Endocrinology Vol. 142, No. 5 2032-2038
Copyright © 2001 by The Endocrine Society
Prolactin-Releasing Peptide as a Novel Stress Mediator in the Central Nervous System1
Minoru Maruyama,
Hirokazu Matsumoto,
Ken Fujiwara,
Jiro Noguchi,
Chieko Kitada,
Masahiko Fujino and
Kinji Inoue
Department of Regulation Biology, Faculty of Science, Saitama
University (M.M., K.F., K.I.), 255 Shimo-ohkubo, Urawa 338-0825, Japan;
and Discovery Research Laboratories I, Pharmaceutical Discovery
Research Division, Takeda Chemical Industries Co., Ltd.
(H.M., J.N., C.K., M.F.), 10 Wadai, Tsukuba, Ibaraki 300-4293,
Japan
Address all correspondence and requests for reprints to: Kinji Inoue, Ph.D., Department of Regulation Biology, Faculty of Science, Saitama University, 255 Shimo-ohkubo, Urawa 338-0825, Japan.
 |
Abstract
|
|---|
A1/A2 noradrenergic neurons in the medulla oblongata are well known to
mediate stress signals in the central nervous system. Stress activates
A1/A2 noradrenergic neurons, and then noradrenaline (NA) stimulates
ACTH secretion through hypothalamic CRH. On the other hand,
PRL-releasing peptide (PrRP) was recently isolated and was found to be
produced by some A1/A2 neurons and the dorsomedial hypothalamic
nucleus. We previously demonstrated that PrRP neurons make synapse-like
contact with hypothalamic CRH neurons. In fact, we demonstrated that
the central administration of PrRP stimulates CRH-mediated ACTH
secretion. Furthermore, it has been reported that PrRP neurons in A1/A2
cell groups are colocalized with tyrosine hydroxylase (TH), which is
known as the marker enzyme of catecholaminergic neurons. These data
strongly suggest that PrRP is related to stress-responsive signal
transduction, and PrRP and NA cooperatively modulate the
hypothalamo-pituitary-adrenal axis. We therefore examined the effect of
water immersion-restraint stress on c-Fos protein accumulation in PrRP-
and TH-immunoreactive neurons. The synergistic effects of PrRP and NA
on plasma ACTH elevation were also examined. The results clearly showed
that c-Fos protein accumulation dramatically increased in the nuclei of
A1/A2 and dorsomedial hypothalamic nucleus PrRP neurons. In addition,
it was revealed that c-Fos protein was specifically expressed in the
PrRP/TH double positive cells in the A1/A2 cell groups. We also
demonstrated that the central administration of PrRP and NA in
combination at subactive (noneffective) doses clearly induced plasma
ACTH elevation. Here we report that PrRP is a novel and important
mediator of the hypothalamo-pituitary-adrenal axis for the stress
response.
|
Introduction
|
|---|
PRL-RELEASING PEPTIDE (PrRP) was recently
isolated as a ligand of an orphan seven-transmembrane domain receptor
(hGR3) (1). PrRP is known to stimulate PRL release both
in vitro (1) and in vivo (2, 3). It has been demonstrated that PrRP-producing cells exist in
the dorsomedial hypothalamic nucleus (DM) and in the A1 region of the
ventrolateral reticular formation and the A2 region of the nucleus of
the solitary tract in medulla oblongata (4, 5, 6, 7, 8, 9, 10, 11). These
PrRP- producing neurons extend their axons to magno- and
parvocellular neurosecretory cells in the paraventricular hypothalamic
nucleus (PVH) and then make synapse-like contact with these cell bodies
(4, 12), in which PrRP receptors are known to exist
(10). These morphological data strongly suggest that PrRP
plays an important biological role in the neuroendocrine system. In
fact, we previously found that intracerebroventricular (icv)
administration of PrRP significantly increases plasma oxytocin and
vasopressin secretion from magnocellular neurosecretory cells in the
PVH (13). In addition, we recently found that central
administration of PrRP stimulates ACTH and ß-endorphin secretion via
CRH from the parvocellular neurosecretory cells in the PVH
(12).
