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-MSH in the regulation of consummatory behavior:
immunohistochemical evidence
1 Minnesota Obesity Center, Research Service, Veterans Affairs Medical Center, Minneapolis 55417; Departments of 2 Medicine and 3 Psychiatry, University of Minnesota, Minneapolis 55455; and 4 Bethel College, Arden Hills, Minnesota 55112
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Central injection of
-melanocyte-stimulating hormone (-MSH) decreases food intake,
suggesting a role for this peptide in the mediation of satiety.
Inasmuch as -MSH also supports the development of taste aversions
under certain conditions, the nature of its influence on ingestive
behavior, i.e., whether it is related to satiety or aversion, remains
unclear. In the present studies, we used immunostaining, including that
for c-Fos as a marker of neuronal activation, to further substantiate
the physiological role for -MSH in the regulation of consummatory
behavior. We found that an increase in activation of -MSH neurons in
the arcuate nucleus coincided with meal termination. Administration of
powerful aversive agents, LiCl and CuSO4, did not stimulate
-MSH cells but did induce pronounced activation of oxytocin (OT) and
vasopressin (VP) neurons, the final components of circuitry mediating
aversion. We observed fewer Fos-positive OT/VP neurons after -MSH
injection into the lateral ventricle or into the hypothalamic
paraventricular nucleus, treatments that cause mild or no aversion,
respectively. The degree of activation of OT/VP neurons paralleled the
magnitude of aversive response to a given treatment. Our data support
the hypothesis that, in the arcuate nucleus, -MSH acts as a satiety mediator independent from aversion-related mechanisms.
melanocortins; feeding; c-Fos; taste aversion; hypothalamus
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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-MELANOCYTE-STIMULATING
HORMONE (-MSH) belongs to a large family of peptides derived
from a common precursor molecule, proopiomelanocortin (POMC). Within
the brain, -MSH acts as an endogenous ligand for the melanocortin-3
and -4 receptors (MC3-R and MC4-R), which are widespread throughout the
central nervous system (18).
A growing body of evidence suggests an inhibitory role for this peptide
in food intake and energy storage. Central administration of -MSH
and the synthetic ligands of the MC3/4-R powerfully inhibits food
intake in rats and mice under various experimental conditions; such
effects have been observed after intracerebroventricular (ICV) as well
as site-specific injections of these compounds (6, 8, 17, 19,
25). The paraventricular nucleus of the hypothalamus (PVN) is
one of the maximally responsive sites in terms of the anorexigenic
effects observed after -MSH injection into this region (8,
14). Also, fasting is accompanied by reduced expression of the
gene encoding POMC in the hypothalamic arcuate nucleus (ARC), and POMC
mRNA is upregulated in the overfed state (9). Huszar et
al. (12) reported that genetic deletion of the MC4-R in
mice leads to obesity. Anatomic studies have revealed the presence of
fibers and fiber terminals containing -MSH and/or receptors recognizing this peptide in areas of the brain involved in the regulation of consummatory behavior, such as the ARC and the
hypothalamic ventromedial (VMH), dorsomedial (DMH), and paraventricular
(PVN) nuclei (10, 18, 26). The ARC and nucleus of the
solitary tract are the sites where POMC-expressing neurons are amassed. The ARC appears to be the source of -MSH-immunoreactive fibers that
innervate the feeding-implicated hypothalamic areas (26). ARC-derived -MSH input to the PVN has been proposed to be a crucial component of the mechanism through which melanocortins affect feeding
(3, 6, 13).
A decrease in food intake is not the only effect of centrally
administered -MSH on consummatory behavior. Several authors have
reported aversive properties of melanocortins. ICV injections of
-MSH and synthetic agonists that bind avidly to MC3-R lead to the
acquisition of conditioned taste aversion (CTA) (1, 25,
29), a well-described phenomenon that develops when a novel
taste is associated with a short-term unpleasant gastrointestinal sensation (5). Intriguingly, -MSH administered directly
into the PVN, a site that mediates not only satiety but also aversive effects (27), does not induce CTA, and a high dose of the
PVN-administered MC3/4-R agonist MTII produces only a weak aversive
response (29). In addition, peripherally injected -MSH
significantly delays the extinction of LiCl-induced CTA
(24). Thus PVN vs. ICV injection data are contradictory,
calling into question whether endogenous ARC-derived -MSH is
involved in the mediation of satiety and/or in the mediation of
aversive effects.
