Research report
Feeding induced by blockade of AMPA and kainate receptors within the ventral striatum: a microinfusion mapping study

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Abstract

The corticostriatal pathway is believed to utilize the excitatory amino acid glutamate as its transmitter, and the striatum contains high levels of all glutamate receptor subtypes. It has recently been demonstrated that blockade of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) and kainate glutamate receptors in the medial part of the accumbens, corresponding to the medial shell subregion, results in a pronounced feeding response. In order to more precisely localize this response, a microinfusion mapping study was conducted. Bilateral microinfusions of 6,7-dinitroquinoxaline-2,3-dione (DNQX, 0, 50, 250, 750 ng/0.5 μl), an antagonist that blocks AMPA and kainate receptors, were carried out in eight striatal subregions in different groups of animals. In non-deprived rats, food intake (normal chow), feeding duration, and several other behavioral measures were assessed during a 30 min test session. DNQX significantly and potently enhanced food intake when injected into the accumbens shell, but not into any other region examined, including accumbens core, anterior dorsal, posterior dorsal, ventromedial, dorsomedial, and ventrolateral striatum. The most sensitive site within the accumbens was found to be the posterior aspects of the shell, in which the lowest dose (50 ng DNQX) augmented feeding. These results suggest that a circumscribed region within the nucleus accumbens has a unique role in the control of feeding. It is postulated that removal of tonic excitatory inputs to this region with DNQX results in disinhibition of brain circuits critical for ingestive behavior.

Introduction

In recent years there has been much interest in the functional role of glutamate and glutamate receptors within the basal ganglia. Glutamate has long been known to be the major neurotransmitter in the corticostriatal pathway 7, 10, 19and the striatum contains high levels of all subtypes of glutamate receptors [1]. It is generally believed that this system integrates a diverse array of sensory, motor, and cognitive information arising from cortical and limbic regions. Moreover, glutamate receptors are localized on the medium spiny output neurons of the striatum, which also receive input from the mesencephalic dopamine system 3, 8, 22, 26. Glutamate receptors within the basal ganglia may play a significant role in neuronal excitability, learning, plasticity, and in neurotoxicity associated with several basal ganglia disorders 2, 15.

One approach to understanding more about the behavioral functions of glutamate receptors within the striatum has been to employ microinfusions of selective antagonists of specific receptor subtypes. For example, microinfusion of the selective antagonist AP-5 into the nucleus accumbens results in disrupted spatial learning, decreased exploratory behavior, and reduced behavioral responses to psychostimulants 14, 17, 21. AMPA/kainate antagonists also reduce the enhancing effects of stimulants on motor activity and reward-related responding 5, 13, 16. We have recently shown that blockade of non-NMDA receptors within the medial aspects of nucleus accumbens (accumbens shell, AcbSh), employing microinjections of antagonists that block AMPA and kainate receptors, results in a pronounced feeding response [18]. This response is not induced by NMDA antagonists, and is blocked by concurrent inhibition of the lateral hypothalamus with muscimol. The response is also induced by direct inhibition of the shell with GABA agonists [25]. In view of these findings we have hypothesized that the nucleus accumbens shell is a region intimately involved in the central circuits that control feeding behavior, most likely via direct or indirect connections with the lateral hypothalamus.

The present study was undertaken in order to further understand the precise regions within the ventral striatum and accumbens that were sensitive to induction of feeding with 6,7-dinitroquinoxaline-2,3-dione (DNQX), a glutamate antagonist that blocks AMPA and kainate receptors [12]. Infusions of DNQX were made in different groups of animals with chronic indwelling cannulae aimed at eight striatal subregions. These subregions were the anterior medial nucleus accumbens (anterior accumbens shell), posterior medial nucleus accumbens (posterior accumbens shell), nucleus accumbens core, anterior dorsal striatum, posterior dorsal striatum, ventromedial striatum, dorsomedial striatum, and ventrolateral striatum. Food intake and duration of feeding were measured in rats maintained on an ad libitum diet.

Section snippets

Animals and surgery

In these experiments, 36 male Sprague-Dawley rats were used. They were group-housed three to a cage and maintained on standard laboratory chow and water ad libitum. They were maintained on a 12:12 light/dark cycle with lights on at 7:00 a.m. For surgery, the animals were anesthesitized with sodium pentobarbital (50 mg/kg) and placed in a Kopf stereotaxic apparatus with the incisor bar at 5.0 mm above the interaural zero. Atropine (0.4 mg/ml s.c.) was administered in a volume of 0.1 ml per rat.

Results

The results from the behavioral tests are shown in Table 2Table 3, and in Fig. 1. Table 2 presents the gram intake data, and Table 3 shows the feeding duration data. First, it should be noted that baseline intake was very low, since these rats were not food-deprived, and it was the light part of the day-night cycle, when normal activity and feeding are fairly low. It can be observed that for both behavioral variables only the accumbens shell groups, both anterior shell and posterior shell,

Discussion

The present findings show that there is a narrow zone within the ventral striatum, confined to the medical accumbens shell, that supports DNQX-induced feeding. The intense feeding observed in both accumbens shell groups confirms our previous report of feeding induced by infusion of this glutamate antagonist into this region [18]. In that report the accumbens core was also found not to support DNQX-induced feeding, suggesting a considerable degree of anatomical specificity. The present work has

Acknowledgements

This work was supported by grant DA 04788 awarded by the National Institute on Drug Abuse. We would like to thank Carol Dizack for her expert help with the histological drawings.

References (27)

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