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, gamma-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.

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 GABA A 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(Ϫ)-AP-5 is known to suppress deprivationinduced feeding. We found that injections of D(Ϫ)-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 GABA A receptor blocker bicuculline or the GABA B receptor blocker saclofen did not significantly affect food intake. Thus, it appears that the expression of the feeding response depends on an NMDA-preferring receptormediated 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(Ϫ)-AP-5Although 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 (MaldonadoIrizarry 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 ...

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