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Appetite and reward

Frontiers in Neuroendocrinology 31 (2010) 85–103 Contents lists available at Frontiers in Neuroendocrinology Appetite and reward Stephanie Fulton * CRCHUM and Montreal Diabetes Research Center, Department of Nutrition, Faculty of Medicine, University of Montreal, Montreal, QC, Canada The tendency to engage in or maintain feeding behaviour is potently influenced by the rewarding prop- Available online 12 October 2009 erties of food. Affective and goal-directed behavioural responses for food have been assessed in responseto various physiological, pharmacological and genetic manipulations to provide much insight into the neural mechanisms regulating motivation for food. In addition, several lines of evidence tie the actions of metabolic signals, neuropeptides and neurotransmitters to the modulation of the reward-relevant cir- cuitry including midbrain dopamine neurons and corticolimbic nuclei that encode emotional and cogni- tive aspects of feeding. Along these lines, this review pulls together research describing the peripheral Nucleus accumbens and central signalling molecules that modulate the rewarding effects of food and the underlying neural Ó 2009 Elsevier Inc. All rights reserved.
rience when coming into contact with an object or when engaging ‘‘We recognize pleasure as the first good innate in us, and from in a particular behaviour can powerfully influence our approach or pleasure we begin every act of choice and avoidance, and to avoidance of that object or behaviour in the future. Consider how pleasure we return again, using the feeling as the standard by eating a delicious morsel of food propels you to take another bite.
which we judge every good." – Epicurus [Letter to Menoeceus, Pleasurable feelings play a significant role in behaviour.
between 306 and 270 BCE] Whether in conditions of hunger or satiety, food intake can be influenced by the pleasurable effects of food. Thus, the joy of eatingcan arise not only from the fulfillment of a vital physiological need but also from the sheer gratification derived from savoring appetiz-ing foods. The word pleasure often refers to a complex experience In one of the first documented accounts of the role of pleasure that involves emotions such as happiness, enjoyment and satisfac- in behaviour, Epicurus captures the notion of pleasure as the expe- tion that are difficult to evaluate in the study of non-human ani- rience that profoundly shapes our evaluations, biases our actions mals. Alternatively, the term reward is commonly used in the and guides our future choices. The degree of pleasure that we expe- scientific literature to refer to a more measurable quality of an ob-ject or action. As used here rewards (1) are objects or actions that Abbreviations: Ach, acetylcholine; AMPA, a-amino-3-hydroxyl-5-methyl-4- prioritize behaviour and promote the continuation of ongoing ac- isoxazole-propionate; AMY, amygdala; ARC, arcuate nucleus; BSR, brain stimulation tions, (2) increase the behaviours that lead to the procurement reward; CCK, cholecystokinin; DA, dopamine; DAT, dopamine transporter; DOR, and/or consumption of the reward (positive reinforcement), and delta opioid receptor; DS, dorsal striatum; fMRI, functional magnetic resonanceimaging; GABA, gamma-aminobutyric acid; HIP, hippocampus; KOR, kappa opioid (3) direct future behavioural actions.
receptor; LH, lateral hypothalamus; GP, globus pallidus; MFB, medial forebrain Subjective estimates of the reward value of food incorporate bundle; MOR, mu opioid receptor; mPFC, medial prefrontal cortex; NAc, nucleus qualities such as taste, texture, smell and post-ingestive conse- accumbens; NT, Neurotensin; OFC, orbital frontal cortex; PBN, parabrachial quences, together with information about the amount and spatio- nucleus; PVN, paraventricular nucleus; PI3, phosphatidylinositol-3; PYY, peptide temporal distribution of food and the metabolic state of the YY; NTS, nucleus of the solitary tract; NMDA, N-methyl-D-aspartic acid; 5-HT,serotonin; SN, substantia nigra; STAT3, signal transducer and activator of tran- organism . Value representations along with information scription; TH, tyrosine hydroxylase; VP, ventral pallidum; VTA, ventral tegmental about the cues and properties associated with attaining food are stored in memory to guide future behaviours, such as orient ani- * Address: Centre de Recherche du CHUM, Technopôle Angus, 2901 Rachel E., mals back to the source of food. The heightened emotional and Rm-302, Montreal, QC, Canada H1W4A4. Fax: +1 (514) 412 7648.
behavioural response to palatable high-fat and -sugar foods that 0091-3022/$ - see front matter Ó 2009 Elsevier Inc. All rights reserved.
doi: S. Fulton / Frontiers in Neuroendocrinology 31 (2010) 85–103 has evolved can be understood in terms of what these foods offer in obtained with electrodes along the medial forebrain bundle caloric value. Indeed, the consumption of tasty, energy-dense foods (MFB) and into the midbrain extension of the MFB . Self- can produce a rewarding effect that strengthens action–outcome stimulation is observed from electrodes located in several brain associations and reinforces future behaviour directed at obtaining areas, including the orbitofrontal cortex, nucleus accumbens these foods. While the rewarding impact of eating high-fat and -su- (NAc), lateral hypothalamus (LH), ventral tegmental area (VTA) gar foods serves as an adaptive element in conditions of food scar- and brainstem structures. Studies combining electrophysiological city the increased abundance and accessibility of these foods in linkage and immunohistochemical mapping approaches many parts of the world has promoted excessive caloric intake with BSR provide much insight into this multi-synaptic and weight gain.
network of brain regions recognized for their contribution to re- Identifying the neural circuitry and mechanisms responsible for ward-relevant processes, including those underlying motivation the rewarding properties of food has significant implications for understanding energy balance and the development of obesity.
From the early findings that rats would continuously self-stim- Although this subject matter has received widespread attention ulate the LH while forgoing physiological needs, such as feeding in more recent years, there is an extensive and rich body of litera- and drinking, emerged the idea that the stimulation tapped into ture on the study of appetite and reward. By and large, these stud- the neural circuitry sub serving natural rewards, such as food ies can be classified into two areas: Those investigating the impact and water Consistent with this view, subsequent of energy states, peptides and neurotransmitter systems on behav- work showed that BSR establishes and maintains response patterns ioural measures of the rewarding effects of food; and those exam- much like those generated by natural rewards Studies of BSR ining the modulation of reward-relevant neural circuitry by also provided some of the first suggestions that reward circuitry is manipulations of energy balance. To convey current understanding subdivided along functional and anatomical lines. Rare observa- of the behavioural processes and neural mechanisms regulating tions of humans with self-stimulating electrodes revealed that food reward it is important to place it in the context of our knowl- stimulation at distinct loci could elicit different subjective reports edge and its evolution of the neural circuitry that underlies all re- Similarly, several lines of evidence obtained in rats provide wards and motivated behaviours, especially since there is strong support for anatomically segregated subpopulations of re- considerable overlap in the associated pathways. Along these gen- ward neurons that code for separate functions .
eral lines, this review discusses selected findings concerning: the Investigations of the brain circuitry that gives rise to rewarding neural basis of reward; the reward efficacy of food, and; the neural self-stimulation not only established a neural basis for reward pathways and mechanisms linked to food reward.
but have made great strides in characterizing the properties ofthe directly activated neurons , their connections andthe manner in which reward circuitry is functionally organized 2. Neural basis of reward The observations that manipulations of the brain dopamine The rewarding effects of stimuli and behaviours have long been (DA) system modulate BSR were among the first to implicate DA studied by measuring the willingness of the subject to work to gain in reward-relevant processes. Certainly, the study of the neural ba- access to the goal object. In the view of Thorndike, behavioural re- sis of reward is well-rooted in investigations of DA circuitry. As the sponses to stimuli that produce satisfying effects are likely to be most studied and tied to reward-relevant functions are the meso- repeated again . The idea that response outcomes can direct corticolimbic and nigrostriatal DA pathways that originate in the subsequent behavioural actions was later formulized in Skinner's midbrain VTA and substantia nigra (SN), respectively, and project theory of reinforcement proposing that the consequence of a re- to various limbic and cortical sites including the NAc, amygdala sponse acts as a positive reinforcer when the probability of that re- (AMY), ventral pallidum (VP), dorsal striatum (DS), hippocampus sponse occurring in the future is increased As a central tenet (HIP) and prefrontal cortex (PFC). Early on it was shown that DA of operant conditioning, Skinner maintained that response strength receptor antagonists and lesioning of DA neurons via 6- can be determined by measuring the frequency or intensity of hydroxydopamine (6-OHDA) inhibit BSR whereas drugs that behavioural responses (e.g. lever presses) . Operant (or directly or indirectly increase DA tone, including amphetamine instrumental) conditioning is a principle concept and procedure cocaine heroine/morphine and nicotine in the experimental analysis of behaviour and serves as an empir- enhance the rewarding effects of MFB stimulation. Despite ical construct in models of behavioural choice and reward mea- the potent impact on BSR produced by modulation of DA signalling, surement By measuring the willingness of the the traversing of DA fibers along portions of the MFB and the facil- subject to work for the goal object, operant measures can offer a itatory action of MFB self-stimulation on DA release , the meaningful index of reward effectiveness.
results of several studies suggest that the neurons directly acti- The discovery by Olds and Milner in 1954 that rats will avidly vated by MFB stimulation are not dopaminergic .
