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The nucleus accumbens (NAc) is a critical region for regulating the appetitive and consummatory aspects of motivated behavior. Previous work has shown differential effects of NAc µ-, δ-, and κ- receptor stimulation on food intake and for shifting motivation within an effort-based choice (EBC) task. However, the motivational role of the nociceptin opioid peptide (NOP) receptor, a fourth member of the opioid receptor family, is less well understood. These experiments therefore characterized the effect of NAc injections of nociceptin, the endogenous ligand for the NOP receptor, on consummatory and appetitive motivation. Three groups of male Sprague-Dawley rats received nociceptin injections into the NAc core prior to testing in a progressive ratio lever pressing task, an EBC task, or a palatable feeding assay. In the feeding experiment, 10 nmol of nociceptin increased consumption in the first 30 min, but this increase was not sustained through the end of the 2-hr session. Additionally, nociceptin injections did not alter breakpoint in the progressive ratio task. However, in the EBC task, nociceptin significantly decreased breakpoint for sugar pellets without affecting consumption of rat chow. These data suggest that NAc NOP receptor stimulation transiently increases consummatory motivation toward palatable diets and inhibits appetitive motivation when alternate food options are freely available. This pattern of effects contrasts with those obtained following NAc stimulation of other opioid receptors, suggesting that the four opioid receptor classes each serve unique roles in modulating food-directed motivation within the NAc core., Competing Interests: Declarations of Competing Interest None., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Previous research has demonstrated that dopamine and Neuropeptide Y (NPY) promote motivated behavior, and there is evidence to suggest that they interact within neural circuitry involved in motivation. NPY and dopamine both modulate appetitive motivation towards food through direct actions in the nucleus accumbens (NAc), although how they interact in this region to promote motivation is presently unclear. In this study, we sought to further elucidate the relationship between NAc NPY and dopamine and their effects on motivated behavior. Specifically, we examined whether NAc injections of NPY might reverse behavioral deficits caused by reduced dopamine signaling due to systemic dopamine receptor antagonism. Appetitive motivation was measured using a progressive ratio-2 paradigm. Male Sprague Dawley rats were treated with systemic injections of the dopamine antagonist, α-flupenthixol or a saline vehicle. Two hours following injections, they were administered infusions of NPY (at 0, 156, or 235 pmol) into either the NAc shell (n = 12) or the NAc core (n = 10) and were placed in operant chambers. In both groups, α-flupenthixol impaired performance on the PR-2 task. NPY receptor stimulation of the NAc shell significantly increased both breakpoint and active lever presses during the PR-2 task, and dose-dependently increased responding following systemic dopamine receptor blockade. NPY did not affect appetitive motivation when injected into the NAc core. These data demonstrate that NPY in the NAc shell can improve motivational impairments that result from dopamine antagonism, and that these effects are site specific. These results also suggest that upregulation of NPY in neurodegenerative diseases may possibly buffer early motivational deficits caused by dopamine depletion in Parkinson's and Huntington's disease patients, both of which show increased NPY expression after disease onset., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Activity of the serotonin 6(5-HT6) receptor impacts food intake and body weight in animal models and has also shown potential as a target for treatment of anhedonia, a symptom of major depressive disorder. The nucleus accumbens (NAc) is a key region involved in motivational processes and has been implicated in the neural mechanisms underlying anhedonia. Here, we assessed the potential role that 5-HT6 receptors in the NAc play in regulating motivation towards food. Rats received surgical implantation of guide cannulas above the NAc shell. On testing days, they were injected with either the selective 5-HT6 agonist EMD 386088 (at 0.0, 1.0, and 4.0 mg/0.5 mL/side) or the 5-HT6 antagonist SB 252585 (at 0, 1.0, and 4.0 µg/0.5 µL/side) prior to completing a 1-h long effort-based choice task. The task simultaneously examined the impact of NAc 5-HT6 receptor manipulation on appetitive motivation, measured as the breakpoint for earning a preferred sugar pellet in a progressive ratio task, and consummatory motivation, quantified as the grams of freely-available rat chow consumed during the session. Stimulation of NAc 5-HT receptors significantly increased both appetitive and consummatory motivation as assessed in this effort-based choice task. In contrast, 5-HT6 antagonism did not affect break point nor the consumption of the freely-available chow. These data suggest that 5-HT6 receptors are functional within the NAc, that their stimulation increases motivated behavior, and that they may therefore be a viable target for the treatment of anhedonia and disorders that inhibit motivational processes., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Overconsumption, or eating beyond the point of homeostasis, is a key feature in the development of obesity. Although people are consuming beyond the point of homeostasis, they are not consuming constantly or indefinitely. Thus, there is likely a mechanism that acts to terminate periods of food intake at some point beyond satiation and prior to aversion, or the negative effects of extreme excess (nausea, bloating, etc.). The purpose of the present study was to assess the lateral habenula as a candidate region for such a mechanism, due to its connectivity to midbrain reward circuitry, sensitivity to metabolic signaling, and pronounced role in drug-related motivated behaviors. Two groups of male Sprague-Dawley rats were surgically implanted with bilateral guide cannula targeting the LHb. Rats were then habituated to feeding chambers, wherein locomotion and food intake were monitored throughout a two-hour session. One experimental group was tested in the presence of rat chow; the second group was instead given access to a sweetened fat diet. Each subject separately received a 0.2 μL vehicle (0.9% saline solution) and baclofen-muscimol (50 ng/0.2 μL of each drug dissolved in 0.9% saline) injection. Additionally, on a third injection day, each rat received an injection of mu-opioid agonist DAMGO (0.1 μg/0.2 μL) prior to placement in the chamber. LHb inactivation did not result in significant alterations in feeding behavior, but produced a consistent increase in locomotor activity in both experimental groups. Mu-opioid receptor stimulation increased feeding on standard chow, but decreased intake of the sweetened-fat diet. Although LHb inactivation did not increase feeding as predicted, the novel finding that mu opioid receptor stimulation decreased feeding on a highly palatable diet, but increased intake of rat chow, highlights a differential role for the LHb in regulating hedonic consummatory behavior., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Serotonin signaling influences satiety and motivation through known actions in the hindbrain and hypothalamus. Recently, we reported that some classes of serotonin receptors also modulate food intake through actions in the ventral tegmentum and the nucleus accumbens. In the current experiments, we examined whether activation or blockade of individual serotonin receptor subtypes in the ventral tegmentum might also affect appetitive motivation for sugar pellets as assessed in a progressive ratio (PR) task. Separate groups of rats were tested following stimulation or blockade of ventral tegmental serotonin 1A, 1B, 2A, 2B, 2C, or 3 receptors. Rats within each group received multiple doses of a single drug across days; each test was separated by 72 h. Progressive ratio break point was significantly affected by stimulation of ventral tegmental serotonin 1A receptors with 8-OH-DPAT (0, 2, 4, 8 μg/side) or stimulation of serotonin 3 receptors with mCPBG (0, 10, & 20 μg/side). High doses of both agents tended to decrease break point. Additionally, stimulation of serotonin 2C receptors with RO60-0175 (at 0, 2, and 5 μg/side) reduced total lever presses and demonstrated a trend towards reducing break point. There were no effects of stimulating ventral tegmental serotonin 1B, 2A, or 2B receptors on break point; neither did antagonism of any of the serotonin receptor subtypes significantly affect performance. These data provide additional evidence that serotonergic signaling in the mesolimbic pathway affects motivated behavior, and demonstrate that a subset of serotonin receptors impact not only food consumption, but appetitive food-seeking as well., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The nucleus accumbens (NAc) is critical for regulating the appetitive and consummatory phases of motivated behavior. These experiments examined the effects of dopamine and opioid receptor manipulations within the NAc during an effort-based choice task that allowed for simultaneous assessment of both phases of motivation. Male Sprague-Dawley rats received bilateral guide cannulas targeting the NAc core and were tested in 1-hr sessions with free access to rat chow and the choice to work for sugar pellets on a progressive ratio 2 (PR2) reinforcement schedule. Individual groups of rats were tested following stimulation or blockade of NAc D1-like or D2-like receptors, stimulation of μ-, δ-, or κ-opioid receptors, or antagonism of opioid receptors. Behavior was examined under ad libitum conditions and following 23-h food restriction. NAc blockade of the D1-like receptors or stimulation of the D2 receptor reduced break point for earning sugar pellets; D2 receptor stimulation also modestly lowered chow intake. NAc μ-opioid receptor stimulation increased intake of the freely-available chow while simultaneously reducing break point for the sugar pellets. In non-restricted conditions, δ-opioid receptor stimulation increased both food intake and breakpoint. There were no effects of stimulating NAc D1 or κ receptors, nor did blocking D2 or opioid receptors affect task behavior. These data support prior literature linking dopamine to appetitive motivational processes, and suggest that μ- and δ-opioid receptors affect food-directed motivation differentially. Specifically, μ-opioid receptors shifted behavior towards consumption, and δ-opioid receptor enhanced both sugar-seeking and consumption of the pabulum chow when animals were not food restricted., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Neuropeptides and peptide hormones affect food-directed motivation, in part, through actions on brain regions associated with reward processing. For instance, previous reports have shown that stimulating glucagon-like peptide-1 (GLP-1) receptors in the nucleus accumbens (NAc), an area that directs motivational processes towards food and drugs of abuse, has an anorectic effect. In contrast, µ-opioid receptor activation of the NAc increases feeding, particularly on highly palatable diets. While both neurotransmitters act within the NAc to impact food intake, it is not clear if and how they might interact to affect feeding. Therefore, these experiments tested the effects of NAc injections of the GLP-1 receptor agonist Exendin 4 (EX4) or antagonist Exendin 9 (EX9) on the consumption of a sweetened fat diet, with and without simultaneous µ-opioid receptor stimulation. Male Sprague-Dawley rats (n = 8/group, EX4 or EX9) underwent surgery to place bilateral cannula above the NAc core. After recovery, animals were tested following NAc injections of saline or the µ-opioid agonist [D-Ala, N-MePhe, Gly-ol]-enkephalin (DAMGO) (0.025 µg/side), combined with varying doses of EX4 (0, 0.05, or 0.10 µg/side) or EX9 (0, 2.5, 5.0 µg/side), counterbalanced across 6 testing days. Food and water intake, along with locomotor activity, was monitored for 2 h. Mu-opioid receptor stimulation significantly increased feeding, and this effect was reduced by GLP-1 receptor stimulation. In contrast, GLP-1 antagonism with EX9 altered the dynamics of DAMGO-induced binge-like feeding, extending µ-opioid-induced binging, and increasing food consumption. These findings are the first to demonstrate an interaction between NAc µ-opioid and GLP-1 receptors on palatable food intake.

