A comparison of adult and adolescent rat behavior in operant learning, extinction, and behavioral inhibition paradigms.

Poor self-control, lack of inhibition, and impulsivity contribute to the propensity of adolescents to engage in risky or dangerous behaviors. Brain regions (e.g., prefrontal cortex) involved in impulse-control, reward-processing, and decision-making continue to develop during adolescence, raising the possibility that an immature brain contributes to dangerous behavior during adolescence. However, very few validated animal behavioral models are available for behavioral neuroscientists to explore the relationship between brain development and behavior. To that end, a valid model must be conducted in the relatively brief window of adolescence and not use manipulations that potentially compromise development. The present experiments used three operant arrangements to assess whether adolescent rats differ from adults in measures of learning, behavioral inhibition, and impulsivity, within the aforementioned time frame without substantial food restriction. In Experiment 1, separate squads of rats were trained to lever-press and then transitioned to two types of extinction. Relative to their baselines, adolescent rats responded more during extinction than adults, suggesting that they were less sensitive to the abolishment of the reinforcement contingency. Experiment 2 demonstrated similar age-related differences during exposure to a differential reinforcement of low rates schedule, a test of behavioral inhibition. Lastly, in Experiment 3, adolescent's responding decreased more slowly than adults during exposure to a resetting delay of reinforcement schedule, suggesting impaired self-control. Results from these experiments suggest that adolescents exhibit impaired learning, behavioral inhibition and self-control, and in concert with recent reports, provide researchers with three behavioral models to more fully explore neurobiology of risk-taking behavior in adolescence.

Operant learning requires NMDA-receptor activation in the anterior cingulate cortex and dorsomedial striatum, but not in the orbitofrontal cortex.

Previous research has shown that corticostriatal N-methyl-D-aspartate receptor (NMDAR) activation is necessary for operant learning. NMDAR activation induces plasticity-related intracellular signaling processes leading to gene expression, which are hypothesized to be important steps in codifying the content of learning. Operant learning induces immediate early gene (IEG) expression in key corticostriatal structures, namely the dorsomedial striatum (DMS), the orbitofrontal (OFC), and anterior cingulate cortices (ACC). Both the ACC and OFC send glutamatergic projections to the DMS, which is a crucial site for operant behavior. However, the role of NMDAR activation in these corticostriatal regions in operant learning is unknown. To test this hypothesis, the NMDA antagonist AP-5 (1 microg/0.5 microl) or saline was bilaterally microinjected into the ACC, OFC, and DMS of food-deprived rats just prior to operant learning sessions. NMDAR antagonism in the ACC and DMS impaired the acquisition of lever pressing for sucrose pellets but had no effect on lever pressing once learned. NMDAR blockade in OFC did not significantly impair operant learning, suggesting that NMDAR activation in operant learning is site-specific. These data extend our understanding of the role of NMDA receptors in operant learning and behavior throughout an extended corticostriatal network.

REM sleep deprivation produces a motivational deficit for food reward that is reversed by intra-accumbens amphetamine in rats.

Prolonged sleep deprivation in rats produces a characteristic syndrome of increase in food intake accompanied by, paradoxically, decrease in weight, suggesting a potential alteration in motivation for food reward. Using the multiple platform method to produce REM sleep deprivation (REMSD), we investigated the effect of REMSD on motivation for food reinforcement with a progressive ratio operant task, which yields a measure of the motor effort that a hungry animal is willing to expend to obtain food (the point at which the animal quits responding is termed the "break-point"). We found that REMSD rats decreased the break point for sucrose pellet reinforcement in comparison to controls, as revealed by a within-session decline in responding. This behavioral deficit is similar to that observed in rats with diminished dopamine transmission within the nucleus accumbens (Acb), and, considering that stimulants are frequently used in the clinical setting to reverse the effects of sleepiness, we examined the effect of systemic or intra-Acb amphetamine on break point in REMSD rats. Animals were given either systemic or intra-Acb amphetamine injections on days 3 and 5 of REMSD. Systemic amphetamine (0.1, 0.5, or 2.5mg/kg) did not increase break point in REMSD rats. In contrast, intra-Acb infusions of amphetamine (1, 10, or 30µg/0.5µl bilaterally) reversed the REMSD-induced suppression of progressive ratio responding. Specifically, the two higher doses of intra-Acb amphetamine were able to prolong responding within the session (resulting in an increased break point) on day 3 of REMSD while only the highest dose was sufficient following 5 days of REMSD. These data suggest that decreased motivation for food reward caused by REMSD may result from a suppression of dopamine function in the Acb.