work to self-administer electrical stimulation to some regions of However, the directly activated neurons may trans-synaptically the brain was a remarkable beginning to the study of brain reward activate DA neurons via a cholinergic input arising from the pedun- circuitry . In addition to the eruption in the scientific commu- culopontine or laterodorsal tegmental nucleus .
nity provoked by this finding, newspaper headlines reading the Much like the effects of electrical brain stimulation, central ‘‘brain pleasure area" had been discovered and that ‘‘it may prove administration of drugs that modulate DA tone can be reinforcing the key to human behaviour" stirred up much public excitement (see ). Several lines of evidence suggest that the reinforcing (The Montreal Star; March 12, 1954) Also known as brain actions of drugs of abuse are due, at least in part, to the modulation stimulation reward (BSR), this phenomenon is considered to tap of DA signalling in the NAc. The actions of amphetamine , co- into the neural circuitry that conveys the rewarding properties of caine and opiates to increase instrumental responding natural stimuli and behaviours. The rewarding stimulation gener- are associated with enhanced DA release in the NAc. Rats will ates a powerful grip on behaviour as revealed by the resistance self-administer amphetamine directly into the NAc whereas to forgo delivery of the stimulation: Rats will cross electrified grids selective DA lesions in the NAc block self-administration of intra- and go without food in conditions of severe deprivation venous amphetamine . Unlike amphetamine, rats will not in order to maintain contact with the manipulator learn to respond for cocaine administration into the NAc, but will that triggers the stimulation. Robust self-stimulation behaviour is self-administer cocaine into another DA terminal region, the S. Fulton / Frontiers in Neuroendocrinology 31 (2010) 85–103 medial PFC (mPFC) . Nonetheless, DA release in the NAc ap- feeding behaviour. The reinforcing effects of food have commonly pears to be important in mediating the reinforcing actions of co- been assessed using operant conditioning procedures that measure caine since DA lesions in the NAc impair intravenous cocaine the willingness to work for food. In other instances, food reinforce- self-administration . Rats will also work for discrete injec- ment has been studied using the conditioned place preference tions of morphine and mu and delta opioid receptor agonists into model. The conditioned place preference paradigm entails Pavlov- both the VTA and NAc and injection of opiates into ian (associative) conditioning in which the reinforcing effects of the VTA increases extracellular levels of DA in the NAc .
the object are evaluated by measuring the amount of time the ani- Although these data highlight the importance of NAc DA in drug mal spends in an environment previously paired (associated) with self-administration, a role for the mPFC in the reinforcing effects that object Therefore, both operant conditioning and condi- of cocaine and NMDA receptor antagonists (i.e., ketamine) tioned place preference models measure acquired and voluntary is well documented.
behavioural responses that are directed at obtaining the goal object The results of experiments investigating the influence of DA on and influenced by prior encounters with the goal object (‘‘goal-di- BSR and drug self-administration contributed to the popular notion rected behaviour").
that DA is responsible for rewarding behaviour. Changing dopami- The hedonic properties of food are commonly assessed by deter- nergic tone influences the behavioural effectiveness of rewards mining the affective evaluations that are generated in response to such as BSR, drugs of abuse, food and sex, however there is dis- direct encounters with food or food-related stimuli. In the case of agreement concerning how and where DA neurons contribute to human participants, the respondent provides a subjective evalua- the circuitry underlying reward. Indeed, the exact functional con- tion of a sensory property of food (often taste) which is reflected tribution of DA has received intense attention on both the empiri- by a rating of pleasantness or liking. The hedonic attributes of food cal and theoretical levels. Discrepancies in the DA literature are have also been studied in animals using the taste reactivity para- likely influenced by variations in DA terminal areas in the forebrain digm which measures spontaneous oral and facial reaction pat- under investigation differences in the electrochemical terns to tastants that are inherent across many mammalian techniques used and the behavioural measurements and species . Research employing these hedonic measures of food models employed (see reward will be reviewed here, however relevant work addressing Despite different views, a large body of work suggests that DA is the role of taste, macronutrient preferences and palatability will important for reward-relevant learning and neural plasticity. This not be thoroughly covered. Therefore, the reader is referred to line of research emerged from the discovery that repeated admin- istration of drugs that stimulate DA release can have long-lasting and palatability .
consequences by potentiating the behavioural effects of these A commonly used measure of the reward efficacy of food is an drugs, a process known as sensitization. Recurrent drug adminis- operant procedure known as the progressive ratio (PR) schedule tration has been shown to enhance locomotor-activating effects of reinforcement. In the PR task, the subject is required to emit an increasing number of operant responses for each successive re- , BSR and opiate-induced feeding Notably, ward. Eventually performance falls below a preset criterion. The the behavioural sensitizing effects of repeated drug intake are number of responses emitted to obtain the last reward (‘‘break linked to elevations in DA release and long-lasting structural point") serves as an index of the willingness to work . While and molecular changes in DA neurons and their striatal targets operant procedures that measure changes in response rate alone Thus, substantial evidence has accumulated over cannot dissociate changes in reward efficacy from alterations in the past two decades to support a role for DA in strengthening ac- performance capacity (e.g., ), the break point derived tion–outcome associations; nonetheless, the precise contribution from the PR schedule is a well-validated measure of the reward of DA in learning-related processes and neuroadaptations is still magnitude of food .
a matter of major investigation and discussion.
To summarize, investigations of BSR and drug self-administra- 3.1. Energy states and metabolic signals tion have been instrumental for establishing the neural founda-tions of reward. Central to this research is the modulation of Initial reports of PR performance for food in rats demonstrated motivated behaviour by neurochemical manipulations revealing that the break point declines when the caloric value of the food is the contribution of neurotransmitter and peptide systems. Numer- reduced whereas it increases as a function of weight loss and the ous findings that drugs that increase DA tone can be self-adminis- quantity of food . Both food restriction and tered and that interfering with DA signalling in the mesolimbic acute food deprivation increase break points and thus en- pathway can dramatically alter BSR and drug self-administration hance the rewarding effects of food. Break points on the PR sche- emphasize the important role for DA in reward-relevant behaviour.
Upon discussing the impact of DA in feeding in later sections, I will demonstrating that motivation for sucrose increases in a manner touch on work characterizing the impact of DA on different moti- that follows sweet taste Furthermore, food restriction and vational and neural processes. This research deserves particular weight loss are reported to increase sucrose motivation as a func- attention to gain a thorough understanding of the contribution of tion of the concentration of sucrose . These findings are com- DA to feeding behaviour and motivation for food. As this literature parable to those obtained in human participants that rated sucrose will not be systematically reviewed here, the reader is referred to solutions as more pleasant following a period of food restriction the following reviews and weight loss Interestingly, while the reward efficacy offood is elevated during conditions of energy deficit it is also elevated in states of increased adiposity. PR performance 3. Reward efficacy of food for chow or sucrose is enhanced in obese Zucker rats relative tolean controls in diet-induced obese rats obesity- Behaviour is an essential component of the energy balance prone rats following discontinuation of a high-fat and – sugar diet equation. Appetitive and consummatory behaviours are the sole and in overweight as compared to lean children . These means through which energy intake is achieved, and all behaviour findings illustrate how PR measures can track changes in the qual- entails energy expenditure. The rewarding properties of food can ity of a food reward and the energy needs and motivational state of dramatically influence the propensity to engage in or continue the organism.
S. Fulton / Frontiers in Neuroendocrinology 31 (2010) 85–103 Human studies were the first to describe the impact of meta- that respond to hormonal and metabolic signals from the periph- bolic manipulations on hedonic evaluation of food. Thompson ery to influence energy balance (this issue). Several neuropeptides and Campbell found cellular glucopenia induced by peripheral 2- localized in the ARC are known to regulate food intake, including deoxyglucose (2-DG) administration increased ratings of the pleas- the orexigenic signals neuropeptide Y (NPY), agouti-related pep- antness of a sucrose solution . Similarly, systemic administra- tide (AgRP) and anorexigenic signals alpha-melanocyte-stimulat- tion of insulin was reported to enhance sucrose pleasantness ing hormone (aMSH) and cocaine and amphetamine-regulated ratings The process whereby insulin increases affective transcript (CART). In addition to stimulating free-feeding intake, ratings may be attributable to reductions in central glucose signal- central administration of NPY potently increases the reward effi- ling elicited by insulin given that sucrose ratings correlated nega- cacy of chow and sucrose by increasing breakpoints in tively with blood glucose concentrations. However, Jewett and a PR schedule of reinforcement. NPY is also synthesized in neurons colleagues found that glucoprivation induced by peripheral 2-DG outside of the hypothalamus which have been linked to reward- in rats failed to alter break points in a PR task for food while it in- relevant processes however the actions of NPY to increase creased the amount of freely available food consumed. The distinc- motivation for food appears to be mediated by hypothalamic tion between the above findings may not be simply due to species NPY as direct administration of NPY into the perifornical LH in- differences but rather the different measurements used, thus 2-DG creases PR performance for sucrose . Coexpressed with NPY, may enhance affective ratings for sweet taste without modulating AgRP also elicits a profound increase in food intake. The actions willingness to work measures for sucrose. Such a discrepancy be- of AgRP to selectively increase fat appetite appears to be mediated tween affective and instrumental measures has been described via the MC4 receptor and mice lacking the MC4 receptor de- and likely reflects the different neural mechanisms recruited velop increased motivation for food in a PR task relative to wild- Evidence obtained in rats suggests that insulin has specific ac- type littermates . Moreover, recent evidence demonstrates tions in the CNS to modulate the reward efficacy of food. Intraven- that AgRP administration in rats can selectively increase the re- tricular (ICV) administration of insulin not only decreases free- ward efficacy of high-fat food, but not sucrose, in a PR task .
