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1 Department of Psychology, University of Alabama at Birmingham, Birmingham, Alabama 35294-1170; and 2 Department of Psychiatry, University of Cincinnati Medical Center, Cincinnati, Ohio 45267
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Agouti-related peptide (AgRP) is a receptor antagonist of central nervous system (CNS) melanocortin receptors and appears to have an important role in the control of food intake since exogenous CNS administration in rats and overexpression in mice result in profound hyperphagia and weight gain. Given that AgRP is heavily colocalized with neuropeptide Y (NPY) and that orexigenic effects of NPY depend on activity at opioid receptors, we hypothesized that AgRP's food-intake effects are also mediated by opioid receptors. Subthreshold doses of the opioid receptor antagonist naloxone blocked AgRP-induced intake when given simultaneously but not 24 h after AgRP injection. Opioids not only influence food intake but food selection as well. Hence, we tested AgRP's effect to alter food choice between matched diets with differing dietary fat content. AgRP selectively enhanced intake of the high-fat but not the low-fat diet. Additionally, AgRP selectively increased chow intake in rats given ad libitum access to a 20% sucrose solution and standard rat chow. The current results indicate that AgRP influences not only caloric intake but food selection as well and that the early effects of AgRP depend critically on an interaction with opioid receptors.
melanocortin; obesity; hyperphagia; enkephalin; naloxone
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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AGOUTI-RELATED PEPTIDE (AgRP) is an endogenous antagonist of central nervous system (CNS) melanocortin receptors, and several lines of evidence point to this peptide as having potent influences on food intake and body weight. AgRP is a peptide synthesized in the arcuate nucleus and projects to other key feeding hypothalamic nuclei and sites throughout the brain (2, 19, 26). Transgenic mice that overexpress AgRP are obese and hyperphagic (13), and mice that are obese as a consequence of deficient circulating leptin (ob/ob) or dysfunctional leptin receptors (db/db) have significant elevations of hypothalamic AgRP mRNA (3, 29, 31, 38). Energy deficiency in animals is associated with increased hypothalamic mRNA (18, 29) and AgRP-like immunoreactivity (25), and central administration of the fragment AgRP-(83-132) (35) increases food intake (16, 36). Thus the hypothesized function of AgRP in the CNS is to promote feeding and weight gain when animals are in negative energy balance.
The mechanisms by which AgRP stimulates feeding are not entirely
understood. One established method of AgRP action is competitive binding as an endogenous antagonist at melanocortin 3 and 4 receptors (MC3/4-R) where AgRP inhibits signaling of 
-melanocyte-stimulating hormone, a proopiomelanocortin-derived hormone indicated to tonically limit food intake (4, 9, 14, 17, 39). However, closer examination of the orexigenic properties of AgRP suggests additional alternate mechanisms of action. For example, a unique property of
AgRP's orexigenic effects is its unparalleled long-lasting stimulation
of food intake (infusion of a single picomolar dose produces
hyperphagia in mice lasting 7 days). Although the acute hyperphagia is
suppressed by central MC3/4-R agonist treatment, the long-term
hyperphagia is not (16). In addition, mice deficient of
MC4-R respond normally to AgRP's orexigenic effects (28).
A recent comparison of c-Fos-like expression induced by AgRP-(83-132) and neuropeptide Y (NPY), another potent orexigenic peptide (6, 30), suggests that both acutely activate parallel neuroanatomic circuits (14a). Hence, unknown mechanisms involved in AgRP-induced feeding may involve those underlying NPY-induced feeding. This hypothesis is supported by evidence of common physiological links between NPY and AgRP. For example, all AgRP terminals detected contain NPY (5), and AgRP mRNA is extensively coexpressed in NPY neurons (18). NPY and AgRP neurons contain leptin-receptor mRNA, and much evidence points to their mutual regulation by leptin (3, 29, 40).
A key CNS mediator of NPY-induced feeding and energy regulation is the
CNS opioid system (22, 37). In light of the aforementioned behavioral and morphological links between NPY and AgRP, we hypothesize that opioid receptors may also play a key role in mediating AgRP's potent effects on food intake. Therefore, we explored the involvement of opioid receptors in AgRP's orexigenic effects by testing the effect
of a µ-
antagonist on the acute and long-term hyperphagia induced
by AgRP infusion. Because opioid receptors have been
hypothesized to be involved in determining not just caloric intake but
aspects of food choice as well, we also compared effects of an opioid receptor antagonist and AgRP on two different food choice situations.