Muscarinic receptor antagonism causes a functional alteration in nucleus accumbens mu-opiate-mediated feeding behavior.

Intra-nucleus accumbens (Acb) infusion of cholinergic muscarinic antagonist, scopolamine (10 microg/0.5 microl), markedly reduced fat intake elicited by intra-Acb treatment of the mu-opioid receptor agonist, DAMGO, with 30 min and 4h pretreatment intervals. Intra-Acb scopolamine infusions also reduced food intake in food-deprived rats, but not water intake in water-deprived rats. Hence, Acb muscarinic manipulations exhibit some specificity for feeding, perhaps via interactions with the striatal opioid system.

PKMzeta maintains spatial, instrumental, and classically conditioned long-term memories.

How long-term memories are stored is a fundamental question in neuroscience. The first molecular mechanism for long-term memory storage in the brain was recently identified as the persistent action of protein kinase Mzeta (PKMzeta), an autonomously active atypical protein kinase C (PKC) isoform critical for the maintenance of long-term potentiation (LTP). PKMzeta maintains aversively conditioned associations, but what general form of information the kinase encodes in the brain is unknown. We first confirmed the specificity of the action of zeta inhibitory peptide (ZIP) by disrupting long-term memory for active place avoidance with chelerythrine, a second inhibitor of PKMzeta activity. We then examined, using ZIP, the effect of PKMzeta inhibition in dorsal hippocampus (DH) and basolateral amygdala (BLA) on retention of 1-d-old information acquired in the radial arm maze, water maze, inhibitory avoidance, and contextual and cued fear conditioning paradigms. In the DH, PKMzeta inhibition selectively disrupted retention of information for spatial reference, but not spatial working memory in the radial arm maze, and precise, but not coarse spatial information in the water maze. Thus retention of accurate spatial, but not procedural and contextual information required PKMzeta activity. Similarly, PKMzeta inhibition in the hippocampus did not affect contextual information after fear conditioning. In contrast, PKMzeta inhibition in the BLA impaired retention of classical conditioned stimulus-unconditioned stimulus (CS-US) associations for both contextual and auditory fear, as well as instrumentally conditioned inhibitory avoidance. PKMzeta inhibition had no effect on postshock freezing, indicating fear expression mediated by the BLA remained intact. Thus, persistent PKMzeta activity is a general mechanism for both appetitively and aversively motivated retention of specific, accurate learned information, but is not required for processing contextual, imprecise, or procedural information.

The dendritically targeted protein Dendrin is induced by acute nicotine in cortical regions of adolescent rat brain.

The response of the brain to addictive substances such as nicotine includes the rapid induction of genes that influence synaptic events. This response is different in adolescent brain, which continues to undergo synaptic remodeling in regions that include reward-associated corticolimbic areas. We report here that acute nicotine (0.4 mg/kg), but not cocaine or exposure to a novel environment, induces the expression of the dendritically targeted, corticolimbic mRNA Dendrin in specific regions of adolescent brain. Acute nicotine resulted in an increase in Dendrin mRNA levels in the adolescent prefrontal cortex that was not evident in adult animals. The induction in Dendrin mRNA was a rapid, short-lived transcriptional event that resulted in changes in Dendrin protein. For example, an increase in Dendrin protein levels following nicotine treatment paralleled enhanced Dendrin immunoreactivity in the dendrites of pyramidal neurons of somatosensory cortex. As Dendrin is an important component of cytoskeletal modifications at the synapse, these results suggest that nicotine influences unique plasticity-related changes in the adolescent forebrain that differ from the adult.

The structural basis for mapping behavior onto the ventral striatum and its subdivisions.

The striatum can be divided into dorsal (caudate-putamen) and ventral parts. In the ventral division, the nucleus accumbens, which subserves adaptive and goal-directed behaviors, is further subdivided into shell and core. Accumbal neurons show different types of experience-dependent plasticity: those in the core seem to discriminate the motivational value of conditioned stimuli, features that rely on the integration of information and enhanced synaptic plasticity at the many spines on these cells, whereas shell neurons seem to be involved with the release of predetermined behavior patterns in relation to unconditioned stimuli, and the behavioral consequences of repeated administration of addictive drugs. In the core, the principal neurons are medium sized and densely spiny, but in the medial shell, these same neurons are much smaller and their dendrites, significantly less spiny, suggesting that morphological differences could mediate unique neuroadaptations associated with each region. This review is focused on evaluating the structural differences in nucleus accumbens core and shell neurons and discusses how such different morphologies could underlie distinguishable behavioral processes.