feeding intake but can inhibit PR responding for sucrose These results provide evidence that the motivational properties Moreover, Figlewicz et al. report that the effects of insulin to de- of food can be divided along nutritional lines.
crease responding for sucrose is mediated via signalling in the arcu- There is less evidence linking anorexigenic neuropeptides to the ate nucleus (ARC) . These investigators also find that the rewarding effects of food. Several lines of evidence link CART to adipose-derived hormone leptin can attenuate sucrose-reinforced mechanisms mediating the reinforcing actions of psychostimulant responding. The above result stands in contrast to findings that ICV drugs , yet while CART administration into the NAc de- administration of insulin fails to alter breakpoints in a PR task for creases breakpoints for cocaine reward it fails to alter motivation food . The discrepancy between the two studies could be due for food . Similarly, corticotropin-releasing hormone (CRH) to the response measures used given that the rates of responding decreases food intake in rats however CRH has been re- for sucrose recorded by Figlewicz et al. may be more sensitize than ported to increase decrease or fail to alter response the breakpoint index measured by Jewett et al. Figlewicz et al. also rates and the number of food reinforcers earned. In other studies, report that insulin and leptin decrease conditioned place preference central administration of a CRH-1 and/or CRH-2 receptor antago- for high-fat food and thereby provide additional evidence that circu- nists did not influence instrumental responding for food but lating satiety hormones reflecting the status of long-term energy a CRH-1 antagonist can attenuate the effects of stress-induced stores can suppress the reinforcing actions of palatable foods reinstatement of lever-pressing for palatable food Modula- Apart from insulin and leptin, several other circulating peptides tion of the CRH system does not appear to suppress the reward effi- act centrally to decrease food intake. Cholecystokinin (CCK) is a cacy of food, rather the actions of CRH to reduce food-motivated gut-derived satiety signal that has been linked to reward-relevant responding appear to be limited to impairments in motor capacity neural processes Systemic CCK injection diminishes the abil- Neurotensin (NT), on the other hand, is among the anorexi- ity of food deprivation to increase instrumental responding for genic signals consistently reported to inhibit instrumental food suggesting that peripherally-derived CCK can modulate the responding for food. NT injections into both the lateral ventricles reinforcing effects of food . Furthermore, CCK-1 receptor defi- and VTA decrease operant responding for food whereas cient rats (OLETF) that are hyperphagic and obese exhibit en- peripheral administration of a NT analog inhibits sucrose-rein- hanced instrumental responding for sucrose relative to wildtype forced responding . While NT is expressed in the hypothalamus controls Released from intestinal cells in proportion to calo- there also exist NT neuronal populations outside of the hypothala- ric intake, peptide YY (PYY) is another gut peptide implicated in mus with ties to feeding and reward .
appetite control In an instrumental task, peripheral admin- Orexin-A and orexin-B are synthesized exclusively in a subset of istration of PYY-36 failed to inhibit responding for high-fat food LH neurons innervated by the ARC neuronal populations described pellets, however it reduced reinstatement of food-seeking induced above. Numerous reports over recent years demonstrate the im- by exposure to the high-fat food and a cue associated with the food pact of orexins on reward circuitry and its influence on goal-direc- . Together, these data demonstrate the effects of some periph- ted behaviour. Orexin-A infusion into the rostral LH elicits a erally-derived satiety signals to suppress the rewarding effects of particularly robust feeding response and enhances break- food. There are a number of circulating peptides that have yet to point responding for sucrose pellets In contrast, systemic be studied in the context of food reinforcement. Specifically, it is infusion of an orexin-1 receptor antagonist failed to alter instru- not known whether other signals release from the digestive tract, mental responding for sucrose . However, in another study including ghrelin, glucagon-like peptide 1 and enterostatin, can peripheral administration of an orexin-1 receptor blocker attenu- modulate the reward efficacy of food. As will be reviewed later ated instrumental responding for high-fat food pellets . Orex- however, there is evidence tying the actions of ghrelin along with in neurons project to the VTA and orexin-A and orexin-B leptin, insulin and PYY to the modulation of reward circuitry.
potentiate excitatory inputs to VTA DA neurons by mechanismsinvolving both orexin-1 and -2 receptors . In addition, 3.2. Endocrine neuropeptides Borgland et al. report that orexin-1 receptor antagonism blocks co-caine-induced locomotor sensitization and potentiation of excit- There has been remarkable progress in the identification and atory currents in VTA DA neurons These and other findings characterization of the hypothalamic and hindbrain neuropeptides implicate orexins in DA signalling and synaptic plasticity and in S. Fulton / Frontiers in Neuroendocrinology 31 (2010) 85–103 the modulation of goal-directed behaviour for food. Like orexin, antagonists suppress preference for sucrose and decrease melanin-concentrating hormone (MCH) is produced exclusively pleasantness ratings for the smell and taste of food . More- in the LH, however in a discrete neuronal subpopulation .
over, naltrexone administration is reported to be more effective Matching the pattern of MCH axonal projections, the MCH-1 recep- at reducing pleasantness ratings for highly palatable foods, regard- tor is expressed in numerous brain regions including the NAc and less of macronutrient content . Consistent with these data, DS . Georgescu et al. reveal a specific role for MCH signalling morphine enhances affective responses of rats for palatable foods in the NAc shell by demonstrating the effects on an MCH-1 recep- as measured by the taste reactivity test Characterizing the tor antagonist to inhibit feeding and produce anti-depressant like receptors and brain sites mediating these opioid-induced re- effects Consistent with these results, work of Pissios et al.
sponses, Berridge and coworker found that morphine infusion in demonstrates enhanced behavioural responses to amphetamine the NAc shell and DAMGO in the VP but not the LH en- and increase stimulation-evoked DA release in the NAc shell of hances taste reactivity patterns to sucrose.
MCH deficient mice Despite these data, it remains to be elu- The use of instrumental response measures demonstrate that cidated whether or not MCH enhances the reinforcing effects of opioids can alter goal-directed behaviour for food. Peripheral injec- tion of the non-selective opioid agonists, buprenorphine and In summary, the data reviewed in this section illustrate that morphine , increased break points for food on a PR schedule several neuropeptides controlling appetite and energy balance, of reinforcement whereas administration of naloxone produced including NPY, AgRP, NT and orexin, can modulate goal-directed the opposite effect . A role for MOR signalling in behaviour for food. It is interesting that studies employing nu- the NAc in the modulation of goal-directed behaviour for food is clei-specific microinfusions suggest that the effects of insulin, suggested by the demonstration that NAc DAMGO increases break- NPY and orexin on PR performance for food are obtained with tar- point responding for sugar pellets . MORs have a high affinity geted injections into hypothalamic regions. This is not surprising in for enkaphalins and endorphins and a low affinity for dynorphins consideration of the multiple reciprocal connections between (which are selective for kappa receptors), and both enkaphalin hypothalamic nuclei and reward-relevant substrates. As discussed and beta-endorphin are released in the NAc and VP. Consistent later, leptin, insulin and ghrelin also regulate DA tone by targeting with the above results, a series of studies by Hayward, Low and col- midbrain DA neurons to suggest there are at least some direct ac- leagues suggest that enkaphalin and beta-endorphin are the tions of these hormones on reward-relevant processes.
endogenous opioid receptor ligands that mediate the actions ofopioids on the motivational properties of food. With the use of genetically engineered mice lacking enkaphalin and beta-endor-phin these investigators report impaired breakpoint responding The neuropeptide group most investigated in the context of the for food in a PR task in knockouts relative to wildtype controls rewarding effects of food and palatability are opioids, namely enk- . Collectively, these findings highlight the important role aphalins, dynorphins and endorphins. Each of these opioids can of the MORs and ligands, enkaphalin and beta-endorphin, in the influence feeding behaviour by acting on opioid receptors (mu, NAc and VP in the rewarding effects of food and the modulation kappa and delta) located throughout the brain. Non-selective opi- of food palatability.