The aim of the present series of experiments was to further
substantiate the role of -MSH in the regulation of consummatory behavior. We examined whether activation of -MSH-containing neurons in the ARC 1) coincides with the time of meal termination
and 2) occurs on the peripheral administration of LiCl and
CuSO4, agents known to induce a powerful aversive response.
In addition, we compared the effect of ICV- and PVN-injected -MSH on
activation of oxytocin (OT) and vasopressin (VP) neurons in the PVN and
supraoptic nucleus (SON) with the effect induced by peripherally
injected LiCl and CuSO4. OT and, to a lesser extent, VP
cells in the hypothalamus are considered the final component of the
circuitry mediating aversive responses (27). Therefore,
activation of neurons containing these peptides may reflect activity of
the pathways involved in the development of CTA. We also assessed
general c-Fos immunoreactivity in the PVN, SON, and ARC after
administration of the aversive agents or -MSH.
Activation of neurons and their biochemical characterization were assessed by applying immunohistochemical techniques that included c-Fos staining as the marker of neuronal activation.
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MATERIALS AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Animals
Adult male Sprague-Dawley rats (Charles River Laboratories, Wilmington, MA), weighing ~300 g at the beginning of the experiment, were housed individually in wire-mesh cages with a 12:12-h light-dark schedule (lights on at 0700) in a temperature- and humidity-controlled room. Water and food (Certified Rodent Chow, Teklad, Indianapolis, IN) were available ad libitum except when noted otherwise.Experiment 1: -MSH as a Mediator of Satiety
Feeding studies and perfusion schedule. Rats had access to chow only once a day from 1100 to 1200 for 2 wk before the experiment. Rats ate 13-18 g of chow per day; they began consumption immediately after presentation of food and finished feeding at ~1150-1200.
On the experimental day, animals were randomly divided into six groups (n = 4-5/each): three groups were allowed access to chow from 1100 to 1200, and the remaining groups had no food available. Inasmuch as maximum c-Fos immunoreactivity can be observed ~60 min after the actual onset of neuronal activation (28), rats were perfused with the fixative at 1200, 1300, and 1400 for visualization of Fos expression in-MSH neurons
coinciding with the time of initiation and termination of a meal as
well as 1 h after completion of a meal. Control animals had no
access to chow on the experimental day and were perfused at the same
times as fed rats.
After the perfusion, brains were removed and processed for further
immunohistochemical analysis: double staining for c-Fos and -MSH in
the ARC.
Experiment 2: -MSH as a Mediator of Taste Aversion
Surgical procedures. Some rats used in these experiments were equipped with an indwelling stainless steel cannula in the right lateral ventricle (20 gauge) or the PVN (26 gauge). The stereotaxic coordinates were assessed according to the atlas of Paxinos and Watson (23) and were as follows: 1) for right lateral ventricle, 1.0 mm lateral to the midline, 1.5 mm caudal to bregma, and 3.5 mm below the surface of the skull and 2) for PVN, 0.5 mm lateral to the midline, 1.9 mm caudal to bregma, and 7.3 mm below the surface of the skull. The injector needle extended 1 mm below the tip of the guide cannula. Dental cement was used to secure the cannula to two screws inserted in the skull. Surgeries were performed under pentobarbital sodium (Nembutal) anesthesia (50 mg/kg body wt ip). Seven days of postoperative recovery were allowed before the experimental trials began.