Multiple laboratories have shown that the stimulation of μ-opioid receptors in the nucleus accumbens (NAcc) powerfully increases intake of palatable and high-fat diets. Separate studies have demonstrated that serotonin agonists advance satiety processes, and several serotonin-targeting agents have been prescribed to promote weight loss. However, it is unknown if serotonin signaling can modulate the increased feeding elicited by activation of NAcc μ-opioid receptors. These experiments assessed the effects of systemic treatments with the serotonin agonists d-fenfluramine and lorcaserin on the binge-like feeding induced by μ-opioid receptor stimulation of the NAcc in Sprague-Dawley rats. Consistent with previous reports, stimulation of NAcc μ-opioid receptors (with 0.025 μg/0.5 μl/side DAMGO) significantly increased consumption of high-fat vegetable shortening, and systemic treatment with d-fenfluramine and lorcaserin dose-dependently decreased intake. Interestingly, d-fenfluramine and lorcaserin reversed the binge-like feeding observed following stimulation of NAcc μ-opioid receptors. Both serotonergic drugs also attenuated the increases of ambulation observed following administration of DAMGO in the NAcc. These data demonstrate that serotonergic anorectics, in addition to their known role in advancing satiety processes during normal feeding, can also inhibit the binge-like feeding that is elicited by activation of μ-opioid receptors within the ventral striatum., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Although serotonin (5-HT) signaling is known to regulate food intake and energy homeostasis, the roles of the 5-HT 3 receptor in feeding processes have been elusive. 5-HT 3 receptors are found throughout mesolimbic circuitry that promote feeding not only in response to hunger, but also to the palatable and rewarding properties of food. These experiments examined if stimulation or blockade of the 5-HT 3 receptor of the nucleus accumbens (NAcc) or ventral tegmentum affected food intake in the rat in response to hunger or the presence of a palatable diet. Rats (N=6-9/group) received bilateral injections of the 5-HT 3 agonist m-chlorophenylbiguanide hydrochloride (mCPBG; at 0.0, 10.0, or 20.0μg/0.5μl/side) or the 5-HT 3 antagonist ondansetron hydrochloride (at 0.0, 1.0, 2.0, or 5.0μg/0.5μl/side) into either the NAcc or the ventral tegmentum. NAcc 5-HT 3 receptor stimulation significantly increased 2-h food intake in food-deprived animals offered rat chow and in a separate group of unrestricted rats offered a sweetened fat diet. In contrast to the feeding increase seen with NAcc treatments, stimulation of 5-HT 3 receptors of the ventral tegmentum significantly reduced food and water intake in food-restricted animals; reductions of intake in non-restricted rats offered the palatable diet did not approach significance. Blockade of the 5-HT 3 receptor had no effect on feeding in either brain region. These data support a functional role for serotonergic signaling in the mesolimbic pathway on motivated behavior, and demonstrate that 5-HT 3 receptors differentially modulate food consumption in a region-dependent manner., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Central serotonin (5-HT) pathways are known to influence feeding and other ingestive behaviors. Although the ventral tegmentum is important for promoting the seeking and consumption of food and drugs of abuse, the roles of 5-HT receptor subtypes in this region on food intake have yet to be comprehensively examined. In these experiments, food restricted rats were given 2-h access to rat chow; separate groups of non-restricted animals had similar access to a sweetened fat diet. Feeding and locomotor activity were monitored following ventral tegmentum stimulation or blockade of 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2B, or 5-HT2C receptors. 5-HT1A receptor stimulation transiently inhibited rearing behavior and chow intake in food-restricted rats, and had a biphasic effect on non-restricted rats offered the palatable diet. 5-HT1B receptor agonism transiently inhibited feeding in restricted animals, but did not affect intake of non-restricted rats. In contrast, 5-HT1B receptor antagonism decreased palatable feeding. Although stimulation of ventral tegmental 5-HT2B receptors with BW723C86 did not affect hunger-driven food intake, it significantly affected palatable feeding, with a trend for an increasing intake at 2.0µg/side but not at 5.0µg/side. Antagonism of the same receptor modestly but significantly inhibited feeding of the palatable diet at 5.0µg/side ketanserin. Neither stimulation nor blockade of 5-HT2A or 5-HT2C receptors caused prolonged effects on intake or locomotion. These data suggest that serotonin's effects on feeding within the ventral tegmentum depend upon the specific receptor targeted, as well as whether intake is motivated by food restriction or the palatable nature of the offered diet., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Rationale: The 5-HT2C receptor agonist lorcaserin (Belviq®) has been approved by the FDA for the treatment of obesity. Impulsivity is a contributory feature of some eating disorders., Objective: Experiments investigated the effect of lorcaserin and the highly selective 5-HT2C agonist CP-809101 on measures of impulsivity and on reinstatement of food-seeking behaviour, a model of dietary relapse. The effect of both drugs on 22-h deprivation-induced feeding was also examined, as was the effect of prefeeding in each impulsivity test., Results: Lorcaserin (0.3-0.6 mg/kg SC) and CP-809101 (0.6-1 mg/kg SC) reduced premature responding in rats trained on the 5-CSRTT and improved accuracy in a Go-NoGo task by reducing false alarms. At equivalent doses, both drugs also reduced reinstatement for food-seeking behaviour. Neither drug altered impulsive choice measured in a delay-discounting task. Lorcaserin (1-3 mg/kg SC) and CP-809101 (3-6 mg/kg SC) reduced deprivation-induced feeding but only at higher doses., Conclusions: These results suggest that in addition to previously reported effects on satiety and reward, altered impulse control may represent a contributory factor to the anti-obesity property of 5-HT2C receptor agonists. Lorcaserin may promote weight loss by improving adherence to dietary regimens in individuals otherwise prone to relapse and may be beneficial in cases where obesity is associated with eating disorders tied to impulsive traits, such as binge eating disorder.

