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The Journal of Neuroscience, December 15, 1999, 19(24):11040-11048
Evidence of a Functional Relationship between the Nucleus
Accumbens Shell and Lateral Hypothalamus Subserving the Control of
Feeding Behavior
Thomas R.
Stratford and
Ann E.
Kelley
Department of Psychiatry, University of Wisconsin-Madison Medical
School, Madison, Wisconsin 53719
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ABSTRACT |
Inhibition of neurons in the nucleus accumbens shell (AcbSh) with
local injections of GABA agonists or glutamate antagonists elicits an
intense, but specific, feeding response resembling that seen after
stimulation of the lateral hypothalamus (LH). To help characterize the
contribution of the LH to the expression of AcbSh-mediated feeding, we
used the immunohistochemical detection of the nuclear protein Fos to
determine whether inhibition of AcbSh cells results in an activation of
LH neurons. Injections of the GABAA agonist muscimol into
the AcbSh greatly increased the number of cells exhibiting Fos-like
immunoreactivity in the LH, as well as in the lateral septum,
paraventricular hypothalamic nucleus, ventral tegmental area,
substantia nigra pars compacta, and nucleus of the solitary tract.
Blocking activation of LH neurons with the selective NMDA receptor
blocker D( )-AP-5 is known to suppress
deprivation-induced feeding. We found that injections of
D()-AP5 into the LH also dose-dependently suppressed
AcbSh-mediated feeding.
It is likely that inhibition of GABAergic neurons in the AcbSh is
responsible for eliciting this feeding. If a behaviorally relevant
GABAergic projection terminates in the LH, we should be able to mimic
the effects seen after inhibition of the projection neurons by applying
a GABA receptor blocker to the area. However, injections of the
GABAA receptor blocker bicuculline or the GABAB receptor blocker saclofen did not significantly affect food intake. Thus, it appears that the expression of the feeding response depends on
an NMDA-preferring receptor-mediated activation of LH neurons and is
not the result of disinhibiting LH cells by disrupting transmission at
GABA synapses.
Key words:
nucleus accumbens shell; lateral hypothalamus; feeding
behavior; c-fos; GABA; NMDA; D()-AP-5
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INTRODUCTION |
Although it is well known that the
nucleus accumbens plays a critical role in the regulation of appetitive
behavior (Salamone, 1994 ; Ikemoto and Panksepp, 1996), several recent
studies have implicated the shell subregion (AcbSh) as an important
component of a neural system specifically involved in the mediation of
feeding behavior. Inhibition of neurons in the AcbSh by administration of excitatory amino acid antagonists (Maldonado-Irizarry et al., 1995;
Stratford et al., 1998) or GABA agonists (Stratford and Kelley, 1997b)
elicits intense feeding in satiated rats. These treatments appear to
affect feeding behavior specifically, because they do not increase
water intake, noningestive gnawing, or locomotor activity (Stratford et
al., 1998). As such, the effect does not appear to be the result of a
general behavioral activation.
The majority of cells projecting from the AcbSh are medium spiny
neurons that use GABA as a neurotransmitter (Meredith et al., 1993),
and both symmetric inhibitory GABAergic terminals and neurochemically
uncharacterized asymmetric (presumably excitatory) terminals have been
shown in apposition to the axon hillock of these neurons (Meredith and
Wouterlood, 1991), placing them in a position to exert a powerful
influence on the output of these cells. It follows that, if we inhibit
GABAergic AcbSh projection neurons through actions at glutamate and
GABA receptors located on those cells, then disrupting GABA
transmission in the terminal fields of those neurons may also elicit
feeding. Currently, the locations of the relevant terminal fields are
unknown; however, a likely candidate appears to be the lateral
hypothalamus (LH). In the paper that initially described the
elicitation of feeding from the AcbSh, the authors noted that the
intensity of the feeding reminded them of that seen after stimulation
of the LH. They subsequently demonstrated a functional relationship
between these two brain regions by showing that AcbSh-mediated feeding
could be attenuated by injections of the GABAA
receptor agonist muscimol into the LH (Maldonado-Irizarry et al.,
1995). Furthermore, it is well known that neurons in the AcbSh project
directly to the LH (Heimer et al., 1991; Zahm and Brog, 1992; Kirouac
and Ganguly, 1995) and that electrical (Delgado and Anand, 1953) or
chemical (Stanley et al., 1993a,b) stimulation of LH neurons can induce
robust feeding in satiated animals.