On the other hand, noradrenergic neurons that project to the PVH are
located in A1/A2 cell groups in the medulla oblongata, and a minor
portion are found in the locus coeruleus (A6 cell group). These
noradrenergic neurons are well known to mediate stress signals in the
central nervous system (CNS) (14, 15, 16, 17, 18, 19). In fact, lesions of
catecholaminergic cell groups in the brainstem or their ascending
fibers block or reduce stress-induced changes in the
hypothalamo-hypophyseal system (15, 20, 21). In addition,
it is commonly accepted that stress activates A1/A2 noradrenergic
neurons (18), and noradrenaline (NA) stimulates ACTH
secretion through a hypothalamic CRH (19). Interestingly,
it has been reported that PrRP neurons in A1/A2 cell groups are
colocalized with NA in A1/A2 cell groups (9, 10, 11). These
data indicate that PrRP mediates stress signals in the CNS as well as
NA. The colocalization of PrRP and NA in the same neurons also suggests
their synergistic effects. Therefore, we examined the effect of stress
on immediate response gene (c-Fos) accumulation in A1/A2 PrRP neurons.
The synergistic effects of PrRP and NA on CRH-mediated ACTH secretion
were also analyzed in this study. We report here that stress is a
potent activator of PrRP neurons, and that PrRP is an important stress
mediator in the CNS.
|
Materials and Methods
|
|---|
Animals
Adult Wistar male rats were housed in group cages illuminated
from 0800–2000 h (12-h cycle). Room temperature varied from 21–24 C.
Tap water and laboratory chow were available ad libitum. All
procedures were performed in accordance with institutional guidelines
for animal care at Saitama University and Takeda Chemical Industries Co., Ltd.
Immunocytochemistry
Proteins were localized as previously described (4, 12, 13). Briefly, the animals were deeply anesthetized and fixed
with 5% acrolein in 0.07 M phosphate buffer (pH
7.4). Frozen sections (40 µm) were prepared from the brains. A mouse
monoclonal antibody (P2L-1T) and rabbit polyclonal anti-bovine PrRP
(no. 8, provided by Takeda Chemical Industries Co., Ltd.)
were used as primary antibodies for PrRP. Mouse monoclonal antityrosine
hydroxylase clone TH2 (Sigma, St. Louis, MO) and rabbit
polyclonal anti-c-Fos (Santa Cruz Biotechnology, Inc.,
Santa Cruz, CA) were used for the detection of tyrosine hydroxylase
(TH) and c-Fos, respectively. For fluorescence immunocytochemistry for
TH and PrRP (shown in Fig. 1
), PrRP
(labeled with no. 8) and TH were visualized, respectively, with
Alexa488-conjugated goat antimouse IgG (Molecular Probes, Inc., Eugene, OR) in red and Alexa594-conjugated goat antirabbit
IgG (Molecular Probes, Inc.) in green. For the double
staining of PrRP and c-Fos (shown in Fig. 2), PrRP (labeled with P2L-1T) and c-Fos
were visualized, respectively, with diaminobenzidine (DAB) in brown and
cobalt-DAB in black after labeling with peroxidase by the
avidin-biotin-peroxidase complex method. For the triple staining of
PrRP, TH, and c-Fos (shown in Fig. 4), PrRP (labeled with no. 8) and TH
were visualized, respectively, with Alexa488-conjugated goat antimouse
IgG (Molecular Probes, Inc.) in red and
Alexa594-conjugated goat antirabbit IgG (Molecular Probes, Inc.) in green, and c-Fos was labeled with peroxidase by the
avidin-biotin-peroxidase complex method and then stained with DAB in
brown, which changed to blue under a confocal laser microscope.
View larger version (74K):
[in this window]
[in a new window]
|
Figure 1. Photomicrographs showing the double fluorescence
immunostaining to locate PrRP and TH in the A1/A2 cell groups. PrRP and
TH are stained red and green,
respectively, and the double positive neurons are shown in
yellow. A–C, Photomicrographs of the A1 region. D–F,
Photomicrographs of the A2 region. A and D, Photomicrographs showing
only PrRP staining. B and E, Photomicrographs showing only TH staining.
C and F, Photomicrographs showing both PrRP and TH staining. G and H,
High magnification photomicrographs of C and F, respectively. All
PrRP-ir neurons were colocalized with TH in the A1 (A–C and G) and A2
(D–F and H) cell groups. However, TH-ir neurons did not always coexist
with PrRP in the A2 cell groups (D–F and H). Arrows
indicate the PrRP-negative/TH-positive neurons. Scale
bars, 100 µm (A–F) and 50 µm (G and H).
|
|
View larger version (148K):
[in this window]
[in a new window]
|
Figure 2. Effect of water immersion-restraint stress on
c-Fos in the PrRP-ir neurons. Photomicrographs show double
immunostaining with PrRP and c-Fos antibodies in the A1 (A and B) and
A2 (C and D) cell groups, and the DM (E and F). PrRP and c-Fos were
stained brown and black, respectively. In
nonstress rats, PrRP-ir neurons expressed some c-Fos protein (A, C, and
E). However, when rats were exposed to water immersion-restraint stress
for 2 h, c-Fos protein expression dramatically increased in the
PrRP-ir neurons (B, D, and F). Scale bars, 50 µm.
|
|
View larger version (35K):
[in this window]
[in a new window]
|
Figure 4. Photomicrographs showing triple
immunostaining with PrRP, TH, and c-Fos antibodies after exposure to
water immersion-restraint stress for 2 h in A1/A2 cell groups.
