ghatei MA, Rossor MN,
Roberts GW, Crow TJ, Tatemoto K, Polak JM 1983 Neuropeptide Y
distribution in human brain. Nature 306:584586[CrossRef][Medline]
-
Allen YS, Adrian TE, Allen JM, Tatemoto K, Crow TJ,
Bloom SR, Polak JM 1983 Neuropeptide Y distribution in the rat
brain. Science 221:877879[Abstract/Free Full Text]
-
Chronwall BM, DiMaggio DA, Massari VJ, Pickel VM,
Ruggiero DA, ODonohue TL 1985 The anatomy of
neuropeptide-Y-containing neurons in rat brain. Neuroscience 15:11591181[CrossRef][Medline]
-
De Quidt ME, Emson PC 1986 Distribution of
neuropeptide Y-like immunoreactivity in the rat central nervous system.
I. Radioimmunoassay and chromatographic characterization. Neuroscience 18:527543[CrossRef][Medline]
-
De Quidt ME, Emson PC 1986 Distribution of
neuropeptide Y-like immunoreactivity in the rat central nervous system.
II. Immunohistochemical analysis. Neuroscience 18:545618[CrossRef][Medline]
-
Hökfelt T, Lundberg JM, Tatemoto K, Mutt V,
Terenius L, Polak J, Bloom S, Sasek C, Elde R, Goldstein M 1983 Neuropeptide Y(NPY)- and FRMFamide neuropeptide-like immunoreactivities
in catecholamine neurons of the rat medulla oblongata. Acta Physiol
Scand 117:315318[Medline]
-
Everitt BJ, Hökfelt T, Terenius L, Tatemoto K,
Mutt V, Goldstein M 1984 Differential co-existence of neuropeptide
Y(NPY)-like immunoreactivity with catecholamines in the central nervous
system of the rat. Neuroscience 11:443462[CrossRef][Medline]
-
Sawchenko PE, Swanson LW, Grzanna R, Howe PRC, Bloom
SR, Polak JM 1985 Colocalization of neuropeptide Y
immunoreactivity in brainstem catecholamine neurons that project to the
paraventricular nucleus of the hypothalamus. J Comp Neurol 24:138153
-
Blessing WW, Howe PRC, Joh TH, Oliver JR, Willoughby
JO 1986 Distribution of tyrosine hydroxylase and neuropeptide
Y-like immunoreactive neurons in rabbit medulla oblongata, with
attention to colocalization studies, presumptive
adrenaline-synthesizing perikarya, and vagal preganglionic cells.
J Comp Neurol 248:285300[CrossRef][Medline]
-
Murakami S, Okamura H, Pelletier G, Ibata Y 1989 Differential colocalization of neuropeptide Y- and
methionine-enkephalin-Arg6-Gly7-Leu8-like
immunoreactivity in catecholaminergic neurons in the rat brain stem.
J Comp Neurol 281:532544[CrossRef][Medline]
-
Liposits Z, Sievers L, Paull WK 1988 Neuropeptide-Y and ACTH-immunoreactive innervation of corticotropin
releasing factor (CRF)-synthesizing neurons in the hypothalamus of the
rat. An immunocytochemical analysis at the light and electron
microscopic levels. Histochemistry 88:227234[CrossRef][Medline]
-
Porter JC, Jones JC 1956 Effect of plasma from
hypophyseal-portal vessel blood on adrenal ascorbic acid. Endocrinology 58:6267
-
Gibbs DM, Vale W 1982 Presence of corticotropin
releasing factor-like immunoreactivity in hypophysial portal blood.
Endocrinology 111:14181420[Abstract/Free Full Text]
-
Plotsky PM, Vale W 1984 Hemorrhage-induced
secretion of corticotropin-releasing factor-like immunoreactivity into
the rat hypophysial portal circulation and its inhibition by
glucocorticoids. Endocrinology 114:164169[Abstract/Free Full Text]
-
Plotsky PM, Bruhn TO, Vale W 1984 Central
modulation of immunoreactive corticotropin-releasing factor secretion
by arginine vasopressin. Endocrinology 115:16391641[Abstract/Free Full Text]
-
Plotsky PM, Bruhn TO, Vale W 1985 Evidence for
multifactor regulation of the adrenocorticotropin secretory response to
hemodynamic stimuli. Endocrinology 116:633639[Abstract/Free Full Text]
-
Plotsky PM, Bruhn TO, Vale W 1985 Hypophysiotropic
regulation of adrenocorticotropin secretion in response to
insulin-induced hypoglycemia. Endocrinology 117:323329[Abstract/Free Full Text]
-
Redekopp C, Irvine CHG, Donald RA, Livesey JH, Sadler
W, Nicholls MG, Alexander SL, Evans MJ 1986 Spontaneous and
stimulated adrenocorticotropin and vasopressin pulsatile secretion in
the pituitary venous effluent of the horse. Endocrinology 118:14101416[Abstract/Free Full Text]
-
Plotsky PM, Otto S, Sapolsky RM 1986 Inhibition of
immunoreactive corticotropin-releasing factor secretion into the
hypophysial-portal circulation by delayed glucocorticoid feedback.
Endocrinology 119:11261130[Abstract/Free Full Text]
-
Plotsky PM, Sawchenko PE 1987 Hypophysial-portal
plasma levels, median eminence content, and immunohistochemical
staining of corticotropin-releasing factor, arginine vasopressin, and
oxytocin after pharmacological adrenalectomy. Endocrinology 120:13611369[Abstract/Free Full Text]
-
Plotsky PM 1987 Facilitation of immunoreactive
corticotropin-releasing factor secretion into the hypophysial-portal
circulation after activation of catecholaminergic pathways or central
norepinephrine injection. Endocrinology 121:924930[Abstract/Free Full Text]
-
Guillaume V, Conte-Devolx B, Szafarczyk A, Malaval F,
Pares-Herbute N, Grino M, Alonso G, Assenmacher I, Oliver C 1987 The corticotropin-releasing factor release in rat hypophysial portal
blood is mediated by brain catecholamines. Neuroendocrinology 46:143146[CrossRef][Medline]
-
Ixart G, Barbanel G, Conte-Devolx B, Grino M, Oliver C,
Assenmacher I 1987 Evidence for basal and stress-induced release
of corticotropin releasing factor in the push-pull cannulated median
eminence of conscious free-moving rats. Neuroendocrinology 74:8589
-
Tannahill LA, Dow RC, Fairhall RM, Robinson ICAF, Fink
G 1988 Comparison of adrenocorticotropin control in Brattleboro,
Long-Evans, and Wistar rats. Measurement of corticotropin-releasing
factor, arginine vasopressin, and oxytocin in hypophysial portal blood.
Neuroendocrinology 48:650657[Medline]
-
Fink G, Robinson ICAF, Tannahill LA 1988 Effects
of adrenalectomy and glucocorticoids on the peptides, CRF-41, AVP and
oxytocin in rat hypophysial portal blood. J Physiol 401:329345[Abstract/Free Full Text]
-
Livesey JH, Donald RA, Irvine CHG, Redekopp C,
Alexander SL 1988 The effects of cortisol, vasopressin (AVP), and
corticotropin-releasing factor administration on pulsatile
adrenocorticotropin,
-melanocyte-stimulating hormone, and AVP
secretion in the pituitary venous effluent of the horse. Endocrinology 123:713720[Abstract/Free Full Text]
-
Eckland DJA, Todd K, Jessop DS, Biswas S, Lightman
SL 1988 Differential effects of hypothalamic catecholamine
depletion on the release of arginine vasopressin and CRF-41 into
hypothalamo-hypophyseal portal blood. Neurosci Lett 90:292296[CrossRef][Medline]
-
Caraty A, Grino M, Locatelli A, Oliver C 1988 Secretion of corticotropin releasing factor (CRF) and vasopressin (AVP)
into the hypophysial portal blood of conscious, unrestrained rams.
Biophys Biochem Res Commun 155:841849
-
Engler D, Pham T, Fullerton MJ, Ooi G, Funder JW,
Clarke IJ 1989 Studies of the secretion of corticotropin-releasing
factor and arginine vasopressin into the hypophysial-portal circulatlon
of the conscious sheep. I. Effect of an audiovisual stimulus and
insulin-induced hypoglycemia. Neuroendocrinology 49:367381[Medline]
-
Canny BJ, Funder JW, Clarke IJ 1989 Glucocorticoids regulate ovine hypophysial portal levels of
corticotropin-releasing factor and arginine vasopressin in a
stress-specific manner. Endocrinology 125:25322539[Abstract/Free Full Text]
-
Irvine CHG, Alexander SL, Donald RA 1989 Effect of
an osmotic stimulus on the secretion of arginine vasopressin and
adrenocorticotropin in the horse. Endocrinology 124:31023108[Abstract/Free Full Text]
-
Guillaume V, Grino M, Conte-Devolx B, Boudouresque F,
Oliver C 1989 Corticotropin-releasing factor secretion increases
in rat hypophysial portal blood during insulin-induced hypoglycemia.
Neuroendocrinology 49:676679[Medline]
-
Sapolsky RM, Armanini MP, Sutton SW, Plotsky PM 1989 Elevation of hypophysial portal concentrations of
adrenocorticotropin secretagogues after fornix transection.
Endocrinology 125:28812887[Abstract/Free Full Text]
-
Caraty A, Grino M, Locatelli A, Guillaume V,
Boudouresque F, Conte-Devolx B, Oliver C 1990 Insulin-induced
hypoglycemia stimulates corticotropin-releasing factor and arginine
vasopressin secretion into hypophysial portal blood of conscious,
unrestrained rams. J Clin Invest 85:17161721
-
Antoni FA, Fink G, Sheward WJ 1990 Corticotrophin-releasing peptides in rat hypophysial portal blood after
paraventricular lesions: a marked reduction in the concentration of
corticotrophin-releasing factor-41, but no change in vasopressin. J
Endocrinol 125:175183[Abstract/Free Full Text]
-
Sapolsky RM, Armanini MP, Packan DR, Sutton SW, Plotsky
PM 1990 Glucocorticoid feedback inhibition of adrenocorticotropic
hormone secretagogue release. Relationship to corticosteroid receptor
occupancy in various limbic sites. Neuroendocrinology 51:328336[Medline]
-
Sheward WJ, Fink G 1991 Effects of corticosterone
on the secretion of corticotrophin-releasing factor, arginine
vasopressin and oxytocin into hypophyseal portal blood in long-term
hypophysectomized rats. J Endocrinol 129:9198[Abstract/Free Full Text]
-
Tannahill LA, Sheward WJ, Robinson ICAF, Fink G 1991 Corticotrophin-releasing factor-41, vasopressin and oxytocin
release into hypophysial portal blood in the rat: effects of electrical
stimulation of the hypothalamus, amygdala and hippocampus. J Endocrinol 129:99107[Abstract/Free Full Text]
-
Plotsky PM, Kjær A, Sutton SW, Sawchenko PE, Vale
W 1991 Central activin administration modulates
corticotropin-releasing hormone and adrenocorticotropin secretion.