The following series of studies was designed to investigate further the
nature of the relationship between these two brain regions. In
experiment 1, we used the immunohistochemical detection of the
c-fos gene product Fos to explore the possibility
that injections of muscimol into the AcbSh increase the firing rate of
neurons in the LH. Experiment 2 involved investigating whether disrupting glutamate transmission in the LH by blocking NMDA
receptors can suppress AcbSh-mediated feeding as it has been shown to
do to deprivation-induced feeding (Stanley et al., 1996). Finally, we
examined the effect blocking GABA receptors in the LH had on food
intake in an attempt to determine whether GABAergic fibers terminating
in the region contribute to a tonic inhibition of LH neurons that
participate in the control of feeding behavior.
Parts of this paper have been published previously in abstract form
(Stratford and Kelley, 1997a)
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MATERIALS AND METHODS |
Subjects. Male Sprague Dawley rats (Harlan, Madison,
WI) weighing between 280 and 300 gm at the time of surgery were
group-housed in acrylic cages and maintained in a temperature- (~ 21°C) and light- (12 hr light/dark) controlled environment with food
(Harlan Teklab Rat Diet 7001) and acidified tap water available
ad libitum.
Surgery. The rats were anesthetized with a mixture of
ketamine HCl and xylazine (100 and 10 mg/kg, respectively; Sigma, St. Louis, MO), and bilateral 23 gauge stainless steel guide
cannulas were implanted using standard, flat-skull stereotaxic
techniques. In experiment 1, eight rats received guide cannulas aimed
at the AcbSh using the following coordinates: anteroposterior (AP),
1.4; lateromedial (LM), ±0.8; dorsoventral (DV), 5.5 (in millimeters from bregma; Paxinos and Watson, 1997). For experiment 2, six rats
received guide cannulas aimed at the LH (AP, 2.5; LM, ±1.8; DV,
6.0). For the third experiment, guide cannulas aimed at both the
AcbSh and the LH were implanted in eight rats. All of the guide
cannulas were held in place using stainless steel screws and denture
lining material, and a stainless steel obturator was inserted into the
lumen of each cannula to help maintain patency. Each rat received a
prophylactic intramuscular injection of sterile penicillin (~40,000
U; Flo-Cillin; Fort Dodge Laboratories, Inc., Fort Dodge, IA) after
surgery and was allowed to recover at least 7 d before the start
of behavioral testing.
Intracerebral injections. To acclimate the rats to the test
procedure, 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 (42 × 20 cm) for 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 cannulas 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 was obtained from Sigma (St. Louis, MO).
Bicuculline methbromide, saclofen, and
D()-2-amino-5-phosphonopentanoic acid
(D()-AP-5) were obtained from Research
Biochemicals (Natick, MA). All drugs were dissolved in sterile 0.15 M saline.