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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. A total of n = 85 male Long-Evans rats, weighing 380-440 g at the onset of the experiments, individually housed and maintained on a 12:12-h light-dark cycle was implanted with a cannula aimed at the third cerebral ventricle (i3vt). Coordinates for this site were midline, 2.2 mm posterior to bregma, and 7.5 mm ventral to dura (32). After a minimum 10 days of recovery, accuracy of the i3vt placement was verified by cannula infusion of 10 ng angiotensin in saline. Only animals that drank at least 5 ml in a 1-h period were used in the experiments. By this criteria, 10 animals were excluded leaving 75 rats of which 26 served in experiments 1, 2A, and 2B, 27 in experiments 3, 4, and 5, and 22 in experiment 6. Protocols were approved by the University of Cincinnati Institutional Animal Care and Use Committee.
Chemicals. AgRP-(83-132) was purchased from Phoenix Pharmaceuticals (Mountain View, CA). Naloxone hydrochloride (NALX) was purchased from Sigma (St. Louis, MO). Both substances were dissolved in physiological saline, which served as the control solution. AgRP and control saline were administered i3vt in a 2-µl volume; NALX and control saline were injected intraperitoneally.
Diets.
Animals were maintained on regular rat chow (Harland-Teklad,
Indianapolis, IN) from the time of weaning. However, high-fat (HF) and
low-fat (LF) pellets manufactured by Dyets (Bethlehem, PA) were used in
experiments 3 and 4. The macronutrient
composition of these diets compared with regular rat chow is given in
Table 1.
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Experiment 1: dose response of NALX on intake of chow. To determine a threshold and subthreshold dose of NALX to suppress intake, a group of 27 animals was weight and baseline-intake matched into one of four groups (n = 6-7/group), each to be injected intraperitoneally with either saline, 0.3, 1.0, or 3.0 mg/kg NALX. Food was taken away 2 h before injections that were administered 30 min before lights off. Premeasured chow was presented 5 min before lights off and measured after 1, 2, 3, 4, and 24 h.
Experiment 2A: effect of NALX on AgRP-(83-132)-induced food intake of chow when injected simultaneous with AgRP-(83-132). To test the involvement of opioid receptors in the acute phase of AgRP-induced intake 2 wk after experiment 1, the animals were counterbalanced for prior drug treatments and also weight and baseline-intake matched into one of four groups (n = 6-7/group). On the day of testing, all food was removed 2 h before lights off, and at 30 min before lights off, animals were infused with either saline + saline, saline + 0.3 mg/kg NALX, 1 nmol AgRP + saline, or 1 nmol AgRP + 0.3 mg/kg NALX. This dose of AgRP elicits a reliable and long-lasting increase in food intake (16, 36). The first (i3vt) injection was followed 10 min later by the second intraperitoneal injection. Five minutes before lights off, premeasured rat chow was placed in the cages. Water was available at all times. Food intake was measured at 1, 2, 3, 4, and 24 h.
Experiment 2B: effect of NALX on AgRP-(83-132)-induced food intake of chow when injected 24 h after AgRP-(83-132). To test the involvement of opioid receptors in the long-term phase of AgRP-induced intake 2 wk after experiment 2A, the animals were again reassigned to one of four groups (saline + saline, saline + NALX, AgRP + saline, or AgRP + NALX), counterbalanced for prior drug treatment. This time, however, the intraperitoneal NALX or control saline injection was administered 24 h after the i3vt AgRP or saline injection. Food presentation and measurements were as in experiment 2A.
Experiment 3: effect of NALX on the intake of an
HF vs. an LF diet.
To further characterize specific properties of food intake mediated by
an opioid AgRP interaction, this experiment was conducted to first test
the effect of opioid blockade on diets varying in fat composition. A
different squad of animals (n = 26) was weight and
baseline-intake matched into one of three groups each receiving either
saline, 0.3 mg/kg NALX, or 5.0 mg/kg NALX ip (n = 8-9/group). It was determined from experiment 1 that
3.0 mg/kg acted as a threshold dose to suppress intake (Fig.