Water intake measurement after the injection of ANG II (100 ng; Sigma Diagnostics, St. Louis, MO) verified cannula placement in the lateral ventricle; those rats that drank <5 ml of water within 20 min after the injection of the peptide were excluded from the study. Placement of the PVN cannula was verified on the basis of the increase in food intake after administration of neuropeptide Y (117 pmol; Peninsula Laboratories, Belmont, CA). Animals that did not consume
3
g of chow within 1 h after injection were considered to have an
incorrectly placed cannula. In addition, after the completion of
experiments, rats were killed and brains were dissected out to
determine cannula positioning by histological examination. Data from
animals with incorrect cannula placements were discarded.
Drug administration and perfusion schedule.
On the experimental day, ad libitum-fed rats were assigned
to groups (n = 5-6/group) and received a single
injection of -MSH (Phoenix Pharmaceuticals, Mountain View, CA) or
isotonic saline in the lateral ventricle or in the PVN. -MSH was
administered ICV at a dose of 6 nmol in a volume of 5 µl and into the
PVN at 0.6 nmol/0.5 µl (29). Animals that had not been
equipped with a cannula were injected intraperitoneally with isotonic
solutions of LiCl (5 meq), CuSO4 (10 mg/kg body wt), or
saline. To prevent c-Fos induction due to feeding or drinking, food and
water were immediately removed from the cages of injected rats. All
injections were performed between 1200 and 1300. At 60 min after the
injection, rats were perfused with the fixative.
-MSH was injected 1) ICV at a dose that inhibits feeding
and causes CTA and 2) into the PVN at a dose that causes
strong anorexigenic response. LiCl and CuSO4 at doses used
in our studies had been shown to produce powerful aversive effects and
the release of OT and VP (27).
After the perfusion, brains were removed and processed for further
immunohistochemical analysis: single staining for the presence of c-Fos
in the PVN, SON, and ARC and double staining for 1) c-Fos and -MSH in the ARC (in rats that had received intraperitoneal injections of LiCl, CuSO4, or saline) or 2)
c-Fos and OT/VP in the SON and PVN (all groups).
Perfusions
Animals were deeply anesthetized with pentobarbital sodium (100 mg/kg body wt ip) and perfused rapidly through the aorta with 75 ml of saline followed by 500 ml of ice-cold 4% paraformaldehyde in 0.1 M phosphate buffer (pH 7.4). Brains were removed and postfixed overnight in the same fixative at 4°C.Sectioning and Immunohistochemistry
Coronal Vibratome sections (40-µm thick) were cut through the regions of the PVN, SON, and ARC. They were processed as free-floating sections for standard double immunostaining.Sections were pretreated for 10 min in 3% H2O2 and 10% methanol [diluted in Tris-buffered saline (TBS), pH 7.4] and routinely incubated for 36 h at 4°C in the primary goat anti-Fos antibody (diluted 1:9,000; Santa Cruz Biotechnology, Santa Cruz, CA). Subsequently, tissue was incubated for 1 h at room temperature in the rabbit anti-goat antibody (1:400; Vector Laboratories, Burlingame, CA). After a 1-h incubation (room temperature) in the avidin-biotin complex, peroxidase in the sections was visualized with 0.05% diaminobenzidine, 0.01% H2O2, and 0.3% nickel sulfate. The vehicle for all incubations in antibodies was a mixture of 0.5% Triton X-100 and 0.25% gelatin in TBS. Intermediate rinsing steps were done in TBS alone.
After the completion of c-Fos staining, sections used for double
immunostaining were further processed for visualization of OT, VP (PVN
and SON), or -MSH (ARC). The general procedure was similar to that
used to stain for the first antigen. However, rabbit anti-OT (1:10,000;
Chemicon, Temecula, CA), rabbit anti-VP (1:6,000; supplied by Dr. Ruud
M. Buijs, The Netherlands Institute of Brain Research, Amsterdam, The
Netherlands), or rabbit anti--MSH was used as primary antibody; thus
sections were incubated for 1 h in goat anti-rabbit antibody
(1:400; Vector Laboratories). Nickel sulfate was not added to the
diaminobenzidene solution to obtain the brown, instead of black, staining.
Sections were mounted on gelatin-coated slides, air-dried, dehydrated in alcohols, soaked in xylene, and embedded in Entellan (Merck, Switzerland).