Prior research has shown that glutamate and dopamine receptors in the nucleus accumbens (NAcc) core are critical for the learning of an instrumental response for food reinforcement. It has also been demonstrated that μ-opioid and adenosine A2A receptors within the NAcc impact feeding and motivational processes. In these experiments, we examined the potential roles of NAcc μ-opioid and A2A receptors on instrumental learning and performance. Sprague-Dawley rats were food restricted and trained to lever press following daily intra-accumbens injections of the A2A receptor agonist CGS 21680 (at 0.0, 6.0, or 24.0ng/side), the A2A antagonist pro-drug MSX-3 (at 0.0, 1.0, or 3.0μg/side), the μ-opioid agonist DAMGO (at 0.0, 0.025, or 0.025μg/side), or the opioid receptor antagonist naltrexone (at 0.0, 2.0 or 20.0μg/side). After five days, rats continued training without drug injections until lever pressing rates stabilized, and were then tested with a final drug test to assess potential performance effects. Stimulation, but not inhibition, of NAcc adenosine A2A receptors depressed lever pressing during learning and performance tests, but did not impact lever pressing on non-drug days. Both μ-opioid receptor stimulation and blockade inhibited learning of the lever-press response, though only naltrexone treatment caused impairments in lever-pressing after the task had been learned. The effect of A2A receptor stimulation on learning and performance were consistent with known effects of adenosine on effort-related processes, whereas the pattern of lever presses, magazine approaches, and pellet consumption following opioid receptor manipulations suggested that their effects may have been driven by drug-induced shifts in the incentive value of the sugar reinforcer., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Re-exposure to either palatable food or to conditioned stimuli associated with food is known to reinstate food-seeking after periods of abstinence. The nucleus accumbens core and shell are important for reinstatement in both food- and drug-seeking paradigms, although their potential differential roles have been difficult to delineate due to methodological differences in paradigms across laboratories. The present studies assessed the effects of temporary inactivation of the core or shell on priming- and cue-induced reinstatement of food-seeking in identically-trained rats. Inactivation of either the nucleus accumbens core (Experiment 1A; N = 10) or medial shell (Experiment 1B; N = 12) blocked priming-induced reinstatement in an equivalent manner. Similarly, inactivation of the core or medial shell (Experiments 2A & 2B; N = 11 each) also blocked cue-induced reinstatement, although there was also a significant treatment day X brain region X drug order interaction. Specifically, rats with core inactivation reinstated lever-pressing on the vehicle injection day regardless of whether that was their first or second test, whereas rats that had medial shell inactivation on the first day did not significantly reinstate lever-pressing on the second day of testing (when they received vehicle). Yohimbine, while a reportedly robust pharmacological stressor, was ineffective at inducing reinstatement in the current stress-induced reinstatement procedure. These data suggest that both the nucleus accumbens core and shell serve important roles in reinstatement of food-seeking in response to priming and cues.