Experimental design. In experiment 1, we investigated the
effects intra-AcbSh injections of muscimol had on the expression of
c-fos in the LH. Rats received guide cannulas aimed at the AcbSh (as described above) and were allowed to recover for 7 d. During that time, the rats were handled daily and were acclimated to
the test cages and injection procedure. To ensure that the treatment
would increase feeding behavior, food and water intakes were recorded
after injections of muscimol or the saline vehicle into the AcbSh. On
the seventh day, all of the rats received simultaneous, bilateral 0.5 µl injections of sterile 0.15 M saline into the AcbSh. The rats were placed in test cages with a preweighed quantity of
food and a graduated bottle containing tap water available, and food
and water intakes were recorded at 30, 60, and 120 min. Three days
later, all of the rats received bilateral injections of muscimol (100 ng/0.5 µl) into the AcbSh, and food and water intake were recorded as
before. Five days later, half of the rats received bilateral injections
of saline and half received bilateral injections of muscimol (100 ng/0.5 µl) into the AcbSh and were placed in the test cages without
food or water present. The rats remained in the test cages for 90 min,
at which time they were anesthetized and perfused as described below.
Experiment 2 was designed to determine whether blocking glutamate
transmission at NMDA receptors in the perifornical hypothalamus could
suppress the intense feeding elicited by bilateral injections of
muscimol into the AcbSh. Rats received bilateral guide cannulas aimed
at both the AcbSh and the perifornical LH. Food and water intake were
recorded after simultaneous, bilateral injections of vehicle at both
sites or after injections of 438 pmol (50 ng) of muscimol into the
AcbSh and 0, 0.1, 1.0, or 10.0 nmol of D()-AP-5 into the
LH. Treatment order was counterbalanced, and the rats were allowed at
least 48 hr between injections.
In experiment 3, we investigated the possibility that blocking GABA
receptors in the perifornical LH could increase food intake in satiated
rats. Guide cannulas aimed at the perifornical LH were implanted into
rats, they were allowed to recover for 1 week, and they were acclimated
to the injection and test procedures as described above. On test days,
the rats received bilateral injections of either vehicle or 10, 50, 100, or 200 ng of the selective GABAA receptor
blocker bicuculline, and food and water intake were recorded at 30, 60, and 120 min. Treatment was counterbalanced, and at least 48 hr were
allowed between injections. After the rats had been tested with each
dose of bicuculline, all of the rats were tested with a single dose
(500 ng) of the selective GABAB receptor blocker saclofen.
Histology. After behavioral testing, all of the animals were
deeply anesthetized using sodium pentobarbital and were 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 of rats in the c-fos study were blocked
between the AcbSh and the LH, and the caudal fragment was post-fixed in
the formalin solution for 2-3 hr, moved to 20% sucrose in 0.01 M phosphate buffer at 4°C for 48 hr, and then
immunohistochemically processed. The rostral brain fragments of the
rats in the c-fos study and the brains of the rats in the
feeding studies were removed and stored in fixative for at least 1 week. They were then frozen, and 60 µm coronal sections were taken
throughout the extent of the injection sites. The sections were stained
with cresyl violet, and the injection sites were examined for placement
accuracy and excessive damage. Data from rats with misplaced cannulas
were not included in the analyses.
Immunocytochemistry. The brains were frozen quickly with a
chemical freeze spray (Freeze-It; Chemtronics Inc., Kennesaw, GA), and
30-µm-thick coronal sections were taken from the level of the median
preoptic nucleus to the caudal pole of the interpeduncular nucleus and
also throughout the extent of the nucleus of the solitary tract (NTS).
Every other section was placed in a blocking serum composed of 0.01 M PBS, pH 7.2, containing 10% normal goat
serum (NGS) (Vector Laboratories, Burlingame, CA) and 0.3% Triton
X-100 (Sigma) for 30 min. The sections were rinsed in PBS and incubated on a rotary shaker table for 20 hr at 4°C in a polyclonal primary antibody (rabbit anti-Fos, diluted 1:50,000 with 0.01 M PBS containing 4% NGS; Oncogene Research
Products, Cambridge, MA). The sections were rinsed again in PBS and
were processed using a Vectastain Elite ABC kit (Vector Laboratories).