Endocrinology 128:25202525[Abstract/Free Full Text]
-
Alexander SL, Irvine CHG, Ellis MJ, Donald RA 1991 The effect of acute exercise on the secretion of
corticotropin-releasing factor, arginine vasopressin and
adrenocorticotropin as measured in pituitary venous blood from the
horse. Endocrinology 128:6572[Abstract/Free Full Text]
-
Kjær A, Knigge U, Plotsky PM, Bach FW, Warberg J 1992 Histamine H1 and H2 receptor activation
stimulates ACTH and ß-endorphin secretion by increasing
corticotropin-releasing hormone in the hypophyseal portal blood.
Neuroendocrinology 56:851855[Medline]
-
Alexander SL, Irvine CHG, Livesey JH, Donald RA 1993 The acute effect of lowering plasma cortisol on the secretion of
corticotropin-releasing hormone, arginine vasopressin, and
adrenocorticotropin as revealed by intensive sampling of pituitary
venous blood in the normal horse. Endocrinology 133:860866[Abstract/Free Full Text]
-
Alexander SL, Irvine CHG, Donald RA 1994 Short-term secretion patterns of corticotropin-releasing hormone,
arginine vasopressin and ACTH as shown by intensive sampling of
pituitary venous blood from horses. Neuroendocrinology 60:225236[Medline]
-
Liu J-P, Clarke IJ, Funder JW, Engler D 1994 Studies of the secretion of corticotropin-releasing factor and arginine
vasopressin into the hypophysial-portal circulation of the conscious
sheep. II. The central noradrenergic and neuropeptide Y pathways cause
immediate and prolonged hypothalamic-pituitary-adrenal activation.
Potential involvement in the Pseudo-Cushings syndrome of endogenous
depression and anorexia nervosa. J Clin Invest 93:14391450
-
Makara GB, Sutton S, Otto S, Plotsky PM 1995 Marked changes of arginine vasopressin, oxytocin, and
corticotropin-releasing hormone in hypophysial portal plasma after
pituitary stalk damage in the rat. Endocrinology 136:18641868[Abstract]
-
Wotjak CT, Kubota M, Liebsch G, Montkowski A, Holsboer
F, Neumann I, Landgraf R 1996 Release of vasopressin within the
rat paraventricular nucleus in response to emotional stress: a novel
mechanism of regulating adrenocorticotropic hormone secretion? J
Neurosci 16:77257732[Abstract/Free Full Text]
-
Clarke IJ, Cummins JT 1982 The temporal
relationship between gonadotropin releasing hormone (GnRH) and
luteinizing hormone (LH) secretion in ovariectomized ewes.
Endocrinology 111:17371739[Abstract/Free Full Text]
-
Irvine CHG, Alexander SL 1987 A novel technique
for measuring hypothalamic and pituitary hormone secretion rates from
collection of pituitary venous effluent in the normal horse. J
Endocrinol 113:183192[Abstract/Free Full Text]
-
Krieger HP, Krieger DT 1970 Chemical stimulation
of the brain: effect on adrenal corticoid release. Am J Physiol 218:16321641[Free Full Text]
-
Weiner RI, Ganong WF 1978 Role of brain monoamines
and histamine in regulation of anterior pituitary secretion. Physiol
Rev 58:905976[Free Full Text]
-
Ganong WF 1980 Neurotransmitters and pituitary
function: regulation of ACTH secretion. Fed Proc 39:29232930[Medline]
-
Szafarczyk A, Alonso G, Ixart G, Malaval F, Assenmacher
I 1985 Diurnal-stimulated and stress-induced ACTH release in rats
is mediated by ventral noradrenergic bundle. Am J Physiol
249:E219E226
-
Gibson A, Hart SL, Patel S 1986 Effects of
6-hydroxydopamine-induced lesions of the paraventricular nucleus, and
of prazosin, on the corticosterone response to restraint in rats.
Neuropharmacology 25:257260[CrossRef][Medline]
-
Al-Damluji S, Perry L, Tomlin S, Bouloux P, Grossman A,
Rees LH, Besser GM 1987
-Adrenergic stimulation of
corticotropin secretion by a specific central mechanism in man.
Neuroendocrinology 45:6876[CrossRef][Medline]
-
Szafarczyk A, Malaval F, Laurent A, Gibaud R,
Assenmacher I 1987 Further evidence for a central stimulatory
action of catecholamines on adrenocorticotropin release in the rat.
Endocrinology 121:883892[Abstract/Free Full Text]
-
Spinedi E, Johnston CA, Chisari A, Negro-Vilar A 1988 Role of central epinephrine on the regulation of
corticotropin-releasing factor and adrenocorticotropin secretion.
Endocrinology 122:19771983[Abstract/Free Full Text]
-
Takao T, Hashimoto K, Ota Z 1988 Central
catecholaminergic control of ACTH secretion. Regul Pept 21:301308[CrossRef][Medline]
-
Al-Damluji S 1988 Review: adrenergic mechanisms in
the control of corticotrophin secretion. J Endocrinol 119:514[Abstract/Free Full Text]
-
Al-Damluji S, Bouloux P, White A, Besser GM 1990 The role of
-2 adrenoceptors in the control of ACTH secretion:
interaction with the opioid system. Neuroendocrinology 51:7681[CrossRef][Medline]
-
Al-Damluji S, White A 1992 Central noradrenergic
lesion impairs the adrenocorticotropin response to release of
endogenous catecholamines. J Neuroendocrinol 4:319323
-
Liu J-P, Clarke IJ, Funder JW, Engler D 1991 Evidence that the central noradrenergic and adrenergic pathways
activate the hypothalamic-pituitary-adrenal axis in the sheep.
Endocrinology 129:200209[Abstract/Free Full Text]
-
Jacobs BL 1986 Single unit activity of locus
coeruleus neurons in behaving animals. Prog Neurobiol 27:183194[CrossRef][Medline]
-
Oomura Y, Ooyama H, Sugimori M, Nakamura T, Yamada
Y 1974 Glucose inhibition of the glucose-sensitive neurone in the
rat lateral hypothalamus. Nature 247:284286[CrossRef][Medline]
-
Ono T, Nishino H, Fukuda M, Sasaki K, Muramoto K,
Oomura Y 1982 Glucoresponsive neurons in rat ventromedial
hypothalamic tissue slices in vitro. Brain Res 232:494499[CrossRef][Medline]
-
Mizuno Y, Oomura Y 1984 Glucose-responding neurons
in the nucleus tractus solitarius of the rat: in vitro
study. Brain Res 307:109116[CrossRef][Medline]
-
Smythe GA, Bradshaw JE, Vining RF 1983 Hypothalamic monoamine control of stress-induced adrenocorticotropin
release in the rat. Endocrinology 113:10621071[Abstract/Free Full Text]
-
De Kloet ER, Vreugdenhil E, Oitzl MS, Joëls
M 1997 Glucocorticoid feedback resistance. Trends Endocrinol Metab 8:2633
-
Itoi K, Suda T, Tozawa F, Dobashi I, Ohmori N, Sakai Y,
Abe K, Demura H 1994 Microinjection of norepinephrine into the
paraventricular nucleus of the hypothalamus stimulates
corticotropin-releasing factor gene expression in conscious rats.
Endocrinology 135:21772182[Abstract]
-
Kiss A, Palkovits M, Aguilera G 1996 Neural
regulation of corticotropin releasing hormone (CRH) and CRH receptor
mRNA in the hypothalamic paraventricular nucleus in the rat. J
Neuroendocrinol 8:103112[CrossRef][Medline]
-
Pacak K, Palkovits M, Makino S, Kopin IJ, Goldstein
DS 1996 Brainstem hemisection decreases corticotropin-releasing
hormone mRNA in the paraventricular nucleus but not in the central
amygdaloid nucleus. J Neuroendocrinol 8:543551[CrossRef][Medline]
-
Makino S, Smith MA, Gold PW 1995 Increased
expression of corticotropin-releasing hormone and vasopressin messenger
ribonucleic acid (mRNA) in the hypothalamic paraventricular nucleus
during repeated stress: association with reduction in glucocorticoid
receptor mRNA levels. Endocrinology 136:32993309[Abstract]
-
Montminy MR, Sevarino KA, Wagner JA, Mandel G, Goodman
RH 1986 Identification of a cyclic-AMP responsive element within
the rat somatostatin gene. Proc Natl Acad Sci USA 83:66826686[Abstract/Free Full Text]
-
Montminy MR, Gonzalez GA, Yamamoto KK 1990 Characteristics of the cAMP response unit. Recent Prog Horm Res 46:219230
-
Habener JF 1990 Cyclic AMP response element
binding proteins: a cornucopia of transcription factors. Mol Endocrinol 4:10871094[Abstract/Free Full Text]
-
Lalli E, Sassone-Corsi P 1994 Signal transduction
and gene regulation: the nuclear response to cAMP. J Biol Chem 269:1735917362[Free Full Text]
-
Gonzalez GA, Montminy MR 1989 Cyclic AMP
stimulates somatostatin gene transcription by phosphorylation of CREB
at serine 133. Cell 59:675680[CrossRef][Medline]
-
Seasholtz AF, Thompson RC, Douglass JO 1988 Identification of a cyclic adenosine monophosphate-responsive element
in the rat corticotropin-releasing hormone gene. Mol Endocrinol 2:13111319[Abstract/Free Full Text]
-
Roche PJ, Crawford RJ, Fernley RT, Tregear GW, Coghlan
JP 1988 Nucleotide sequence of the gene coding for ovine
corticotropin-releasing factor and regulation of its mRNA levels by
glucocorticoids. Gene 71:421431[CrossRef][Medline]
-
Dorin RI, Takahashi H, Nakai Y, Fukata J, Naitoh Y,
Imura H 1989 Regulation of human corticotropin-releasing hormone
gene expression by 3',5'-cyclic adenosine monophosphate in a
transformed mouse corticotroph cell line. Mol Endocrinol 3:15371544[Abstract/Free Full Text]
-
Van LP, Spengler DH, Holsboer F 1990 Glucocorticoid repression of 3',5'-cyclic-adenosine
monophosphate-dependent human corticotropin-releasing hormone gene
promoter activity in a transfected mouse anterior pituitary cell line.
