Wayne E. Pratt

Corticostriatal-hypothalamic circuitry and food motivation: integration of energy, action and reward.

Work over the past decade has supported the idea that discrete aspects of appetitive motivation are differentially mediated by separate but interacting neurochemical systems within the nucleus accumbens (Acb). We review herein a series of studies in rats comparing the effects of manipulating Acb amino acid, opioid, acetylcholine, and dopamine systems on tests of free-feeding and food-reinforced operant responding. Results from our laboratory and in the literature support three general conclusions: (1) GABA output neurons localized exclusively within the Acb shell directly influence hypothalamic effector mechanisms for feeding motor patterns, but do not participate in the execution of more complex food-seeking strategies; (2) enkephalinergic neurons distributed throughout the Acb and caudate-putamen mediate the hedonic impact of palatable (high sugar/fat) foods, and these neurons are under modulatory control by striatal cholinergic interneurons; and (3) dopamine transmission in the Acb governs general motoric and arousal processes related to response selection and invigoration, as well as motor learning-related plasticity. These dissociations may reflect the manner in which these neurochemical systems differentially access pallido-thalamo-cortical loops reaching the voluntary motor system (in the case of opioids and dopamine), versus more restricted efferent connections to hypothalamic motor/autonomic control columns (in the case of Acb shell GABA and glutamate systems). Moreover, we hypothesize that while these systems work in tandem to coordinate the anticipatory and consummatory phases of feeding with hypothalamic energy-sensing substrates, the striatal opioid network evolved a specialized capacity to promote overeating of energy-dense foods beyond acute homeostatic needs, to ensure an energy reserve for potential future famine.

A proposed hypothalamic-thalamic-striatal axis for the integration of energy balance, arousal, and food reward.

We elaborate herein a novel theory of basal ganglia function that accounts for why palatable, energy‐dense foods retain high incentive value even when immediate physiological energy requirements have been met. Basal ganglia function has been studied from the perspective of topographical segregation of processing within parallel circuits, with primary focus on motor control and cognition. Recent findings suggest, however, that the striatum can act as an integrated unit to modulate motivational state. We describe evidence that the striatal enkephalin system, which regulates the hedonic impact of preferred foods, undergoes coordinated gene expression changes that track current motivational state with regard to food intake. Striatal enkephalin gene expression is also downregulated by an intrastriatal infusion of a cholinergic muscarinic antagonist, a manipulation that greatly suppresses food intake. To account for these findings, we propose that signaling through a hypothalamic–midline thalamic–striatal axis impinges on the cholinergic interneurons of the striatum, which via their large, overlapping axonal fields act as a network to modulate enkephalin‐containing striatal output neurons. A key relay in this circuit is the paraventricular thalamic nucleus, which receives convergent input from orexin‐coded hypothalamic energy‐sensing and behavioral state‐regulating neurons, as well as from circadian oscillators, and projects to cholinergic interneurons throughout the striatal complex. We hypothesize that this system evolved to coordinate feeding and arousal, and to prolong the feeding central motivational state beyond the fulfillment of acute energy needs, thereby promoting “overeating” and the consequent development of an energy reserve for potential future food shortages. J. Comp. Neurol. 493:72–85, 2005.

Nucleus accumbens acetylcholine regulates appetitive learning and motivation for food via activation of muscarinic receptors.

These experiments tested whether nucleus accumbens muscarinic or nicotinic acetylcholine receptor activation is required for rats to learn to lever press for sucrose. Muscarinic blockade with scopolamine (1.0 microg/side or 10.0 microg/side), but not nicotinic antagonism with mecamylamine (10.0 microg/side), inhibited learning and performance when applied to the core or shell. Further experiments showed that acute accumbens scopolamine treatment increased locomotor activity and reduced sucrose consumption. However, microanalyses of behavioral events in the instrumental chamber revealed that reductions of lever press performance during muscarinic blockade were not due to gross motor dysfunction. Accumbens core scopolamine was subsequently shown to reduce the amount of work rats would expend under a progressive ratio paradigm. These novel results implicate nucleus accumbens muscarinic receptors in the modulation of appetitive learning, performance, and motivation for food.

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.

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 µg/0.5 µL 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.

Nucleus accumbens acetylcholine and food intake: Decreased muscarinic tone reduces feeding but not food-seeking

Separate groups of food-deprived rats were given 2h access to food after receiving bilateral nucleus accumbens infusions of the muscarinic antagonist scopolamine methyl bromide (at 0, 1.0, and 10.0 microg/side), the M2-preferring agonist oxotremorine sesquifumarate (Oxo-S; at 0, 1.0, or 10.0 microg/side) or the M2 antagonist AFDX-116 (at 0, 0.2, or 1.0 microg/side). Injections of scopolamine or Oxo-S, but not AFDX-116, reduced food consumption across the 2h. These experiments confirm a critical role for Acb acetylcholine in promoting food ingestion, and suggest that decreased acetylcholine tone at post-synaptic muscarinic receptors disrupts normal consummatory behavior.

Selective serotonin receptor stimulation of the medial nucleus accumbens causes differential effects on food intake and locomotion.