Muscarinic receptor antagonism of the nucleus accumbens core causes avoidance to flavor and spatial cues.

Pharmacological blockade of muscarinic receptors in the nucleus accumbens reduces food intake and instrumental behaviors that are reinforced by food delivery. Nucleus accumbens muscarinic antagonism may specifically suppress the hedonic or reinforcing effects of food, thus blocking its capacity to direct behavior. Alternatively, muscarinic receptor blockade may cause a negative hedonic state that interferes with appetitive learning and food intake. In these experiments, rats received infusions of scopolamine methyl bromide (10 microg/0.5 microl) into the nucleus accumbens core, following exposure to a novel flavor of liquid diet (Experiment 1) or prior to being placed into a place preference apparatus (Experiment 2). In both experiments, nucleus accumbens muscarinic receptor antagonism caused subsequent avoidance of the paired cue (flavor or spatial location). This effect was specific to cholinergic manipulation; no conditioned taste avoidance was observed after pairing the novel flavor with nucleus accumbens core antagonism of N-methyl-D-aspartate, dopamine D-sub-1, or opioid receptors (Experiment 3). These experiments confirm previous reports of a critical role for striatal acetylcholine in modulating goal-directed behaviors, but suggest caution when interpreting behavioral effects of pharmacological manipulation of striatal acetylcholine.

Food-associated cues alter forebrain functional connectivity as assessed with immediate early gene and proenkephalin expression.

BACKGROUND: Cues predictive of food availability are powerful modulators of appetite as well as food-seeking and ingestive behaviors. The neurobiological underpinnings of these conditioned responses are not well understood. Monitoring regional immediate early gene expression is a method used to assess alterations in neuronal metabolism resulting from upstream intracellular and extracellular signaling. Furthermore, assessing the expression of multiple immediate early genes offers a window onto the possible sequelae of exposure to food cues, since the function of each gene differs. We used immediate early gene and proenkephalin expression as a means of assessing food cue-elicited regional activation and alterations in functional connectivity within the forebrain. RESULTS: Contextual cues associated with palatable food elicited conditioned motor activation and corticosterone release in rats. This motivational state was associated with increased transcription of the activity-regulated genes homer1a, arc, zif268, ngfi-b and c-fos in corticolimbic, thalamic and hypothalamic areas and of proenkephalin within striatal regions. Furthermore, the functional connectivity elicited by food cues, as assessed by an inter-regional multigene-expression correlation method, differed substantially from that elicited by neutral cues. Specifically, food cues increased cortical engagement of the striatum, and within the nucleus accumbens, shifted correlations away from the shell towards the core. Exposure to the food-associated context also induced correlated gene expression between corticostriatal networks and the basolateral amygdala, an area critical for learning and responding to the incentive value of sensory stimuli. This increased corticostriatal-amygdalar functional connectivity was absent in the control group exposed to innocuous cues. CONCLUSION: The results implicate correlated activity between the cortex and the striatum, especially the nucleus accumbens core and the basolateral amygdala, in the generation of a conditioned motivated state that may promote excessive food intake. The upregulation of a number of genes in unique patterns within corticostriatal, thalamic, and hypothalamic networks suggests that food cues are capable of powerfully altering neuronal processing in areas mediating the integration of emotion, cognition, arousal, and the regulation of energy balance. As many of these genes play a role in plasticity, their upregulation within these circuits may also indicate the neuroanatomic and transcriptional correlates of extinction learning.

Discrete neurochemical coding of distinguishable motivational processes: insights from nucleus accumbens control of feeding.