Endocrinology 127:14121418[Abstract/Free Full Text]
-
Adler GK, Smas CM, Fiandaca M, Frim DM, Majzoub JA 1990 Regulated expression of the human corticotropin releasing hormone
gene by cyclic AMP. Mol Cell Endocrinol 70:165174[CrossRef][Medline]
-
Vamvakopoulos NC, Karl M, Mayol V, Gomez T, Stratakis
CA, Margioris A, Chrousos GP 1990 Structural analysis of the
regulatory region of the human corticotropin releasing hormone gene.
FEBS Lett 267:15[CrossRef][Medline]
-
Spengler D, Rupprecht R, Van LP, Holsboer F 1992 Identification and characterization of a 3',5'-cyclic adenosine
monophosphate-responsive element in the human corticotropin-releasing
hormone gene promoter. Mol Endocrinol 6:19311941[Abstract/Free Full Text]
-
Itoi K, Horiba N, Tozawa F, Sakai Y, Sakai K, Abe K,
Demura H, Suda T 1996 Major role of 3',5'-cyclic adenosine
monophosphate-dependent protein kinase A pathway in
corticotropin-releasing factor gene expression in the rat hypothalamus
in vivo. Endocrinology 137:23892396[Abstract]
-
Wahlestedt C, Skagerberg G, Ekman R, Heilig M, Sundler
F, Håkanson R 1987 Neuropeptide Y (NPY) in the area of the
hypothalamic paraventricular nucleus activates the
pituitary-adrenocortical axis in the rat. Brain Res 417:3338[CrossRef][Medline]
-
Haas DA, George SR 1987 Neuropeptide Y
administration acutely increases hypothalamic corticotropin-releasing
factor immunoreactivity: lack of effect in other rat brain regions.
Life Sci 41:27252731[CrossRef][Medline]
-
Chabot J-G, Enjalbert A, Pelletier G, Dubois PM, Morel
G 1988 Evidence for a direct action of neuropeptide Y in the rat
pituitary gland. Neuroendocrinology 47:511517[Medline]
-
Tsagarakis S, Rees LH, Besser GM, Grossman A 1989 Neuropeptide-Y stimulates CRF-41 release from rat hypothalami in
vitro. Brain Res 502:167170[CrossRef][Medline]
-
Haas DA, George SR 1989 Neuropeptide Y-induced
effects on hypothalamic corticotropin-releasing factor content and
release are dependent on noradrenergic/adrenergic neurotransmission.
Brain Res 498:333338[CrossRef][Medline]
-
Inoue T, Inui A, Okita M, Sakatani N, Oya M, Morioka H,
Mizuno N, Oimomi M, Baba S 1989 Effect of neuropeptide Y on the
hypothalamic-pituitary-adrenal axis in the dog. Life Sci 44:10431051[CrossRef][Medline]
-
Inui A, Inoue T, Nakajima M, Okita M, Sakatani N,
Okimura Y, Chihara K, Baba S 1990 Brain neuropeptide Y in the
control of adrenocorticotropic hormone secretion in the dog. Brain Res 510:211215[CrossRef][Medline]
-
Suda T, Tozawa F, Iwai I, Sato Y, Sumitomo T, Nakano Y,
Yamada M, Demura H 1993 Neuropeptide-Y increases the
corticotropin-releasing factor messenger ribonucleic acid level in the
rat hypothalamus. Brain Res Mol Brain Res 18:311315[Medline]
-
Brooks AN, Howe DC, Porter DWF, Naylor AM 1994 Neuropeptide-Y stimulates pituitary-adrenal activity in fetal and adult
sheep. J Neuroendocrinol 6:161166[CrossRef][Medline]
-
Sainsbury A, Rohner-Jeanrenaud F, Grouzmann E,
Jeanrenaud B 1996 Acute intracerebroventricular administration of
neuropeptide Y stimulates corticosterone output and feeding but not
insulin output in normal rats. Neuroendocrinology 63:318326[Medline]
-
Wahlestedt C, Grundemar L, Håkanson R, Heilig M, Shen
GH, Zukowska-Grojec Z, Reis DJ 1990 Neuropeptide Y receptor
subtypes, Y1 and Y2. Ann NY Acad Sci 611:726[Medline]
-
Michel MC 1991 Receptors for neuropeptide Y:
multiple subtypes and multiple second messengers. Trends Pharmacol Sci 12:389384[CrossRef][Medline]
-
Larhammar D, Blomqvist AG, Yee F, Jazin E, Yoo H,
Wahlestedt C 1992 Cloning and functional expression of a human
neuropeptide Y/peptide YY receptor of the Y1 type. J Biol Chem 267:1093510938[Abstract/Free Full Text]
-
Herzog H, Hort YJ, Ball HJ, Hayes G, Shine J, Selbie
LA 1992 Cloned human neuropeptide Y receptor couples to two
different second messenger systems. Proc Natl Acad Sci USA 89:57945798[Abstract/Free Full Text]
-
Rose PM, Fernandes P, Lynch JS, Frazier ST, Fisher SM,
Kodukula K, Kienzle B, Seethala R 1995 Cloning and functional
expression of a cDNA encoding a human type 2 neuropeptide Y receptor.
J Biol Chem 270:2266122664[Abstract/Free Full Text]
-
Gerald C, Walker MW, Vaysse P J-J, He C, Branchek TA,
Weinshank RL 1995 Expression cloning and pharmacological
characterization of a human hippocampal neuropeptideY/peptide YY Y2
receptor subtype. J Biol Chem 270:2675826761[Abstract/Free Full Text]
-
Bard JA, Walker MW, Branchek TA, Weinshank RL 1995 Cloning and functional expression of a human Y4 subtype receptor for
pancreatic polypeptide, neuropeptide Y, and peptide YY. J Biol
Chem 270:2676226765[Abstract/Free Full Text]
-
Gerald C, Walker MW, Criscione L, Gustafson EL,
Batzl-Hartmann C, Smith KE, Vaysse P, Durkin MM, Laz TM, Linemeyer DL,
Schaffhauser AO, Whitebread S, Hofbauer KG, Taber RI, Branchek TA,
Weinshank RL 1996 A receptor subtype involved in
neuropeptide-Y-induced food intake. Nature 382:168171[CrossRef][Medline]
-
Hu Y, Bloomquist BT, Cornfield LJ, DeCarr LB,
Flores-Riveros JR, Friedman L, Jiang P, Lewis-Higgins L, Sadlowski Y,
Schaefer J, Velazquez N, McCaleb ML 1996 Identification of a novel
hypothalamic neuropeptide Y receptor associated with feeding behavior.
J Biol Chem 271:2631526319[Abstract/Free Full Text]
-
Small CJ, Morgan DGA, Meeran K, Heath MM, Gunn I,
Edwards CMB, Gardiner J, Taylor GM, Hurley JD, Rossi M, Goldstone AP,
OShea D, Smith D, Ghatei MA, Bloom SR 1997 Peptide analogue
studies of the hypothalamic neuropeptide Y receptor mediating pituitary
adrenocorticotrophic hormone release. Proc Natl Acad Sci USA 94:1168611691[Abstract/Free Full Text]
-
Parkes D, Rivest S, Lee S, Rivier C, Vale W 1993 Corticotropin-releasing factor activates c-fos, NGFI-B, and
corticotropin-releasing factor gene expression within the
paraventricular nucleus of the rat hypothalamus. Mol Endocrinol 7:13571367[Abstract/Free Full Text]
-
Uotila UU 1939 On the role of the pituitary stalk
in the regulation of the anterior pituitary, with special reference to
the thyrotrophic hormone. Endocrinology 25:605614[Abstract/Free Full Text]
-
Keller AD, Breckenridge CG 1947 Retention of
normal insulin tolerance and adrenal cortex after extirpation of the
hypophysial stalk in the dog. Am J Physiol 150:222228[Free Full Text]
-
Cheng C-P, Sayers G, Goodman LS, Swinyard CA 1949 Discharge of adrenocorticotrophic hormone in the absence of neural
connections between the pituitary and the hypothalamus. Am J
Physiol 158:4550[Free Full Text]
-
Barrnett RJ, Greep RO 1951 Regulation of secretion
of adrenotropic and thyrotropic hormone after stalk section. Am J
Physiol 167:569575[Free Full Text]
-
Tang PC, Patton HD 1951 Effect of hypophysial
stalk section on adenohypophysial function. Endocrinology 49:8698
-
Fortier C, Harris GW, McDonald IR 1957 The effect
of pituitary stalk section on the adrenocortical response to stress in
the rabbit. J Physiol 136:344363
-
Keller AD, Lynch JR, Batsel HL, Witt DM, Galvin RD 1954 Anatomical and functional integrity of adrenal cortices not
dependent on structural integrity of ventral hypothalamus. Retention of
eosinopenic response to surgery after ventral hypothalamectomy in the
dog. Am J Physiol 179:514[Free Full Text]
-
Egdahl RH 1960 Adrenal cortical and medullary
responses to trauma in dogs with isolated pituitaries. Endocrinology 66:200216
-
Egdahl RH 1961 Corticosteroid secretion following
caval constriction in dogs with isolated pituitaries. Endocrinology 68:226231
-
Egdahl RH 1962 Further studies on adrenal cortical
function in dogs with isolated pituitaries. Endocrinology 71:926935[Abstract/Free Full Text]
-
Halász B, Pupp L 1965 Hormone secretion of
the anterior pituitary gland after physical interruption of all nervous
pathways to the hypophysiotrophic area. Endocrinology 77:553562[Abstract/Free Full Text]
-
Halász B, Slusher MA, Gorski RA 1967 Adrenocorticotrophic hormone secretion in rats after partial or total
deafferentation of the medial basal hypothalamus. Neuroendocrinology 2:4355
-
Halász B, Vernikos-Danellis J, Gorski RA 1967 Pituitary ACTH content in rats after partial or total interruption
of neural afferents to the medial basal hypothalamus. Endocrinology 81:921924[Abstract/Free Full Text]
-
Kendall JW, Roth JG 1969 Adrenocortical function
in monkeys after forebrain removal or pituitary stalk section.