PrRP and TH are stained red and green,
respectively, and neurons stained with both are
yellow. c-Fos is stained blue. When
rats were exposed to water immersion-restraint stress for 2 h,
most PrRP/TH-double positive neurons showed expression of c-Fos protein
in the A1 (A) and A2 (B) cell groups. However, TH-ir neurons that
showed no PrRP-positive reaction did not always show expression of
c-Fos protein in the A2 cell groups (C). D–F, Individual images
comprising C, which represent PrRP, TH, and c-Fos, respectively.
Scale bars, 25 µm (A and B) and 50 µm (C–F).
|
|
For morphometry, a complete series of frontal sections (40 µm each)
from the caudal end of the area postrema to 1.4 mm posteriorly were
analyzed. All neurons in the lateral half of each nuclear area were
counted. To avoid double counting, only neurons with a complete nucleus
were counted.
Water immersion-restraint stress
Water immersion-restraint stress was performed as previously
described (22). Rats were immobilized in stainless
restrainers (Natsume, Tokyo, Japan) with the lower half of their bodies
immersed in water (25 ± 1 C). They were decapitated 2 or 6 h
after the onset of immobilization. Intact (nonstressed) rats were used
as a control group.
Synthetic peptide
Rat PrRP31 was synthesized using a combination of recombinant
DNA technology and a cysteine-specific cyanylation reaction
(23).
Intracerebroventricular administration, blood sampling, and
measurement
For icv administration of PrRP, male Wistar rats were
anesthetized with sodium pentobarbital (50 mg/kg, ip) and then fixed on
a stereotaxic apparatus (Narishige, Tokyo, Japan) with the incisor bars
adjusted to 3.3 mm below the interaural line. A stainless steel guide
cannula (id, 0.4 mm; od, 0.5 mm; AG-8, Eicom, Kyoto, Japan) was
inserted into the right lateral ventricle. The stereotaxic coordinates,
set according to the atlas of Paxinos and Watson (24),
were: anterior-posterior, 7.7 mm above the interaural line; lateral,
1.8 mm from the midline; and height, 6.8 mm above the interaural
line. The cannula was fixed to the skull with acrylic dental cement and
screws. The guide cannula was occluded with a dummy cannula (od, 0.35
mm; AD-8, Eicom) until the experiments could be performed. The
cannula-implanted rats were housed as described above for at least 7
days after the operation. The rats were anesthetized as described
above, and then polyethylene tubing (id, 0.5 mm; od, 0.9 mm; SP35,
Natsume) for blood sampling was inserted into the right atrium through
the jugular vein 1 day before the experiment. PrRP31, NA, or PBS
containing 0.5% BSA was injected into the right lateral ventricle.
Blood samples were collected via the venous catheter in ice-cooled
tubes containing 0.01 M EDTA, 300 kallikrein inhibitor
units/ml aprotinin, and 2.5 x
10-4 M
o-phenanthroline at 15 min pre- and post-icv injection.
Plasma was separated from blood and stored at -40 C until the
measurement of ACTH. The plasma ACTH concentration was measured with a
RIA kit for ACTH (Mitsubishi Yuka Co., Tokyo, Japan). All plasma ACTH
measurements were performed between 0900 and 1200 h to avoid the
influence of the circadian rhythm. The entire procedure has been
described previously (12, 13).
Statistical analysis
The data were analyzed by one-way ANOVA with repeated
measurements, and differences between treatment groups were evaluated
using Dunnett’s multiple test. The statistical significance level was
set at P < 0.05.
|
Results
|
|---|
Double immunocytochemistry with PrRP and TH
To determine the relationship between PrRP and A1/A2 NA cell
groups, we examined the localization of immunoreactive PrRP and TH in
A1/A2 cell groups by fluorescence immunocytochemistry. As previously
reported (9, 10, 11), the PrRP-immunoreactive (ir) neurons
were colocalized with TH-ir neurons in the A1/A2 cell groups (Fig. 1
).