BACKGROUND AND OBJECTIVES: The idea that nucleus accumbens (Acb) dopamine transmission contributes to the neural mediation of reward, at least in a general sense, has achieved wide acceptance. Nevertheless, debate remains over the precise nature of dopamine's role in reward and even over the nature of reward itself. In the present article, evidence is reviewed from studies of food intake, feeding microstructure, instrumental responding for food reinforcement, and dopamine efflux associated with feeding, which suggests that reward processing in the Acb is best understood as an interaction among distinct processes coded by discrete neurotransmitter systems. RESULTS: In agreement with several theories of Acb dopamine function, it is proposed here that allocation of motor effort in seeking food or food-associated conditioned stimuli can be dissociated from computations relevant to the hedonic evaluation of food during the consummatory act. The former appears to depend upon Acb dopamine transmission and the latter upon striatal opioid peptide release. Moreover, dopamine transmission may play a role in 'stamping in' associations between motor acts and goal attainment and perhaps also neural representations corresponding to rewarding outcomes. Finally, evidence is reviewed that amino acid transmission specifically in the Acb shell acts as a central 'circuit breaker' to flexibly enable or terminate the consummatory act, via descending connections to hypothalamic feeding control systems. CONCLUSIONS: The heuristic framework outlined above may help explain why dopamine-compromising manipulations that strongly diminish instrumental goal-seeking behaviors leave consummatory activity relatively unaffected.

Striatal opioid peptide gene expression differentially tracks short-term satiety but does not vary with negative energy balance in a manner opposite to hypothalamic NPY.

It has long been known that central opioid systems play an important role in certain aspects of appetite and food intake, particularly with regard to the hedonic or rewarding impact of calorically dense food, such as fat and sugar. Ventral striatal enkephalin may be a key component of this system, as infusions of mu-opiate agonists into this region strongly increase feeding, whereas infusions of opiate antagonists decrease food intake. While pharmacological analysis has consistently supported such a role, direct measurement of enkephalin gene expression in relation to differing food motivational conditions has not been examined. In this study, the effects of a restricted laboratory chow diet (resulting in negative energy balance) as well has recent consumption of chow (short-term satiety) on striatal preproenkephalin (PPE) and prodynorphin (PD) mRNA expression were measured in rats, using both Northern blot analysis and in situ hybridization methods. As a comparison, hypothalamic (arcuate nucleus) neuropeptide Y (NPY) was also measured in these conditions. PPE expression was broadly downregulated throughout the striatum in animals that had recently consumed a meal, whereas it was unaffected by negative energy balance. Expression of an additional striatal peptide gene, PD, did not follow this pattern, although diet restriction caused a decrease in accumbens core dynorphin mRNA. Conversely, as expected, arcuate nucleus NPY mRNA expression was markedly upregulated by negative energy balance, but was unchanged by recent food consumption. This double dissociation between striatal and hypothalamic peptide systems suggests a specific role for striatal PPE in relatively short-term food motivational states, but not in long-term metabolic responses to diet restriction.

Acute stress and nicotine cues interact to unveil locomotor arousal and activity-dependent gene expression in the prefrontal cortex.

BACKGROUND: This study examines the interactive effects of acute stress and nicotine-associated contextual cues on locomotor activity and activity-dependent gene expression in subregions of the prefrontal cortex. METHODS: Locomotor activity of rats was measured in a context associated with either low-dose nicotine or saline administration with or without 5 minutes of pre-exposure to ferrets, a nonphysical stressor. After 45 minutes in the test environment, plasma corticosterone levels and mRNA levels of the immediate-early genes Arc, NGFI-B, and c-Fos in prefrontal and primary motor cortical subregions were measured. RESULTS: Stress alone increased plasma corticosterone and prefrontal cortex gene expression. Low-dose nicotine cues had no effect on corticosterone levels nor did they elicit conditioned motor activation, and they caused minor elevations in gene expression. Stress and low-dose nicotine cues, however, interacted to elicit conditioned motor activation and further increases in early response gene expression in prefrontal but not in the primary motor cortical subregions. CONCLUSIONS: Stress interacts with nicotine-associated cues to uncover locomotor arousal, a state associated with prefrontal neuronal activation and immediate early gene expression. Thus, in nicotine-experienced individuals, stress may be an important determinant of subjective reactivity and prefrontal cortex activation that occurs in response to nicotine-associated cues.

Is extinction the hallmark of operant discrimination? Reinforcement and S(Delta) effects.