Rationale: Intra-striatal infusions of the muscarinic antagonist, scopolamine, markedly suppress feeding; however, the underlying mechanisms are unclear. Recent findings suggest that scopolamine influences opioid-dependent mechanisms of feeding modulation. Robust mu-opioid-mediated feeding responses are obtained in anterior, ventral sectors of the striatum with progressively weaker effects posteriorly and dorsally. One might therefore expect the effects of scopolamine to conform to similar boundaries, but a systematic mapping of scopolamine-induced feeding suppression has not yet been undertaken., Objective: This study aimed to assess the overlap between the striatal sites mediating scopolamine-induced feeding suppression and mu-opioid-induced hyperphagia., Methods: Dose-effect functions for scopolamine (0, 1, 5, and 10 μg) were obtained in the nucleus accumbens (Acb), anterior dorsal striatum (ADS), and posterior dorsal striatum (PDS) in three different groups of rats. In the same subjects, the mu-opioid receptor agonist (D-Ala2-N-MePhe4, Glyol)-enkephalin (DAMGO; 0.25 μg) was infused on a separate test day. The dependent variables were food and water intake, ambulation, and rearing., Results: The greatest dose sensitivity for scopolamine-induced feeding suppression was observed in the Acb. Only the highest dose was effective in the ADS, and no effects were seen in the PDS. Water intake and general motor activity were not altered by scopolamine in any site. DAMGO infusions produced hyperphagia only in the Acb., Conclusions: These results support a model in which the behavioral effects of muscarinic blockade are limited by the same anatomical constraints that govern mu-opioid receptor-mediated control of feeding. These constraints are likely imposed by the topographic arrangement of feeding-related afferent inputs and efferent projections of the striatum.

