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Minnesota Obesity Center, Departments of Psychiatry, Psychology, and Medicine, Veterans Affairs Medical Center and the University of Minnesota, Minneapolis, Minnesota, 55417
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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There is evidence that opioids may affect food consumption through mechanisms as diverse as reward or energy metabolism. However, these hypotheses are derived from studies employing peripheral or, more rarely, intracerebroventricular administration of drugs. Opioid receptors have a wide distribution in the central nervous system and include a number of regions implicated in food intake such as the hypothalamic paraventricular nucleus (PVN) and the central nucleus of the amygdala (ACe). It is not known whether local opioid receptor blockade in either of these regions will produce similar effects on food intake. To examine this issue, a chronic cannula was aimed at either the PVN or ACe of rats that were fed a choice of a high-fat and high-carbohydrate diet, which allows for the measurement of both preference and total energy consumption. Naltrexone influenced preferred and nonpreferred food consumption, depending on the site of administration. Consumption of both preferred and nonpreferred diets was suppressed after PVN naltrexone administration, whereas only preferred diet intake was reduced after ACe injection of naltrexone. The present evidence indicates that direct stimulation of different brain regions with naltrexone may be associated with diverse effects on diet selection, which may be accounted for by manipulation of specific functional neural circuitry.
feeding behavior; food deprivation; high-fat diet; high-carbohydrate diet
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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VARIOUS HYPOTHESES HAVE BEEN proposed to account for opioid-feeding effects (4, 13). For example, because opioid agonists increase and opioid antagonists decrease consumption of fat in rats given a choice among separate sources of fat, carbohydrates, proteins, or high-carbohydrate and -fat diets (26, 27, 43), it has been suggested that the opioid system affects fat consumption (8, 9). However, this idea remains highly controversial (9). It has also been hypothesized that opioids play a role in mediating consumption of preferred foods (8, 9). For example, morphine increased, whereas opioid antagonists decreased, consumption of the preferred diet in rats allowed to select from high-fat and high-carbohydrate diets (10, 12, 17). Alternatively, when rats are allowed to self select between high-fat and high-carbohydrate diets, naloxone, at doses of 1.0 and 3.0 mg/kg, is shown to suppress total diet consumption independent of diet type or preference when the rats are stimulated to eat by neuropeptide Y (NPY) (10).
Route of drug administration may help to account for some of the alternative effects of opioids on diet consumption. The results described above were derived from nonspecific peripheral or intracerebroventricular drug administration, which would presumably affect widespread areas of the brain and periphery. Given the functional heterogeneity of neural circuitry, peripherally administered drugs would be expected to affect multiple feeding-related processes, including food palatability or energy regulation. Opioid receptors have been localized within the hypothalamus and amygdala (24), and blockade of opioid receptors in each of these regions has been shown to decrease food intake (7, 11, 18). The hypothalamus, particularly the paraventricular nucleus (PVN) and surrounding areas, has been implicated in regulating homeostatic functions such as coordination of energy balance by regulating food consumption and energy expenditure (3, 21), whereas the amygdala, especially the central nucleus of the amygdala (ACe), has been suggested to play a role in affective processes (1, 34) and may influence food preferences (41).
We hypothesized that a blockade of opioid receptors in anatomically distant neural regions, diverging in functional properties, might affect different aspects of feeding behavior. For example, injection of the opioid antagonist naltrexone aimed at the PVN might affect intake of both preferred and nonpreferred diets because this area is a site of energy coordination. In contrast, naltrexone injection aimed at the ACe might only affect preferred diet intake because this region processes "emotional events." We tested this hypothesis in rats given a choice between a high-fat and a high-carbohydrate diet by injecting naltrexone into the PVN or ACe and by determining the intake of the preferred and nonpreferred diets.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Animals. Male Sprague-Dawley rats (Harlan, Madison, WI) weighing 250-350 g were individually housed in conventional hanging cages with a 12:12-h light-dark photoperiod (lights on at 0700) in a temperature-controlled room (21-22°C). Teklad Lab Chow and water were allowed ad libitum, except where noted.