oid receptor blockade by peripheral and central naloxone administration decreases food intake in rats, especially 3.4. Neurotransmitters when highly preferred foods such as sucrose or saccharin are used. The effect of central opioid action to modulate feed- As with BSR and drugs of abuse, the reinforcement efficacy of ing appears to be due, in part, to actions in the NAc and VTA. Direct food can be modulated by alterations in DA tone. Systemic injec- administration of opioid agonists into the NAc stimulates food in- tions of a D1/D2 receptor antagonist can decrease instrumental re- take whereas VTA administration of opioid agonists sponses and conditioned place preference for food yet or antagonists increases and decreases food intake, fails to alter taste reactivity measures Similarly, a D2/D3 respectively. The influence of opioids in the VTA and striatum to receptor antagonist decreases PR performance for sucrose pellets stimulate appetite are mainly attributed to mu opioid receptors without affecting taste reactivity patterns . The D2 but (MOR) . The important role of MOR-induced feeding not the D3 receptor appears to be specifically involved in food- in the striatum is underscored by the work of Kelley and cowork- reinforced responding given that a selective D3 receptor agonist ers. Stimulation of MOR and delta (DOR), but not kappa (KOR) fails to modulate PR performance and conditioned place preference receptors in the dorsal and ventral striatum increases intake of for food . Consistent with these findings, specific ablation of DA chow and sucrose, while particularly robust increases in food in- neurons in the NAc using 6-hydroxydopamine (6-OHDA) signifi- take are seen following infusions into the NAc shell These cantly attenuates goal-directed behaviour for food , but investigators further show that MOR stimulation in the NAc shell does not influence taste reactivity measures in rats and either by D-Ala2, N-MePhe4, Gly-ol-enkephalin (DAMGO) preferentially fails to alter or slightly augments free-feeding intake In and dramatically increases intake of high-fat food In- an opposite manner, Zhang et al. discovered that increasing DA sig- creased intake of palatable foods by NAc DAMGO injection is med- nalling in the NAc shell (and to a lesser extent the NAc core (but see iated by the LH given that GABA receptor blockade in the LH blocks via direct amphetamine administration increases the willing- the feeding response . Characterizing the neural outputs ness to work for sugar pellets on a PR schedule of reinforcement mediating NAc MOR-induced feeding, Zheng et al. demonstrated whereas others found that it actually inhibits free-feeding in- that orexin neurons of the LH and their projections to the VTA take and fails to alter taste reactivity patterns The are involved . Apart from striatal regions, DAMGO adminis- influence of DA on goal-directed behaviour for food is not limited tration in the VP is also reported to increase food intake. To- to the NAc as viral restoration of DA to the DS in DA-deficient mice gether, these data illustrate the unique role of MOR signalling in rescues learning and performance of an instrumental task for food the VTA, NAc shell, DS and VP in the modulation of palatability and feeding by opioids.
During encounters with food animals rapidly learn about the Several lines of evidence support the idea that opioids influence sensory qualities and the environmental cues associated with both affective evaluations and goal-directed behaviour for food. In attaining food. These representations are stored in memory to help humans, systemic administration of non-selective opioid receptor guide subsequent behavioural actions directed towards feeding.
S. Fulton / Frontiers in Neuroendocrinology 31 (2010) 85–103 The findings above illustrate how different measures provide a of 5-HT on the reward efficacy of food Interestingly, 5-HT2C useful way to disambiguate the influence of DA in distinct facets receptors are located in the NAc and VTA among other loci, and 5- of motivation for food. Collectively, the data suggest DA is impor- HT release in the VTA from axons originating in the dorsal raphe tant for learning about and maintaining goal-directed behaviour inhibits DA release These findings illustrate the impact of 5- for food rather than food consumption by itself or processes, such HT to attenuate instrumental responding for food, an effect that as affective reactions, that are closely connected with the consum- may be mediated by the actions of 5-HT to reduce DA matory phase of feeding. This view bodes well with several inves- tigations of Salamone et al. demonstrating the impact of DA Serving as the primary inhibitory and excitatory amino acids in manipulations on the effort required in work-related instrumental the brain, gamma-aminobutyric acid (GABA) and glutamate elicit response measures . There is also general agreement in the disparate effects on feeding depending on the site of injection associative learning literature that DA is important to acquire and feeding measurement employed. A GABA(A) receptor agonist information about rewards and the behavioural responses to ob- in the NAc shell potently increases food intake yet does not aug- tain them. Peripheral administration of DA receptor antagonists ment PR responding for food Correspondingly, increasing inhibits the development of conditioned place preferences for pal- GABAergic tone via peripheral delivery of a GABA transaminase atable foods without affecting food consumption . In addi- inhibitor or the GABA(B) agonist, baclofen, either modestly tion, D1 receptor blockade in the LH and NAc shell can decreases instrumental PR responding for food or has no effect prevent learning of a taste aversion whereas D1 receptor blockade . Nevertheless, in one other case systemic infusion in the NAc core and medial PFC impairs learning of an of baclofen significantly reduced responding for a fatty food more instrumental task. Finally, systemic D1 receptor blockade or so than normal chow Like GABA, glutamate signalling in specific D1 blockade in the NAc shell or core attenuates the NAc shell modulates food intake, an effect mediated via actions acquisition of flavor preferences conditioned by intragastric glu- at AMPA and kainate receptors Operant responding for cose. Intriguingly, the results derived from studies of DA-deficient food is reduced following peripheral AMPA antagonist (NBQX) mice suggest that some form of learning or memory formation can administration, but this result appears to be due to impairments still take place in the absence of DA, but is only evident in the con- in motor function In addition, blocking metabotropic gluta- text of goal-directed behaviours when DA is restored to the DS mate receptor 5 (mGluR5) by peripheral MPEP infusion did not al- ter food-maintained responding in two reports yet By signalling at nicotinic and muscarinic receptors, central cho- reduced breakpoints for food in one other study . While both linergic systems also participate in the regulation of appetite. As GABA and glutamate plays a critical modulatory role in neuro- the major addictive component of tobacco, nicotine acts centrally transmission in brain regions implicated in the rewarding effects to reduce food intake whereas smoking cessation is accompanied of food, the data taken together do not provide strong evidence by hyperphagia and weight gain . Nicotine administration that these neurotransmitters by themselves have an important into the LH suppresses food intake , an effect mediated by influence on food-reinforced responding.
activation of nicotinic receptors located on GABA terminals that re- Collectively, the results of behavioural studies cited above sults in the inhibition of local MCH neurons On the other implicate DA, Ach and 5-HT neurotransmitter systems in the mod- hand, muscarinic receptor blockade in the SN NAc or DS ulation of food reward. Targeted modulation of DA and Ach tone in or selective lesion of acetylcholine (Ach) neurons in limbic areas brings to light the influence of D1, D2 and muscarinic the NAc potently decreases food intake. The action of musca- receptor signalling in the NAc and dorsal striatum in the acquisi- rinic receptor antagonists in the striatum to decrease food intake is tion and strength of food-motivated instrumental behaviour. Sim- associated with reductions in enkaphalin gene expression, and ilarly, one can speculate that the effects of 5HT2C receptor thus reduced enkaphalin binding to MORs may mediate the stimulation to inhibit food-motivated responding could involve anorexigenic effects Non-selective muscarinic, but not nico- receptors expressed in the NAc. It is interesting that while these tinic, receptor blockade in the NAc core or shell suppresses break- neurotransmitter systems are implicated in the voluntary and points in a PR task for sucrose and inhibits learning an learned behavioural responses for food they do not appear ger- instrumental task . Similarly, selective Ach lesion in the stri- mane to affective taste reactions. Research is shedding light on atum impairs reward-related learning . However, other inves- the possible configuration of these pathways for the regulation of tigators find that microinfusions of a muscarinic agonist in the NAc food reward. Immunohistochemical localization of the various does not increase responding for food in a PR task Despite receptors reveals that the interaction between Ach, DA and opioid discrepancies in the above findings, several studies implicate stri- systems in the NAc is complex (see Clearly, more work is atal Ach activity and release in satiety-related responses needed in order to tease apart the neural pathways and signalling and encoding of rewarding and aversive outcomes events that are involved.
These actions of striatal Ach are attributed to a small pop-ulation of cholinergic interneurons that target muscarinic and nic- 3.5. Endocannabinoids otinic receptors expressed on local striatal neurons and axonalinputs from midbrain (including DA neurons) and corticolimbic re- The endocannabinoids, 2-arachidonoylglycerol (2-AG) and anandamide, are lipid molecules that bind to cannabinoid (CB) A common pharmaceutical target for weight loss treatment, receptors to engage in numerous biological functions . Located serotonin (5-HT) has long been known to influence appetite. By on presynaptic terminals releasing GABA or glutamate, the CB1 means of pharmacological and genetic tools, 5-HT1B, 5-HT2C and receptor is widely expressed in the brain, including moderate to 5-HT6 subtypes were shown to be the primary receptors through strong levels of expression in cortex, HIP, AMY, striatum and which 5-HT exerts its anorectic effects . Chronic blockade or HYP. Due to its localization on inhibitory and excitatory presynap- deletion of the 5-HT transporter decreases instrumental respond- tic terminals, retrograde activation of CB1 receptors can regulate ing for food . Direct infusion of 5-HT into the NAc inhibits the release and/or signalling of several neurotransmitters and neu- operant responding for food in a PR task, an effect that is not med- ropeptides, including dopamine, MCH and orexin and are thus con- iated by the 5-HT1B receptor However, peripheral infusion of a selective 5-HT2C agonist is reported to decrease PR responding The endocannabinoid system has received much recent atten- for food suggesting a role for this receptor in mediating the action tion for its role in regulating food intake and palatability. As the ac-

S. Fulton / Frontiers in Neuroendocrinology 31 (2010) 85–103 Fig. 1. Model of basal ganglia circuit organization This prominent model consists of parallel ascending cortico-basal ganglia–thalamus–cortico ‘‘loops". The NAcsends projections back to the source of DA neurons in the midbrain VTA. VTA DA neurons that receive afferents from the NAc shell send DA projections back to the NAc shelland core. In turn, NAc core neurons project back to the DA neurons from which they received input in addition to DA neurons of the SN that innervate the DS . Thismodel has been used to explain the process whereby goal-directed behaviour persists and can eventually develop into a habit by a gradual shift in its control from ventralstriatal regions to more dorsal areas of the striatum .
be obtained with targeted injections in the NAc shell region Moreover, anandamide injections in the NAc shell significantly in-crease affective taste reactivity patterns for a sucrose solution There is growing evidence for an interaction between endo-cannabinoids and opioids in the regulation of food preferences andfood reward. Solinas and Goldberg discovered that the effect ofTHC to increase breakpoints for food in a PR task could be blockedby the non-specific opioid antagonist naloxone . In turn, these authors show that the effect of morphine to enhance breakpoints is prevented by administration of the CB1 antagonist rimonabant.