Data Analysis
Activation of OT, VP, and-MSH cells was studied by the
analysis of c-Fos expression in the immunohistochemically characterized neurons in the SON, PVN, and ARC. Twelve sections per region that contained neurons expressing VP, OT, or -MSH (Table
1) were used for the analysis in each
animal. The following estimates per section and then, by adding up the
numbers, per region were assessed: 1) the total number of
OT, VP, and -MSH neurons and 2) the total number of
Fos-immunoreactive nuclear profiles colocalizing with these peptides.
In the brains of IP- and ICV-injected or schedule-fed animals, PVN OT
and VP cells were counted bilaterally, whereas in PVN-injected rats,
only cells on the cannulated side of the nucleus were counted.
The percentage of Fos-positive OT, VP, and -MSH neurons was
calculated per region per animal. The percentages were averaged over
the particular region and peptide for each experimental group.
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The analysis of single staining for c-Fos was performed on six sections per region per animal. Images provided by Dage-MTI DC triple charge coupled device camera attached to a Nikon Eclipse 400 microscope were analyzed using Scion Image software. Densities of Fos-positive nuclei (per 1 mm2/region) were averaged per animal and then per experimental group.
Statistical analysis of data was performed using ANOVA followed by Fisher's least significance test. Values were considered significantly different when P < 0.05. Values are means ± SE.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Experiment 1: -MSH as a Mediator of Satiety
-MSH neurons
colocalizing with c-Fos was detected only in animals that had been given access to food and were perfused at 1300 (Figs.
1 and 2). The time
corresponding to the termination of a meal is 1300, with a 60-min delay
in the peak of Fos immunoreactivity taken into account.
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Experiment 2: -MSH as a Mediator of Taste Aversion
-MSH-immunoreactive (IR) neurons in the ARC (Fig.
5).
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ICV administration of -MSH induced activation of OT and VP cells in
both analyzed hypothalamic regions, with 21-40% of these neurons
coexpressing c-Fos (Figs. 3 and 4).
Enhanced activation of OT and VP neurons in the PVN was also observed
as a result of direct administration of -MSH into the PVN; however,
the levels of colocalization did not exceed 19%. PVN-administered
-MSH had no effect on activation of OT or VP cells within the SON
(Figs. 3 and 4).
Studies employing a single antigen staining for c-Fos revealed that
ICV-injected -MSH had a stimulatory effect similar to that of
intraperitoneally injected LiCl and CuSO4 on induction of
c-Fos immunoreactivity in unidentified PVN and SON neurons. In
contrast, administration of the melanocortin receptor agonist directly
into the PVN did not result in a statistically significant increase in
the number of Fos-positive nuclear profiles in the PVN or SON. Neither
of the treatments had an effect on Fos immunoreactivity in the ARC
(Table 2).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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The majority of data suggesting that -MSH is involved in the
control of feeding comes from injection studies showing that this
peptide and other ligands of the MC3/4-R administered centrally induce
anorexigenic responses (6, 8, 14, 17, 19, 25). Research
utilizing molecular techniques, as well as anatomic analyses, provides
additional evidence supporting this notion (3, 6, 9, 10, 13, 18,
26). However, several investigators reported aversive actions of
melanocortins (1, 25), which calls into question the
nature of influence that the -MSH system exerts on consummatory
behavior, i.e., whether it is related to satiety/energy balance- or
aversion-mediating mechanisms. The present studies demonstrate that
enhanced c-Fos immunoreactivity in ARC -MSH neurons coincides with
the termination of a meal. Activation of -MSH-containing cells at
the beginning of the meal as well as 1 h after completion of the
meal was very low; the percentage of Fos-positive -MSH neurons was
as low as that seen in animals that had received no food. To our
knowledge, this is the first study that shows that activation of ARC
-MSH neurons and meal termination occur simultaneously, suggesting
that ARC-derived -MSH plays a physiological role in the regulation
of food intake, serving as a central satiety mediator.