Substantial evidence suggests that pharmacological manipulations of neural serotonin pathways influence ingestive behaviors. Despite the known role of the nucleus accumbens in directing appetitive and consummatory behavior, there has been little examination of the influences that serotonin receptors may play in modulating feeding within nucleus accumbens circuitry. In these experiments, the authors examined the effects of bilateral nucleus accumbens infusions of the 5-HT1/7 receptor agonist 5-CT (at 0.0, 0.5, 1.0, or 4.0 microg/0.5 microl/side), the 5-HT receptor agonist EMD 386088 (at 0.0, 1.0, and 4.0 microg/0.5 microl/side), or the 5-HT2C preferential agonist RO 60-0175 (at 0.0, 2.0, or 5.0 microg/0.5 microl/side) on food intake and locomotor activity in the rat. Intra-accumbens infusions of 5-CT caused a dose-dependent reduction of food intake and rearing behavior, both in food-restricted animals given 2-hr free access to Purina Protab RMH 3000 Chow, as well as in nondeprived rats offered 2-hr access to a highly palatable fat/sucrose diet. In contrast, stimulation of 5-HT receptors with EMD 386088 caused a dose-dependent increase of intake under both feeding conditions, without affecting measures of locomotion. Infusions of the moderately selective 5-HT2C receptor agonist RO 60-0175 had no effects on feeding or locomotor measures in food-restricted animals, but did reduce intake of the fat/sucrose in nonrestricted animals at the 2.0 microg, but not the 5.0 microg dose. Intra-accumbens infusions of selective antagonists for the 5-HT (SB 269970), 5-HT (SB 252585), and 5-HT2C (RS 102221) receptors did not affect locomotion, and demonstrated no lasting changes in feeding for any of the groups tested. These data are the first to suggest that the activation of different serotonin receptor subtypes within the feeding circuitry of the medial nucleus accumbens differentially influence consummatory behavior.

Nucleus accumbens dopamine and mu-opioid receptors modulate the reinstatement of food-seeking behavior by food-associated cues

The high attrition rates for dietary interventions aimed at promoting a healthier body mass may be caused, at least in part, by constant exposure to environmental stimuli that are associated with palatable foods. In both humans and animals, conditioned stimuli (CSs) that signal reward availability reliably reinstate food- and drug-seeking behaviors. The nucleus accumbens (NAcc) is critically involved in the cue-evoked reinstatement of food-seeking, but the role of individual neurotransmitter systems within the NAcc remains to be determined. These experiments tested the effects of intra-accumbal pharmacological manipulations of dopamine (DA) D(1) and D(2) receptors, mu-opioid receptors, or serotonin (5-HT) receptors on cue-evoked relapse to food-seeking. Rats were trained to lever press for sucrose pellets and the concurrent presentation of a light-tone CS. Once training was complete, lever-pressing was extinguished in the absence of either sucrose or CS presentation. Once each rat had reached extinction criterion, they received two reinstatement sessions in which lever pressing was renewed by response-contingent presentation of the CS. Prior to each reinstatement test, rats received NAcc microinfusions of saline or the selective D(1) receptor antagonist SCH 23390, the D(2) receptor antagonist raclopride, the mu-opioid receptor agonist [D-Ala2, N-MePhe4, Gly-ol]-enkephalin (DAMGO), or 5-HT hydrogen maleate. Compared to saline test days, intra-accumbens infusions of SCH 23390 (1 μg/0.5 μL), raclopride (1 μg/0.5 μL), or DAMGO (0.25 μg/0.5 μL) effectively blocked the cue-evoked reinstatement of food-seeking. In contrast, stimulation of serotonin (5-HT) receptors by 5-HT hydrogen maleate (5 μg/0.5 μL) had no effect on cue-induced reinstatement. These novel data support roles for NAcc DA D(1), D(2), and mu-opioid receptors in the cue-evoked reinstatement of food seeking.

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.

CB1 receptors modulate the intake of a sweetened-fat diet in response to mu-opioid receptor stimulation of the nucleus accumbens.

Previous research has demonstrated that concurrent systemic administration of CB(1) cannabinoid and mu-opioid receptor agonists increases feeding in rats. However, the possible neural loci of this cooperative effect have yet to be identified. These studies tested whether the nucleus accumbens shell may be one site of the interactive effects of opioid and cannabinoid ligands on feeding. Injection of the mu-opioid agonist DAMGO (at 0, 0.025, 0.25, or 2.5 µg/0.5 µl/side) directly into the rat nucleus accumbens shell increased feeding on a sweetened-fat diet, and this effect was blocked by pretreatment with either the mu-opioid antagonist naltrexone (20 µg/0.5 µl/side) or the CB(1) antagonist SR141716 (0.5 µg/0.5 µl/side). Activation of nucleus accumbens shell CB(1) receptors with WIN55212-2 alone (at 0.1 or 0.5 µg/0.5 µl/side) had no apparent effect on food intake. However, local injections of the low dose of DAMGO (.025 µg/0.5 µl/side) in this region along with WIN55212-2 (at 0.25 or 0.50 µg/0.5 µl/side) increased feeding above that induced by DAMGO alone. These data suggest an important modulatory role for cannabinoid receptors in the expression of feeding behaviors in response to mu-opioid receptor activation of the nucleus accumbens shell.