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Volume 17, Number 11, Issue of June 1, 1997 pp. 4434-4440
Copyright ©1997 Society for NeuroscienceGABA in the Nucleus Accumbens Shell Participates in the Central Regulation of Feeding Behavior
Thomas R. Stratford and Ann E. Kelley Department of Psychiatry, University of Wisconsin-Madison Medical School, Madison, Wisconsin 53719
ABSTRACT
We have demonstrated previously that injections of 6,7-dinitroquinoxaline-2,3-dione into the nucleus accumbens shell (AcbSh) elicits pronounced feeding in satiated rats. This glutamate antagonist blocks AMPA and kainate receptors and most likely increases food intake by disrupting a tonic excitatory input to the AcbSh, thus decreasing the firing rate of a population of local neurons. Because the application of GABA agonists also decreases neuronal activity, we hypothesized that administration of GABA agonists into the AcbSh would stimulate feeding in satiated rats. We found that acute inhibition of cells in the AcbSh via administration of the GABAA receptor agonist muscimol or the GABAB receptor agonist baclofen elicited intense, dose-related feeding without altering water intake. Muscimol-induced feeding was blocked by coadministration of the selective GABAA receptor blocker bicuculline, but not by the GABAB receptor blocker saclofen. Conversely, baclofen-induced feeding was blocked by coadministration of saclofen, but was not affected by bicuculline. Furthermore, we found that increasing local levels of GABA by administration of a selective GABA-transaminase inhibitor,
Key words: GABA; food intake; nucleus accumbens shell; muscimol; baclofen; feeding behavior;-vinyl-GABA, elicited robust feeding in satiated rats, suggesting a physiological role for endogenous AcbSh GABA in the control of feeding. A mapping study showed that although some feeding can be elicited by muscimol injections near the lateral ventricles, the ventromedial AcbSh is the most sensitive site for eliciting feeding. These findings demonstrate that manipulation of GABA-sensitive cells in the AcbSh can have a pronounced, but specific, effect on feeding behavior in rats. They also constitute the initial description of a novel and potentially important component of the central mechanisms controlling food intake.
INTRODUCTION
The nucleus accumbens is a basal forebrain structure that is perhaps best known for being an important constituent of the neural systems mediating reward and reinforcement (Koob and Bloom, 1988
; Salamone, 1996
Although numerous studies have investigated the role of the nucleus accumbens in the control of food intake (Majeed et al., 1986
Recent work in this laboratory has involved an attempt to elucidate the function of glutamate in the AcbSh. We have found that blockade of AMPA and kainate receptors in the AcbSh, but not the AcbC, elicits a strong feeding response in satiated rats (Maldonado-Irizarry et al., 1995
MATERIALS AND METHODS
Subjects. Male Sprague Dawley rats (Harlan Sprague Dawley, Indianapolis, IN) weighing between 280 and 300 gm at the time of surgery were group-housed in acrylic cages and maintained in a temperature-controlled (~21°C) and light-controlled (12 hr light/dark) environment with food (Harlan Teklad Rat Diet 7001) and acidified tap water available ad libitum.
Surgery. The rats were anesthetized with a mixture of ketamine HCl and xylazine (100 mg/kg and 10 mg/kg, respectively) (Sigma, St. Louis, MO), and bilateral 23-gauge stainless steel guide cannulae were implanted using standard, flat-skull stereotaxic techniques (Paxinos and Watson, 1986 5.5 mm from bregma. For Experiment 5, six rats were implanted with guide cannulae aimed at the AcbC (AP, 1.4; L, ± 2.0; DV,
Intracerebral injections. To acclimate the rats to the test procedure, they were restrained, the obturators were removed, and a 30-gauge injection cannula, extending 2.5 mm beyond the ventral tip of the guide, was inserted into each guide cannula on 3 consecutive days. The obturators were replaced, and the rats were placed in the test cages for either 30 or 120 min. On the final acclimation day, each rat received a 0.5 µl intracerebral injection of 0.15 M saline. On test days, each rat received simultaneous bilateral injections of 0.5 µl of drug or the 0.15 M saline vehicle at a rate of 0.32 µl/min. After the infusion, the injection cannulae were left in place for an additional 60 sec to minimize leakage up the cannula track. At least 48 hr were allowed between injections.