In these areas PrRP-ir neurons were always coexpressed with TH-ir
neurons (data not shown). Inversely, most TH-ir neurons in A1 cell
groups were also positive for PrRP (Fig. 1, A–C and G), but TH-ir
neurons in A2 cell groups were not always positive for PrRP (Fig. 1, D–F and H). The results of morphometry are shown in Table 1. In nonstressd rats, the percentages of
PrRP-ir cells among the total number of TH-ir cells were 98.4 ±
2.8% and 81.7 ± 3.2% in the A1 and A2 regions, respectively.
These values did not significantly change after exposure to water
immersion-restraint stress for 2 h in A1/A2 cell groups (Table 1).
Effect of water immersion-restraint stress on the c-Fos expression
in PrRP neurons
The immediate response gene c-Fos was used as a marker of neural
activation in this study. Rats exposed to nonstress and water
immersion-restraint stress for 2 and 6 h were analyzed. Double
immunocytochemistry for PrRP and c-Fos clearly showed that water
immersion-restraint stress dramatically increased the number of
c-Fos-positive nuclei in A1/A2 and DM PrRP-ir neurons (Fig. 2).
Morphometry showed that the percentage of c-Fos expression in the
PrRP-ir cells of A1/A2 cell groups was significantly increased by water
immersion-restraint stress for 2 h compared with that in
nonstressed rats, i.e. 8.1-fold (P < 0.01)
in A1 and 3.3-fold (P < 0.01) in A2 neurons (Fig. 3). After 6-h stress exposure, it became
8.3-fold (P < 0.01) in A1 and 3.5-fold
(P < 0.01) in A2 neurons. However, the c-Fos
activation in DM was weaker than that in A1/A2 cell groups,
i.e. 1.7-fold (P < 0.01) at 2 h and
1.6-fold (P < 0.01) at 6 h.
View larger version (17K):
[in this window]
[in a new window]
|
Figure 3. The percentage of c-Fos expression in PrRP-ir
neurons was determined in rats after nonstress (Control) and after
exposure to water immersion-restraint stress for 2 and 6 h. The
percentage of c-Fos expression in the PrRP-ir neurons was significantly
increased in the A1 (A) and A2 (B) cell groups and the DM (C) after
exposure to water immersion-restraint stress. Values are the mean
± SEM (n = 3–6). *, P < 0.01
vs. control.
|
|
Triple immunocytochemistry for PrRP, TH, and c-Fos in A1/A2 cell
groups after exposure to water immersion-restraint stress
Triple immunocytochemistry for PrRP, TH, and c-Fos in A1/A2 cell
groups clearly showed that most PrRP/TH double positive neurons also
become positive for c-Fos under water immersion-restraint stress
compared with those in nonstressed rats (Fig. 4, A and B). However, most
PrRP-negative/TH-positive neurons in A2 cell groups were not reactive
to c-Fos (Fig. 4, C–F), i.e. PrRP-containing NA neurons
responded specifically to water immersion-restraint stress in the A1/A2
cell groups. The results of morphometric analysis are shown in Table 2. Morphometry showed that the percentage
of c-Fos expression in PrRP/TH-double positive neurons was 17.8 ±
5.0% in nonstressed rats in the A2 region, and that of
PrRP-negative/TH-positive neurons was 0.5 ± 0.8%. In the A1
region, the percentage of c-Fos expression in PrRP/TH double positive
neurons was 10.8 ± 13.1% in nonstressed rats. On the other hand,
the percentage of c-Fos expression PrRP/TH double positive neurons was
90.5 ± 6.2% after exposure to water immersion-restraint stress
in the A2 region, whereas that of PrRP-negative/TH-positive neurons was
2.2 ± 2.2%. In the A1 region, the percentage of c-Fos expression
in PrRP/TH double positive neurons was 87.9 ± 6.3% after
exposure to water immersion-restraint stress. The value for
PrRP-negative/TH-positive neurons in the A1 region was not determined
because there are almost no PrRP-negative/TH-positive neurons in the A1
region.
View this table:
[in this window]
[in a new window]
|
Table 2. Percentages of c-Fos protein expression in
PrRP/TH-double positive (PrRP+/TH+) and
PrRP-negative/TH-positive (PrRP-/TH+) neurons
|
|
Effects of icv administration of PrRP and NA on the plasma ACTH
level
The colocalization of NA and PrRP in the A1/A2 cell groups
suggests the synergistic actions of these factors on the
hypothalamo-pituitary-adrenal axis. We therefore performed
coadministration (icv) of subactive (noneffective) doses of PrRP (1
nmol) and NA (0.1 nmol) to examine their synergistic effects on the
plasma ACTH level. Blood was collected 15 min pre- and post-icv
injection, and the blood collected 15 min before icv injection was used
for measurement of basal ACTH levels in individual rats. PrRP (1 nmol)
and NA (0.1 nmol) had no effect compared with basal plasma ACTH levels.