The sections were incubated in the biotinylated goat anti-rabbit
secondary antibody (containing 4% NGS) for 60 min at room temperature,
were rinsed in PBS (three times for 10 min each), and were
incubated in the avidin-biotin complex solution for 60 min. After
another series of rinses in PBS, the peroxidase was visualized by
incubating the tissue for 5 min in the chromogen solution from a Vector
Laboratories 3,3'-diaminobenzidine tetrahydrochloride peroxidase
substrate kit.
Quantification. The number of Fos-positive nuclei were
counted unilaterally in matched coronal sections from saline- and
muscimol-injected rats at three different levels of the rostral LH. The
most rostral section was at the level of the suprachiasmatic nuclei,
the middle section at the level of the caudal paraventricular
hypothalamic nuclei (PVNs), and the most caudal section at the level of
the dorsomedial hypothalamic nuclei. These levels correspond
approximately to plates 23, 25, and 28 of the Paxinos and Watson atlas
(1997), respectively.
Statistical analyses. In experiment 1, the mean number of
Fos-immunoreactive nuclei were compared at each of the three levels examined using a Student's t test. In experiments 2 and 3, 2 hr food and water intake data were analyzed across doses using a one-factor ANOVA with repeated measures. Where an overall
significant effect of dose was found, individual comparisons with the
AcbSh-muscimol-LH-vehicle control condition (experiment 2) or vehicle
treatment (experiment 3) were examined using Dunnett's multiple
comparison method.
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RESULTS |
Experiment 1
A schematic illustration of a typical AcbSh injector placement is
given in Figure 1A. As
we have reported previously, bilateral microinjections of 100 ng of
muscimol into the AcbSh elicited intense feeding in satiated rats and
greatly increased consumption of chow over a 2 hr period compared with
intake after vehicle injections (vehicle: 1.6 ± 0.47 gm;
muscimol: 10.1 ± 0.74 gm). Injections of muscimol into the AcbSh
also greatly increased the number of cells showing Fos-like
immunoreactivity (Fos-LI) in the LH (Figs.
2, 3).
Although a significant increase in Fos-LI was observed throughout the
rostrocaudal extent of the LH, the largest increase was seen in the
perifornical region of the nucleus. Cell counts on comparable LH
sections demonstrated that AcbSh injections of muscimol significantly
increased the number of neurons exhibiting Fos-LI compared with
saline-injected rats (p < 0.001 at each level
examined) (Fig. 4).
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Figure 1.
Schematic representation of bilateral injection
sites centered in AcbSh (A) and perifornical LH
(B) (modified from Paxinos and Watson,
1997).
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Figure 2.
Photomicrographs of Fos-LI in serial coronal
sections taken through the central LH after intra-AcbSh injections of
saline (A-D) or 100 ng of muscimol
(E-H). Muscimol injections greatly increased the
number of LH cells demonstrating Fos-LI, particularly in the
perifornical region of the LH. SO, Supraoptic nucleus;
opt, optic tract; f, fornix.
Magnification, 40×.
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Figure 3.
Higher power view of Fig. 1, C and
G, showing Fos-LI in the LH after intra-AcbSh injections
of saline (A) or muscimol
(B). f, Fornix. Magnification,
100×.
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Figure 4.
Schematic illustration of the mean number and
location of cells exhibiting Fos-LI at three levels of the LH. The
left depicts Fos-LI after injection of saline into the
AcbSh, and the right depicts Fos-LI after injection of
muscimol into the AcbSh. Each dot represents
approximately five labeled cells. The mean ± SEM number of
hypothalamic cells exhibiting Fos-LI on one side of the brain at each
level are as follows: rostral LH: saline 35 ± 6, muscimol
377 ± 50; middle LH: saline 24 ± 3, muscimol 692 ± 63; caudal LH: saline 49 ± 6, muscimol 322 ± 40. Cpu, Caudate putamen; VMH, ventromedial
hypothalamic nucleus; ic, internal capsule;
f, fornix.