Endocrinology 84:686691[Abstract/Free Full Text]
-
Krey LC, Butler WR, Knobil E 1975 Surgical
disconnection of the medial basal hypothalamus and pituitary function
in the rhesus monkey. I. Gonadotropin secretion. Endocrinology 96:10731087[Abstract/Free Full Text]
-
Krey LC, Lu K-H, Butler WR, Hotchkiss J, Piva F, Knobil
E 1975 Surgical disconnection of the medial basal hypothalamus and
pituitary function in the rhesus monkey. II. GH and cortisol secretion.
Endocrinology 96:10881093[Abstract/Free Full Text]
-
Butler WR, Krey LC, Lu K-H, Peckham WD, Knobil E 1975 Surgical disconnection of the medial basal hypothalamus and
pituitary function in the rhesus monkey. IV. Prolactin secretion.
Endocrinology 96:10991105[Abstract/Free Full Text]
-
Ferin M, Antunes JL, Zimmerman E, Dyrenfurth I, Frantz
AG, Robinson A, Carmel PW 1977 Endocrine function in female rhesus
monkeys after hypothalamic disconnection. Endocrinology 101:16111620[Abstract/Free Full Text]
-
Vaughan L, Carmel PW, Dyrenfurth I, Frantz AG, Antunes
JL, Ferin M 1980 Section of the pituitary stalk in the rhesus
monkey. Endocrine studies. Neuroendocrinology 30:7075[Medline]
-
Antunes JL, Louis K, Cogen P, Zimmerman EA, Ferin
M 1980 Section of the pituitary stalk in the rhesus monkey. II.
Morphological studies. Neuroendocrinology 30:7682[Medline]
-
Clarke IJ, Cummins JT, de Kretser DM 1983 Pituitary gland function after disconnection from direct hypothalamic
influences in the sheep. Neuroendocrinology 36:376384[Medline]
-
Clarke IJ, Clements JA, Cummins JT, Dench F, Smith AI,
Robinson PM, Funder JW 1986 Elevated plasma levels of POMC-derived
peptides in sheep following hypothalamo-pituitary disconnection.
Neuroendocrinology 44:508514[Medline]
-
Engler D, Pham T, Fullerton MJ, Funder JW, Clarke
IJ 1988 Studies of the regulation of the
hypothalamic-pituitary-adrenal axis in sheep with
hypothalamic-pituitary-disconnection. I. Effect of an audiovisual
stimulus and insulin-induced hypoglycemia. Neuroendocrinology 48:551560[Medline]
-
Frantz AG 1978 Prolactin. N Engl J Med 298:201207[Medline]
-
Neill JD 1980 Neuroendocrine regulation of
prolactin secretion. In: Martini L, Ganong WF (eds) Frontiers in
Neuroendocrinology. Raven Press, New York, pp 129155
-
Abe H, Engler D, Molitch ME, Bollinger-Gruber J,
Reichlin S 1985 Vasoactive intestinal peptide is a physiological
mediator of prolactin release in the rat. Endocrinology 116:13831390[Abstract/Free Full Text]
-
Thomas GB, Cummins JT, Cavanagh L, Clarke IJ 1986 Transient increase in prolactin secretion following
hypothalamo-pituitary disconnection in ewes during anoestrus and the
breeding season. J Endocrinol 111:425431[Abstract/Free Full Text]
-
Ben-Jonathan N 1985 Dopamine: a prolactin
inhibiting hormone. Endocr Rev 6:564589[Abstract/Free Full Text]
-
Samson WK, Lumpkin MD, McCann SM 1986 Evidence for
a physiological role for oxytocin in the control of prolactin
secretion. Endocrinology 119:554560[Abstract/Free Full Text]
-
Lamberts SWJ, Macleod RM 1990 Regulation of
prolactin secretion at the level of the lactotroph. Physiol Rev 70:279318[Free Full Text]
-
Hinuma S, Habata Y, Fujii R, Kawamata Y, Hosoya M,
Fukusumi S, Kitada C, Masuo Y, Asano T, Matsumoto H, Sekiguchi M,
Kurokawa T, Nishimura O, Onda H, Fujino M 1998 A
prolactin-releasing peptide in the brain. Nature 393:272276[CrossRef][Medline]
-
Engler D, Pham T, Liu J-P, Fullerton MJ, Clarke IJ,
Funder JW 1990 Studies of the regulation of the
hypothalamic-pituitary-adrenal axis in sheep with
hypothalamic-pituitary-disconnection. II. Evidence for in
vivo ultradian hypersecretion of proopiomelanocortin peptides by
the isolated anterior and intermediate pituitary. Endocrinology 127:19561966[Abstract/Free Full Text]
-
Carnes M, Lent SJ, Goodman B, Mueller C, Saydoff J,
Erisman S 1990 Effects of immunoneutralization of
corticotropin-releasing hormone on ultradian rhythms of plasma
adrenocorticotropin. Endocrinology 126:19041913[Abstract/Free Full Text]
-
Boyle LL, Brownfield MS, Lent SJ, Goodman B, Vo-Hill H,
Litwin J, Carnes M 1997 Intensive venous sampling of
adrenocorticotropic hormone in rats with sham or paraventricular
nucleus lesions. J Endocrinol 153:159167[Abstract/Free Full Text]
-
Mercer JE, Clements JA, Clarke IJ, Funder J 1989 Glucocorticoid regulation of proopiomelanocortin gene expression in the
pituitary gland of hypothalamopituitary intact and hypothalamopituitary
disconnected sheep. Neuroendocrinology 50:280285[Medline]
-
Antolovich GC, Clarke IJ, McMillen IC, Perry RA,
Robinson PM, Silver M, Young R 1990 Hypothalamo-pituitary
disconnection in the fetal sheep. Neuroendocrinology 51:19[Medline]
-
Ozolins IZ, Young R, McMillen IC 1990 Effect of
cortisol infusion on basal and corticotropin-releasing factor
(CRF)-stimulated plasma ACTH concentrations in the sheep fetus after
surgical isolation of the pituitary. Endocrinology 127:18331840[Abstract/Free Full Text]
-
Antolovich GC, McMillen IC, Robinson PM, Silver M,
Young IR, Perry RA 1991 The effect of hypothalamo-pituitary
disconnection on the functional and morphological development of the
pituitary-adrenal axis in the fetal sheep in the last third of
gestation. Neuroendocrinology 54:254261[Medline]
-
Ozolins IZ, Young IR, McMillen IC 1992 Surgical
disconnection of the hypothalamus from the fetal pituitary abolishes
the corticotrophic response to intrauterine hypoglycemia or hypoxemia
in the sheep during late gestation. Endocrinology 130:24382445[Abstract/Free Full Text]
-
Antolovich GC, McMillen IC, Robinson PM, Silver M,
Young IR, Perry RA 1992 Effect of cortisol infusion on the
pituitary-adrenal axis of the hypothalamo-pituitary-disconnected sheep.
Neuroendocrinology 56:312319[Medline]
-
Deayton JM, Young IR, Hollingworth SA, White A, Crosby
SR, Thorburn GD 1994 Effect of late hypothalamo-pituitary
disconnection on the development of the HPA axis in the ovine fetus and
the initiation of parturition. J Neuroendocrinol 6:2531[CrossRef][Medline]
-
Briggs FN, Munson PL 1955 Studies on the mechanism
of stimulation of ACTH secretion with the aid of morphine as a blocking
agent. Endocrinology 57:205219
-
George R, Way EL 1959 The role of the hypothalamus
in pituitary-adrenal activation and antidiuresis by morphine. J
Pharmacol Exp Ther 125:111115[Abstract/Free Full Text]
-
McDonald RK, Evans FT, Weise VK, Patrick RW 1959 Effect of morphine and nalorphine on plasma hydrocortisone levels in
man. J Pharmacol Exp Ther 125:241247[Abstract/Free Full Text]
-
Stubbs WA, Delitala G, Jones A, Jeffcoate WJ, Edwards
CRW, Ratter SJ, Besser GM, Bloom SR, Alberti KGMM 1978 Hormonal
and metabolic responses to an enkephalin analogue in normal man. Lancet 2:12251227[CrossRef][Medline]
-
Volavka J, Cho D, Mallya A, Bauman J 1979 Naloxone increases ACTH and cortisol levels in man. N Engl J
Med 300:10561057[Medline]
-
Pittman QJ, Hatton JD, Bloom SR 1980 Morphine and
opioid peptides reduce paraventricular neuronal activity: studies on
the hypothalamic slice preparation. Proc Natl Acad Sci USA 77:55275531[Abstract/Free Full Text]
-
Morley JE, Baranetsky NG, Wingert TD, Carlson HE,
Hershman JM, Melmed S, Levin SR, Jamison KR, Weitzman R, Chang RJ,
Varner AA 1980 Endocrine effects of naloxone-induced opiate
receptor blockade. J Clin Endocrinol Metab 50:251257[Abstract/Free Full Text]
-
Spiler IJ, Molitch ME 1980 Lack of modulation of
pituitary hormone stress response by neural pathways involving opiate
receptors. J Clin Endocrinol Metab 50:516520[Abstract/Free Full Text]
-
Eisenberg RM 1980 Effects of naloxone on plasma
corticosterone in the opiate-naive rat. Life Sci 26:935943[CrossRef][Medline]
-
Tapp WN, Mittler JC, Natelson BH 1981 Effects of
naloxone on corticosterone response to stress. Pharmacol Biochem Behav 14:749751[CrossRef][Medline]
-
Morley JE 1981 The endocrinology of the opiates
and opioid peptides. Metabolism 30:195209[CrossRef][Medline]
-
Buckingham JC 1982 Secretion of corticotrophin and
its hypothalamic releasing factor in response to morphine and opioid
peptides. Neuroendocrinology 35:111116[CrossRef][Medline]
-
Grossman A, Gaillard RC, McCartney P, Rees LH, Besser
GM 1982 Opiate modulation of the pituitary-adrenal axis: effects
of stress and circadian rhythm. Clin Endocrinol (Oxf) 17:279286[Medline]
-
Siegel RA, Chowers I, Conforti N, Feldman S, Weidenfeld
J 1982 Effects of naloxone on basal and stress-induced ACTH and
corticosterone secretion in the male rat-site and mechanism of action.