1). To evaluate the anorectic effect of
NALX between an HF and an LF diet, we chose to inject a clearly
suprathreshold dose, 5.0 mg/kg NALX. To avoid neophobia to the novel
diets, the animals were given ad libitum amounts of HF and LF pellets
in separate food hoppers alongside of each other in their cages for 2 days before the infusions. On the day of testing, procedures were as in
experiments 2A and 2B, except that two hoppers
were placed side by side in the cages, each containing premeasured HF
and LF pellets. Food intake was measured at 1, 2, 3, 4, and 24 h
after injection. During the following week, animals were maintained on
regular chow and water only and then reassigned into three groups. The
experiment was repeated, except animals that previously received saline
now were injected with either 5.0 mg/kg NALX or 0.3 mg/kg NALX, and
those that were previously injected with NALX were now injected with
saline.
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Experiment 4: effect of AgRP-(83-132) on the intake of an HF vs. an LF diet. To compare the anorectic effect of opioid blockade to the orexigenic effect of AgRP on an HF vs. an LF diet, the animals were maintained on regular chow for 2 wk after completion of experiment 3 and then counterbalanced for prior drug treatments as well as weight and baseline intake into two groups (n = 13-14/group), one to be injected i3vt with 1 nmol AgRP-(83-132) and the other with i3vt saline. As in experiment 3, the animals were allowed to once again acclimate to the HF and LF diets, and the same injection and food presentation procedures were followed. Food intake was measured at 1, 2, 3, 4, 24, 48, and 72 h after injection.
Experiment 5: effects of AgRP-(83-132) on the intake of a 20% sucrose solution vs. chow. This test was conducted to test whether AgRP-induced selective hyperphagia for the HF diet may have been influenced by an increased motivation toward intake of a preferred food. Two weeks after experiment 4, the animals were acclimated to a 20% sucrose solution for 2 days, and 4-h baseline intake of sucrose solution and chow was recorded on the second day. The sucrose concentration was chosen based on its hedonic properties in rats (20, 23). The animals were then counterbalanced for prior drug treatment and total chow + sucrose kilocalories consumed on the second day of acclimation and were assigned to two groups to receive either i3vt saline (n = 7) or 1 nmol AgRP (n = 8). Procedures were as in experiment 4, except the animals were presented with premeasured 20% sucrose solution, chow, and water. Amount of intake was recorded after 1, 2, 3, 4, 24, and 48 h.
Experiment 6: effect of AgRP-(83-132) on the intake of a 20% sucrose solution as the only available choice. This experiment was conducted to test whether AgRP might have induced hyperphagia of the 20% sucrose solution if chow had not been available as a choice. A different group of animals (n = 22) was surgically prepared and evaluated for cannula placement as in experiment 1. Also as previously described, they were assigned to two groups (n = 11/group) and injected i3vt with either 1 nmol AgRP or saline. For the first 4 h from dark onset, only ad libitum 20% sucrose solution was given, and for the following 20 h, chow was presented along with the sucrose. Water was available at all times. Sucrose intake was measured during the first 30 min, 1, 2, and 24 h of presentation, and chow was measured 20 h after presentation.
Data analysis. Data represent mean food intake (kcal) ± SE. Each experiment was analyzed with a one-way or a two-way ANOVA (for experiments where doses of both NALX and AgRP were administered). Significant main effects were analyzed for differences between groups using Tukey's HSD post hoc test with significance set at P < 0.05.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Experiment 1: dose response of NALX on intake of chow. As shown in Fig. 1, doses of intraperitoneal NALX from 0.3 to 3.0 mg/kg did not significantly suppress intake in the first hour, and only 3 mg/kg significantly reduced intake from 2 to 4 h after injection. Animals compensated for the early anorectic effect of NALX so that by 24 h, no difference in total intake was detected between groups that received AgRP + saline and AgRP + NALX (data not shown).
Experiment 2A: effect of NALX on
AgRP-(83-132)-induced food intake when injected
simultaneous with AgRP-(83-132).
As shown in Fig. 2A, a dose of
0.3 mg/kg NALX did not in itself affect food intake. AgRP + saline
produced intake 85% greater than saline + saline-treated animals
and, although not shown, continued to stimulate intake at 24 h
(23.6 ± 2 vs. 37 ± 4 g; P < 0.001).