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Large increases in Fos-LI also were observed in a number of brain
regions other than the LH, including the lateral septum (LS) and
dorsolateral preoptic region (Fig. 5),
the PVN, and the caudal LH- ventral tegmental area (VTA) transition
zone in the vicinity of the supramammillary nucleus (SuM) (Fig.
6), the VTA and medial substantia nigra
pars compacta (SNC) (Fig. 7), and the NTS
(Fig. 8).
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Figure 5.
Fos-LI at the level of the lateral septum after
intra-AcbSh injections of saline (A) or muscimol
(B). Although muscimol increased Fos-LI in cells
throughout the LS, the greatest effect was noted in the ventral aspect
of the nucleus. LPO, Lateral preoptic area;
ac, anterior commissure. Magnification, 40×.
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Figure 6.
Fos expression in the central (A,
C, D, F) and caudal
(B, E) hypothalamus after saline
(A-C) or muscimol (D-F)
injections in the AcbSh. Muscimol greatly increased the number of
Fos-positive nuclei in cells located in the PVN and the caudal pole of
the LH at the level of the SuM. C and F
are higher power views of the PVN. mp, Mammillary
peduncle; f, fornix. Magnification: A,
B, D, E, 40×;
C, F, 100×.
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Figure 7.
Coronal sections through the midbrain showing
Fos-LI after saline (A, B) or muscimol
(C, D) infusion into the AcbSh. Fos
expression was increased by muscimol in both the VTA and medial
substantia nigra, pars compacta. IP, Interpeduncular
nucleus; SNR, substantia nigra, pars reticulata.
Magnification: A, C, 40×;
B, D, 100×.
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Figure 8.
Fos expression at the level of the NTS after
intra-AcbSh infusions of saline (A-C) or
muscimol (D-F). The number of cells exhibiting
Fos-LI was increased at both intermediate (A,
D) and caudal (B, E)
levels of the NTS. C and F are higher
power views of the caudal NTS. Gr, Gracile nucleus;
XII, hypoglossal nucleus. Magnification:
A, B, D, E,
40×; C, F, 100×.
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Experiment 2
A schematic illustration of a typical perifornical LH injector
placement is given in Figure 1B. Simultaneous
administration of the GABAA receptor agonist
muscimol into the AcbSh and saline into the perifornical LH elicited
intense feeding in satiated rats (p < 0.01).
This feeding response was dose-dependently attenuated by injections of
the selective NMDA antagonist D()-AP-5 into the
perifornical LH (Fig. 9).
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Figure 9.
Mean ± SEM food intake after simultaneous
bilateral injections of muscimol into the AcbSh and various doses of
AP-5 into the perifornical lateral hypothalamus. AP-5 dose-dependently
suppressed muscimol-elicited food intake. *p < 0.05;  p < 0.01, significant difference from
control trial.
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Experiment 3
Bilateral injections of the selective GABAA
receptor blocker bicuculline (10-200 ng/side) or the selective
GABAB receptor blocker saclofen (500 ng/side) did
not alter food or water intake significantly in satiated rats (Fig.
10).
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Figure 10.
Mean ± SEM food and water intake after
injection of various doses of GABA receptor blockers into the
perifornical LH. Neither food nor water intake was significantly
altered by blockade of GABAA receptors with bicuculline or
GABAB receptors with saclofen in the LH.