Brain Res 249:103109[CrossRef][Medline]
-
Delitala G, Grossman A, Besser GM 1983 Differential effects of opiate peptides and alkaloids on anterior
pituitary hormone secretion. Neuroendocrinology 37:275279[Medline]
-
Taylor T, Dluhy RG, Williams GH 1983 ß-Endorphin
suppresses adrenocorticotropin and cortisol levels in normal human
subjects. J Clin Endocrinol Metab 57:592596[Abstract/Free Full Text]
-
Zis AP, Haskett RF, Albala AA, Carroll BJ 1984 Morphine inhibits cortisol and stimulates prolactin secretion in man.
Psychoneuroendocrinology 9:423427[CrossRef][Medline]
-
Rittmaster RS, Cutler Jr GB, Sobel DG, Goldstein DS,
Koppelman MCS, Loriaux DL, Chrousos GP 1985 Morphine inhibits the
pituitary-adrenal response to ovine corticotropin-releasing hormone in
normal subjects. J Clin Endocrinol Metab 60:891895[Abstract/Free Full Text]
-
Pfeiffer A, Herz A, Loriaux DL, Pfeiffer DG 1985 Central
- and µ-opiate receptors mediate ACTH-release in rats.
Endocrinology 116:26882690[Abstract/Free Full Text]
-
Grossman A, Moult PJA, Cunnah D, Besser M 1986 Different opioid mechanisms are involved in the modulation of ACTH and
gonadotrophin release in man. Neuroendocrinology 42:357360[Medline]
-
Plotsky PM 1986 Opioid inhibition of
immunoreactive corticotropin-releasing factor secretion into the
hypophysial-portal circulation of rats. Regul Pept 16:235242[CrossRef][Medline]
-
Yajima F, Suda T, Tomori N, Sumitomo T, Nakagami Y,
Ushiyama T, Demura H, Shizume K 1986 Effects of opioid
peptides on immunoreactive corticotropin-releasing factor release from
the rat hypothalamus in vitro. Life Sci 39:181186[CrossRef][Medline]
-
Koenig JI, Meltzer HY, Devane GD, Gudelsky
GA 1986 The concentration of arginine vasopressin in pituitary
stalk plasma of the rat after adrenalectomy or morphine. Endocrinology 118:25342539[Abstract/Free Full Text]
-
Grossman A, Delitala A, Mannelli M, Al-Damluji S, Coy
DH, Besser GM 1986 An analogue of met-enkephalin attenuates the
pituitary-adrenal axis response to ovine corticotrophin-releasing
factor. Clin Endocrinol (Oxf) 25:421426[Medline]
-
Allolio B, Schulte HM, Deuss U, Kallabis D, Hamel E,
Winkelman W 1987 Effect of oral morphine and naloxone on
pituitary-adrenal response in man induced by human
corticotropin-releasing hormone. Acta Endocrinol (Copenh) 114:509514[Abstract/Free Full Text]
-
Nikolarakis K, Pfeiffer A, Stalla GK, Herz A 1987 The role of CRF in the release of ACTH by opiate agonists and
antagonists in rats. Brain Res 421:373376[CrossRef][Medline]
-
Tsagarakis S, Navara P, Rees LH, Besser M, Grossman
A 1989 Morphine directly modulates the release of stimulated
corticotrophin-releasing factor-41 from rat hypothalamus in
vitro. Endocrinology 124:23302335[Abstract/Free Full Text]
-
Cover PO, Buckingham JC 1989 Effects of selective
opioid-receptor blockade on the hypothalamo-pituitary-adrenocortical
responses to surgical trauma in the rat. J Endocrinol 121:213220[Abstract/Free Full Text]
-
Sheward WJ, Coombes JE, Bicknell RJ, Fink G, Russell
JA 1990 Release of oxytocin but not corticotrophin-releasing
factor-41 into rat hypophysial portal vessel blood can be made opiate
dependent. J Endocrinol 124:141150[Abstract/Free Full Text]
-
Tsagarakis S, Rees LH, Besser M, Grossman A 1990 Opiate receptor subtype regulation of CRF-41 release from rat
hypothalamus in vitro. Neuroendocrinology 51:599605[Medline]
-
Delitala G, Trainer PJ, Oliva O, Fanciulli G, Grossman
AB 1994 Opioid peptide and
-adrenoceptor pathways in the
regulation of the pituitary-adrenal axis in man. J Endocrinol 141:163168[Abstract/Free Full Text]
-
Alexander SL, Irvine CHG 1995 The effect of
naloxone administration on the secretion of corticotropin-releasing
hormone, arginine vasopressin, and adrenocorticotropin in unperturbed
horses. Endocrinology 136:51395147[Abstract]
-
Porter JC, Mical RS, Ben-Jonathan N, Ondo JG 1973 Neurovascular regulation of the anterior hypophysis. Recent Prog Horm
Res 29:161198
-
Page RB, Bergland RM 1977 The neurohypophyseal
capillary bed. I. Anatomy and blood supply. Am J Anat 148:345351[CrossRef][Medline]
-
Saffran M, Schally AV 1955 The release of
corticotrophin by anterior pituitary tissue in vitro. Can
J Biochem Physiol 33:408415
-
McCann SM 1957 The ACTH-releasing activity of
extracts of the posterior lobe of the pituitary in vivo.
Endocrinology 60:664676
-
Itoh S, Nishimura Y, Yamamoto M, Takahashi H 1964 Adrenocortical response to epinephrine in neurohypophysectomized rats.
Jpn J Physiol 14:177187
-
Arimura A, Yamaguchi T, Yoshimura K, Imazeki T, Itoh
S 1965 Role of the neurohypophysis in the release of
adrenocorticotrophic hormone in the rat. Jpn J Physiol 15:278295
-
Baertschi AJ, Vallet P, Baumann JB, Girard J 1980 Neural lobe of pituitary modulates corticotropin release in the rat.
Endocrinology 106:878882[Abstract/Free Full Text]
-
Fagin KD, Wiener SG, Dallman MF 1985 ACTH and
corticosterone secretion in rats following removal of the
neurointermediate lobe of the pituitary gland. Neuroendocrinology 40:352362[Medline]
-
Thomas GB, Cummins JT, Canny BJ, Rundle SE, Griffin N,
Katsahambas S, Clarke IJ 1989 The posterior pituitary regulates
prolactin, but not adrenocorticotropin or gonadotropin, secretion in
the sheep. Endocrinology 125:22042211[Abstract/Free Full Text]
-
Sayers G, Hanzmann E, Bodanszky M 1980 Hypothalamic peptides influencing secretion of ACTH by isolated
adenohypophysial cells. Two corticotrophin releasing factors and a
potentiator. FEBS Lett 116:236238[CrossRef][Medline]
-
Gillies GE, Puri A, Linton EA, Lowry PJ 1984 Comparative chromatography of hypothalamic corticotrophin-releasing
factors. Neuroendocrinology 38:1724[Medline]
-
Rédei E, Endröczi E 1983 Hypothalamic
factor of inhibitory activity on pituitary adrenocortical function. In:
Endröczi E, de Wied D, Angelucci L, Scapagnini U (eds)
Developments in Neuroscience: Integrative Neurohumoral Mechanisms.
Elsevier, Amsterdam, vol 16:377383
-
Redei E, Evans CJ 1989 Dual control of
corticotropin secretion: Isolation of corticotropin-inhibiting factor.
In: Taché Y, Morley JE, Brown MR (eds) Neuropeptides and Stress.