Drugs. Muscimol and baclofen were obtained from Sigma. All other drugs were obtained from Research Biochemicals International (Natick, MA). All drugs were dissolved in 0.15 M saline. Where group numbers permitted, drug doses were administered in a counterbalanced order. Where full counterbalancing was not possible, a semi-counterbalanced order was used, with individual exceptions noted below.
Experimental design. In Experiment 1 we examined the effects of intra-AcbSh infusions of equimolar doses of the GABAA agonist muscimol and the GABAB agonist baclofen on short-term food and water intake in satiated rats. One group of rats received bilateral injections of 0, 10, 20, 50, or 100 ng (0, 88, 175, 438, or 876 pmol) of muscimol. The second group of rats received equimolar doses (0, 19, 37, 94, or 188 ng) of baclofen. The rats were placed in test cages (42 × 20 cm) with a preweighed quantity of food and a bottle containing tap water available. During the 30 min test, various behavioral parameters were recorded using a computer-based multi-channel event recording system (Paul Fray Ltd.). These behavioral measurements included latency to begin feeding, total time spent feeding, locomotor activity (as indicated by number of cage crossings), and total time spent rearing. At the end of the test, food intake (corrected for spillage) and water intake were calculated.
In Experiment 2 we attempted to determine whether the behavioral effects of muscimol and baclofen were being mediated solely through local GABAA and GABAB receptors, respectively. In this study, the feeding response of one group of rats was tested after injections of 0 or 50 ng of muscimol. After each rat had been tested under the drug and vehicle conditions, it received injections a mixture of either 50 ng of muscimol and 75 ng of the specific GABAA receptor antagonist (
Experiment 3 was a study of the effects of various doses of muscimol on 2 hr food and water intake. Rats in this group were tested after 0, 10, 20, 50, 100, or 200 ng of muscimol. After the microinjections, the rats were placed in test cages with food and tap water available. Food intake (corrected for spillage) was calculated at 30, 60, and 120 min. Total water intake was determined at the end of the 120 min test.
Because the preceding experiments all concerned the administration of exogenous GABA agonists, we sought to determine whether endogenous GABA played a role in the central control of feeding behavior. Experiment 4 examined this question by attempting to increase local levels of GABA through the administration of (±)-nipecotic acid, a GABA uptake inhibitor, or (±)-
The fifth experiment was designed to identify the most sensitive site in the medial basal forebrain for eliciting feeding with muscimol. One group of six rats was implanted with guide cannulae aimed at the AcbC and was tested as described in Experiment 1 after bilateral injections of the saline vehicle, 50 ng of muscimol, or 94 ng of baclofen. To determine the response gradient along the rostral-caudal axis, separate groups of rats were prepared with guide cannulae positioned at either our standard placement or 1 mm rostral, 1 mm caudal, or 2 mm caudal to it (as detailed under Surgery). The rats received injections of either 0 or 50 ng of muscimol through injection cannulae terminating 1 mm below the guide. After this series of tests was completed, rats were given another series of tests with drugs injected through cannulae terminating 2.5 mm below the guide. Thus, rats in this study each received saline and muscimol injections at two sites, one 1.5 mm above the other. After each treatment, the rats were tested as described in Experiment 3.
Histology. After behavioral testing, all of the animals were anesthetized deeply with sodium pentobarbital and perfused transcardially with 50 ml of a 0.15 M saline solution followed immediately by 500 ml of a 10% buffered formalin solution. The brains were removed and stored in fixative for at least 1 week. The brains were then frozen, and 60 µm coronal sections were taken throughout the extent of the AcbSh. The sections were stained with cresyl violet, and the injection sites were examined for placement accuracy and excessive damage. Data from rats with misplaced cannulae were not included in the analyses.