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DISCUSSION |
Data obtained in this series of experiments provide important
evidence of a functional relationship between the AcbSh and LH as they
relate to the control of feeding behavior. Injections of muscimol into
the AcbSh greatly increased the synthesis of the nuclear protein Fos in
neurons located in the LH. Although the number of neurons expressing
Fos-LI was increased significantly throughout the rostrocaudal extent
of the LH (Fig. 4), the number of Fos-positive nuclei was greatest in
the perifornical LH at the level of the PVN. Because increased
synthesis of Fos is generally accepted as a marker for neuronal
activation (Sheng and Greenberg, 1990), this result suggests that these
cells increase their rate of firing in response to the activation of
GABAA receptors located on AcbSh neurons. The LH
is well known for playing a critical role in the control of ingestive
behavior (for review, see Bernardis and Bellinger, 1996). It is
especially interesting that cells in the LH appear to be activated by
application of a GABA agonist to AcbSh neurons, because electrical
(Miller, 1960) or chemical (Stanley et al., 1993a,b) excitation of LH
neurons is known to induce intense feeding in satiated rats. These data
strongly suggest that AcbSh neurons may control feeding behavior
through their influence on the firing rate of LH neurons. Our results
extend those presented in a recent report in which an increase in LH Fos accompanied the reverse dialysis of muscimol at a site located on
the border between the core and shell subregions (Yoshida et al.,
1997). Because we verified our injection sites histologically and
behaviorally, it appears likely that increased synthesis of Fos in the
LH is the result of specifically inhibiting neurons in the AcbSh.
Still, it is important to note that this technique does not address the
question of whether the AcbSh influences the firing rate of LH neurons
directly through monosynaptic efferents or indirectly through a
polysynaptic pathway involving one or more intervening brain
structures. Furthermore, although our 90 min postinjection survival
period was chosen to help maximize Fos levels (Müller et al.,
1984), it would be interesting to perform a time course analysis of Fos
synthesis using shorter survival times to determine how quickly Fos
synthesis is stimulated in LH neurons.
We also noted that injections of muscimol into the AcbSh increased
Fos-LI in a number of brain regions in addition to the LH. These areas
included the LS (Fig. 5) and PVN (Fig. 6) in the forebrain, the VTA and
medial SNC (Fig. 7) in the midbrain, and the NTS (Fig. 8) in the
hindbrain. Along with the LH, the LS, PVN, and NTS are well known
components of the central circuitry involved in the mediation of
feeding behavior (Stanley and Leibowitz, 1985; King and Nance, 1986;
Stanley et al., 1988; Tempel et al., 1993; Kotz et al., 1997; Treece et
al., 1998; Pu et al., 1999). The fact that manipulations of the AcbSh
can alter the activity of neurons in these regions reinforces the
concept that the medial nucleus accumbens plays an important role in
the control of food intake. It is particularly interesting that neurons
in the NTS are activated by injections of muscimol into the AcbSh, even
in the absence of food intake. This result provides evidence that the
medial accumbens can influence neuronal activity at an important hindbrain feeding site thought to be involved in the integration of
gustatory and visceral information.
Activation of GABAA receptors in the AcbSh also
resulted in a small, but relatively consistent, increase in Fos-LI in
neurons located in the medial ventral pallidum (VPm). The VPm is one of the primary sites of termination of AcbSh efferents (Heimer et al.
1991) and has been demonstrated recently to play a role in the control
of food intake (Stratford et al., 1999). However, evaluation of Fos-LI
throughout the ventral pallidum is complicated by the fact that the
rostral VPm is located in close proximity to our muscimol injection
site. Intracerebral injections often result in Fos synthesis by neurons
surrounding the infusion site, and the extent to which this phenomenon
contributed to labeling in the VPm is currently unclear.
Interestingly, muscimol injections in the AcbSh increased the
expression of Fos in the VTA and medial SNC, two sites from which
dopaminergic mesolimbic projections terminating in the AcbSh and other
areas of the forebrain originate. The VTA and medial SNC are innervated
by monosynaptic projections from the AcbSh (Heimer et al., 1991), and
the observed increase in Fos-LI probably reflects a disinhibition of
neurons in the region. Although it is not yet known whether the
activated cells are dopaminergic, the results suggest that inhibiting
cells in the AcbSh may increase forebrain levels of dopamine. Thus, in
addition to a behaviorally specific effect on food intake,
manipulations of the AcbSh may prove to have more general effects on
neural systems subserving reward and reinforcement.