In contrast, coadministration of PrRP (1 nmol) and NA (0.1 nmol)
significantly increased (3.2-fold; P < 0.01) the
plasma ACTH level compared with basal plasma ACTH levels (Fig. 5). These data suggest that PrRP and NA
act synergistically to induce CRH-mediated plasma ACTH elevation.
View larger version (17K):
[in this window]
[in a new window]
|
Figure 5. Effect of coadministration of PrRP and NA into the
right lateral ventricle on ACTH release in conscious male rats. The
plasma ACTH levels, pretreatment (pre) and 15 min after icv injection
(15 min) were compared. The icv administration of 0.5% BSA in PBS
(control), 1 nmol PrRP, or 0.1 nmol NA had no effect on ACTH elevation.
However, coadministration of 1 nmol PrRP and 0.1 nmol NA induced a
large increase in the plasma ACTH level, which suggested that PrRP and
NA acted synergistically to induce CRH-mediated plasma ACTH elevation.
Values are the mean ± SEM (n = 4). *,
P < 0.01 vs. pre.
|
|
|
Discussion
|
|---|
It is generally accepted that A1/A2 NA neurons extend their axons
to the PVH and play an important role as stress mediators. These NA
stimulate ACTH secretion through hypothalamic CRH
(14, 15, 16, 17, 18, 19, 20, 21); A1 NA neurons particularly promote vasopressin
and oxytocin secretion (25, 26, 27). On the other hand, it was
recently revealed that PrRP-producing cells exist in the DM in the
hypothalamus and the A1/A2 region of the medulla oblongata
(4). The axons of PrRP neurons project to the PVH
(4), and central administration of PrRP clearly stimulates
oxytocin and vasopressin secretion (13) and CRH-mediated
ACTH secretion (12). In addition, it has been reported
that A1/A2 PrRP neurons as well as the DM are retrogradely labeled
after tracer injections in the PVH (11), which indicates
that PrRP neurons in A1/A2 regions and also the DM are in direct
contact with neurons in the PVH. These locations and the functional
coincidence between NA and PrRP neurons strongly suggest that PrRP as
well as NA may be related to stress responses in the CNS.
In this study we confirmed previous reports (9, 10, 11)
showing that PrRP and TH are colocalized in A1/A2 cell groups (Fig. 1).
Morphometry showed that PrRP-ir neurons were colocalized, with
81.7 ± 3.2% of the TH-ir neurons in the A2 region and 98.4
± 2.8% of those in the A1 region (Table 1). Morales et al.
reported that some TH-ir neurons in the A1/A2 regions also contain PrRP
messenger RNA, i.e. 36.6 ± 13.7% of the TH-ir neurons
in the A2 region and 35.2 ± 9.4% of those in the A1 cell groups
are positive for PrRP messenger RNA (11). Their results
were different from our data; however, this may be due to the different
detection methods. At least both sets of data show that NA neurons in
the A2 cell group are dividable into two subpopulations,
i.e. PrRP-positive and -negative neurons. To determine
whether these PrRP neurons respond to stress, we examined c-Fos
expression in PrRP neurons under stress. Our results clearly indicated
that water immersion-restraint stress activates A1/A2 PrRP-ir neurons.
In addition, triple immunostaining for PrRP, TH, and c-Fos in the A1/A2
cell groups showed that PrRP/TH double positive and
PrRP-negative/TH-positive neurons are distinct in the response to water
immersion-restraint stress. Morphometry after triple immunostaining for
PrRP, TH, and c-Fos also indicated that the percentage of c-Fos
expression in PrRP/TH double positive neurons was 90.5 ± 6.2%
after exposure to water immersion-restraint stress in the A2 region,
whereas that of PrRP-negative/TH-positive neurons was 2.2 ±
2.2%. These data suggest that a subpopulation of PrRP/TH double
positive neurons in the A2 cell group predominantly responded to water
immersion-restraint stress.
On the other hand, we previously demonstrated that PrRP (10 nmol)
significantly increased plasma ACTH and ß- endorphin levels
(12). We also reported that this elevation was completely
blocked by treatment with 
-helical CRH, which clearly
indicated that PrRP elevated pituitary ACTH secretion through CRH
stimulation. However, we failed to achieve ACTH stimulation with a low
concentration of PrRP (1 nmol) (12). To explain the low
activity of PrRP on CRH secretion, we examined the colocalization of
PrRP and NA in the A1/A2 cell groups. As is well known, the PrRP and NA
receptors are localized in the PVH (10, 28), which
suggests that PrRP and NA may cooperatively stimulate CRH neurons.