Intriguingly, CB1 receptors are co-localized with MORs on the pro- cesses of striatal medium spiny neurons and there is evi- dence for functional interaction between these receptors in the NAc that regulates the release of GABA and glutamate Tosummarize, endocannabinoids in the NAc shell enhance the Fig. 2. Striatal targets of midbrain DA neurons and their outputs. GABAergic rewarding effects of food, possibly via a CB1 receptor – MOR inter- medium spiny neurons exist in two subpopulations: (1) GABA/dynorphin neurons action. CB1 receptors are also present in the VTA where they in- that mainly express D1 receptors and project directly to basal ganglia output nuclei crease DA firing and release and thus endocannabinoid including the SN (striatonigral pathway), (2) GABA/enkaphalin neurons that expresshigh levels of D2 receptors and MORs and project indirectly to basal ganglia output action in the VTA may contribute to the modulation of food reward.
nuclei (striatopallidal pathway). Only the signalling molecules and receptors(denoted by symbols) implicated in the rewarding effects of food are illustrated.
Ach, acetylcholine; CB1, cannabinoid-1 receptor; D1; dopamine-1 receptor; D2,dopamine-2 receptor; Dyn, dynorphin; Enk, enkaphalin; M, muscarinic receptor(mostly M1 and M4); MOR, mu opioid receptor. Illustration created thanks to A great deal has been discovered about the signals and neural Servier Medical Art.
pathways contributing to the rewarding effects of food by investi-gations of the neurochemical and genetic basis of affective andgoal-directed behaviour for food. The NAc shell stands out as a tive ingredient in cannabis, delta-9 tetrahydrocannabinol (THC), key brain region that coordinates neurotransmitter, opioid and has long been known to increase food intake, particularly for palat- endocannabinoids signals to control feeding behaviour. Among able sucrose Moreover, THC enhances the rewarding effect the important signalling molecules in the NAc shell are DA, Ach, of food by increasing PR responding for food pellets A opioids (enkaphalin and beta-endorphin) and cannabinoids and specific role for the CB1 receptor in the reinforcing actions of food their respective actions at DA (D1 and D2), muscarinic (likely M1 is highlighted by several demonstrations that CB1 antagonism de- and M4), MOR and CB1 receptors. The means by which these differ- creases instrumental responding for foods .
ent signals interact to differentially modulate free-feeding intake, These data are supported by finding obtained in CB1 receptor food-motivated behaviour versus affective reactions for food re- knockout mice demonstrating reduced responding for sucrose mains to be fully elucidated. For instance, MOR and CB1 receptor . However, when standard food pellets served as the rein- activation in the NAc shell enhances goal-directed and affective re- forcer, CB1 receptor knockout mice were not different than controls sponses for palatable foods in addition to free-feeding intake. In . Indeed, the effects of a CB1 receptor antagonist or agonist to contrast, increasing DA signalling in the NAc strengthens instru- decrease and increase, respectively, food-reinforced responding are mental behaviour yet fails to augment free-feeding intake and reported to be selective for a sweet reinforcer as compared to a taste reactivity responses. Finally, while GABA A receptor activa- pure fat reinforcer tion in the NAc shell stimulates free-feeding it fails to augment Much like opioid-induced feeding, a particularly robust stimula- PR responding for food. The distinction between the behavioural tory effect of the endogenous CB1 receptor ligand, anandamide, can responses produced by these signals undoubtedly lies in the spe- S. Fulton / Frontiers in Neuroendocrinology 31 (2010) 85–103 cific neuronal subpopulations and outputs involved. Research has one subpopulation consists of GABA/dynorphin neurons that made progress in delineating the anatomical and physiological mainly express D1 receptors and project directly to basal ganglia interactions between neurotransmitter and peptide systems in output nuclei including the SN, also known as the direct or stria- midbrain and corticolimbic areas. The findings from these studies, tonigral pathway. The other pathway consists of GABA/enkapha- which will be elaborated on in the next section, can provide valu- lin neurons that express high levels of D2 receptors and MORs able input for dissecting the processes underlying different facets and project indirectly to basal ganglia output nuclei via the exter- of food reward. As this circuitry is uncovered we will be able to nal GP and subthalamic nucleus, also known as the indirect or gain more insight into the genes and epigenetic modifications that striatopallidal pathway. Integration between these parallel striatal promote individual susceptibility to intake of rewarding high-fat outputs and their corresponding circuit loops (as described and sugar foods as a means to determine which mechanisms are above) is considered to be essential for coherent behaviour contributing to overeating and obesity.
and Ach interneurons are purported to play a role in thecommunication between the different pathways and striatal com-partments . Each striatal output pathway is differen- 4. Neural pathways and mechanisms of food reward tially modulated by DA: DA excites the direct pathway via theD1 receptor whereas it inhibits the indirect pathway by way of 4.1. Corticolimbic circuitry: basic anatomy and function the D2 receptor . In this regards, it is interesting that themajority of NAc neurons differentially respond to either primary The central nervous system integrates numerous metabolic sig- rewarding or aversive taste stimuli and to the cues that predict nals from the periphery and thereby generates adaptive behav- of their availability. Specifically, some NAc neurons are inhibited ioural responses to changing energy demands. Information about by tasting a sucrose solution (or exposure to a cue paired with su- the metabolic state of the organism is preferentially encoded in crose) whereas others are excited by an aversive quinine solution hypothalamic and hindbrain sites whereas emotional and cogni- , and these actions are opposite to the effects of these tive aspects are processed in limbic and cortical loci that assign sal- tastants on DA neurotransmission in the NAc shell While ience and motivational valence to objects and behavioural actions.
these findings demonstrate anatomically and functionally distinct As used here, corticolimbic substrates refer to components of cor- NAc outputs in response to rewarding versus aversive taste stim- tex, striatum and pallidum which each give rise to descending pro- uli it should be noted that it is not known whether these differ- jections to the motor system (including basal ganglia output nuclei) ences reflect direct and indirect striatal output pathways.
whereby motivation is converted into action This circuitry is The NAc is considered as an interface for emotion, motivation organized such that ventral components, including the AMY and and action due to its excitatory glutamatergic inputs from limbic NAc, are more implicated in the processing of emotions and emo- and cortical structures such as the AMY, HIP and PFC .
tional learning, and more dorsal portions, including the PFC and DS, Among the limbic inputs to the NAc is the AMY which receives are more involved in cognitive processes and habit formation food-related sensory information from the hindbrain and the cor- tex, in addition to physiological signals related to hunger and sati- The neural networks that give rise to goal-directed behaviour ety via hindbrain nuclei . Moreover, the AMY is a key rely on basal ganglia outputs to channel motivation into behav- substrate for processing emotion and associative condition- ioural action. Central to many research and theoretical approaches ing of food-related instrumental responses . These and other is an influential model of basal ganglia circuit organization which observations suggest that the AMY connects external and internal consists of parallel ascending cortico-basal ganglia–thalamus–cor- sensory information with motivational systems of the brain. Pro- tico ‘‘loops" As a component of one circuit, the viding additional input to NAc, the HIP serves a crucial role in NAc sends projections back to the source of DA neurons in the mid- memory formation and retrieval of internal and external cues, brain VTA. VTA DA neurons that receive afferents from the NAc and new developments link the HIP to the control of food intake shell send DA projections back to the NAc shell and core. In turn, Finally, the PFC is responsible for higher-order cognitive NAc core neurons project back to the DA neurons from which they processes related to attention, working memory, decision-making received input in addition to DA neurons of the SN that innervate and planning . The mPFC receives input from insular cortex the DS Although often linked with regulation of motor regions that relay gustatory information , and mPFC inputs control, the DS and its DA inputs from the SN are well-implicated to the NAc have an important influence on NAc signalling in reward-relevant learning and habit formation ). This . As a common element among the NAc, AMY, HIP and model serves as an intriguing conceptual framework to describe PFC are the inputs of DA neurons originating in the VTA that to- the process whereby goal-directed behaviour becomes less flexible gether form the mesocorticolimbic DA pathway ().
and more persistent (as during the development of addiction) by a The anatomical and functional division of the NAc into different gradual shift in its control from ventral striatal regions to more subterritories, namely the shell and core, is well-recognized .
dorsal areas of the striatum While the relevancy of this model Pharmacological manipulation of opioid, cannabinoid, GABA, gluta- to the behavioural controls of feeding remain to be empirically mate and MCH receptor signalling selectively in the NAc shell pro- tested, it is interesting to consider how such processes may partic- duces particularly robust effects on feeding which is ipate in motivation and craving for palatable high-energy foods reflected by the convergence of neurotransmitter and peptide sig- and overeating.
nals in this region. Consistent with its distinctive role in the regu- The striatum receives the bulk of DA afferents from the mid- lation of feeding behaviour and food reward, the NAc shell is brain. The majority of striatal neurons are medium spiny neurons innervated by subcortical structures involved in energy homeosta- that are so-called because of their high spine density ().