As part of an ongoing series of studies that have elucidated the
importance of glutamatergic systems in the LH for the control of food
intake, Stanley et al. (1996) have demonstrated that activation of NMDA
receptors in the LH is necessary for the full expression of feeding
induced by food deprivation. Similarly, the current study shows that
blocking LH NMDA receptors with the selective antagonist
D()-AP-5 can potently suppress feeding elicited by injections of muscimol into the AcbSh. This strongly suggests that the
expression of feeding behavior elicited by inhibition of neurons in the
AcbSh depends on an NMDA receptor-mediated activation of LH neurons. It
also raises the possibility that inhibition of cells in the AcbSh and
food deprivation induce feeding through activation of a common neural
pathway involving neurons in the LH.
The question arises as to whether the LH cells are under direct control
of AcbSh neurons or whether information from the AcbSh is relayed
transynaptically through one or more intervening nuclei. Because the
axons of some projection neurons located in the AcbSh terminate in the
LH (Heimer et al., 1991; Zahm and Brog, 1992; Kirouac and Ganguly,
1995) and because most AcbSh projection neurons are thought to use GABA
as a neurotransmitter (Meredith et al., 1993), the most parsimonious
route of control would be through a direct GABAergic projection from
the AcbSh to the LH. In this case, inhibition of AcbSh projection
neurons by activation of dendritic and/or somatic
GABAA receptors would suppress the release of
GABA from fibers terminating in the LH. This, in turn, would disinhibit
LH neurons, resulting in an increase in food intake. If this model were
correct, then blocking GABA receptors in the LH should have similar
behavioral results and should result in an acute increase in food
intake. We found that the selective blockade of
GABAA or GABAB receptors in
the region had no effect on food or water intakes. This is persuasive
evidence that a tonically inhibitory feeding-related GABAergic
projection originating in the AcbSh, or anywhere else, does not
terminate in the region of the LH we know to be activated by our
manipulations of the AcbSh. The possibility remains, of course, that a
direct AcbSh-LH projection using some other neurotransmitter is
involved. An additional possibility is that GABA in the LH is involved
in the control of intake of specific macronutrients. In fact, an early
study reported that injections of bicuculline methiodide into the LH did increase intake of a diet high in fat and carbohydrates during the
initial 30 min of a 3 hr test (Kelly et al., 1977). It is important to
reiterate, however, that under the same test conditions in which
manipulations of the AcbSh elicit such large increases in food intake
(120 min intake of the maintenance diet in non-deprived rats),
injections of GABA antagonists into the specific region of the LH in
which we saw the largest increases in Fos expression and in which
administration of an NMDA receptor antagonist blocked AcbSh-mediated
feeding, did not increase food intake.
In summary, the feeding elicited by injecting muscimol into the AcbSh
is accompanied by an increase in the synthesis of Fos in neurons
located in the LH, suggesting that these cells are increasing their
firing rates in response to the stimulus. Furthermore, the NMDA
receptor-mediated activation of LH neurons is necessary for the
expression of the AcbSh-mediated feeding. Neurons in the AcbSh,
however, do not appear to control the firing rate of LH neurons through
a direct GABAergic projection to the LH. We have discovered recently
that blocking GABA receptors in the medial ventral pallidum, a brain
region anatomically interposed between the AcbSh and LH, induces robust
feeding in rats (Stratford et al., 1999). Together with our current
results, the data raise the interesting possibility that an
AcbSh-VPm-LH circuit is involved in the control of food intake.
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FOOTNOTES |
Received May 10, 1999; revised Sept. 10, 1999; accepted Oct. 1, 1999.
This work was supported by National Institute on Drug Abuse Grant DA04788.
Correspondence should be addressed to Thomas R. Stratford at his
present address: Neuropsychiatric Research Institute, 700 First Avenue
South, Fargo, ND 58103. E-mail: tstratford{at}nrifargo.com.
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ABSTRACT
INTRODUCTION