Statistical analyses. In Experiment 1, food and water intake and each of the behavioral parameters collected were analyzed using two-way ANOVA (drug × dose; ANOVA) with repeated measures on the dose factor. In addition to the overall analysis, the method of linear contrast was used to compare the effects of each dose of drug with the saline-injected control trial. In Experiment 3, data were analyzed across doses using a one-way ANOVA with repeated measures. Where an overall significant effect of dose was found, individual comparisons with the vehicle treatment were examined using Dunnett's method. Food and water intake data from Experiments 2 and 4 were analyzed the same way, with individual treatments being handled as levels for the sake of statistical analysis.
In Experiment 5, data from the AcbC group were analyzed using a repeated-measures one-factor ANOVA. Data from the remaining sites were analyzed with a one-factor ANOVA followed by planned comparisons of the saline and drug treatments at each site using a Bonferroni adjustment to determine significance.
RESULTS
Experiment 1
Bilateral activation of AcbSh GABAA receptors with muscimol significantly increased food intake at all doses above 88 pmol (probability values for individual comparisons are given in Fig. 1a). Similarly, activation of GABAB receptors with baclofen significantly increased feeding at all doses tested (Fig. 1a). Equimolar doses of muscimol and baclofen were equipotent at eliciting feeding. All doses tested of both drugs significantly decreased latency to begin feeding and increased feeding duration without affecting water intake or locomotor activity (probability values for individual comparisons are given in Table 1). The amount of time spent rearing tended to be reduced at the higher doses of both drugs.
Fig. 1. Mean (±SEM) 30 min food intake after bilateral microinjections of various doses of GABA agonists and antagonists into the AcbSh. a, Intake was increased significantly with all doses of baclofen tested and with all doses of muscimol over 88 pmol. b, As demonstrated in the previous experiment, injection of 188 ng of baclofen significantly increased food intake (p < 0.01). The baclofen-induced feeding was eliminated by coadministration of 500 ng of the selective GABAB antagonist saclofen, but was not affected by 75 ng of the GABAA antagonist bicuculline. c, In a separate group of rats, 50 ng of muscimol significantly increased food intake (p < 0.01), and this increase was abolished by coadministration of 75 ng of bicuculline. Coadministration of 500 ng saclofen had no effect on the feeding elicited by muscimol. Symbols denote significant increases in intake as compared with saline treatment. *p < 0.05;p < 0.01;
p < 0.001.
[View Larger Version of this Image (37K GIF file)]
Table 1. Behavioral parameters recorded (in addition to food intake illustrated in Figure 1a) during the 30 min subsequent to injections of various doses of baclofen or muscimol into the AcbSh
Baclofen (pmol) Muscimol (pmol) 0 88 175 438 876 0 88 175 438 876 Latency to 1212 106 509 78 152 1610 623 324 338 205 feed (sec) ± 211 ± 59 ± 264 ± 37 ± 115 ± 110 ± 229 ± 140 ± 143 ± 121 Feeding 65 409 410 622 895 32 265* 453 735 1295 duration (sec) ± 28 ± 66 ± 106 ± 76 ± 96 ± 18 ± 98 ± 65 ± 65 ± 174 Water 0.4 1.1 1.5 0.2 0.2 1.7 1.8 1.4 2.2 0.4 intake (ml) ± 0.2 ± 0.6 ± 0.6 ± 0.2 ± 0.1 ± 0.5 ± 0.7 ± 0.6 ± 0.8 ± 0.4 Locomotor 30 32 22 29 18 22 19 21 21 24 activity ± 3.4 ± 6.1 ± 4.2 ± 10.0 ± 8.1 ± 2.5 ± 3.0 ± 2.7 ± 2.4 ± 7.1 Rearing 190 154 85 62 27 136 75 45* 57 37* duration (sec) ± 36 ± 17 ± 16 ± 24 ± 11 ± 28 ± 18 ± 8 ± 14 ± 21 All doses of baclofen and muscimol tested significantly decreased latency to feed and increased feeding duration without affecting water intake or locomotor activity. Values given are means ± SEM. * p < 0.05; p < 0.01;
Experiment 2
As demonstrated in the previous experiment, 188 ng of baclofen significantly increased food intake as compared with the saline treatment (p < 0.01; Fig. 1b). The baclofen-induced feeding was eliminated by coadministration of 500 ng of the selective GABAB antagonist saclofen (p < 0.01), but was not affected by 75 ng of the GABAA antagonist bicuculline methbromide. In a separate group of rats, injection of 50 ng of muscimol significantly increased food intake (p < 0.01; Fig. 1c). This increase was abolished by coadministration of 75 ng of bicuculline methbromide (p < 0.01). Coadministration of 500 ng of saclofen had no effect on the feeding elicited by muscimol.Experiment 3
The overall effect of bilateral muscimol injections into the AcbSh on 2 hr food intake was highly significant (F(5,20) = 15.8; p < 0.0001). Muscimol increased food intake in a dose-dependent manner with a maximal effect at 100 ng (Fig. 2). Planned comparisons showed that the effect was significant at every dose above 10 ng; however, muscimol injections had no effect on water intake.