Springer-Verlag, New York, pp 6172
-
Bunzow JR, Van Tol HHM, Grandy DK, Albert P,
Salon J, Christie M, Machida CA, Neve KA, Civelli O 1988 Cloning
and expression of a rat D2 dopamine receptor cDNA. Nature 336:783787[CrossRef][Medline]
-
Straub RE, Frech GC, Joho RH, Gershengorn MC 1990 Expression cloning of a cDNA encoding the mouse pituitary
thyrotropin-releasing hormone receptor. Proc Natl Acad Sci USA 87:95149518[Abstract/Free Full Text]
-
Pisegna JR, Wank SA 1993 Molecular cloning and
functional expression of the pituitary adenylate cyclase-activating
polypeptide type I receptor. Proc Natl Acad Sci USA 90:63456349[Abstract/Free Full Text]
-
Mayo KE, Miller TL, DeAlmeida V, Zheng J, Godfrey
PA 1996 The growth-hormone-releasing hormone receptor: signal
transduction, gene expression, and physiological function in growth
regulation. Ann NY Acad Sci 805:184203[Medline]
-
Fehm HL, Voigt KH, Lang R, Beinert KE, Raptis S,
Pfeiffer EF 1976 Somatostatin: a potent inhibitor of
ACTH-hypersecretion in adrenal insufficiency. Klin Wochenschr 54:173175[CrossRef][Medline]
-
Voigt KH, Fehm HL, Lang RE, Walter R 1977 The
effect of somatostatin and of prolyl-leucyl-glycinamide (MIF) on ACTH
release in dispersed pituitary cells. Life Sci 21:739746[CrossRef][Medline]
-
Abe H, Kato Y, Chiba T, Taminato T, Fujita T 1978 Plasma immunoreactive somatostatin levels in rat hypophysial portal
blood: effect of glucagon administration. Life Sci 23:16471654[CrossRef][Medline]
-
Chihara K, Arimura A, Schally AV 1979 Immunoreactive somatostatin in rat hypophyseal portal blood: effects of
anesthetics. Endocrinology 104:14341441[Abstract/Free Full Text]
-
Finley JCW, Maderdrut JL, Roger LJ, Petrusz P 1981 The immunocytochemical localization of somatostatin-containing neurons
in the rat central nervous system. Neuroscience 6:21732192[CrossRef][Medline]
-
Richardson UI, Schonbrunn A 1981 Inhibition of
adrenocorticotropin secretion by somatostatin in pituitary cells in
culture. Endocrinology 108:281290[Abstract/Free Full Text]
-
Heisler S, Reisine TD, Hook VYH, Axelrod J 1982 Somatostatin inhibits multireceptor stimulation of cyclic AMP formation
and corticotropin secretion in mouse pituitary tumor cells. Proc Natl
Acad Sci USA 79:65026506[Abstract/Free Full Text]
-
Schlegel W, Wuarin F, Wollheim CB, Zahnd G 1984 Somatostatin lowers the cytosolic free Ca2+ concentration
in clonal rat pituitary cells (GH3 cells). Cell Calcium 5:223236[CrossRef][Medline]
-
Brown MR, Rivier C, Vale W 1984 Central nervous
system regulation of adrenocorticotropin secretion: role of
somatostatins. Endocrinology 114:15461549[Abstract/Free Full Text]
-
Nicholson SA, Adrian TE, Gillham B, Jones MT, Bloom
SR 1984 Effect of hypothalamic neuropeptides on corticotrophin
release from quarters of rat anterior pituitary gland in
vitro. J Endocrinol 100:219226[Abstract/Free Full Text]
-
Kraicer J, Gajewski TC, Moor BC 1985 Release of
pro-opiomelanocortin-derived peptides from the pars intermedia and pars
distalis of the rat pituitary: effect of corticotrophin-releasing
factor and somatostatin. Neuroendocrinology 41:363373[Medline]
-
Plotsky PM, Vale W 1985 Patterns of growth
hormone-releasing factor and somatostatin secretion into the
hypophysial-portal circulation of the rat. Science 230:461463[Abstract/Free Full Text]
-
Luini A, Lewis D, Guild S, Schofield G, Weight F 1986 Somatostatin, an inhibitor of ACTH secretion, decreases cytosolic
free calcium and voltage-dependent calcium current in a pituitary cell
line. J Neurosci 6:31283132[Abstract]
-
Petraglia F, Facchinetti F, DAmbrogio G, Volpe A,
Genazzani AR 1986 Somatostatin and oxytocin infusion inhibits the
rise of plasma ß-endorphin, ß-lipotrophin and cortisol induced by
insulin hypoglycemia. Clin Endocrinol (Oxf) 24:609616[Medline]
-
Lamberts SWJ 1988 The role of somatostatin in the
regulation of anterior pituitary hormone secretion and the use of its
analogs in the treatment of human pituitary tumors. Endocr Rev 9:417436[Abstract/Free Full Text]
-
Stafford PJ, Kopelman PG, Davidson K, McLoughlin L,
White A, Rees LH, Besser GM, Coy DH, Grossman A 1989 The
pituitary-adrenal response to CRF-41 is unaltered by intravenous
somatostatin in normal subjects. Clin Endocrinol (Oxf) 30:661666[Medline]
-
Lamberts SW, Zuyderwijk J, den Holder F, van Koetsveld
P, Hofland L 1989 Studies on the conditions determining the
inhibitory effect of somatostatin on adrenocorticotropin, prolactin and
thyrotropin release by cultured rat pituitary cells. Neuroendocrinology 50:4450[Medline]
-
Frohman LA, Downs TR, Clarke IJ, Thomas GB 1990 Measurement of growth hormone-releasing hormone and somatostatin in
hypothalamic-portal plasma of unanesthetized sheep. Spontaneous
secretion and response to insulin-induced hypoglycemia. J Clin
Invest 86:1724
-
Bell GI, Reisine T 1993 Molecular biology of
somatostatin receptors. Trends Neurol Sci 16:3438[CrossRef][Medline]
-
Patel YC, Panetta R, Escher E, Greenwood M, Srikant
CB 1994 Expression of multiple somatostatin receptor genes in
AtT-20 cells. J Biol Chem 269:15061509[Abstract/Free Full Text]
-
Patel YC, Greenwood MT, Panetta R, Demchyshyn L, Niznik
H, Srikant CB 1995 The somatostatin receptor family. Life Sci 57:12491265[CrossRef][Medline]
-
OCarroll A-M, Krempels K 1995 Widespread
distribution of somatostatin receptor messenger ribonucleic acids in
rat pituitary. Endocrinology 136:52245227[Abstract]
-
Björklund A, Moore RY, Nobin A, Stenevi U 1973 The organization of tubero-hypophyseal and reticulo-infundibular
catecholamine neuron systems in the rat brain. Brain Res 51:171191[CrossRef][Medline]
-
Ben-Jonathan N, Oliver C, Weiner HJ, Mical RS,
Porter JC 1977 Dopamine in hypophysial portal plasma of the rat
during the estrous cycle and throughout pregnancy. Endocrinology 100:452458[Abstract/Free Full Text]
-
Gibbs DM, Neill JD 1978 Dopamine levels in
hypophysial stalk blood in the rat are sufficient to inhibit prolactin
secretion in vivo. Endocrinology 102:18951900[Abstract/Free Full Text]
-
Caron MG, Beaulieu M, Raymond JV, Gagné B, Drouin
J, Lefkowitz RJ, Labrie F 1978 Dopaminergic receptors in the
anterior pituitary gland. Correlation of
[3H]dihydroergocryptine binding with the dopaminergic
control of prolactin release. J Biol Chem 253:22442253[Free Full Text]
-
Kennedy AL, Sheridan B, Montgomery DAD 1978 ACTH
and cortisol responses to bromocriptine, and results of long-term
therapy in Cushings disease. Acta Endocrinol (Copenh) 89:461468[Abstract/Free Full Text]
-
Gudelsky GA, Porter JC 1979 Release of newly
synthesized dopamine into the hypophysial portal vasculature of the
rat. Endocrinology 104:583587[Abstract/Free Full Text]
-
Goldsmith PC, Cronin MJ, Weiner RI 1979 Dopamine
receptor sites in the anterior pituitary. J Histochem Cytochem 27:12051207[Abstract]
-
Ben-Jonathan N, Neill MA, Arbogast LA, Peters LL,
Hoefer MT 1980 Dopamine in hypophysial portal blood: relationship
to circulating prolactin in pregnant and lactating rats. Endocrinology 106:690696[Abstract/Free Full Text]
-
Tam SW, Dannies PS 1980 Dopaminergic inhibition of
ionophore A23187-stimulated release of prolactin from rat anterior
pituitary cells. J Biol Chem 255:65956599[Free Full Text]
-
Foord SM, Peters J, Scanlon MF, Rees Smith B, Hall
R 1980 Dopaminergic control of TSH secretion in isolated rat
pituitary cells. FEBS Lett 121:257259[CrossRef][Medline]
-
Lamberts SWJ, Klijn JGM, de Quijada M, Timmermans HAT,
Uitterlinden P, de Jong FH, Birkenhäger JC 1980 The
mechanism of the suppressive action of bromocriptine on
adrenocorticotropin secretion in patients with Cushings disease and
Nelsons syndrome. J Clin Endocrinol Metab 51:307311[Abstract/Free Full Text]
-
Ishibashi M, Yamaji T 1981 Direct effects of
thyrotropin-releasing hormone, cyproheptadine, and dopamine on
adrenocorticotropin secretion from human corticotroph adenoma cells
in vitro. J Clin Invest 68:10181027
-
Sibley DR, De Lean A, Creese A 1982 Anterior
pituitary dopamine receptors. Demonstration of interconvertible high
and low affinity states of the D-2 dopamine receptor. J Biol Chem 257:63516361[Abstract/Free Full Text]
-
Swennen L, Denef C 1982 Physiological
concentrations of dopamine decrease adenosine 3',5'-monophosphate
levels in cultured rat anterior pituitary cells and enriched
populations of lactotrophs: evidence for a causal relationship to
inhibition of prolactin release. Endocrinology 111:398405[Abstract/Free Full Text]
-
Schettini G, Cronin MJ, Macleod RM 1983 Adenosine
3',5'-monophosphate (cAMP) and calcium-calmodulin interrelation in the
control of prolactin secretion: evidence for dopamine inhibition of
cAMP accumulation and prolactin release after calcium mobilization.
Endocrinology 112:18011807[Abstract/Free Full Text]
-
Reymond MJ, Speciale SG, Porter JC 1983 Dopamine
in plasma of lateral and medial hypophysial portal vessels: evidence
for regional variation in the release of hypothalamic dopamine into
hypophysial portal blood. Endocrinology 112:19581963[Abstract/Free Full Text]
-
Canonico PL, Valdenegro CA, Macleod RM 1983 The
inhibition of phosphatidylinositol turnover: a possible postreceptor
mechanism for the prolactin secretion-inhibiting effect of dopamine.