sis including the ARC, LH, VTA, nucleus of the solitary tract (NTS) There is also a small subset of cholinergic interneurons localized and parabrachial nucleus (PBN) . In turn, the NAc shell sends to the striatum with dense local arborizations that are descending outputs to feeding-related sites such as the VP, VTA implicated in satiety-related mechanisms sucrose bingeing and in the encoding of rewarding and aversive out- With its reciprocal connections with the NAc, the LH serves as comes . Medium spiny neurons express GABA and can be an important moderator between limbic motivational processes grouped into at least two different subtypes based on their axonal and motor output pathways (). A long line of neurophysiologi- projections and gene expression . As illustrated in cal and neuroanatomical research implicates the LH in the

S. Fulton / Frontiers in Neuroendocrinology 31 (2010) 85–103 Fig. 3. Corticolimbic circuitry integrates metabolic information via multiple inputs. Present knowledge of the sites targeted by leptin, insulin and ghrelin to impact reward-relevant behaviour and circuitry. Leptin targets the VTA and LH neurons that project to the VTA , inhibits food intake when infused into these nucleiand is important for regulating DA tone Insulin targets the VTA and striatum and reduces DA tone VTA insulin decreases MOR-inducedfeeding while ARC insulin inhibits sucrose responding Ghrelin targets VTA DA neurons , enhances DA tone and increases food intake whenadministered to the VTA and NAc Midbrain DA neurons project to limbic and cortical sites that regulate emotion, cognition and learning. The NAc is well-positionedto assimilate information about emotion, cognition, metabolic state and gustation arising from AMY, mPFC and HIPPO, ARC, LH, VTA and hindbrain afferent inputs (not alldepicted here). Corticolimbic nuclei send descending projections to basal ganglia motor outputs to convert motivation into behavioural actions. GABAergic medium spinyneurons of the NAc shell (feeding hotspot) also reach motor output pathways by way of LH neurons that are critical for NAc shell modulation of feeding behaviour.
regulation of energy homeostasis. LH cells can respond to the taste will be discussed in the next section, studies of brain stimulation , sight and smell of food and receive gustatory reward (BSR) implicate a subset of reward-related neurons located afferents from the thalamus and hindbrain . Moreover, in or coursing through the perifornical LH in the regulation of en- LH cells receive information about peripheral energy stores from ergy balance.
hormones like leptin nutrients signals such as glu-cose and afferents originating from energy-sensing mecha- 4.2. Brain stimulation reward and energy balance nisms in the ARC Among the important LH neuronal populations involved in the The landmark study of Anand and Brobeck in 1951 showing that control of food intake are those expressing the orexigenic peptides bilateral electrolytic lesions of the LH resulted in a profound de- orexin and MCH. MCH and orexin neurons innervate several re- crease in feeding, drinking and body weight likely inspired the gions including the NAc and VTA, respectively, and thus may estab- view that the LH signals the rewarding properties of foods lish another means whereby information about metabolic state Thereafter, similar findings documented the reliable symptomolo- and sensory modalities influence corticolimbic circuitry. Corre- gy of LH electrolytic lesions which collectively became known as spondingly, increased food intake by MOR or GABA receptor the LH syndrome. The significance of the LH was reinforced by stimulation in the NAc shell appears to rely on projections be- demonstrations that electrical stimulation through the same LH tween the NAc and the LH that stimulate orexin neurons. More- electrode that could give rise to the BSR could also elicit a feeding over, orexin-1 receptor signalling in the VTA is an essential response Furthermore, using conventional rate measures, downstream mediator of the process whereby MOR stimulation self-stimulation of the LH in rats was shown to increase in re- in the NAc shell enhances high-fat feeding . Thus, LH orexin sponse to acute food deprivation and decrease following neurons may be part of a striatal–hypothalamic–basal ganglia– force feeding and spontaneous meal consumption in a manner striatal loop which controls intake of fatty foods. Finally, recent resembling the influence of these manipulations on food intake findings demonstrate the existence of a subpopulation of GABAer- Collectively, these findings encouraged the notion of gic LH neurons that express leptin receptors and project to the VTA.
the LH as a ‘‘feeding center" (see Direct leptin administration into the LH decreases food intake Subsequent studies employing threshold measures (e.g., curve- while increasing VTA TH expression and NAc DA content in ob/ob shift method ) to determine changes in the reward effective- leptin-deficient mice that exhibit diminished TH expression in ness of BSR yielded different results. An acute period of food depri- the VTA. Still much remains to be learned about the LH and the dis- vation has little or no effect on rate-frequency thresholds for BSR tinct connections and characteristics of its subdivisions .
In addition, while rats choose between gustatory stimuli The complexity of this heterogeneous area is also derived from the and the LH stimulation in a manner that implies that the two re- numerous fibers of passage coursing rostrally and caudally through wards are being evaluated along a common dimension, there is more lateral portions of the LH that comprise the medial forebrain compelling data that self-stimulation can be quite different from bundle (MFB) . The MFB is a common locus for electrical stim- the signal generated by a rewarding piece of food When ulation that gives rise to rewarding self-stimulation behaviour. As rats are given a choice between LH stimulation and either a sucrose S. Fulton / Frontiers in Neuroendocrinology 31 (2010) 85–103 reward alone or a compound reward consisting of sucrose plus a scribed by Shizgal et al., one possibility is that the restriction-sen- fixed train of stimulation, Conover and Shizgal found that BSR re- sitive subpopulation of reward neurons is tied to the regulation of mained stable as the sucrose solution accumulated in the gut non-ingestive behaviours that defend body weight, such as food whereas responding for the compound reward was substantially hoarding Indeed, food hoarding behaviour is highly corre- suppressed . Therefore, models that proposed that rewarding lated with body weight, as rats loose weight they will hoard pro- LH stimulation is analogous to food reward are faced with para- portionally more food . Moreover, food hoarding is not doxical findings that manipulations that dramatically increase food influenced by acute food deprivation nor NPY administration intake largely fail to alter BSR in a similar manner.
An alternative possibility draws on developments regard- There are several lines of evidence suggesting that stimulation ing the circuits and peptides affecting fat intake to suggest that of a subset of LH sites close to the fornix activates a stage of reward the restriction-sensitive subset of reward neurons contribute to circuitry that contributes to the regulation of energy balance. Early the rewarding properties of high-fat food. Consistent with this investigations of Blundell and Herberg showed that response rates view is evidence that preference for high-fat food is modulated for rewarding LH stimulation increased with chronic food restric- by manipulations similar to those affecting BSR at restriction-sen- tion and body weight loss only when the stimulating electrodes sitive sites, including chronic food restriction and weight loss were located in the perifornical region of the LH Carr and and opioids . These ideas remain speculative but provide Wolinsky obtained similar results when employing thresholds to interesting prospects for empirical investigation.
measure changes in BSR over a period of food restriction andweight loss. In the same study these authors show that ICV injec- 4.3. Dopaminergic correlates of feeding tion of the non-selective opioid antagonist, naltrexone, reversesthe potentiation of BSR by food restriction at perifornical sites Based on his classical studies in the early 1970s in which severe . The modulation of BSR by weight loss has been replicated aphagia and adipsia was induced by 6-OHDA DA lesions, Unger- several times , and depends on the site of stim- stedt proposed that the LH syndrome resulting from lesions of ulation in the LH . These data suggest that stimulation of the the LH is the consequence of damage to ascending DA pathways LH recruits at least two anatomically and functionally distinct sub- Later work demonstrated that the feeding and metabolic populations of rewards neurons, one of which is linked to the reg- impairments could result from the loss of intrinsic LH neurons ulation of body weight and can be activated by stimulating (see ), nonetheless, this early demonstration was the beginning neurons residing in or coursing through the perifornical LH.
of an extensive line of work investigating the impact of DA in feed- Through which circulating signals does food restriction and ing. Indeed, a central focus of much of the research on the neuro- weight loss enhance the rewarding effect of perifornical stimula- chemical basis of feeding is the mesocorticolimbic DA pathway.
tion? Fulton et al. investigated the impact of ICV leptin on the To set the stage for evidence that DA neurons and their inputs rewarding stimulation obtained from LH self-stimulation sites that are targets of hormones involved in energy balance, key findings are either sensitive or insensitive to weight loss Leptin sup- regarding the physiological properties of DA neurons and their re- pressed the rewarding effect of the stimulation only at ‘‘restriction- sponses to feeding are discussed below.