Cannulation. Rats (n = 32/group) were anesthetized with Nembutal (40 mg/kg) and were fitted with one 26-gauge stainless steel guide cannula (Plastics One, Austin, TX) placed just above the PVN or ACe. Stereotaxic coordinates were determined from the rat brain atlas by Paxinos and Watson (31); for the PVN, the cannula was placed 1.9 mm posterior and 0.5 mm lateral to bregma and 7.3 mm below the skull surface, and for the ACe, the cannula was placed 2.3 mm posterior and 4.0 mm lateral to bregma and 7.0 mm below the skull surface. The injector extended 1 mm beyond the end of the guide cannula. For all cannulations, the incisor bar was set at 3.3 mm below the ear bars. At least 7 days elapsed after surgery before experimental trials.
Injections. Injections into the PVN and ACe were given in a 0.5-µl volume over 20 s with the use of a 33-gauge internal cannula (Plastics One). The injector extended 1 mm beyond the end of the guide cannula.
Diet selection.
Diet selection was determined after 24-h food deprivation (FD) with
several doses of naltrexone. After a 24-h fast (testing time:
1000-1100), animals were injected with naltrexone (0, 10, 30, 100 nmol). A repeated-measures counterbalanced design was used for this
experiment. Fifteen minutes after the naltrexone injection, rats were
returned to their home cages that contained two preweighed food jars,
one high-fat and the other high-carbohydrate diet (Table
1). Given prior evidence that
nutrient type can affect drug-stimulated diet selection, the source of
the high-carbohydrate diet was varied (cornstarch or sucrose based;
Table 1). In the PVN-treated animals, 12 rats were maintained on the
cornstarch, high-fat regimen, whereas 16 rats were maintained on the
sucrose, high-fat regimen. In the ACe group, 13 rats were maintained on the cornstarch, high-fat regimen, whereas 15 rats were maintained on
the sucrose, high-fat regimen. Food intake was quantified and corrected
for spillage after 1 h. Rats were excluded from all analyses if
they ate <0.1 g of food after FD.
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Assignment of diet preference for analysis. Food intake was divided into preferred and nonpreferred categories. For this analysis, the diet predominantly consumed (on the basis of kcal intake) was defined as the preferred diet. Thus the analysis includes intake of both preferred and nonpreferred diets by each individual rat. For example, a rat eating 20 kcal of high-carbohydrate diet and 8 kcal of high-fat diet would have the high-carbohydrate intake included in the preferred category and the high-fat intake in the nonpreferred category. The next animal's intake may have been 6 kcal from the high-carbohydrate diet and 35 kcal from high-fat diet. In this case, the high-fat intake was included in the preferred category and the high-carbohydrate diet in the nonpreferred category. Thus both preferred and nonpreferred categories contained energy intakes (kcal) from high-carbohydrate and high-fat diets.
Verification of cannula placement.
After experiments, brains were dissected out and stored in a 10%
formaldehyde solution for later placement verification by histologic
examination. Data from animals with incorrectly placed cannulas were
excluded from the final analysis. Several rats pulled off their
cannulas during the course of the feeding studies. Due to misplaced or
lost cannulas, 8 rats from the ACe group and 10 from the PVN group were
eliminated. Placement of cannulas, which were included in the
analysis, are shown in Fig. 1. All
cannula injection points within 0.5 mm of the site were included.
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Drugs. Naltrexone was purchased from RBI (Natick, MA). All drugs were dissolved in 0.9% saline just before use.
Statistics. Data are expressed as means ± SE and were analyzed with one- and two-way, repeated-measures ANOVA (dose = repeated measure). Comparisons were conducted with Scheffé's test.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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ACe cornstarch.