Endocrinology 113:714[Abstract/Free Full Text]
-
de Bold AJ, Borenstein HB, Veress AT, Sonnenberg H 1981 A rapid and potent natriuretic response to intravenous injection
of atrial myocardial extract in rats. Life Sci 28:8994[CrossRef][Medline]
-
Sonnenberg H, Cupples WA, de Bold AJ, Veress AT 1982 Intrarenal localization of the natriuretic effect of cardiac
atrial extract. Can J Physiol Pharmacol 60:11491152[Medline]
-
Flynn TG, de Bold ML, de Bold AJ 1983 The amino
acid sequence of an atrial peptide with potent diuretic and natriuretic
properties. Biochem Biophys Res Commun 117:859865[CrossRef][Medline]
-
Yamanaka M, Greenberg B, Johnson L, Seilhamer J, Brewer
M, Friedemann T, Miller J, Atlas S, Laragh J, Lewicki J, Fiddes J 1984 Cloning and sequence analysis of the cDNA for the rat atrial
natriuretic factor precursor. Nature 309:719722[CrossRef][Medline]
-
Maki M, Takayanagi R, Misono KS, Pandey KN, Tibbetts C,
Inagami T 1984 Structure of rat atrial natriuretic factor
precursor deduced from cDNA sequence. Nature 309:722724[CrossRef][Medline]
-
Oikawa S, Imai M, Ueno A, Tanaka S, Noguchi T, Nakazato
H, Kangawa K, Fukuda A, Matsuo H 1984 Cloning and sequence
analysis of cDNA encoding a precursor for human atrial natriuretic
polypeptide. Nature 309:724726[CrossRef][Medline]
-
Kangawa K, Tawaragi Y, Oikawa S, Mizuno A, Sakuragawa
Y, Nakazato H, Fukuda A, Minamino N, Matsuo H 1984 Identification
of rat
-atrial natriuretic polypeptide and characterization of the
cDNA encoding its precursor. Nature 312:152155[CrossRef][Medline]
-
Currie MG, Geller DM, Cole BR, Siegel NR, Fok KF, Adams
SP, Eubanks SR, Galluppi GR, Needleman P 1984 Purification and
sequence analysis of bioactive atrial peptides (Atriopeptins). Science 223:6769[Abstract/Free Full Text]
-
Seidah NG, Lazure C, Chrétien M, Thibault G,
Garcia R, Cantin M, Genest J, Nutt RF, Brady SF, Lyle TA, Paleveda WJ,
Colton CD, Ciccarone TM, Veber DF 1984 Amino acid sequence of
homologous rat atrial peptides: natriuretic activity of native and
synthetic forms. Proc Natl Acad Sci USA 81:26402644[Abstract/Free Full Text]
-
Quirion R, Dalpé M, De Lean A, Gutkowska J,
Cantin M, Genest M 1984 Atrial natriuretic factor (ANF) binding
sites in brain and related structures. Peptides 5:11671172[CrossRef][Medline]
-
Kawata M, Nakao K, Morii N, Kiso Y, Yamashita H, Imura
H, Sano Y 1985 Atrial natriuretic polypeptide:topographical
distribution in the rat brain by radioimmunoassay and
immunohistochemistry. Neuroscience 16:521546[CrossRef][Medline]
-
Skofitsch G, Jacobowitz DM, Eskay RL, Zamir N 1985 Distribution of atrial natriuretic factor-like immunoreactive neurons
in the rat brain. Neuroscience 16:917948[CrossRef][Medline]
-
Schwartz D, Geller DM, Manning PT, Siegel NR, Fok KF,
Smith CE, Needleman P 1985 Ser-Leu-Arg-Arg-Atriopeptin III: the
major circulating form of atrial peptide. Science 229:397400[Abstract/Free Full Text]
-
Miyata A, Kangawa K, Toshimori T, Hatoh T, Matsuo
H 1985 Molecular forms of atrial natriuretic polypeptide in
mammalian tissues and plasma. Biochem Biophys Res Commun 129:248255[CrossRef][Medline]
-
Yamaji T, Ishibashi M, Takaku F 1985 Atrial
natriuretic factor in human blood. J Clin Invest 76:17051709
-
Lang RE, Thölken H, Ganten D, Luft FC, Ruskoaho
H, Unger Th 1985 Atrial natriuretic factor-a circulating hormone
stimulated by volume loading. Nature 314:264266[CrossRef][Medline]
-
Shiono S, Nakao K, Morii N, Yamada T, Itoh H, Sakamoto
M, Sugawara A, Saito Y, Katsuura G, Imura H 1986 Nature of atrial
natriuretic polypeptide in rat brain. Biochem Biophys Res Commun 135:728734[CrossRef][Medline]
-
Standaert DG, Needleman P, Saper CB 1986 Organization of atriopeptin-like immunoreactive neurons in the central
nervous system of the rat. J Comp Neurol 253:315341[CrossRef][Medline]
-
Shibasaki T, Naruse M, Yamauchi N, Masuda A, Imaki T,
Naruse K, Demura H, Ling N, Inagami T, Shizume K 1986 Rat atrial
natriuretic factor suppresses proopiomelanocortin-derived peptides
secretion from both anterior and intermediate lobe cells and growth
hormone release from anterior lobe cells of rat pituitary in
vitro. Biochem Biophys Res Commun 136:10351041
-
Simard J, Hubert J-F, Labrie F, Israël-Assayag E,
Heisler S 1986 Atrial natriuretic factor-induced cGMP accumulation
in rat anterior pituitary cells in culture is not coupled to hormonal
secretion. Regul Pept 15:269278[CrossRef][Medline]
-
Heisler S, Simard J, Assayag E, Mehri Y, Labrie F 1986 Atrial natriuretic factor does not affect basal, forskolin- and
CRF-stimulated adenylate cyclase activity, cAMP formation or ACTH
secretion, but does stimulate cGMP synthesis in anterior pituitary. Mol
Cell Endocrinol 44:125131[CrossRef][Medline]
-
Hashimoto K, Hattori T, Suemaru S, Sugawara M, Takao T,
Kageyama J, Ota Z 1987 Atrial natriuretic peptide does not affect
corticotropin-releasing factor-, arginine vasopressin- and angiotensin
II-induced adrenocorticotropic hormone release in vivo or
in vitro. Regul Pept 17:5360[CrossRef][Medline]
-
Abou-Samra A-B, Catt KJ, Aguilera G 1987 Synthetic
atrial natriuretic factors (ANFs) stimulate guanine 3',5'-monophosphate
production but not hormone release in rat pituitary cells: peptide
contamination with a gonadotropin-releasing hormone agonist explains
luteinizing hormone-releasing activity of certain ANFs. Endocrinology 120:1824[Abstract/Free Full Text]
-
Koch B, Boujada T, Lutz-Bucher B 1988 Characterization of high affinity receptor sites for atrial natriuretic
factor in anterior pituitary gland: evidence for the existence of two
receptor forms. Biochem Biophys Res Commun 152:904909[CrossRef][Medline]
-
Antoni F, Dayanithi G 1989 Guanosine 3':5':cyclic
monophosphate and activators of guanylate cyclase inhibit
secretagogue-induced corticotropin release by rat anterior pituitary
cells. Biochem Biophys Res Commun 158:824830[CrossRef][Medline]
-
King MS, Baertschi AJ 1989 Physiological
concentrations of atrial natriuretic factors with intact N-terminal
sequences inhibit corticotropin-releasing factor-stimulated
adrenocorticotropin secretion from cultured anterior pituitary cells.
Endocrinology 124:286292[Abstract/Free Full Text]
-
Lim AT, Sheward WJ, Copolov D, Windmill D, Fink
G 1990 Atrial natriuretic factor is released into hypophysial
portal blood: direct evidence that atrial natriuretic factor may be a
neurohormone involved in hypothalamic pituitary control. J
Neuroendocrinol 2:1518[CrossRef][Medline]
-
Lim AT, Dean B, Copolov D 1990 Evidence for
post-translational processing of auriculin B to atriopeptin III
immediately prior to secretion by hypothalamic neurons in culture.
Endocrinology 127:25982600[Abstract/Free Full Text]
-
Kovåcs KJ, Antoni FA 1990 Atriopeptin inhibits
stimulated secretion of adrenocorticotropin in rats: evidence for a
pituitary site of action. Endocrinology 127:30033008[Abstract/Free Full Text]
-
Dayanithi G, Antoni FA 1990 Atriopeptins are
potent inhibitors of ACTH secretion by rat anterior pituitary cells
in vitro: involvement of the atrial natriuretic factor
receptor domain of membrane-bound guanylyl cyclase. J Endocrinol 125:3944[Abstract/Free Full Text]
-
Fink G, Dow RC, Casley D, Johnston CI, Lim AT, Copolov
DL, Bennie J, Carroll S, Dick H 1991 Atrial natriuretic peptide is
a physiological inhibitor of ACTH release: evidence from
immunoneutralization in vivo. J Endocrinol 131:R9R12
-
Sheward WJ, Lim A, Alder B, Copolov D, Dow RC, Fink
G 1991 Hypothalamic release of atrial natriuretic factor and
ß-endorphin into rat hypophysial portal plasma: relationship to
oestrous cycle and effects of hypophysectomy. J Endocrinol 131:113125[Abstract/Free Full Text]
-
Ur E, Faria M, Tsagarakis S, Anderson JV, Besser GM,
Grossman A 1991 Atrial natriuretic peptide in physiological doses
does not inhibit the ACTH or cortisol response to
corticotrophin-releasing hormone-41 in normal human subjects. J
Endocrinol 131:163167[Abstract/Free Full Text]
-
Fink G, Dowe RC, Casley D, Johnston CI, Bennie J,
Carroll S, Dick H 1992 Atrial natriuretic peptide is involved in
the ACTH response to stress and glucocorticoid negative feedback in the
rat. J Endocrinol 135:3743[Abstract/Free Full Text]
-
Antoni FA, Hunter EFM, Lowry PJ, Noble JM, Seckl
JR 1992 Atriopeptin: an endogenous corticotropin-releasing
inhibiting hormone. Endocrinology 130:17531755[Abstract/Free Full Text]
-
Kellner M, Wiedemann K, Holsboer F 1992 Atrial
natriuretic factor inhibits the CRH-stimulated secretion of ACTH and
cortisol in man. Life Sci 50:18351842[CrossRef][Medline]
-
Wittert GA, Espiner EA, Richards AM, Donald RA, Livesey
JH, Yandle TG 1993 Atrial natriuretic factor reduces vasopressin
and angiotensin II but not the ACTH response to acute hypoglycaemic
stress in normal men. Clin Endocrinol (Oxf) 38:183189[Medline]
-
Tan TT, Yang Z, Huang W, Lim AT 1994 ANF(128) is a potent suppressor of pro-opiomelanocortin (POMC) mRNA
but a weak inhibitor of ßEP-LI release from AtT-20 cells. J
Endocrinol 143:R1R4
-
Lim AT, Dow RC, Yang Z, Fink G 1994 ANP(528) is
the major molecular species in hypophysial portal blood of the rat.
Peptides 15:15571559[CrossRef][Medline]
-
Mulligan RS, Livesey JH, Evans MJ, Ellis MJ, Donald
RA 1997 Atrial natriuretic peptide and C-type natriuretic peptide
do not acutely inhibit the release of adrenocorticotropin from equine
pituitary cells in vitro. Neuroendocrinology 65:6469[Medline]
-
Bowman ME, Robinson PJ, Smith R 1997 Atrial
natriuretic peptide, cyclic GMP analogues and modulation of guanylyl
cyclase do not alter stimulated POMC peptide release from perifused rat
or sheep corticotrophs. J Neuroendocrinol 9:929936[CrossRef][Medline]
-
Bøler J, Enzmann F, Folkers K, Bowers CY, Schally
AV 1969 The identity of chemical and hormonal properties of the
thyrotropin releasing hormone and pyroglutamyl-histidyl-proline amide.