More importantly, NALX, at the subthreshold dose, significantly reduced
AgRP-induced eating to the level of saline + saline intake as
early as hour 1 and continued to suppress it for 3 h
(P < 0.05; not shown). The anorectic effect of NALX on AgRP-induced eating disappeared by hour 4, and by 24 h,
animals treated with AgRP + NALX compensated for their early
decreased intake to match that of animals treated with saline + AgRP (44.2 ± 1 vs. 38.5 ± 4 g, not significant;
P < 0.01 different from saline + saline
intake).
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Experiment 2B: effect of NALX on AgRP-(83-132)-induced food intake when injected 24 h after AgRP-(83-132). After 24 h, rats receiving AgRP were still hyperphagic as shown in Fig. 2B. However, and in contrast to experiment 2A, when NALX was injected 24 h after AgRP, it failed to reduce the sustained AgRP-induced hyperphagia at 1 h (Fig. 2B) or 2-4 h after NALX injection (not shown). This result indicates that the long-term effects of AgRP do not depend on continued activation of opioid receptors. Additionally, this result indicates that the subthreshold dose of NALX is truly subthreshold even when the baseline intake is higher than in an untreated rat and that the results of experiment 2A are not simply the result of NALX's effects depending on the baseline to which it is compared.
Experiment 3: effect of NALX on the intake of an
HF vs. an LF diet.
Intake measures taken on the second day of acclimation to the novel
diets (a day before injections) showed that 100% of the animals ate
more kilocalories from the HF than LF diet in a 24-h period, and
94 ± 3% of this intake was composed of the HF diet compared with
6 ± 1% of the LF diet. The subthreshold dose of 0.3 mg/kg used in experiment 1 on the intake of regular rat chow also proved to be subthreshold for reducing intake of the HF and LF
diets. However, and as depicted in Fig.
3A, an anorectic dose of 5.0 mg/kg NALX significantly and preferentially reduced intake of the HF
diet to 38, 52, and 64% of controls' intake at hours 1,
2, and 3, respectively. NALX did not reduce
intake of the LF diet and, in fact, as shown in Fig. 3B, the
trend was for NALX to increase intake of the less- preferred LF diet,
although this was not statistically significant.
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Experiment 4: effect of AgRP-(83-132) on the
intake of an HF vs. an LF diet.
Measures taken on the second day of acclimation to the novel diets and
a day before injections showed that 100% of the animals ate more
kilocalories of the HF than LF diet in a 24-h period, and 84 ± 2% of this intake was composed of the HF diet compared with 16 ± 2% of the LF diet. As shown in Fig.
4A, AgRP did not change the
animals' apparent preference for the HF diet but increased it to 77, 91, and 79% more than controls' HF intake during hours 2,
3, and 4 postinjection, respectively.
Interestingly, AgRP had no effect on the LF diet, with animals eating
equally low amounts of this diet as controls (Fig. 4B). The
long-lasting orexigenic effects of AgRP are illustrated in Fig.
5A. AgRP sustained hyperphagia of the HF diet with animals eating 55% more of the diet than controls, even 72 h after AgRP injection. LF intakes beyond 24 h
remained low under both treatments, differing only at 72 h when
controls ate more of the LF diet than AgRP-treated animals (6.5 ± 1.2 vs. 2 ± 0.5 kcal; P < 0.001; data not
shown). As shown in Fig. 5B, a consequence of AgRP-induced
HF intake was considerable overnight weight gain.
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Experiment 5: effects of AgRP-(83-132) on the
intake of a 20% sucrose solution vs. chow.
Baseline intakes at 4 h revealed that a majority of the 15 rats
consumed more kilocalories of sucrose solution than chow, 9 consumed
more sucrose (5-15 more kcal) than chow, 4 consumed approximately
as much sucrose and chow (a <3-kcal difference between choices),
and 2 consumed more chow than sucrose (3-9 more kcal). As shown in
Fig. 6A, animals treated with
AgRP ate significantly more kilocalories of chow than sucrose solution
when given a choice (Fig. 6B), and the hyperphagia remained
specific for chow long term (Fig.