In the cornstarch regimen, there was a main effect of naltrexone
administered into the ACe
[F(3,54) = 6.43, P = 0.0008], of diet type
[F(1,18) = 30.1, P
= 0.0001], and of a naltrexone × diet interaction
[F(3,54) = 3.6, P = 0.019] on food intake. There was no main effect of
naltrexone on cornstarch intake
[F(3,39) = 1.45, P = 0.25], but there was a main effect of naltrexone
on fat intake [F(3,39) = 5.66, P = 0.004], where fat consumption was significantly
suppressed at both the 30- and 100-nmol doses (Table
2). There was a main effect of naltrexone
on total energy intake of the cornstarch and fat diets
[F(3,39) = 9.60, P
= 0.0002], where total energy intake was significantly decreased
at the 30- and 100-nmol doses (Table 2).
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ACe sucrose. There was no main effect of naltrexone administered into the ACe [F(3,78) = 2.65, P = 0.055], but there was a main effect of diet type [F(1,26) = 10.59, P = 0.0032] on food intake. There was no naltrexone × diet interaction [F(3,78) = 0.82, P = 0.49] on intake under the sucrose/fat regimen. There was a main effect of naltrexone on total energy intake of the sucrose and fat diets [F(3,39) = 9.60, P = 0.0002], where total energy intake was significantly decreased at the 100-nmol dose (Table 2).
ACe preference.
To analyze the role of preference on ACe administration of naltrexone,
analyses were conducted after food intake was categorized in terms of
preferred and nonpreferred food (see METHODS). To facilitate comparisons, graphs are presented in terms of percent control. There was a main effect of ACe naltrexone administration on
preferred diet consumption [kcal:
F(3,95) = 8.91, P
= 0.0001; grams: F(3,95) = 9.32, P = 0.0001], where intake was significantly reduced
at all doses tested (Table 3 and Fig.
2). However, there was no main effect
of naltrexone on intake of the nonpreferred diet [kcal:
F(3,95) = 1.031, P = 0.38; grams:
F(3,95) = 1.69, P
= 0.18], and diet consumption was not suppressed at any of the tested doses (Fig. 2). Naltrexone had a main effect on total energy intake of both the preferred and nonpreferred diets with the 30- and
100-nmol doses of naltrexone decreasing intake significantly [F(3,95) = 6.81, P
= 0.0004] (Table 3).
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PVN cornstarch. There was a main effect of PVN naltrexone administration [F(3,48) = 5.15, P = 0.004] on food intake under the cornstarch regimen, but there was neither an effect of diet type [F(1,16) = 2.65, P = 0.122] nor a naltrexone × diet interaction [F(3,48) = 0.34, P = 0.79]. There was a main effect of naltrexone on cornstarch intake [F(3,35) = 4.47, P = 0.012], but there was no main effect of naltrexone on fat intake [F(3,35) = 1.49, P = 0.24] (Table 2). There was a main effect of naltrexone on total energy intake of the cornstarch and fat diets [F(3,35) = 6.45, P = 0.002], where total energy intake was significantly decreased at the 30- and 100-nmol doses (Table 2).
PVN sucrose. There were main effects of both PVN administration of naltrexone [F(3,72) = 23.75, P = 0.0001] and diet type [F(1,24) = 25.46, P = 0.0001] as well as a naltrexone × diet interaction [F(3,72) = 8.19, P = 0.0001] on food intake under the sucrose/fat regimen. There was a main effect of naltrexone on sucrose intake [F(3,51) = 27.67, P = 0.0001], where consumption was significantly suppressed at both the 30- and 100-nmol doses (Table 2). There was no main effect of naltrexone on fat intake [F(3,51) = 2.68, P = 0.06] (Table 2). There was a main effect of naltrexone on total energy intake of the sucrose and fat diets [F(3,51) = 21.74, P = 0.0001], where total energy intake was significantly decreased at the 10-, 30-, and 100-nmol doses (Table 2).