Using a successive discrimination procedure with rats, three experiments investigated the contribution of reinforcement rate and amount of S(Delta) exposure on the acquisition of an operant discrimination. S(D) components and were always 2 min in length, while S(Delta) (extinction) components were either 1 min or 4 min in length; responses in S(D) were reinforced on one of four schedules. In Experiment 1, each of eight groups were exposed to one possible combination of rate of reinforcement and S(Delta) component length. At every level of reinforcement, the 4 min S(Delta) groups acquired the discrimination more quickly. However, within each level of reinforcement, the proportions of responding in S(D) as a function cumulative S(Delta) exposure were equivalent, regardless of the number of reinforcers earned in S(D), suggesting that extinction is the "hallmark" of discrimination. Experiment 2 sought to replicate these results in a within-subjects design, and although the 4 min S(Delta) conditions always produced superior discriminations, the lack of discriminated responding in some conditions suggested that stimulus disparity was reduced. Experiment 3 clarified those results and extended the finding that the acquisition of operant discrimination closely parallels extinction of responding in S(Delta). In sum, it appears that higher reinforcement rates and longer S(Delta) exposure facilitate the acquisition of discriminated operant responding.

Worms clear the smoke surrounding nicotine addiction.

In this issue of Cell, Feng et al. report a worm model of nicotine dependence that shows behavioral adaptations surprisingly similar to those in humans. These authors show a critical link between nicotinic receptors and TRP channels, which may represent a new therapeutic target for treating nicotine addiction.

Dynamic shifts in corticostriatal expression patterns of the immediate early genes Homer 1a and Zif268 during early and late phases of instrumental training.

Adaptive motor actions require prior knowledge of instrumental contingencies. With practice, these actions can become highly automatic in nature. However, the molecular and anatomical substrates mediating these related forms of learning are not understood. In the present study, we used in situ hybridization to measure the mRNA levels of two immediate early genes (IEGs) in an instrumental paradigm where rats learned to lever-press for food. We report that after three training sessions, Homer 1a and Zif268 (an effector and regulatory IEG, respectively) were significantly induced within an extensive corticostriatal network relative to untrained controls. With extended training (23 sessions), however, a shift in the expression patterns of the two genes was evident. Expression of Homer 1a (official symbol Homer1) decreased significantly in frontal and cingulate cortices, whereas striatal expression was generally maintained. Interestingly, Homer 1a expression markedly increased with extensive training in the ventrolateral region of the striatum (VLS) relative to early learners, suggesting that plasticity in the VLS is required for the efficient production of the learned behavior or in habit formation. Zif268 (official symbol Egr1) expression generally decreased with extensive training; however, these changes were not significant. These results demonstrate for the first time, on a molecular level, a dynamic shift in the contribution of corticostriatal systems mediating the early acquisition and consolidation of goal-directed responses to those engaged after extensive training.

Pharmacological characterization of high-fat feeding induced by opioid stimulation of the ventral striatum.

Nucleus accumbens mu-opioid stimulation causes marked increases in the intake of highly palatable foods, such as a high-fat diet. However, to date there has been little examination of how other striatal neurotransmitters may mediate opioid-driven feeding of palatable foodstuffs. In the current study, free feeding rats with bilateral cannulae aimed at the nucleus accumbens received intra-accumbens pretreatment with antagonists for dopamine D-1 (SCH23390; 0 microg or 1 microg/0.5 microl/side), dopamine D-2 (raclopride; 0 microg or 2.0 microg/0.5 microl/side), AMPA (LY293558; 0 microg, 0.01 microg or 0.10 microg/0.5 microl/side), muscarinic (scopolamine 0 microg, 0.1, 1.0, or 10 microg/0.5 microl/side) or nicotinic (mecamylamine; 0 microg, 10 microg/0.5 microl/side) receptors, immediately prior to infusions of the mu-receptor agonist D-Ala2, NMe-Phe4, Glyol5-enkephalin (DAMGO; 0.25 microg/0.5 microl) or vehicle. The effects of these pretreatments on 2 hr fat intake was compared to pretreatment with a general opioid antagonist (naltrexone; 0 microg or 20 microg/0.5 microl/side). DAMGO-induced feeding was unaffected by prior antagonism of dopamine, glutamate, or nicotinic receptors. As expected, naltrexone infusions blocked DAMGO-elicited fat intake. Antagonism of muscarinic acetylcholine receptors reduced feeding in both the DAMGO and vehicle-treated conditions. In an additional experiment, cholinergic receptor stimulation alone did not affect intake of the fat diet, suggesting that nucleus accumbens cholinergic stimulation is insufficient to alter feeding of a highly palatable food. These data suggest that the feeding effects caused by striatal opioid stimulation are independent from or downstream to the actions of dopamine and glutamate signaling, and provide novel insight into the role of striatal acetylcholine on feeding behaviors.

