the present review is concerned with the actions of a circulating appetitepromoting hormone ghrelin 1 , produced mostly by the stomach , on the reward system of the brain .
the idea that the gut utilises enteroendocrine hormones to communicate with pathways involved in rewarding aspects of food intake is a new and emerging field 2 suggesting the existence of an endocrine gut 
brain reward axis that can modify reward signalling for food , a system important for survival .
ghrelin appears to have a physiological role in hunger and meal initiation 3 , orchestrating a variety of behaviours that ensure animals go out into the environment to seek out and consume a variety and plentiful supply of nutrients .
we focus especially on the effects of ghrelin on rewardlinked behaviour for food , including the mechanisms and pathways involved .
ghrelin is a 28amino acid octanoylated peptide hormone 1 secreted predominantly from a specific type of endocrine cell of the stomach located within the gastric oxyntic mucosa and named p / d1type cells in humans 4 or a liketype cells in rodents 5 .
ghrelin mediates its actions via its unique specific receptor , the ghsr1a 6 , which is a g proteincoupled receptor highly expressed in the central nervous system 7 , 8 .
ghrelin is the only known naturallyoccurring peptide to be posttranslationally modified by a ooctanoylation , a reaction catalysed by the enzyme ghrelin oacyl transferase ( goat ) 9 .
ghrelin plays a welldefined variety of physiological roles and is recognised for being the only known circulating peptide hormone that stimulates food intake 10 , 11 .
as discussed below , ghrelin stimulates appetite via diverse mechanisms that promote food intake and that stimulate food rewardrelated behaviours . in plasma ,
a nonoctanoylated form of ghrelin , named desacylghrelin that represents more than 90% of total ghrelin immunoreactivity , has been shown to exist 12 .
the ghsr1aindependent effects of this peptide on food intake regulation have been described , although the physiological significance of desacylghrelin remains a matter of debate 13 .
one of the most striking features about the 24h secretory pattern of ghrelin in man is the large rise in plasma levels that occur just before mealtimes 3 .
some of the metabolic and hormonal factors able to directly regulate ghrelin secretion have been identified .
using ghrelinproducing cell lines , it has been shown that low dglucose concentrations stimulate ghrelin release , whereas high dglucose and glucose metabolism block ghrelin release 16 .
also , norepinephrine enhances ghrelin release by binding to 1adrenergic receptors on ghrelin cells ; indeed , this mechanism has been proposed to modulate ghrelin secretion during fasting when the sympathetic tone is increased 17 .
it has also been shown that natural ( i.e. linolenic acid ) or chemical agonist for the g proteincoupled receptor 120 inhibit the secretion of ghrelin , suggesting that the decrease of ghrelin release after feeding is induced partially by longchain fatty acids acting directly on gastric cells 18 .
importantly , ghrelin release is also coordinated by a descending pathway ( e.g. via the vagus nerve ) signalling either a food anticipatory signal 19 or a cry for nutrients by the brain .
anticipatory cues associated with the delivery of food have been shown to trigger ghrelin release in mice 20 .
food anticipatory behaviour , including anticipation for palatable food , is decreased in models of suppressed ghrelin signalling , suggesting that ghrelin may , in turn , activate food anticipatory pathways 21 , 22 .
one of the key physiological targets of the ghrelin / ghsr1a system is the brain .
the dedicated ghrelin receptor , ghsr1a , was identified in 1996 and was found to be expressed in many brain areas linked to feeding control , including hypothalamic , brainstem and mesolimbic pathways 6 , 7 , 8 .
ghrelin is able to drive a feeding response when microinjected into many of these sites , including the arcuate nucleus of the hypothalamus ( arc ) , ventromedial nucleus 23 , lateral hypothalamic area ( lha ) 24 , caudal brainstem 25 , ventral tegmental area ( vta ) , nucleus accumbens ( nac ) 26 , 27 , lateral amygdala 28 and ventral hippocampus 29 .
the orexigenic effects of ghrelin appear to be exclusively signalled through ghsr1a 6 because ghrelin fails to elicit a feeding response in mice lacking this receptor 30 , as well as in rats pretreated with central injection with a ghsr1a antagonist 31 .