Individuals struggling with obesity often have difficulty maintaining dietary regimens. One source of dietary relapse is the reinstatement of previous feeding behaviors following the presentation of cues indicating the availability of palatable but highly caloric food reward. The drugs fenfluramine and sibutramine have previously been prescribed because they enhance satiety mechanisms and decrease meal size. However, it is unclear whether these anorectic agents are also effective in blocking the cue-induced reinstatement of food-seeking behaviors. In these three experiments, we compared the effects of systemic treatment of d-fenfluramine (3mg/kg; N=10) and sibutramine (3mg/kg; N=11) with that of the D1 antagonist SCH 23390 (6μg/kg; N=11) at a dose that has previously been shown to attenuate cue-induced reinstatement. d-Fenfluramine treatment blocked the cue's ability to reinstate lever pressing as compared to the saline injection day. In contrast, sibutramine had no effect on cue-induced reinstatement; all animals reinstated their lever pressing during the first reinstatement test, and this was unaffected by sibutramine treatment. SCH 23390 treatment did not significantly reduce cue-induced reinstatement in this set of experiments. The results suggest that the motivational effects of d-fenfluramine is not limited to the promotion of satiety once a meal has been initiated, and demonstrate that some anorectic treatments may inhibit the effectiveness of conditioned cues to elicit relapse of food-seeking behavior., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Serotonin (5-HT) signaling has been widely implicated in the regulation of feeding behaviors in both humans and animal models. Recently, we reported that co-stimulation of 5-HT1&7 receptors of the anterior medial nucleus accumbens with the drug 5-CT caused a dose-dependent decrease in food intake, water intake, and locomotion in rats (Pratt et al., 2009). The current experiments sought to determine which of three serotonin receptor subtypes (5-HT1A, 5-HT1B, or 5-HT7) might be responsible for these consummatory and locomotor effects. Food-deprived rats were given 2-h access to rat chow after stimulation of nucleus accumbens 5-HT1A, 5-HT1B, or 5-HT7 receptors, or blockade of the 5-HT1A or 5-HT1B receptors. Stimulation of 5-HT1A receptors with 8-OH-DPAT (at 0.0, 2.0, 4.0, and 8.0 μg/0.5 μl/side) caused a dose-dependent decrease in food and water intake, and reduced rearing behavior but not ambulation. In contrast, rats that received the 5-HT1B agonist CP 93129 (at 0.0, 1.0, 2.0 and 4.0 μg/0.5 μl/side) showed a significant dose-dependent decrease in water intake only; stimulation of 5-HT7 receptors (AS 19; at 0.0, 1.0, and 5.0 μg/0.5 μl/side) decreased ambulatory activity but did not affect food or water consumption. Blockade of 5-HT1A or 5-HT1B receptors had no lasting effects on measures of food consumption. These data suggest that the food intake, water intake, and locomotor effects seen after medial nucleus accumbens injections of 5-CT are due to actions on separate serotonin receptor subtypes, and contribute to growing evidence for selective roles of individual serotonin receptors within the nucleus accumbens on motivated behavior., (© 2013.)