The fact that the extinction of c-Fos immunoreactivity in -MSH
neurons could be seen in animals killed as soon as 2 h after completion of the meal is interesting, inasmuch as some c-Fos expression generally can be detected immunohistochemically even 2-5 h after the stimulus was applied. One possible explanation of
this rapid shutoff of neuronal activation is that although -MSH
neurons may participate in meal termination, they are unlikely to play
a role in the continuing satiety that persists after meal termination.
This phenomenon may be also linked to the nature of feeding induced by
time restriction: in a relatively short time, animals have to satisfy
their daily food intake requirement; thus they ingest amounts of food
that are much greater than those consumed in one meal (of several that
occur during a 24-h period) by ad libitum-fed rats. Therefore,
in schedule-fed animals, satiety signaling in the brain, including that
provided by the -MSH system, may be to some extent modified by
factors that maintain food intake. This assumption can be supported by
the recent findings that showed a functional relationship between the
opioid system, which is thought to play a role in the maintenance of
feeding, and melanocortins in the regulation of food intake.
Certain chemical agents induce aversive responses when paired with
novel flavors; LiCl and CuSO4 have been found to be
particularly effective in generating CTA (20). Peripheral
injections of these compounds result in the onset of complex neural and
endocrine mechanisms that underlie the development of CTA (21,
27). Our studies reveal that peripheral administration of LiCl
or CuSO4 does not increase the percentage of ARC -MSH
neurons colocalizing with c-Fos-IR nuclear profiles, indicating that
ARC-derived -MSH does not mediate CTA induced by these compounds.
This suggests that, in general, the population of cells containing this
peptide may not be a component of aversive mechanisms. Single
c-Fos-staining data, which showed no effect of taste aversion-inducing
treatments on Fos immunoreactivity in the ARC, indicate that other
neuronal populations present in this region are also unlikely to
participate in the acquisition of CTA.
Anatomic studies have revealed that the SON and PVN contain the major
populations of OT and VP cells. These neurons send projections to
various brain regions, ranging from the autonomic centers in the brain
stem to limbic structures and neocortex. Numerous terminals of OT and
VP neurosecretory axons originating from the PVN and SON are present in
the neurohypophysis (11). Neurohypophysial secretion of OT
and VP has been observed after peripheral administration of LiCl and
CuSO4 at doses similar to those utilized in our experiments (27). A significant increase in c-Fos immunoreactivity of
OT and VP neurons as a result of CTA-inducing treatments has been previously reported (22). We found that 40-55% of OT
and VP neurons encompassed in the PVN and SON were activated after the injection of LiCl and CuSO4. ICV injection of -MSH,
which generates relatively mild and short-lasting taste aversion
(29), induced a less robust (21-40%) response of
these neurons. However, the doses of LiCl and CuSO4 used in
our experiments were higher than those required to induce CTA
(27). Probably the use of lower doses of these compounds
would have produced activation of OT and VP neurons more equivalent to
that observed after ICV -MSH administration. Interestingly,
PVN-administered -MSH, the treatment that does not produce aversive
behavioral effects (29), caused an increase in the
percentage of activated OT and VP neurons in the PVN. However, the
levels of Fos-OT/VP colocalization were relatively low and did not
exceed 19%. Also, activation of OT/VP neurons in the SON was not
affected by a direct infusion of -MSH into the PVN. Our data
indicate that the degree of activation of OT and VP neurons can
parallel the magnitude of aversive response to a given treatment. As
reflected by the presence of c-Fos-positive nuclei in OT and VP cells
after a direct PVN administration of -MSH, these cells might be the
target neurons for the melanocortins. As revealed by single staining
for c-Fos, -MSH infusion into the PVN did not cause a significant
increase in the total number of Fos-positive nuclear profiles in this
region. Although c-Fos staining does not exclude a possibility that the
melanocortin receptor agonist acts on populations of PVN cells other
than those that contain OT and VP, it provides strong evidence
that OT and VP neurons may play an important role in mediating
-MSH-induced satiety.