Therefore, we examined the effect of coadministration (icv) of PrRP and
NA on the plasma ACTH level via the hypothalamic CRH. As a result, we
demonstrated that the central administration of PrRP (1 nmol) and NA
(0.1 nmol) in combination at subactive doses clearly induced plasma
ACTH elevation. This clearly showed that PrRP and NA cooperatively
stimulate the hypothalamo-pituitary-adrenal axis.
Some functions of PrRP in the CNS (12, 13, 29, 30, 31) have
been reported; however, the biological significance of A1/A2 PrRP
neurons has not been discussed. In this study we first found that PrRP
neurons in the brainstem are related to stress. We also showed that
PrRP synergistically acts with NA to induce ACTH secretion. Our data
showed that a subpopulation of A1/A2 NA cells expressing PrRP plays a
more integral and specific role in stress responses in the CNS compared
with neighboring non-PrRP-containing NA neurons. This novel
stress-related signal pathway is schematically illustrated in Fig. 6. We believe that our findings suggest
the biological significance of PrRP in the CNS. This may be supported
by the previous report that icv administration of PrRP increases blood
pressure (31) and plasma oxytocin and vasopressin levels
(13), which are known to be common stress responses
(32, 33). PrRP maybe regulate these stress-relating
phenomena as a stress mediator.
View larger version (43K):
[in this window]
[in a new window]
|
Figure 6. Schematic representation showing the
stress-related function of PrRP. PrRP coexists with medullary A1/A2 NA
neurons, and these cells are peculiarly activated by stress. PrRP and
NA are discharged from the neural terminals of the PVH and act
synergistically to induce CRH-mediated ACTH elevation. ME, Median
eminence.
|
|
The functional differences between PrRP-producing nuclei are not been
understood at present. However, it is also known that A1 NA neurons
mainly project to the magnocellular division of the PVH and regulate
vasopressin and oxytocin neurons, whereas A2 NA neurons mainly project
to the parvocellular division of the PVH and regulate CRH neurons
(25, 26, 27). This indicates the possibility that a functional
difference may exist between A1 and A2 PrRP neurons as well as NA. In
addition, the c-Fos expression study showed that not only A1/A2 cell
groups but also the PrRP-positive cell group in the DM respond to
stress stimuli. To explain this phenomenon it is noteworthy that the DM
is known to be related to food intake (34), and that PrRP
suppresses food intake (30). This suggests that the DM may
be related to suppression of food intake during an acute stress
response. However, further study is needed to clarify the details of
PrRP related-stress signal transduction.
|
Acknowledgments
|
|---|
We thank Mr. K. Uchida for the technical advice.
|
Footnotes
|
|---|
1 This work was supported in part by grants for research fellowships
from the Japan Society for the Promotion of Science for Young
Scientists. 
Received September 8, 2000.
|
References
|
|---|
-
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 393:272–276[CrossRef][Medline]
-
Matsumoto H, Noguchi J, Horikoshi Y, Kawamata Y, Kitada
C, Hinuma S, Onda H, Nishimura O, Fujino M 1999 Stimulation of
prolactin release by prolactin-releasing peptide in rats. Biochem
Biophys Res Commun 259:321–324[CrossRef][Medline]
-
Tokita R, Nakata T, Katsumata H, Konishi S, Onodera H,
Imaki J, Minami S 1999 Prolactin secretion in response to
prolactin-releasing peptide and the expression of the
prolactin-releasing peptide gene in the medulla oblongata are estrogen
dependent in rats. Neurosci Lett 276:103–106[CrossRef][Medline]
-
Maruyama M, Matsumoto, H, Fujiwara K, Kitada C, Hinuma
S, Onda H, Fujino M, Inoue K 1999 Immunocytochemical localization
of prolactin- releasing peptide in the rat brain. Endocrinology 140:2326–2333[Abstract/Free Full Text]
-
Yamakawa K, Kudo K, Kanbe S, Arita J 1999 Distribution of prolactin-releasing peptide-immunoreactive neurons in
the rat hypothalamus. Neurosci Lett 267:113–116[CrossRef][Medline]
-
Lee Y, Yang SP, Soares MJ, Voogt JL 2000 Distribution of prolactin-releasing peptide mRNA in the rat brain.