Circuits that participate in specific subcomponents of feeding (e.g., gustatory perception, peripheral feedback relevant to satiety and energy balance, reward coding, etc.) are found at all levels of the neural axis. Further complexity is conferred by the wide variety of feeding-modulatory neurotransmitters and neuropeptides that act within these circuits. An ongoing challenge has been to refine the understanding of the functional specificity of these neurotransmitters and circuits, and there have been exciting advances in recent years. We focus here on foundational work of Dr. Ann Kelley that identified distinguishable actions of striatal opioid peptide modulation and dopamine transmission in subcomponents of reward processing. We also discuss her work in overlaying these neuropharmacological effects upon anatomical pathways that link the telencephalon (cortex and basal ganglia) with feeding-control circuits in the hypothalamus. Using these seminal contributions as a starting point, we will discuss new findings that expand our understanding of (1) the specific, differentiable motivational processes that are governed by central dopamine and opioid transmission, (2) the manner in which other striatal neuromodulators, specifically acetylcholine, endocannabinoids and adenosine, modulate these motivational processes (including via interactions with opioid systems), and (3) the organization of the cortical-subcortical network that subserves opioid-driven feeding. The findings discussed here strengthen the view that incentive-motivational properties of food are coded by substrates and neural circuits that are distinguishable from those that mediate the acute hedonic experience of food reward. Striatal opioid transmission modulates reward processing by engaging frontotemporal circuits, possibly via a hypothalamic-thalamic axis, that ultimately impinges upon hypothalamic modules dedicated to autonomic function and motor pattern control. We will conclude by discussing implications for understanding disorders of "non-homeostatic" feeding., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

One of the defining characteristics of the research of Ann E. Kelley was her recognition that the neuroscience underlying basic learning and motivation processes also shed significant light upon mechanisms underlying drug addiction and maladaptive eating patterns. In this review, we examine the parallels that exist in the neural pathways that process both food and drug reward, as determined by recent studies in animal models and human neuroimaging experiments. We discuss contemporary research that suggests that hyperphagia leading to obesity is associated with substantial neurochemical changes in the brain. These findings verify the relevance of reward pathways for promoting consumption of palatable, calorically dense foods, and lead to the important question of whether changes in reward circuitry in response to intake of such foods serve a causal role in the development and maintenance of some cases of obesity. Finally, we discuss the potential value for future studies at the intersection of the obesity epidemic and the neuroscience of motivation, as well as the potential concerns that arise from viewing excessive food intake as an "addiction". We suggest that it might be more useful to focus on overeating that results in frank obesity, and multiple health, interpersonal, and occupational negative consequences as a form of food "abuse"., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