Fig. 2. Mean (±SEM) food and water intake after injection of various doses of muscimol into the AcbSh. Muscimol dose-dependently increased food intake at all doses >10 ng, with 60-70% of the feeding occurring in the initial 30 min. Muscimol had no effect on 120 min water intake at any dose. *p < 0.05;
[View Larger Version of this Image (32K GIF file)]
Experiment 4
Food intake was increased dramatically by bilateral injection of either 10 or 20 µg of the specific GABA-T inhibitor GVG into the AcbSh (p < 0.01 in both cases) (Fig. 3). Water intake was not altered by either dose. Administration of 3 µg of the GABA uptake inhibitor nipecotic acid did not affect food or water intake.
Fig. 3. Mean (±SEM) food intake after injections of the GABA-T inhibitor GVG or the GABA reuptake inhibitor nipecotic acid into the AcbSh. Although GVG significantly increased food intake at both doses tested (
[View Larger Version of this Image (26K GIF file)]
Experiment 5
Injections of muscimol or baclofen into the AcbC did not significantly affect food intake (30 min intake: saline, 0.2 ± 0.08; muscimol, 0.2 ± 0.04; baclofen, 0.9 ± 0.50). Although bilateral injections of muscimol into the AcbSh increased food intake significantly (p < 0.001), injections rostral, dorsal, or caudal to this region did not significantly affect feeding behavior (Fig. 4). Injections dorsocaudal to the AcbSh that involved the lateral ventricles did increase food intake (p < 0.01), although the mean intake was approximately half as great as that seen after injections into the AcbSh. Water intake was not altered by muscimol injections into any of the sites.
Fig. 4. Mean (±SEM) food intake after injections of saline or 50 ng of muscimol into the AcbSh and several surrounding sites. Although muscimol injections near the lateral ventricles increased food intake, the ventromedial AcbSh was the most sensitive site for eliciting feeding.
[View Larger Version of this Image (39K GIF file)]
DISCUSSION
The results obtained in this series of experiments demonstrate that manipulations of the AcbSh GABAergic system can have profound, but specific, effects on feeding behavior in rats. This system has not been described previously and is potentially an important component of the central mechanisms controlling food intake.
We have demonstrated that activation of either GABAA or GABAB receptors is sufficient to increase food intake. Furthermore, equimolar doses of the two GABA agonists are equipotent at increasing food intake (Fig. 1a), and the behavioral profile for animals receiving muscimol or baclofen is similar (Table 1). After either treatment, rats show a dose-dependent increase in food intake, with a corresponding decrease in latency to begin feeding. GABA agonists seem to act selectively on a feeding system, because they do not significantly alter water intake or locomotor activity. There is a tendency, however, for rearing duration to be decreased, especially after administration of high doses of baclofen or muscimol. Rearing behavior is often used as an index of exploratory activity, and this is most likely a concomitant of the large increase in the proportion of time the animal spends either feeding or in a period of post-ingestive quiescence.