Brain Res Bull 51:171–176[CrossRef][Medline]
-
Minami S, Nakata T, Tokita R, Onodera H, Imaki J 1999 Cellular localization of prolactin-releasing peptide messenger RNA
in the rat brain. Neurosci Lett 266:73–75[CrossRef][Medline]
-
Iijima N, Kataoka Y, Kakihara K, Bamba H, Tamada Y,
Hayashi S, Matsuda T, Tanaka M, Honjyo H, Hosoya M, Hinuma S, Ibata
Y 1999 Cytochemical study of prolactin-releasing peptide (PrRP) in
the rat brain. NeuroReport 10:1713–1716[Medline]
-
Chen CT, Dun SL, Chang JK 1999 Prolactin-releasing
peptide immunoreactivity in A1 and A2 noradrenergic neurons of the rat
medulla. Brain Res 822:276–279[CrossRef][Medline]
-
Roland BL, Sutton SW, Wilson SJ, Luo L, Pyati J, Huvar
R, Erlander MG, Lovenberg TW 1999 Anatomical distribution of
prolactin-releasing peptide and its receptor suggests additional
functions in the central nervous system and periphery. Endocrinology 140:5736–5745[Abstract/Free Full Text]
-
Morales T, Hinuma S, Sawchenko PE 2000 Prolactin-releasing peptide is expressed in afferents to the endocrine
hypothalamus, but not in neurosecretory neurons. J Neuroendocrinol 12:131–140[CrossRef][Medline]
-
Matsumoto H, Maruyama M, Noguchi J, Horikoshi Y,
Fujiwara K, Kitada C, Hinuma S, Onda H, Nishimura O, Inoue K, Fujino
M 2000 Stimulation of corticotropin-releasing hormone-mediated
adrenocorticotropin secretion by central administration of
prolactin-releasing peptide in rats. Neurosci Lett 285:234–238[CrossRef][Medline]
-
Maruyama M, Matsumoto H, Fujiwara K, Noguchi J, Kitada
C, Hinuma S, Onda H, Nishimura O, Fujino M, Higuchi T, Inoue K 1999 Central administration of prolactin-releasing peptide stimulates
oxytocin release in rats. Neurosci Lett 276:193–196[CrossRef][Medline]
-
Pacak K, Palkovits M, Kvetnansky R, Kopin IJ, Goldstein
DS 1993 Stress-induced norepinephrine release in the
paraventricular nucleus of rats with brainstem hemisections: a
microdialysis study. Neuroendocrinology 58: 196–201
-
Gaillet S 1993 Effects of discrete lesions in the
ventral noradrenergic ascending bundle on the corticotropic stress
response depending on the site of the lesion and on the plasma levels
of adrenal steroids. Neuroendocrinology 58:408–419[Medline]
-
Liposits Z, Phelix C, Paull WK 1986 Adrenergic
innervation of corticotropin-releasing factor (CRF)-synthesizing
neurones in the hypothalamic paraventricular nucleus of the rat: a
combined light and electron microscopic immunocytochemical study.
Histochemistry 84:201–205[CrossRef][Medline]
-
Palkovits M, Zaborszky L, Feminger A, Mezey E, Fekete
MI, Herman JP, Kanyicska B, Szabo D 1980 Noradrenergic innervation
of the rat hypothalamus: experimental biochemical and electron
microscopic studies. Brain Res 191:161–171[CrossRef][Medline]
-
Pezzone MA, Lee WS, Hoffman GE, Pezzone KM, Rabin
BS 1993 Activation of brainstem catecholaminergic neurons by
conditioned and unconditioned aversive stimuli as revealed by c-Fos
immunoreactivity. Brain Res 608:310–318[CrossRef][Medline]
-
Ito K 1994 Microinjection of norepinephrine into
the paraventricular nucleus of the hypothalamus stimulates
corticotropin-releasing factor gene expression in conscious rats.