7A) with no increase in
sucrose intake compared with saline treatment (Fig. 7B).
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Experiment 6: effect of AgRP-(83-132) on the
intake of a 20% sucrose solution as the only available choice.
As shown in Fig. 8A, even when
the only nutrient available to the rats was a palatable 20% sucrose
solution, AgRP did not increase its intake relative to saline. However,
when chow was also made available, AgRP produced hyperphagia, but only
on the intake of chow (Fig. 8B), with AgRP-treated rats
consuming 207% more chow kilocalories than controls, indicating that
the AgRP infusion had been effective. Even at this time point, the
intake of sucrose with AgRP treatment did not significantly differ from amounts consumed with saline treatment (45 vs. 35 ± 6 g,
respectively; P > 0.05; not shown).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Central administration of AgRP-(83-132) produces a potent and unique long-lasting hyperphagic pattern in rats. We previously found that although the acute increase in food intake after AgRP injection involves antagonistic actions at the MC3/4-R, other CNS receptor systems are likely to be involved (16). The main goal of this study was to test the participation of opioid receptors in mediating AgRP's effects on feeding. Results showed that a subthreshold dose of NALX suppressed AgRP's acute stimulation of food intake but failed to suppress it when delivered 24 h after AgRP administration. Critically, this indicates that the effect of NALX is not simply to lower intake from an elevated baseline. Instead, this rather specifically indicates that the short-term effects of AgRP are mediated by activity at opioid receptors but that the unique long-term effects of AgRP are not. Consistent with the notion that AgRP increases activity at opioid receptors, AgRP was also found to preferentially increase intake of an HF diet over an LF diet, and opioid antagonism preferentially was found to suppress the HF diet over the LF diet.
This suggests that a function of AgRP's early interaction with opioid systems is to drive ingestion of foods with higher fat-to-carbohydrate ratios. Although opioid interactions may not be involved in AgRP's sustained selection of HF food, the response may be dependent on the initial activity change at opioid receptors. Further data will be needed to test this hypothesis with longer-acting opioid antagonists.
Numerous studies support the contribution of opioids in mediating fat-selective intake (7, 15, 27, 41), but evidence also exists to attribute opioids not with stimulation of fat intake per se but with increased intake of an inherently preferred food, regardless of its macronutrient content (8, 12). Baseline intakes taken before our HF vs. LF diet experiment determined that 100% of the animals consumed significantly more of the HF over the LF diet, indicating a preference for the HF diet. Therefore, it was reasonable to argue that if AgRP engaged opioid mechanisms to increase intake of the HF diet, it might do so primarily by increasing the animals' motivation for a preferred food rather than for dietary fat. However, our results showed that the rats greatly preferred the sucrose solution to the plain chow diet in terms of calories consumed. AgRP treatment uniformly stimulated intake of chow in all of the rats including ones with the highest and lowest sucrose preference. Admittedly, this preference is confounded by the physical states of the choices, but an AgRP-induced selective increase for a higher fat diet is consistent with the recent finding that agouti (Ay/a) mice with chronic melanocortin receptor antagonism consume a greater proportion of their intake and gain the most weight from fat when provided with three-choice macronutrient diets (21). Another possibility that must be considered is a function of AgRP on the selective intake of other macronutrients (e.g., carbohydrates). Close neuroanatomic links between AgRP and NPY (5, 18) suggest they may have common macronutrient-selective functions on food intake. Analogous to our results for AgRP, NPY has been shown to preferentially increase intake of chow in a choice test with access to a sucrose solution and rat chow (10).
As with food selection, neuroanatomic sites of AgRP opioid interaction on feeding may also be shared with NPY, specifically with sites implicated in NPY opioid interactions on feeding including the central amygdala, nucleus of the solitary tract, and paraventricular nucleus (11, 21, 34). We have observed increased c-Fos in these nuclei after i3vt injection of AgRP as well as in the nucleus accumbens, a site critical in opioid-mediated rewarding properties of food intake (33). Interestingly, chronic morphine is shown to downregulate MC4-R expression in the nucleus accumbens (1), and OLEFT rats, which are obese and hyperphagic, show normal MC-R binding in hypothalamic nuclei but significantly reduced MC-R binding in the nucleus accumbens shell (25). Further studies targeting discrete hypothalamic and extrahypothalamic sites should help determine the exact site of AgRP's interaction with opioids and the precise nature of its effect on the macronutrient and hedonic properties of food selection.