Fewer OT/VP cells exhibit Fos immunoreactivity after a direct injection
of -MSH into the PVN, rather than ICV administration. Also, general
levels of c-fos expression in the PVN and SON are higher
because of the action of ICV- vs. PVN-administered -MSH. These
results suggest that, as a result of ICV infusion, binding of -MSH
to its receptors in various regions surrounding the ventricles occurs,
leading to activation of numerous pathways via direct and indirect
input. Simultaneous activation by -MSH of various types of circuitry
involved in different physiological processes, including those
unrelated to feeding regulation, may potentially cause nonspecific
effects. PVN injection of this peptide may limit the affected
melanocortin receptors to those that are directly engaged in satiety
mechanisms. Therefore, we propose that CTA observed after ICV
administration of -MSH may be due to the massive binding of this
peptide occurring simultaneously in numerous sites, thus engaging
multiple actions of -MSH. Other anorexigenic peptides follow a
pattern similar to that observed with -MSH, e.g., glucagon-like peptide-1-(7-36) amide generates aversive effects
when injected ICV but not site specifically (16).
The PVN appears to be one of the most important areas of melanocortin
action on feeding. It is one of the sites where -MSH modulates the
orexigenic signal of neuropeptide Y, a potent inducer of food
intake (4). Anatomic studies have revealed the presence of
melanocortin receptors and -MSH-IR fibers and terminals in this
region. -MSH-containing terminals form synaptic connections with
neurons thought to be involved in the regulation of food intake
(7). The current set of experiments suggests that OT and
VP cells in the PVN may be target neurons for melanocortinergic input:
we observed that direct PVN administration of -MSH affected activation of these neurons. OT and VP, apart of their involvement in
the aversive processes, have been implicated in the mediation of
satiety (2, 15). It has been recently suggested that MC4-R is particularly engaged in the regulation of satiety-related
mechanisms, whereas aversive effects are related to MC3-R
(1). Thus it would be of particular importance to
investigate whether OT and VP cells express the melanocortin receptors,
which could help define the nature of -MSH influence on OT and VP systems.
The present studies provide further evidence that ARC-derived
-MSH acts as a mediator of satiety, not aversion. In addition, the
results indicate that OT and VP cells in the PVN may be target neurons
for -MSH.
Perspectives
The majority of data on the role of-MSH in feeding regulation
comes from injection studies (6, 8, 14, 17, 19, 25). In
those studies, -MSH was shown to induce anorexigenic responses and
play a role in energy balance regulation. The present set of
experiments allows a more accurate description of the physiological importance of the -MSH system in feeding, placing this system in the
cascade of neural events underlying consummatory behavior. On the basis
of the results of the present study, we more confidently use the phrase
"satiety mediator" in reference to -MSH, inasmuch as we have
shown that the actual activation of neurons that contain -MSH
coincides with the meal termination, which, one may assume, reflects satiety.
Most probably, -MSH exerts its influence on food consumption by
interacting with other systems containing a variety of neuropeptides, being a part of circuitry responsible for the mediation of satiety. Inasmuch as direct PVN administration of -MSH affected activation of
OT and VP cells encompassed in the PVN, OT/VP cells in this region may
be target neurons for melanocortinergic input. Importantly, OT and VP
have been proposed to be satiety factors, in addition to their
involvement in a variety of other processes and mechanisms (2,
15). Thus it would be of particular interest to determine 1) whether -MSH affects OT/VP neurons directly, through
the melanocortin receptors present on these cells, or
indirectly, via other neurons that form synaptic connections with OT/VP
cells, and 2) whether interactions between the -MSH and
OT/VP systems are indeed related to feeding regulation.
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ACKNOWLEDGEMENTS |
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This work was supported by the Department of Veterans Affairs, National Institute on Drug Abuse Grant DA-03999, and National Institute of Diabetes and Digestive and Kidney Diseases Grants DK-42698 and P30 DK-50456.
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FOOTNOTES |
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Address for reprint requests and other correspondence: A. S. Levine, Veterans Affairs Medical Center, Research Service 151, One Veterans Dr., Minneapolis, MN 55417 (E-mail: allenl{at}tc.umn.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 2 November 2000; accepted in final form 23 March 2001.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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