Methylphenidate preferentially increases catecholamine neurotransmission within the prefrontal cortex at low doses that enhance cognitive function.

BACKGROUND: Low doses of psychostimulants, such as methylphenidate (MPH), are widely used in the treatment of attention-deficit/hyperactivity disorder (ADHD). Surprisingly little is known about the neural mechanisms that underlie the behavioral/cognitive actions of these drugs. The prefrontal cortex (PFC) is implicated in ADHD. Moreover, dopamine (DA) and norepinephrine (NE) are important modulators of PFC-dependent cognition. To date, the actions of low-dose psychostimulants on PFC DA and NE neurotransmission are unknown. METHODS: In vivo microdialysis was used to compare the effects of low-dose MPH on NE and DA efflux within the PFC and select subcortical fields in male rats. Doses used (oral, 2.0 mg/kg; intraperitoneal, .25-1.0 mg/kg) were first determined to produce clinically relevant plasma concentrations and to facilitate both PFC-dependent attention and working memory. RESULTS: At low doses that improve PFC-dependent cognitive function and that are devoid of locomotor-activating effects, MPH substantially increases NE and DA efflux within the PFC. In contrast, outside the PFC these doses of MPH have minimal impact on NE and DA efflux. CONCLUSIONS: The current observations suggest that the therapeutic actions of low-dose psychostimulants involve the preferential activation of catecholamine neurotransmission within the PFC.

Dissociating ventral and dorsal subicular dopamine D1 receptor involvement in instrumental learning, spontaneous motor behavior, and motivation.

A series of experiments investigating the role of dopamine D1 receptors in the ventral subiculum (vSUB) and dorsal subiculum (dSUB), 2 subregions of the hippocampal formation, found that D1 receptor antagonism (3.0 nmol/0.5 microl SCH-23390 bilaterally) in the vSUB impaired instrumental learning and performance, reduced break point in progressive ratio (PR) tests, and produced an intrasession decline in responding during test sessions, but had no effect on spontaneous motor or food-directed behavior. In contrast, D1 receptor blockade in the dSUB had no effect on instrumental learning, performance, PR break point, or food-directed behavior, but reduced spontaneous motor behavior. These results suggest a dissociation between the vSUB and dSUB with respect to the role of dopamine in various aspects of motivated and motor behavior. Further, D1 activation in the vSUB may be a critical component of motivational arousal associated with learned contextual cues.

Striatal muscarinic receptor antagonism reduces 24-h food intake in association with decreased preproenkephalin gene expression.

Cholinergic interneurons of the striatum respond to motivationally relevant stimuli and are involved in appetitive learning. However, there has been relatively little inquiry into the role of striatal acetylcholine in food motivation. Here we show in rats that a single infusion of the muscarinic receptor antagonist scopolamine (0, 5.0 or 10.0 microg/0.5 microL bilaterally) potently reduced 24-h food intake following injections into either the ventral or dorsal striatum, without affecting water intake. Furthermore, muscarinic receptor blockade induced reliable and widespread reductions in striatal preproenkephalin, but not preprodynorphin, mRNA expression. These data suggest a novel role for striatal acetylcholine in modulating feeding behavior via its effects on enkephalin gene expression. As prior research indicates a critical role for striatal enkephalin in consummatory behaviors and palatability, we hypothesize that cholinergic interneurons assist in translating hypothalamic energy state signals into food-directed behaviors via their regulation of striatal opioid peptides.

Hyperphagia induced by GABAA receptor-mediated inhibition of the nucleus accumbens shell: dependence on intact neural output from the central amygdaloid region.

To investigate the role of corticolimbic input in modulating feeding-related nucleus accumbens (Acb) circuitry, researchers temporarily deactivated sites within the basolateral amygdaloid complex (BLA) or central amygdaloid region (CeA) via GABA(A) agonist (muscimol) infusions and measured feeding responses following muscimol infusions into the Acb shell. Hyperphagia elicited by intra-Acb shell muscimol was not altered by coinfusions of intra-BLA muscimol. In contrast, muscimol infusions into the CeA dose-dependently reduced feeding elicited either by intra-Acb shell GABA(A) receptor stimulation or by food deprivation and produced a syndrome of forepaw treading. Intra-CeA tetrodotoxin infusions also blocked intra-Acb shell muscimol-induced hyperphagia. Hence, feeding elicited by intra-Acb shell GABA(A) receptor stimulation requires intact neural output from the CeA but not the BLA.