The subthalamic nucleus (STN) serves important functions in regulating movement, cognition, and motivation and is connected with cortical and basal ganglia circuits that process reward and reinforcement. In order to further examine the role of the STN on motivation toward food in non-deprived rats, these experiments studied the effects of pharmacological inhibition or μ-opioid receptor stimulation of the STN on the 2-h intake of a sweetened fat diet, the amount of work exerted to earn sucrose on a progressive ratio 2 (PR-2) schedule of reinforcement, and performance on a differential reinforcement of low-rate responding (DRL) schedule for sucrose reward. Separate behavioral groups (N=6-9) were tested following bilateral inhibition of the STN with the GABA(A) receptor agonist muscimol (at 0-5 ng/0.5 μl/side) or following μ-opioid receptor stimulation with the agonist D-Ala², N-MePhe⁴, Gly-ol-enkephalin (DAMGO; at 0, 0.025 or 0.25 μg/0.5 μl/side). Although STN inhibition increased ambulatory behavior during 2-h feeding sessions, it did not significantly alter intake of the sweetened fat diet. STN inhibition also did not affect the breakpoint for sucrose pellets during a 1-h PR-2 reinforcement schedule or impact the number of reinforcers earned on a 1-h DRL-20s reinforcement schedule in non-deprived rats. In contrast, STN μ-opioid receptor stimulation significantly increased feeding on the palatable diet and reduced the reinforcers earned on a DRL-20 schedule, although DAMGO microinfusions had no effect on PR-2 performance. These data suggest that STN inhibition does not enhance incentive motivation for food in the absence of food restriction and that STN μ-opioid receptors play an important and unique role in motivational processes., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Previously, we reported that stimulation of selective serotonin (5-HT) receptor subtypes in the nucleus accumbens shell differentially affected consumption of freely available food. Specifically, activation of 5-HT(6) receptors caused a dose-dependent increase in food intake, while the stimulation of 5-HT(1/7) receptor subtypes decreased feeding [34]. The current experiments tested whether similar pharmacological activation of nucleus accumbens serotonin receptors would also affect appetitive motivation, as measured by the amount of effort non-deprived rats exerted to earn sugar reinforcement. Rats were trained to lever press for sugar pellets on a progressive ratio 2 schedule of reinforcement. Across multiple treatment days, three separate groups (N=8-10) received bilateral infusions of the 5-HT(6) agonist EMD 386088 (at 0.0, 1.0 and 4.0 μg/0.5 μl/side), the 5-HT(1/7) agonist 5-CT (at 0, 0.5, 1.0, or 4.0 μg/0.5 μl/side), or the 5-HT(2C) agonist RO 60-0175 fumarate (at 0, 2.0, or 5.0 μg/0.5 μl/side) into the anterior medial nucleus accumbens prior to a 1-h progressive ratio session. Stimulation of 5-HT(6) receptors caused a dose-dependent increase in motivation as assessed by break point, reinforcers earned, and total active lever presses. Stimulation of 5-HT(1/7) receptors increased lever pressing at the 0.5 μg dose of 5-CT, but inhibited lever presses and break point at 4.0 μg/side. Injection of the 5-HT(2C) agonist had no effect on motivation within the task. Collectively, these experiments suggest that, in addition to their role in modulating food consumption, nucleus accumbens 5-HT(6) and 5-HT(1/7) receptors also differentially regulate the appetitive components of food-directed motivation., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

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., (Copyright © 2011 Elsevier B.V. All rights reserved.)