Biochem Biophys Res Commun 37:705710[CrossRef][Medline]
-
Burgus R, Dunn TF, Ward DN, Vale W, Amoss M, Guillemin
R 1969 Dérivés polypeptidiques de synthèse
doués dactivité hypophysiotrope TRF. C R Acad Sci Paris 268:21162118
-
Jackson IMD, Reichlin S 1974 Thyrotropin-releasing
hormone (TRH): distribution in hypothalamic and extrahypothalamic brain
tissues of mammalian and submammalian chordates. Endocrinology 95:854862[Abstract/Free Full Text]
-
Leppäluoto J, Koivusalo F, Kraama R 1978 Thyrotropin-releasing factor:distribution in neural and
gastrointestinal tissues. Acta Physiol Scand 104:175179[Medline]
-
Martino E, Seo H, Lernmark Å, Refetoff S 1980 Ontogenetic patterns of thyrotropin-releasing hormone-like material in
rat hypothalamus, pancreas, and retina:selective effect of light
deprivation. Proc Natl Acad Sci USA 77:43454348[Abstract/Free Full Text]
-
Engler D, Scanlon MF, Jackson IMD 1981 Thyrotropin-releasing hormone in the systemic circulation of the
neonatal rat is derived from the pancreas and other extraneural
tissues. J Clin Invest 67:800808
-
Engler D, Chad D, Jackson IMD 1982 Thyrotropin-releasing hormone in the pancreas and brain of the rat is
regulated by central noradrenergic and dopaminergic pathways. J
Clin Invest 69:13101320
-
Lechan RM, Jackson IMD 1982 Immunohistochemical
localization of thyrotropin-releasing hormone in the rat hypothalamus
and pituitary. Endocrinology 111:5565[Abstract/Free Full Text]
-
Jackson IMD, Wu P, Lechan RM 1985 Immunohistochemical localization in the rat brain of the precursor for
thyrotropin-releasing hormone. Science 229:10971099[Abstract/Free Full Text]
-
Lechan RM, Wu P, Jackson IMD, Wolf H, Cooperman S,
Mandel G, Goodman RH 1986 Thyrotropin-releasing hormone precursor:
characterization in rat brain. Science 231:159161[Abstract/Free Full Text]
-
Lechan RM, Wu P, Jackson IMD 1986 Immunolocalization of the thyrotropin-releasing hormone prohormone in
the rat central nervous system. Endocrinology 119:12101216[Abstract/Free Full Text]
-
Segerson TP, Hoefler H, Childers H, Wolfe HJ, Wu P,
Jackson IMD, Lechan RM 1987 Localization of thyrotropin-releasing
hormone prohormone messenger ribonucleic acid in rat brain by in
situ hybridization. Endocrinology 121:98107[Abstract/Free Full Text]
-
Wu P, Lechan RM, Jackson IMD 1987 Identification
and characterization of thyrotropin-releasing hormone precursor
peptides in rat brain. Endocrinology 108:108115
-
Lechan RM, Wu P, Jackson IMD 1987 Immunocytochemical distribution in rat brain of putative peptides
derived from thyrotropin-releasing hormone prohormone. Endocrinology 121:18791891[Abstract/Free Full Text]
-
Lee SL, Stewart K, Goodman RH 1988 Structure of
the gene encoding rat thyrotropin releasing hormone. J Biol Chem 263:1660416609[Abstract/Free Full Text]
-
Liao N, Bulant M, Nicolas P, Vaudry H, Pelletier G 1988 Immunocytochemical distribution of neurons containing a peptide
derived from thyrotropin-releasing hormone precursor in the rat brain.
Neurosci Lett 85:2428[CrossRef][Medline]
-
Bulant M, Delfour A, Vaudry H, Nicolas P 1988 Processing of thyrotropin-releasing hormone prohormone (pro-TRH)
generates pro-TRH-connecting peptides. Identification and
characterization of prepro-TRH-(160169) and prepro-TRH-(178199) in
the rat nervous system. J Biol Chem 263:1718917196[Abstract/Free Full Text]
-
Bulant M, Roussel J-P, Astier H, Nicolas P, Vaudry
H 1990 Processing of thyrotropin-releasing hormone prohormone
(pro-TRH) generates a biologically active peptide,
prepro-TRH-(160169), which regulates TRH-induced thyrotropin
secretion. Proc Natl Acad Sci USA 87:44394443[Abstract/Free Full Text]
-
Kawano H, Tsuruo Y, Bando H, Daikoku S 1991 Hypophysiotrophic TRH-producing neurons identified by combining
immunohistochemistry for pro-TRH and retrograde tracing. J Comp
Neurol 307:531538[CrossRef][Medline]
-
Valentijn K, Tranchand Bunel D, Liao N, Pelletier G,
Vaudry H 1991 Release of pro-thyrotropin-releasing hormone
connecting peptides PS4 and PS5 from perifused rat hypothalamic slices.
Neuroscience 44:223233[CrossRef][Medline]
-
Redei E, Hilderbrand H, Aird F 1995 Corticotropin
release inhibiting factor is encoded within prepro-TRH. Endocrinology 136:18131816[Abstract]
-
Redei E, Hilderbrand H, Aird F 1995 Corticotropin
release-inhibiting factor is preprothyrotropin-releasing
hormone-(178199). Endocrinology 136:35573563[Abstract]
-
Brown-Grant K, Harris GW, Reichlin S 1954 The
effect of emotional and physical stress on thyroid activity in the
rabbit. J Physiol 126:2940
-
Brown-Grant K, Harris GW, Reichlin S 1954 The
influence of the adrenal cortex on thyroid activity in the rabbit.
J Physiol 126:4151
-
Brown-Grant K, Pethes G 1960 The response of the
thyroid gland of the guinea-pig to stress. J Physiol 151:4050
-
Hanson ES, Levin N, Dallman MF 1997 Elevated
corticosterone is not required for the rapid induction of neuropeptide
Y gene expression by an overnight fast. Endocrinology 138:10411047[Abstract/Free Full Text]
-
Ahima RS, Prabakaran D, Mantzoros C, Qu D, Lowell B,
Maratos-Flier E, Flier JS 1996 Role of leptin in the
neuroendocrine response to fasting. Nature 382:250252[CrossRef][Medline]
-
Van Haasteren GAC, Linkels E, Klootwijk W, van Toor H,
Rondeel JMM, Themmen APN, de Jong FH, Valentijn K, Vaudry H, Bauer K,
Visser TJ, de Greef WJ 1995 Starvation-induced changes in the
hypothalamic content of prothyrotropin-releasing hormone (proTRH) mRNA
and the hypothalamic release of proTRH-derived peptides: role of the
adrenal gland. J Endocrinol 145:143153[Abstract/Free Full Text]
-
Stacpoole PW, Interlandi JW, Nicholson WE, Rabin D 1982 Isolated ACTH deficiency: a heterogeneous disorder. Critical
review and report of four new cases. Medicine 61:1324[Medline]
-
Yamamoto T, Fukuyama J, Hasegawa K, Sugiura M 1992 Isolated corticotropin deficiency in adults. Report of 10 cases and
review of literature. Arch Intern Med 152:17051712[Abstract/Free Full Text]
-
Nicholson WE, Orth DN 1996 Preprothyrotropin-releasing hormone-(178199) does not inhibit
corticotropin release. Endocrinology 137:21712174[Abstract]
-
McGivern RF, Rittenhouse P, Aird F, Van de Kar LD,
Redei E 1997 Inhibition of stress-induced neuroendocrine and
behavioral responses in the rat by prepro-thyrotropin-releasing hormone
178199. J Neurosci 17:48864894[Abstract/Free Full Text]
-
Robertson DM, Foulds LM, Leversha L, Morgan FJ, Hearn
MTW, Burger HG, Wettenhall REH, de Kretser DM 1985 Isolation of
inhibin from bovine follicular fluid. Biochem Biophys Res Commun 126:220226[CrossRef][Medline]
-
Mason AJ, Hayflick JS, Ling N, Esch F, Ueno N,
Ying S- Y Guillemin R, Niall H, Seeburg PH 1985 Complementary DNA
sequences of ovarian follicular fluid inhibin show precursor structure
and homology with transforming growth factor-ß. Nature 318:659663[CrossRef][Medline]
-
Mason AJ, Niall HD, Seeburg PH 1986 Structure of
two ovarian inhibins. Biochem Biophys Res Commun 135:957964[CrossRef][Medline]
-
Forage RG, Ring JM, Brown RW, McInerney BV, Cobon
GS, Gregson RP, Robertson DM, Morgan FJ, Hearn MTW, Findlay JK,
Wettenhall REH, Burger HG, de Kretser DM 1986 Cloning and sequence
analysis of cDNA species coding for the two subunits of inhibin from
bovine follicular fluid. Proc Natl Acad Sci USA 83:30913095[Abstract/Free Full Text]
-
Mayo KE, Cerelli GM, Spiess J, Rivier J, Rosenfeld MG,
Evans RM, Vale W 1986 Inhibin A-subunit cDNAs from porcine ovary
and human placenta. Proc Natl Acad Sci USA 83:58495853[Abstract/Free Full Text]
-
Vale W, Rivier J, Vaughan J, McClintock R, Corrigan A,
Woo W, Karr D, Spiess J 1986 Purification and characterization of
an FSH releasing protein from porcine ovarian follicular fluid. Nature 321:776779[CrossRef][Medline]
-
Ling N, Ying S-Y, Ueno N, Shimasaki S, Esch F, Hotta M,
Guillemin R 1986 Pituitary FSH is released by a heterodimer of the
ß-subunits of the two forms of inhibin. Nature 321:779782[CrossRef][Medline]
-
Esch FS, Shimasaki S, Cooksey K, Mercado M, Mason AJ,
Ying S-Y, Ueno N, Ling N 1987 cDNA cloning and DNA sequence
analysis of rat ovarian inhibins. Mol Endocrinol 1:388396[Abstract/Free Full Text]
-
Ying S-Y 1988 Inhibins, activins, and follistatin:
gonadal proteins modulating the secretion of follicle-stimulating
hormone. Endocr Rev 9:267293[Abstract/Free Full Text]
-
de Kretser DM, Robertson DM 1989 The isolation and
physiology of inhibin and related proteins. Biol Reprod 40:3347[Abstract]
-
Meunier H, Rivier C, Evans RM, Vale W 1988 Gonadal and extragonadal expression of inhibin
, ßA, and ßB
subunits in various tissues predicts diverse functions. Proc Natl Acad
Sci USA 85:247251[Abstract/Free Full Text]
-
Sawchenko PE, Plotsky PM, Pfeiffer SW, Cunningham Jr
ET, Vaughan J, Rivier J, Vale W 1988 Inhibin ß in central neural
pathways involved in the control of oxytocin secretion. Nature 334:615617[CrossRef][Medline]
-
Bilezikjian LM, Blount AL, Campen CA, Gonzalez-Manchon
C, Vale W 1991 Activin-A inhibits proopiomelanocortin messenger
RNA accumulation and adrenocorticotropin secretion of AtT20 cells. Mol
Endocrinol 5:13891395[Abstract/Free Full Text]
-
Clarke IJ, Jessop D, Millar R, Morris M, Bloom S,
Lightman S, Coen CW, Lew R, Smith I 1993 Many peptides that are
present in the external zone of the median eminence are not secreted
into the hypophysial portal blood of sheep. Neuroendocrinology 57:765775[Medline]
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