Perspectives
The current data indicate significant cross talk between melanocortin and opioidergic signaling in the CNS. The function of this AgRP opioid circuit may be to motivate the organism to seek out and ingest calorically dense foods (e.g., fat-containing foods) possibly by also increasing the rewarding properties of these foods so as to favor their overconsumption. The question remains as to whether this functional circuit is important in mediating the increased intake and obesity that result from exposure to HF diets in humans and rats. Even more interesting is whether differences in this functional circuit could account for the dramatically different responses observed between individual rats or humans exposed to these diets.| |
ACKNOWLEDGEMENTS |
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This work was supported by several grants from National Institutes of Health (DK-54080, DK-54890, DK-17844) and funds from Procter & Gamble.
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FOOTNOTES |
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Address for reprint requests and other correspondence: M. M. Hagan, Dept. of Psychology, 415 Campbell Hall,Univ. of Alabama at Birmingham, Birmingham, AL 35294-1170 (E-mail: mhagan{at}uab.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 21 July 2000; accepted in final form 31 October 2000.
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REFERENCES |
|---|
|
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
1.
Alvaro, JD,
Tatro JB,
Quillan JM,
Fogliano M,
Eisenhard M,
Lerner MR,
Nestler EJ,
and
Duman RS.
Morphine down-regulates melanocortin-4 receptor expression in brain regions that mediate opiate addiction.
Mol Pharmacol
50:
583-591,
1996[Abstract].
2.
Bagnol, D,
Lu XY,
Kaelin CB,
Day HE,
Ollmann M,
Gantz I,
Akil H,
Barsh GS,
and
Watson SJ.
Anatomy of an endogenous antagonist: relationship between agouti-related protein and proopiomelanocortin in brain.
J Neurosci
19:
RC26,
1999.
3.
Baskin, DG,
Hahn TM,
and
Schwartz MW.
Leptin sensitive neurons in the hypothalamus.
Horm Metab Res
31:
345-350,
1999[ISI][Medline].
4.
Benoit, SC,
Schwartz MW,
Lachey JL,
Hagan MM,
Rushing PA,
Blake KA,
Yagaloff KA,
Kurylko G,
Franco L,
Danhoo W,
and
Seeley RJ.
A novel selective melanocortin-4 receptor agonist reduces food intake in rats and mice without producing aversive consequences.
J Neurosci
20:
3442-3448,
2000
5.
Broberger, C,
Johansen J,
Johansson C,
Schalling M,
and
Hokfelt T.
The neuropeptide Y/agouti gene-related protein (AGRP) brain circuitry in normal, anorectic, and monosodium glutamate-treated mice.
Proc Natl Acad Sci USA
95:
15043-15048,
1998
6.
Clark, JT,
Kalra PS,
Crowley WR,
and
Kalra SP.
Neuropeptide Y and human pancreatic polypeptide stimulate feeding behavior in rats.
Endocrinology
115:
427-429,
1984[Abstract].
7.
Cole, JL,
Ross A,
and
Bodnar J.
Dietary history affects the potency of chronic opioid receptor subtype antagonist effects upon body weight in rats.
Nutritional Neuroscience
1:
405-417,
2000.
8.
Cooper, SJ,
and
Turkish S.
Effects of naltrexone on food preference and concurrent behavioral responses in food-deprived rats.
Pharmacol Biochem Behav
33:
17-20,
1989[ISI][Medline].
9.
Fan, W,
Boston B,
Kesterson R,
Hruby V,
and
Cone R.
Role of melanocortinergic neurons in feeding and the agouti obesity syndrome.
Nature
385:
165-168,
1997[Medline].
10.
Giraudo, SQ,
Grace MK,
Billington CJ,
and
Levine AS.
Differential effects of neuropeptide Y and the mu-agonist DAMGO on "palatability" vs. "energy".
Brain Res
834:
160-163,
1999[ISI][Medline].
11.
Glass, MJ,
Billington CJ,
and
Levine AS.
Naltrexone administered to central nucleus of amygdala or PVN neural dissociation of diet and energy.