Endocrinology 135:2177–2182[Abstract]
-
Alonso G, Szafarczyk A, Balmefrezol M, Assenmacher
I 1986 Immunocytochemical evidence for stimulatory control by the
ventral noradrenergic bundle of parvocellular neurons of the
paraventricular nucleus secreting corticotropin releasing hormone and
vasopressin in rats. Brain Res 397:297–307[CrossRef][Medline]
-
Sawchenko PE 1988 Effects of
catecholamine-depleting medullary knife cuts on corticotropin-releasing
factor and vasopressin immunoreactivity in the hypothalamus of normal
and steroid-manipulated rats. Neuroendocrinology 48:459–470[Medline]
-
Nishioka T, Iyota K, Nakayama T, Suemaru S, Numata Y,
Hashimoto K 1993 Effects of ether-laparotomy and water
immersion-restraint stress on CRH concentration in the hypothalamus,
extrahypothalamic tissues and peripheral blood. Endocr J 40:213–220[Medline]
-
Nishimura O, Moriya T, Suenaga M, Tanaka Y, Itoh T,
Koyama N, Fujii R, Hinuma S, Kitada C, Fujino M 1998 Synthesis of
new peptides with prolactin-releasing activity by a combination of
recombinant DNA technology and a cysteine-specific cyanylation
reaction. Chem Pharm Bull 46:1490–1492
-
Paxinos G, Watson C 1986 The Rat Brain in
Stereotaxic Coordinates, ed 2. Academic Press, Sydney
-
Cunningham Jr ET, Sawchenko PE 1988 Anatomical
specificity of noradrenergic inputs to the paraventricular and
supraoptic nuclei of the rat hypothalamus. J Comp Neurol 274:60–76[CrossRef][Medline]
-
Day TA 1989 Control of neurosecretory vasopressin
cells by noradrenergic projection of the caudal venrolateral medulla.
Prog Brain Res 81:303–317[Medline]
-
Onaka T, Palmer JR, Yagi K 1996 A selective role of
brainstem noradrenergic neurons in oxytocin release from the
neurohypophysis following noxious stimuli in the rat. Neurosci Res 25:67–75[CrossRef][Medline]
-
Watson A, Abbott A 1991 TiPS receptor nomenclature
supplement. Trends Pharmacol Sci 12:1–13
-
Seal LJ, Small CJ, Kim MS, Stanley SA, Taheri S, Ghatei
MA, Bloom SR 2000 Prolactin releasing peptide (PrRP) stimulates
luteinizing hormone (LH) and follicle stimulating hormone (FSH) via a
hypothalamic mechanism in male rats. Endocrinology 141:1909–1912[Abstract/Free Full Text]
-
Lawrence CB, Celsi F, Brennand J, Luckman SM 2000 Alternative role for prolactin-releasing peptide in the regulation of
food intake. Nat Neurosci 3:645–646[CrossRef][Medline]
-
Samson WK, Resch ZT, Murphy TC 2000 A novel action
of the newly described prolactin-releasing peptides: cardiovascular
regulation. Brain Res 858:19–25[CrossRef][Medline]
-
Nakata T, Berard W, Kogosov E, Alexander N 1993 Cardiovascular change and hypothalamic norepinephrine release in
response to environmental stress. Am J Physiol 264:R784–R789
-
Gibbs DM 1984 Dissociation of oxytocin, vasopressin
and corticotropin secretion during different types of stress. Life Sci 35:487–491[CrossRef][Medline]
-
Bernardis LL, Bellinger LL 1987 The dorsomedial
hypothalamic nucleus revisited: 1986 update. Brain Res 434:321–381[Medline]
This article has been cited by other articles:
|
|
|
|
 
D. A Bechtold and S. M Luckman
The role of RFamide peptides in feeding
J. Endocrinol.,
January 1, 2007;
192(1):
3 - 15.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. Ohiwa, H. Chang, T. Saito, T. Onaka, T. Fujikawa, and H. Soya
Possible inhibitory role of prolactin-releasing peptide for ACTH release associated with running stress
Am J Physiol Regulatory Integrative Comp Physiol,
January 1, 2007;
292(1):
R497 - R504.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. A. Bechtold and S. M. Luckman
Prolactin-Releasing Peptide Mediates Cholecystokinin-Induced Satiety in Mice
Endocrinology,
October 1, 2006;
147(10):
4723 - 4729.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Ueta, Y. Ozaki, J. Saito, and T. Onaka
Involvement of Novel Feeding-Related Peptides in Neuroendocrine Response to Stress
Experimental Biology and Medicine,
November 1, 2003;
228(10):
1168 - 1174.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. B. Lawrence, K. L. J. Ellacott, and S. M. Luckman
PRL-Releasing Peptide Reduces Food Intake and May Mediate Satiety Signaling
Endocrinology,
February 1, 2002;
143(2):
360 - 367.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. L. J. Ellacott, C. B. Lawrence, N. J. Rothwell, and S. M. Luckman
PRL-Releasing Peptide Interacts with Leptin to Reduce Food Intake and Body Weight
Endocrinology,
February 1, 2002;
143(2):
368 - 374.
[Abstract]
[Full Text]
[PDF]
|
|
|
Top
Abstract
Introduction