PVN preference. To analyze the role of preference on PVN administration of naltrexone, analyses were conducted after food intake was categorized in terms of preferred and nonpreferred food (see METHODS). There was a main effect of naltrexone administered into the PVN on intake of the preferred diet [kcal: F(3,87) = 23.03, P = 0.0001; grams: F(3,87) = 23.86, P = 0.0001], and consumption was significantly decreased at both the 30- and 100-nmol doses (Table 3 and Fig. 2). In distinction to the case of the ACe, there was a main effect of PVN naltrexone administration on nonpreferred diet consumption [kcal: F(3,87) = 4.03, P = 0.01; grams: F(3,87) = 4.00, P = 0.01], where intake was significantly reduced at both the 30- and 100-nmol doses (Fig. 2). Naltrexone had a main effect on total energy intake of both the preferred and nonpreferred diets with the 30- and 100-nmol doses of naltrexone decreasing intake significantly [F(3,87) = 25.12, P = 0.0001] (Table 3).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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We hypothesized that blockade of opioid receptors in anatomically distant neural regions differing in functional properties might affect particular aspects of feeding behavior. It was found that naltrexone's effect on preferred or nonpreferred food consumption was dependent on the neural region of administration. Consumption of both preferred and nonpreferred diets was suppressed after PVN naltrexone infusions, whereas only preferred diet intake was reduced after ACe injection of naltrexone. There is evidence that each area may be somewhat differentiated in terms of its place within neural functional processing streams, and it may be presumed that naltrexone's effects are due to manipulation of region-dependent functional actions mediated by opioid receptors. The region in and around the hypothalamic PVN may play a crucial role in neural circuits underlying homeostatic regulation, whereas the regions in and surrounding the ACe may be a key portion of pathways subserving emotional processes. Thus consideration of the present pattern of results will be analyzed in terms of the hypothesized role of each respective region within food intake control circuitry.
With respect to the PVN, naltrexone's nonspecific effects on diet consumption may be consistent with the hypothesized role of this nucleus and the surrounding area as a coordinator of energy balance (21). The PVN plays a crucial role as an integrator of autonomic, endocrine, and behavioral responses by its afferent and efferent connections with autonomic and motor nuclei in the brain stem and innervation of the posterior pituitary (40). The PVN contains a variety of aminergic and peptide transmitters, most notably NPY (2), which affects food intake and body weight when administered into the PVN (36). Chronic PVN administration of NPY (37) or animals with alterations of PVN neuromodulatory systems (5) (e.g., genetically obese Zucker rats) are associated with hyperphagia and obesity. Furthermore, some PVN neuroregulatory systems, for example NPY, respond to changes in energy need (15). However, hypothalamic NPY does not change in response to ingestion of high-sucrose/-fat foods, which are reported to be pleasant tasting to humans and are avidly consumed by rats (16), and PVN lesions in the rat do not affect saccharin consumption (42). In addition, intracerebroventricularly administered NPY, which would be expected to reach the PVN, only weakly stimulates intake of noncaloric solutions (22). Thus the role of the PVN in feeding circuitry may not be crucially influenced by sensory properties of foods.
Postingestive processing may be one arm of hypothalamic energy balance control, and influences on postingestive feedback could account for the present effects. For example, the PVN receives afferents from the gastrointestinal tract by way of the brain stem (14, 33), and it has been shown that the satiety normally induced by peripheral administration of CCK is attenuated by lesions of the PVN (6), whereas c-Fos expression is increased in the PVN in response to peripheral CCK (28). As a potential participant in gastric processing, the PVN may be more closely attuned to monitoring of food quantity rather than with food quality. Thus the evidence presented here may reflect drug-induced blockade of the functional actions of opioid receptors within hypothalamic feeding circuitry related to postingestive functions.