Am J Physiol Regulatory Integrative Comp Physiol
279:
R86-R92,
2000
12.
Gosnell, BA,
Krahn DD,
and
Majchrzak MJ.
The effects of morphine on diet selection are dependent upon baseline diet preferences.
Pharmacol Biochem Behav
37:
207-212,
1990[ISI][Medline].
13.
Graham, M,
Shutter JR,
Sarmiento U,
Sarosi I,
and
Stark KL.
Overexpression of Agrt leads to obesity in transgenic mice.
Nat Genet
17:
273-275,
1997[ISI][Medline].
14.
Grill, HJ,
Ginsberg AB,
Seeley RJ,
and
Kaplan JM.
Brainstem application of melanocortin receptor ligands produces long-lasting effects on feeding and body weight.
J Neurosci
18:
10128-10135,
1998
14a.
Hagan MM, Benoit SC, Rushing PA, Pritchard LM, Woods SC, and Seeley RJ.
Immediate and prolonged patterns of AgRP(83-132)-induced
c-Fos activation in hypothalamic and extrahypothalamic sites.
Endocrinology. In press.
15.
Hagan, MM,
Holguin FD,
Cabello CE,
Hanscom DR,
and
Moss DE.
Combined naloxone and fluoxetine on deprivation-induced binge eating of palatable foods in rats.
Pharmacol Biochem Behav
58:
1103-1107,
1997[ISI][Medline].
16.
Hagan, MM,
Rushing PA,
Pritchard LM,
Schwartz MW,
Strack AM,
Van der Ploeg LHT,
Woods SC,
and
Seeley RJ.
Long-term orexigenic effects of AgRP-(83-132) involve mechanisms other than melanocortin receptor blockade.
Am J Physiol Regulatory Integrative Comp Physiol
279:
R47-R52,
2000
17.
Hagan, MM,
Rushing PA,
Schwartz MW,
Yagaloff KA,
Burn P,
Woods SC,
and
Seeley RJ.
Role of the CNS melanocortin system in the response to overfeeding.
J Neurosci
19:
2362-2367,
1999
18.
Hahn, TM,
Breininger JF,
Baskin DG,
and
Schwartz MW.
Coexpression of Agrp and NPY in fasting-activated hypothalamic neurons.
Nature Neuroscience
1:
271-272,
1998[ISI][Medline].
19.
Haskell-Luevano, C,
Chen P,
Li C,
Chang K,
Smith MS,
Cameron JL,
and
Cone RD.
Characterization of the neuroanatomical distribution of agouti-related protein immunoreactivity in the rhesus monkey and the rat.
Endocrinology
140:
1408-1415,
1999
20.
Kirkham, TC,
and
Cooper SJ.
Naloxone attenuation of sham feeding is modified by manipulation of sucrose concentration.
Physiol Behav
44:
491-494,
1988[Medline].
21.
Koegler, FH,
Schaffhauser RO,
Mynatt RL,
York DA,
and
Bray GA.
Macronutrient diet intake of the lethal yellow agouti (Ay/a) mouse.
Physiol Behav
67:
809-812,
1999[Medline].
22.
Kotz, CM,
Glass MJ,
Levine AS,
and
Billington CJ.
Regional effect of naltrexone in the nucleus of the solitary tract in blockade of NPY-induced feeding.
Am J Physiol Regulatory Integrative Comp Physiol
278:
R499-R503,
2000
23.
Leventhal, L,
Kirkham TC,
Cole JL,
and
Bodnar RJ.
Selective actions of central mu and kappa opioid antagonists upon sucrose intake in sham-fed rats.
Brain Res
685:
205-210,
1995[ISI][Medline].
24.
Li, JY,
Finniss S,
Yang KK,
Zeng Q,
Qu SY,
Barsh G,
Dickinson C,
and
Gantz I.
Agouti-related protein-like immunoreactivity: characterization of release from hypothalamic tissue and presence in serum.
Endocrinology
141:
1942-1950,
2000
25.
Lindblom, J,
Schioth HB,
Watanobe H,
Suda T,
Wikberg JE,
and
Bergstrom L.
Downregulation of melanocortin receptors in brain areas involved in food intake and reward mechanisms in obese (OLETF) rats.
Brain Res
852:
180-185,
2000[ISI][Medline].
26.