Although not investigated in the AcbSh, baclofen has been shown to inhibit glutamate release in the AcbC (Uchimura and North, 1991
Further evidence that muscimol and baclofen are acting exclusively through activation of GABAA and GABAB receptors, respectively, was obtained by the coadministration of receptor-selective GABA antagonists. Feeding elicited by muscimol injections was completely suppressed by coadministration of 75 ng of the GABAA receptor antagonist bicuculline, but was not affected by 500 ng of the GABAB antagonist saclofen (Fig. 1c). Conversely, baclofen-induced feeding was eliminated by coadministration of saclofen, but was unaffected by bicuculline (Fig. 1b). Pilot studies showed that coadministration of 50 ng of muscimol and doses of bicuculline >100 ng often precipitated seizures in our rats. These were not apparent with the 75 ng dose of bicuculline used in this experiment, and the fact that baclofen-induced feeding was not affected by coadministration of this dose of bicuculline suggests that the rats were not nonspecifically impaired to any significant degree and were still fully capable of normal ingestion. No seizure activity or other abnormal behavior was observed after coadministration of saclofen.
The feeding elicited by microinjections of muscimol into the AcbSh was dose-related and relatively long lasting (Fig. 2). Two hour food intake was significantly increased at every dose >10 ng, with 100 ng eliciting the largest increase. With each dose of muscimol tested, 60-70% of the food was consumed during the initial 30 min of the test. Intake was not as great after 200 ng of muscimol, but this was attributable largely to a reduction in the amount of feeding performed during the second hour of the test. This may suggest that the muscimol was diffusing to a site mediating a competing behavior and that expression of this behavior during the second hour of the test interfered with the feeding.
It seems that endogenous GABA in the AcbSh plays a role in the regulation of food intake. Microinjections of the GABA-T inhibitor GVG elicited intense, dose-related feeding (Fig. 3). By blocking the metabolism of GABA, this pharmacological intervention increases levels of endogenous GABA (Halonen et al., 1991
Food intake was not affected by injections of GABA agonists into the AcbC. Instead, the ventromedial AcbSh was the most sensitive site tested for eliciting feeding behavior with injections of muscimol (Fig. 4). Although injections placed immediately rostral, lateral, or caudal to this region did not affect food intake, there was a trend for injections near the ventricles to increase feeding that became significant with the most caudal placement. Intracerebroventricular administration of muscimol has been reported previously to increase food intake (Olgiati et al., 1980
Although the ventromedial AcbSh proved to be the most sensitive site tested for eliciting feeding, little can be said regarding the distribution of this system throughout the AcbSh. The dorsal and lateral poles of the AcbSh remain uninvestigated, and injections involving the rostral aspect of the AcbSh did not increase food intake, suggesting that the relevant cells may be distributed heterogeneously within this nucleus. A further caveat deserves mention. Embedded in the ventromedial AcbSh are other neuronal structures, most notably the islands of Calleja and rostral extensions of the ventral pallidum. Although our injections involved primarily the AcbSh, the possibility that one of these other structures plays a role in the mediation of feeding behavior by GABA agonists cannot be discounted.
Our results suggest strongly that food intake is regulated, in part, by a population of neurons located in the ventromedial AcbSh and that inhibition of these neurons is the cellular event that leads to the observed feeding response. These neurons are probably GABAergic, medium-sized, spiny projection neurons. On the basis of data obtained in a previous study showing that feeding can be induced by blocking AMPA and kainate receptors in this region (Maldonado-Irizarry et al., 1995
It is interesting to consider the present findings in relation to other functional attributes of the nucleus accumbens. Traditionally, the nucleus accumbens has been considered a structure that plays a key role in central reinforcement and reward mechanisms. It is well established that this region subserves the reinforcing effects of self-administered drugs (Roberts et al., 1980
In summary, our results indicate that GABA-sensitive neurons located in the ventromedial AcbSh have the ability to mediate feeding behavior in rats. Furthermore, we have shown that an increase in levels of endogenous GABA in the AcbSh induces feeding, suggesting that this system may participate in the physiological regulation of food intake. The magnitude and behavioral specificity of these effects suggest that the AcbSh is potentially an important component of the neural systems controlling feeding behavior in the rat.
FOOTNOTES
Received Jan. 16, 1997; revised March 10, 1997; accepted March 20, 1997.
This study was supported by research Grant DA04788 from the National Institute on Drug Abuse.
Correspondence should be addressed to Dr. Thomas R. Stratford, Department of Pharmacology, Allegheny University of the Health Sciences, 3200 Henry Avenue, Philadelphia, PA 19129.
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