In contrast to the results from hypothalamic infusions, reductions in preferred diet consumption after opioid receptor blockade in the amygdala may reflect actions on affective processing. Classic lesion studies of the temporal lobes in the monkey as well as case reports of humans with lesions in this area demonstrated the importance of the amygdala on affect, and some of these reports also described changes in food preferences (1). However, given the complexity of amygdalar organization, these effects may be dependent on the processing carried out by specific nuclei (39). The ACe, which traditionally has been considered to be part of the "limbic" taste pathway (30), may be more closely related to processing of emotional properties of stimuli (1, 34), including foods. Rats with ablation of the ACe display a small reduction in body weight (41), in distinction to the more profound obesity seen after PVN (35). Furthermore, ACe-lesioned rats display lower preferences for saccharin solutions compared with normal rats (41). In addition to the present results, there are data indicating that opioids within the ACe may modulate these effects. For example, levels of the early gene transcription factor c-Fos are elevated in the ACe of rats injected with naloxone after 3 wk of ingestion of a 10% sucrose solution compared with saline-injected controls (32).
There appear to be important connections between opioids in the hypothalamus and amygdala. It has been previously shown that naltrexone injected into the PVN inhibits food intake stimulated by administration of the opioid agonist DAMGO into the ACe (7). The ACe may play a role as an interface between forebrain sensory/affective systems and PVN-feeding circuitry (39), and as such the ACe may modulate PVN activity by coupling sensory processes to a metabolic state.
It should be noted that studies using injections of neurally active substances aimed at selected brain nuclei are always open to criticism due to the potential distribution of the substance away from the intended target. In the current study, we used an injection volume of 0.5 µl, a volume we assumed would not result in widespread distribution of naltrexone. However, the theory that larger volumes of neurally active agents would distribute further has not been empirically demonstrated for substances which bind to neural receptors. The work of C. Nicholson (29) indicates that distribution is highly susceptible to receptor-mediated uptake of the injected compound. If an agent is avidly bound to a receptor at the site of injection, there will be a very limited distribution. The distribution of most compounds with relatively high-binding constants is limited to a 0.5-mm spread from the site of injection. Kotz et al. (19) have studied the effect of naltrexone injection into the nucleus of the solitary tract (NTS) on NPY-induced feeding. She reported that naltrexone's anorectic effect was most robust in the medial NTS compared with other areas only 1 mm away. If naltrexone readily diffused, one would have expected similar responses in all regions studied. Given the spatial distance between each respective region as well as the relatively low concentrations of naltrexone infused, it is extremely unlikely that the drug was diffusing from the hypothalamus to the amygdala or vice versa.
The present evidence indicates that direct naltrexone injections into anatomically separated and functionally distinct brain regions may be associated with differing effects on diet selection, which may be accounted for by manipulation of specific functional neural circuitry.
Perspectives
Although the present results indicate that opioid receptors in different brain regions may participate in particular functional processes, as noted above the precise localization of these patterns to specific nuclei remains to be unequivocally demonstrated. The underlying anatomy is complex; whether there are more circumscribed actions of discrete subunits in and around each respective injection site will have to await cannula-mapping studies (i.e., Ref. 38) as well as metabolic mapping in these areas in response to palatability or energy manipulations. Furthermore, the type and density of opioid receptors differ for each region (23, 25), and this is an important factor given the nonselectivity of naltrexone. Thus identification of specific receptor subtypes as well as their molecular substrates also awaits further inquiry (i.e., Ref. 20).| |
ACKNOWLEDGEMENTS |
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This work was supported by the Department of Veterans Affairs, by National Institute of Drug Abuse Grants DA-03999 and TA-DA-07097, and by the 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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Present address of M. J. Glass: Dept. Neurology and Neuroscience, Weill Medical College of Cornell University, 411 E. 69th St., KB410, New York, NY 10021.
Address for reprint requests and other correspondence: A. S. Levine, Research Service 151, Veterans Affairs Medical Center, One Veterans Drive, 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. §1734 solely to indicate this fact.
Received 19 April 1999; accepted in final form 3 February 2000.
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REFERENCES |
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TOP
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METHODS
RESULTS
DISCUSSION
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