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., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Sibutramine hydrochloride monohydrate is the only centrally active weight-modifying agent currently approved by the FDA for long-term use in the treatment of obesity. Systemic sibutramine treatment has been shown to reduce food intake in humans and rodent models in a manner that is consistent with the enhancement of satiety mechanisms. Although it is generally assumed that the hypophagic effects of the drug are mediated by actions within the brain, the locus or loci of these effects remains unclear. These experiments compared the effects of systemic and intracranial injections of sibutramine on the intake of a palatable diet in non-deprived animals. Consistent with prior reports, systemic injections of sibutramine hydrochloride (at 0, 0.5, 1.0, or 3.0mg/kg sibutramine i.p.) dose-dependently reduced feeding on a high fat/high sucrose diet across a 2-h feeding session, but did not alter water intake or locomotor activity. In contrast, bilateral injections of sibutramine (at 0.0, 2.0, 4.0 and 10.0μg/0.5μl/side) into either the paraventricular nucleus of the hypothalamus (PVN) or the medial nucleus accumbens shell (ACb) significantly and dose-dependently increased food intake of the sweetened fat diet. ACb treatment also modestly inhibited locomotor behavior; intracranial injections had no effect on water consumption. These experiments are the first to suggest that sibutramine treatment may have distinct actions upon separate neural circuits that modulate food intake behavior in the rat., (Copyright 2010 Elsevier Ireland Ltd. All rights reserved.)

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.

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.

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.

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.

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.

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., ((c) 2005 Wiley-Liss, Inc.)

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.

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.

Little is known about how memories of new voluntary motor actions, also known as procedural memory, are formed at the molecular level. Our work examining acquisition of lever-pressing for food in rats has shown that activation of glutamate NMDA receptors, within broadly distributed but interconnected regions (e.g., nucleus accumbens core, prefrontal cortex, basolateral amygdala), is critical for such learning to occur. This receptor stimulation triggers intracellular cascades that involve protein phosphorylation and new protein synthesis. In support of this idea, we have found that posttrial inhibition of protein synthesis in the ventral striatum impairs learning, whereas posttrial NMDA receptor blockade does not. More recent data show extension of this network to the central amygdala, where infusions of NMDA antagonists also impair learning. We hypothesize that activity in this distributed network (including dopaminergic activity and perhaps muscarinic cholinergic activity) computes coincident events and thus enhances the probability that temporally related actions and events (e.g., lever pressing and delivery of reward) become associated. Such basic mechanisms of plasticity within this reinforcement learning network also appear to be profoundly affected in addiction.

The present study electrophysiologically examined the contribution of prelimbic and infralimbic neurons in the medial prefrontal cortex (mPFC) to integration of reward and spatial information while rats performed multiple memory trials on a differentially rewarded eight arm radial maze. Alternate arms consistently held one of two different reward amounts. Similar to previous examinations of the rat mPFC, few cells showed discrete place fields or altered firing during a delay period. The most common behavioral correlate was a change in neuronal firing rate prior to reward acquisition at arm ends. A small number of reward-related cells differentiated between high and low reward arms. The presence of neurons that anticipate expected reward consequences based on information about the spatial environment is consistent with the hypothesis that the mPFC is part of a neural system which merges spatial information with its motivational significance.

In the field of the neurobiology of learning, significant emphasis has been placed on understanding neural plasticity within a single structure (or synapse type) as it relates to a particular type of learning mediated by a particular brain area. To appreciate fully the breadth of the plasticity responsible for complex learning phenomena, it is imperative that we also examine the neural mechanisms of the behavioral instantiation of learned information, how motivational systems interact, and how past memories affect the learning process. To address this issue, we describe a model of complex learning (rodent adaptive navigation) that could be used to study dynamically interactive neural systems. Adaptive navigation depends on the efficient integration of external and internal sensory information with motivational systems to arrive at the most effective cognitive and/or behavioral strategies. We present evidence consistent with the view that during navigation: 1) the limbic thalamus and limbic cortex is primarily responsible for the integration of current and expected sensory information, 2) the hippocampal-septal-hypothalamic system provides a mechanism whereby motivational perspectives bias sensory processing, and 3) the amygdala-prefrontal-striatal circuit allows animals to evaluate the expected reinforcement consequences of context-dependent behavioral responses. Although much remains to be determined regarding the nature of the interactions among neural systems, new insights have emerged regarding the mechanisms that underlie flexible and adaptive behavioral responses.

Previous research has shown that spatial, movement, and reward information is integrated within the ventral striatum (VS). The present study examined the possible contribution of the basolateral nuclei of the amygdala (BLA) to this interaction by examining behavioral correlates of BLA neurons while rats performed multiple memory trials on an 8-arm radial maze. Alternate arms consistently held 1 of 2 different amounts of reward. Recorded cells were correlated with motion, auditory input, space, and reward acquisition. Reward-related units were found that anticipated reward encounter, that responded during reward consumption, and that differentiated between high and low reward magnitude. This is consistent with the hypothesis that BLA neurons may provide the VS with reward-related information that could then be integrated with spatial information to ultimately affect goal-directed behavior.