sensitive" perifornical sites, thus leptin reversed the effects of There has been much research devoted to understanding the weight loss on BSR. Conversely, leptin enhanced the rewarding ef- regulation of firing patterns of DA neurons and several influential fect of the stimulation at the majority of ‘‘restriction-insensitive" findings have tied the activity state of DA neurons to specific cod- sites. These contrasting effects of leptin at restriction-sensitive ing and behavioural functions. DA neurons recorded in vivo are re- and -insensitive sites are interpreted in terms of the different ways ported to exhibit three patterns of activity: an inactive state; a in which leptin can contribute to the regulation of energy balance slow, single-spike state, known as tonic firing pattern; and a burst On the one hand, leptin may suppress the reward- or phasic mode The tonic firing pattern of DA neurons re- ing effects of behaviours that promote energy intake while, on sults in relatively low and more diffuse extracellular DA levels the other, augment those compatible with increased energy expen- and is driven by an intrinsic pacemaker , whereas phasic diture, such as physical activity. Along with leptin, the circulating activity has been show to rely on afferent input to DA neurons levels of insulin also vary as a function of the amount of adipose and to produce high synaptic DA concentrations which acti- tissue. Two reports by Carr and colleagues implicate insulin in vate post-synaptic DA receptors . Importantly, the phasic the modulation of BSR by food restriction and weight loss. In one pattern of DA firing and release has been functionally tied to goal- study they found that streptozotocin administration, a manipula- directed behaviour and the prediction of rewards . The tion that decreases insulin levels, potentiated the rewarding effects dynamics of DA release in mesolimbic and nigrostriatal DA path- of the stimulation . Conversely, ICV administration of insulin ways are also influenced by D2-autoreceptors which provide neg- attenuates the rewarding effect of the stimulation Leptin ative feedback by rapidly inhibiting DA release . Bearing in and insulin may alter BSR via their well-characterized influence mind these and other characteristics, it is increasingly evident that on neuropeptide systems. However, while central CRH and NPY striatal DA transmission is not a unitary phenomenon, but can be infusions altered food intake they largely failed to modulate BSR separated into distinct functional components based on DA termi- at restriction-sensitive sites Together, the data suggest nal region and activity state.
that CRH and NPY are not intermediates in the process whereby DA transmission in the NAc has been linked exclusively with leptin and insulin modulate the rewarding stimulation at restric- the consummatory rather than anticipatory aspects of feeding tion-sensitive sites, but do not exclude the possibility that other (e.g., and related to the amount of food ingested .
neuropeptides, such as AgRP and orexin, could be involved.
Nonetheless, the results of several studies suggest that DA firing Collectively, the data demonstrate that food restriction, opioids, and release is closely tied to novel food stimuli and/or to the re- leptin and insulin alter a subset of reward-relevant circuitry in a sponses and stimuli that are predictive of food reward. Using manner that is consistent with their impact on behaviours that in vivo microdialysis to sample extracellular DA concentration, contribute to energy intake. However, it is not plausible that early studies of Hoebel and colleague found DA levels are elevated restriction-sensitive reward neurons produce a signal of that is in the NAc during lever-pressing for food in food-restricted rats generally related to hunger given that manipulations that increase and DA release remains elevated during and after food consump- the rewarding effects of food, including acute food deprivation, do tion . In other studies, DA release in the NAc is specifically not modulate BSR at restriction-sensitive sites As de- associated with the instrumental response required to get access S. Fulton / Frontiers in Neuroendocrinology 31 (2010) 85–103 to familiar food but not with food consumption an effect that DA is critical for long-lasting cellular changes in the striatum, is more pronounced in the NAc shell region Bassareo and Di including homeostatic neuroadaptations synaptic plasticity Chiara found that DA release is stimulated in the NAc shell during and structural modifications . In particular, there initial exposure and consumption of novel food but not during sub- have been great advancements in our understanding of the molec- sequent presentations, suggesting that DA release undergoes ular mechanisms in the NAc that correspond to behavioural adap- habituation to food stimuli . These authors also find that DA tations in response to rewarding drugs of abuse in which DA is is preferentially released into the NAc shell as compared to the core purported to play a central role . How these molecular adap- in response to unpredicted food, but following repeated exposure tations figure in the regulation of food reward is beginning to be to food stimuli the DA response shows habituation only in the shell In a compatible manner, DA release is stimulated in the NAcshell only during conditions in which a food reinforcement is 4.4. Impact of metabolic signals on reward circuitry unpredictable . Similar results have been obtained with singleunit recordings whereby VTA DA neurons exhibit phasic firing in Of the objectives that must be met for an animal to survive the response to unpredicted food rewards . However, once food goal of maintaining adequate energy levels occupies a command- is associated with stimuli that predict its availability, phasic DA ing position. The energy state of the animal not only influences activation is then triggered in response to these predictive stimuli behaviours oriented towards attaining and consuming food but also has direct bearing on all other behavioural actions necessitat- Employing cyclic voltammetry which measures DA release over ing energy expenditure. Thus, it is not surprising that the brain much shorter-time frames (100 ms) than microdialysis, Roitman comprises numerous mechanisms by which it can sense the status et al. discovered that phasic DA released is stimulated in the NAc of energy fuels so that it may adjust sensory, autonomic and core in response to familiar sucrose-associated cues and peaks dur- behavioural systems to efficiently meet energy demands. The ing lever-pressing responses for sucrose reward but returns to study of the pathways and mechanisms by which hormones and baseline during food consumption In another study that uses nutrient signals influence food intake has substantially advanced novel food stimuli, these investigators found that phasic DA release our knowledge of the CNS controls of energy homeostasis. The is triggered in the NAc shell during oral sucrose infusions which view that sensing of peripherally-derived energy signals is the persisted during the consummatory phase In contrast, these exclusive function of hypothalamic and hindbrain cells has been authors report that intra-oral infusions of novel aversive stimuli modified by several lines of evidence indicating that hormonal sig- (quinine) produced significant decreases in DA release. In a reverse nals, like leptin and insulin, target neuronal populations through- manner, a subset of NAc neurons are inhibited by tasting a sucrose out the brain to affect sensory modalities, solution whereas another subset are excited by quinine to suggest biological rhythms, memory and reward-relevant processes.
that behavioural responses to rewarding and aversive stimuli are The modulation of reward circuitry by leptin has been described anatomically divided at the level of the NAc and its outputs in both rodents and humans. Leptin inhibits the rewarding effects . Interestingly, NAc DA release and the activity of NAc neu- of LH self-stimulation goal-directed behaviour for food rons in response to sucrose ingestion are not contingent on func- food-deprivation induced heroin seeking and en- tional taste transduction suggesting that DA release can be modulated by post-ingestive controls that condition feeding Shedding light on the sites that may mediate such ef- fects, leptin receptors are localized to midbrain DA neurons DA release has been measured during conditions of feeding in and leptin administration decreases basal and feeding- DA terminal regions other than the NAc, although these reports evoked extracellular DA levels in the NAc shell Demonstrat- are less common. DA release is elevated following feeding in the ing a direct action of leptin on DA neurons, Hommel et al. report DS but not the HIP in food deprived rats . In contrast, another that infusion of leptin in the VTA activates STAT3 in DA neurons study found no increase in extracellular DA release in the DS dur- and decreases food intake Conversely, conditional leptin ing and following food intake Consumption of a novel food receptor knockdown in the VTA increased food intake and locomo- stimulates DA release in the mPFC in non-deprived rats and tor activity. As a potential mechanism mediating the influence of mPFC DA release has been shown to increase just prior to the deliv- leptin on feeding, these authors demonstrate that systemic leptin ery of predictable and familiar food rewards but not during food administration or direct leptin application to the slice bath de- consumption . Moreover, mPFC DA release has been shown creases the tonic firing of VTA DA neurons. Complementing these to exert an important inhibitory influence on NAc DA release and findings, Fulton et al. reported that leptin activates STAT3 in DA food-reinforced responding . Finally, there is a strong correla- and GABA neurons of the VTA and that a subset of pSTAT3-positive tion between the magnitude of DA release in the mPFC and perfor- neurons project to the NAc core and/or shell Obese leptin- mance on a food-associated memory task deficient ob/ob mice showed substantially reduced locomotor re- As illustrated by the studies above, there are different DA re- sponses to amphetamine and failed to sensitize to repeated sponses in the NAc shell versus core which reflect the functional amphetamine administration, impairments which were restored differences between these compartments and their inputs .
by peripheral leptin infusion . As an explanation for the DA release is elevated in the NAc and mPFC during both appetitive diminished locomotor response to amphetamine, stimulation- and consummatory phases of feeding for novel food, but phasic DA evoked DA release in the NAc shell was significantly reduced in release in the NAc shell is no longer triggered during food con- ob/ob mice along with DA and TH content in the NAc. This finding sumption upon subsequent presentation of the food. Thus, in the is in agreement with evidence of Roseberry et al., showing that co- case of familiar foods, DA release in the NAc and mPFC appears caine-induced somatodendritic DA release, as measured by D2 to be preferentially linked to predictive instrumental responses autoreceptor inhibitory post-synaptic potentials, is reduced in ob/ or conditioned stimuli rather than actual food consumption. DA re- ob mice . These authors also provide evidence to suggest that lease in the mPFC appears to also play a role in the retrieval of cue- impaired vesicular packaging of DA contributes to reduced DA re- associated memories that correctly guide animals towards food.
lease in ob/ob mice. Finally, Leinninger et al. recently demonstrated These finding are consistent with the view that DA serves as a that infusions of leptin into the LH reduce food intake and increase teaching signal to influence future commerce with food stimuli.