Lu, D,
Willard D,
Patel I,
Kadwell S,
Overton L,
Kost T,
Luther M,
Chen W,
Woychik R,
Wilkison W,
and
Cone RD.
Agouti protein is an antagonist of the melanocyte-stimulating-hormone receptor.
Nature
371:
799-802,
1994[Medline].
27.
Marks-Kaufman, R,
and
Kanarek RB.
Diet selection following a chronic morphine and naloxone regimen.
Pharmacol Biochem Behav
35:
665-669,
1990[ISI][Medline].
28.
Marsh, D,
Hollopeter G,
Huszar D,
Laufer R,
Yagaloff K,
Fisher S,
Burn P,
and
Palmiter R.
Response of melanocortin-4 receptor-deficient mice to anorectic and orexigenic peptides.
Nat Genet
21:
119-122,
1999[ISI][Medline].
29.
Mizuno, TM,
and
Mobbs CV.
Hypothalamic agouti-related protein messenger ribonucleic acid is inhibited by leptin and stimulated by fasting.
Endocrinology
140:
814-817,
1999
30.
Morley, JE,
Levine AS,
Gosnell BA,
Kneip J,
and
Grace M.
Effect of neuropeptide Y on ingestive behaviors in the rat.
Am J Physiol Regulatory Integrative Comp Physiol
252:
R599-R609,
1987
31.
Ollmann, M,
Wilson B,
Yang Y,
Kerns J,
Chen Y,
Gantz I,
and
Barsh G.
Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein.
Science
278:
135-138,
1997
32.
Paxinos, G,
and
Watson C.
The Rat Brain in Stereotaxic Coordinates. Orlando, FL: Academic, 1986.
33.
Percina, S,
and
Berridge KC.
Opioid site in nucleus accumbens shell mediated eating and hedonic "liking" for food: map based on microinjection fos plumes.
Brain Res
863:
71-86,
2000[ISI][Medline].
34.
Pomonis, JD,
Levine AS,
and
Billington CJ.
Interaction of the hypothalamic par ventricular nucleus and central nucleus of the amygdala in naloxone blockade of neuropeptide Y-induced feeding revealed by c-fos expression.
J Neurosci
17:
5175-5182,
1997
35.
Quillan, JM,
Sadee W,
Wei ET,
Jimenez C,
Ji L,
and
Chang JK.
A synthetic human Agouti-related protein-(83-132)-NH2 fragment is a potent inhibitor of melanocortin receptor function.
FEBS Lett
428:
59-62,
1998[ISI][Medline].
36.
Rossi, M,
Kim M,
Morgan D,
Small C,
Edwards C,
Sunter D,
Abusnana S,
Goldstone A,
Russell S,
Stanley S,
Smith D,
Yagaloff K,
Ghatei M,
and
Bloom S.
A C-terminal fragment of Agouti-related protein increases feeding and antagonizes the effect of -melanocyte stimulating hormone in vivo.
Endocrinology
139:
4428-4431,
1998
37.
Rudski, JM,
Grace M,
Kuskowski MA,
Billington CJ,
and
Levine AS.
Behavioral effects of naloxone on neuropeptide Y-induced feeding.
Pharmacol Biochem Behav
54:
771-777,
1996[ISI][Medline].
38.
Shutter, J,
Graham M,
Kinsey A,
Scully S,
Luthy R,
and
Stark K.
Hypothalamic expression of ART, a novel gene related to agouti, is up-regulated in obese and diabetic mutant mice.
Genes Dev
11:
593-602,
1997
39.
Thiele, TE,
van Dijk G,
Yagaloff KA,
Fisher SL,
Schwartz M,
Burn P,
and
Seeley RJ.
Central infusion of melanocortin agonist MTII in rats: assessment of c-Fos expression and taste aversion.
Am J Physiol Regulatory Integrative Comp Physiol
274:
R248-R254,
1998
40.
Tritos, NA,
Elmquist JK,
Masxtaitis JW,
Flier JS,
and
Maratos-Flier E.
Characterization of expression of hypothalamic appetite-regulating peptides in obese hyperleptinemic brown adipose tissue-deficient (uncoupling protein-promoter-driven diphtheria toxin A) mice.
Endocrinology
139:
4634-4641,
1998
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