An examination of the effects of nucleus accumbens core nociceptin on appetitive and consummatory motivation for food.

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.

Administration of neuropeptide Y into the rat nucleus accumbens shell, but not core, attenuates the motivational impairment from systemic dopamine receptor antagonism by α-flupenthixol.

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.

Stimulation of nucleus accumbens 5-HT6 receptors increases both appetitive and consummatory motivation in an effort-based choice task.

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.

Stimulation of mu opioid, but not GABAergic, receptors of the lateral habenula alters free feeding in rats.

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.

Selective serotonin receptor stimulation of the ventral tegmentum differentially affects appetitive motivation for sugar on a progressive ratio schedule of reinforcement.

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.

Shifting motivational states: The effects of nucleus accumbens dopamine and opioid receptor activation on a modified effort-based choice task.

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.

Glucagon-like peptide-1 receptors modulate the binge-like feeding induced by µ-opioid receptor stimulation of the nucleus accumbens in the rat.

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.

d-Fenfluramine and lorcaserin inhibit the binge-like feeding induced by µ-opioid receptor stimulation of the nucleus accumbens in the rat.

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.

Contrasting effects of 5-HT3 receptor stimulation of the nucleus accumbens or ventral tegmentum on food intake in the rat.

Although serotonin (5-HT) signaling is known to regulate food intake and energy homeostasis, the roles of the 5-HT3 receptor in feeding processes have been elusive. 5-HT3 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-HT3 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-HT3 agonist m-chlorophenylbiguanide hydrochloride (mCPBG; at 0.0, 10.0, or 20.0µg/0.5µl/side) or the 5-HT3 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-HT3 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-HT3 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-HT3 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-HT3 receptors differentially modulate food consumption in a region-dependent manner.

A systematic investigation of the differential roles for ventral tegmentum serotonin 1- and 2-type receptors on food intake in the rat.

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.

Lorcaserin and CP-809101 reduce motor impulsivity and reinstatement of food seeking behavior in male rats: Implications for understanding the anti-obesity property of 5-HT2C receptor agonists.

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.

The effects of nucleus accumbens µ-opioid and adenosine 2A receptor stimulation and blockade on instrumental learning.

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.

Inactivation of the nucleus accumbens core or medial shell attenuates reinstatement of sugar-seeking behavior following sugar priming or exposure to food-associated cues.

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.

Overlapping striatal sites mediate scopolamine-induced feeding suppression and mu-opioid-mediated hyperphagia in the rat.

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.

Serotonin 1A, 1B, and 7 receptors of the rat medial nucleus accumbens differentially regulate feeding, water intake, and locomotor activity.

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.

Systemic treatment with D-fenfluramine, but not sibutramine, blocks cue-induced reinstatement of food-seeking behavior in the rat.

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.

Principles of motivation revealed by the diverse functions of neuropharmacological and neuroanatomical substrates underlying feeding behavior.

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.

The contribution of brain reward circuits to the obesity epidemic.

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".

An examination of the effects of subthalamic nucleus inhibition or µ-opioid receptor stimulation on food-directed motivation in the non-deprived rat.

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.

Selective serotonin receptor stimulation of the medial nucleus accumbens differentially affects appetitive motivation for food on a progressive ratio schedule of reinforcement.

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.