VTA TH and NAc DA content in ob/ob mice. These investigators Consistent with these data is the wealth of evidence showing that identify a novel subpopulation of GABAergic LH neurons that S. Fulton / Frontiers in Neuroendocrinology 31 (2010) 85–103 innervate the VTA and are functionally targeted by leptin, and the VTA or NAc increases food intake in rats This orexigenic thereby reveal a means by which leptin may modulate DA avail- effect of ghrelin may be due to its ability to stimulate DA release ability in the mesoaccumbens pathway.
as central ghrelin administration potentiates extracellular levels Human imaging research draws attention to the NAc as a locus of DA in the NAc . Illustrating the direct action of ghrelin mediating the impact of leptin on food reward. Farooqi et al. dem- on VTA DA neurons, Abizaid and coworkers demonstrated that onstrated that NAc activation, as measured by functional magnetic ghrelin binds to VTA cells and increases DA firing The in- resonance imaging (fMRI), is positively correlated with affective crease in DA firing is associated with ghrelin-induced increases ratings of visual food stimuli in fed and fasted leptin-deficient hu- in the number excitatory synaptic inputs and decreased inhibi- mans . Following leptin treatment the association between tory inputs to VTA DA neurons observed by these authors. These NAc responses and affective reactions remain in the fasted condi- investigators also find that ghrelin increases DA turnover in the tions but disappear in the fed state. These findings do not implicate ventral striatum and stimulates food intake when administered changes in leptin signalling to altered DA tone in the NAc, however into the VTA. Likewise, NAc DA release is elevated following di- they pinpoint the NAc as a site that integrates information about rect VTA infusion of ghrelin whereas recent work suggests leptin signalling, metabolic state and affective responses for food.
that peripheral ghrelin stimulates DA release exclusively in the Collectively, the rodent and human studies demonstrate that leptin NAc shell and not the core . Finally, ghrelin is reported to modulates feeding behaviour via direct actions in the VTA and LH, enhance human cerebral responses to visual food cues in the modulates affective responses for food that coincide with NAc neu- AMY, insula, orbitofrontal cortex (OFC) and striatum as measured ral activity and regulates DA signalling and plasticity in the VTA to by fMRI In this study, ghrelin treatment increased hunger NAc pathway. On the one hand, leptin reduces the tonic firing of ratings as a function of the degree of activation in the AMY and DA neurons, while on the other, leptin is important for DA avail- OFC to suggest that increased motivation for food induced by ability, packaging and release. While these studies implicate the ghrelin treatment is mediated by processes encoded in these re- mesolimbic DA system and inputs from the LH as regions involved gions. Collectively, the rodent and humans studies strongly impli- in leptin action, additional investigations that measure reward cate ghrelin in the modulation of the neural networks controlling (e.g., operant responses for food), in particular, are required in or- der to identify the neurons and mechanisms involved.
Human imaging studies have offered great insight into the Insulin receptors are abundantly expressed throughout the neural responses associated with motivation for food in different brain, including the striatum and midbrain, and insulin is in- metabolic states. Investigating the neural responses that are pre- volved in the modulation of reward-relevant processes . Fig- dictive of later food consumption, Batterham et al. measured neu- lewicz et al. identified insulin receptors on DA neurons of the VTA ral activity in response to the anorexigenic gut hormone PYY .
and SN These investigators report that insulin and leptin These investigators found that when circulating PYY levels were administration to the VTA increases immunoreactivity for phos- low, as during the fasted state, changes in neural activity in the phatidylinositol-3 (PI3) kinase, a signalling molecule activated hypothalamus were predictive of later food intake. In contrast, by insulin and leptin receptor signalling . In addition, they changes in activity of the caudolateral OFC predicted feeding show that VTA infusion of insulin and leptin attenuates the feed- when PYY levels were high . These results demonstrate how ing response induced by opioids in this region. Earlier studies a postprandial satiety factor can switch neural controls of food in- demonstrate the ability of insulin to decrease DA release in stria- take from hypothalamic to corticolimbic regions and thereby implicate corticolimbic processes in excessive caloric intake. Con- hypoinsulinemia increases striatal DA release . Central insulin sistent with this idea, Volkow, Wang and colleagues provide evi- administration augments DAT mRNA levels in the SN and VTA dence of reduced striatal D2 dopamine receptor binding in obese whereas DAT mRNA levels are diminished during reduced humans to suggest that there is reduced DA tone in these individ- insulin signalling Carvelli et al. demonstrate the functional uals Correspondingly, DS activation is attenuated in actions of insulin to increase dopamine reuptake and facilitate the obese humans, an effect that is even more pronounced in individ- cell surface expression of DAT in vitro, and they provide evidence uals with the A1 allele of Taq1A polymorphism which is associ- that these effects are mediated by PI3-kinase signalling ated with the D2 receptor gene and reduced striatal DA Moreover, this group found that amphetamine-stimulated DA re- signalling Interestingly, the results of several studies in hu- lease in the striatum is impaired in insulin-deficient rats whereas mans and rodents link diminished insulin microinfusion into the striatum recovers this PI3-kinase striatal DA signalling to hyperphagia and obesity. Thus, while mediated effect . Together, the data suggest that insulin sup- the consumption of palatable foods may stimulate striatal DA presses striatal DA tone by increasing DA clearance. It remains to be determined whether insulin directly influences DA neurotrans- impairments in the amount of DA available for release may be mission, although this possibility is supported by the observation a factor promoting increased caloric intake.
that insulin interacts with opioids in the VTA to decrease food in- As summarized in , information regarding the status of en- take. Interestingly, opioids down-regulate the insulin-receptor ergy reserves is being relayed to corticolimbic sites by the actions substrate-2 (IRS2) thymoma viral proto-oncogene (Akt) pathway of leptin, insulin and ghrelin to modulate DA and/or striatal cell in DA neurons of the VTA to regulate the cellular and behavioural signalling. It is possible that these and other hormones affect cor- effects of morphine thus activation of IRS2-Akt pathway by ticolimbic controls of food motivation by also signalling in up- insulin may be responsible for attenuating opioid-induced stream neural pathways in the hypothalamus and hindbrain.
Indeed, recent data shows that leptin targets LH-VTA projection Like leptin and insulin, the gut-derived hormone ghrelin mod- neurons to increase DA content . Moreover, insulin adminis- ulates reward-relevant behaviour and targets DA neurons of the tration in the ARC suppresses sucrose-reinforced instrumental VTA. Ghrelin binds to growth hormone secretagogue receptors responding . There remains several questions concerning the (GHSR) to stimulate food intake and adiposity . GHSR recep- precise mechanisms by which metabolic and central signals mod- tors are expressed in several brain regions including the VTA ulate DA activity states and release, which corticolimbic targets Peripheral ghrelin enhances the locomotor-activating and signalling molecules are affected and how these processes re- effects of cocaine and conditioned place preference lates to immediate and long-term behavioural changes. It also re- Naleid and coworkers discovered that ghrelin injected in either mains to be determined whether or not leptin, insulin and S. Fulton / Frontiers in Neuroendocrinology 31 (2010) 85–103 ghrelin target the same DA neuronal subpopulations and, if so, if nings for energy-rich food (e.g., ). Despite the complexity of there are functional interactions between their respective receptor these circuits, the use of cell-specific gene targeting, tract tracing, signalling pathways. Finally, it is not yet clear to what extent the pharmacological and electrophysiological approaches along with signalling of these hormones in midbrain and limbic sites specifi- precise behavioural measures offers great promise that future cally influence the appetitive and/or consummatory aspects of work will continue to tease apart the pathways and mechanisms feeding. It could well be that hormonal sensing at these loci has responsible for the rewarding effects of food.
more general actions to orient attention and motivation towardbehavioural actions that are compatible with the current energy state of the animal.
The author thanks Thierry Alquier, Vincent Poitout and Marc Prentki for valuable input on the manuscript.
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Know Your FSA /HSA Eligible and Ineligible Expenses Maximize the Value of Your Reimbursement Account Your Flexible Spending Account (FSA) and Health Savings Account (HSA) dol ars can be used for a variety of out-of-pocket health care expenses. Take a look at the fol owing lists for a better understanding of what is and is not eligible. Eligible Expenses

Fall 2012 Edition Website Updates Personalizing Tamoxifen Therapy in London The Lawson Translational Cancer Research Team (LTCRT) based in London has been facilitating the development and adoption of personalized cancer medicine using pharmacogenomics. Dr. Richard Kim, a recipient of the Cancer Care Ontario (CCO) Research Chair (Tier-1) Award in 2010 and leader of a program of Personalized Medicine at the London Health Sciences Centre, has been working closely with a team of oncologists and the LTCRT to ensure a group of breast cancer patients experience the best outcomes possible. Tamoxifen is an important drug for the treatment and prevention of certain breast cancers, and is metabolized in the liver by a drug metabolizing enzyme called CYP2D6. This enzyme is responsible for converting tamoxifen to its active form, endoxifen. The CYP2D6 enyzme occurs in different forms in human beings (called "polymorphisms") which may metabolize the same drugs differently. There is compelling research that shows that women with less active variants of CYP2D6 are at greater risk for breast cancer recurrence compared to those without such polymorphisms when treated with tamoxifen. In March of 2010, Dr. Kim started a personalized medicine clinic for breast cancer patients on tamoxifen therapy using the research funds available through his CCO Chair award. Patients referred to his clinic have their CYP2D6 genotyped as well as tamoxifen and endoxifen blood levels assessed using state-of-the-art genotyping and drug level analysis technologies. Dr. Kim then provides a detailed report to the referring oncologist in terms of the patient's ability to metabolize tamoxifen. He now has data from over 200 patients that show not only are CYP2D6 polymorphisms important to tamoxifen bioactivation to endoxifen, but so are polymorphisms in a another enzyme (CYP3A4) and the patient's vitamin D level.