food intake appears to be a common goal of the ghrelinappetitory networks , an endpoint achieved through integration with brain pathways involved in many diverse constructs and behaviours .
indeed , ghrelin signalling pathways are involved in hunger sensation 32 , food anticipatory behaviour 21 , 33 , food reward 34 , motivated ( rewardlinked ) behaviour for food 35 , 36 , memory 37 , noveltyseeking behaviour 38 and anxiety / stresslike behaviour 28 , 39 , 40 . in the present review , we focus especially on recent advances implicating the central ghrelin signalling system in food reward . the first indication that central ghsr1a signalling could be implicated in food intake regulation
was noted in 1993 , when it was found that the growth hormonereleasing peptide 6 ( a growth hormone secretagogue that is now recognised to be a ghrelin mimetic ) activates cells in the arc , as reflected by an increase in the number of cells detected that express fos protein 41 .
it emerged that approximately half of the arc cells activated by this ghrelin mimetic expressed neuropeptide y ( npy ) mrna , a potent orexigenic signal 42 .
these ghrelinsensitive npy neurones , which coexpress another orexigenic peptide , agoutirelated protein ( agrp ) , are considered as a major node in the appetiteregulatory circuitry . in line with this hypothesis
, it was later found that npy / agrp neurones of the arc express high levels of ghsr1a 43 , 44 .
moreover , ghrelin fails to increase food intake in mice lacking npy and agrp 45 , 46 , suggesting that these peptides play a pivotal role in the effects of ghrelin on food intake .
ghrelin signalling engages a complex network of neuronal circuitries to modulate feedinglinked behaviour . for example , ghrelininduced food intake also appears to depend on orexin neurones of the lha , where ghsr1a is expressed 24 , 48 and the action of ghrelin on food reward requires intact orexin signalling 35 .
ghsr1a is expressed in vagal afferent neurones of the nodose ganglia and in the dorsal vagal complex 8 , 49 , providing an alternative route through which peripheral ghrelin could signal to appetitive neurocircuitry .
indeed , it has been suggested that vagus nerve integrity is required for ghrelininduced food intake 50 , 51 , although a subsequent study did not find this to be the case 52 .
the presence of ghsr1a in dopaminergic vta neurones 8 , 53 , 54 , as well as other cell types in this region , supports the possibility that ghrelin can regulate rewarding aspects of eating .
ghrelin may also regulate mesolimbic circuits indirectly via the cholinergic neurones of the laterodorsal tegmental area ( ldtg ) , which also express ghsr1a 55 , 56 .
the action of ghrelin at the level of the hippocampus , another brain area where ghsr1a is present in abundance 7 , 8 , also appears to be important for both motivational and learned aspects of feeding behaviour 29 .
thus , the neuroanatomical distribution of the ghrelin receptor supports a role for the ghrelin / ghsr1a system in the regulation of both homeostatic and rewarding aspects of feeding . in humans ,
the response of the brain 's reward system to food cues , as measured using functional resonance imaging , is enhanced by fasting 57 .
the relevance of the ghrelin signalling in this observation was suggested by a functional magnetic resonance imaging study showing that ghrelin can mimic the effects of fasting on the reward networks 58 and was further confirmed by another imaging study in humans showing that ghrelin increases the neural response in brain centres implicated in rewarding aspects of feeding 59 . in particular , ghrelin administration to human subjects increases the activation of some rewardrelated brain centres , including the substance nigra and the vta , in response to tempting food pictures 59 .
a more recent imaging study has not only confirmed previous observations , but also shown that subjects with polymorphisms in the fat mass and obesityassociated gene genotype exhibited divergent neural responsiveness to peripheral ghrelin within brain regions that regulate rewarding aspects of appetite 60 .
thus , several functional resonance imaging studies in healthy subjects strongly support a role for ghrelin in rewarding aspects of eating in human subjects .
the neurobiological mechanisms sensing energy need , food availability and coordinating appetitive and foodseeking behaviours are complex . feeding control involves an integrated regulatory system of homeostatic brain circuits that drive food intake depending on energy store levels : processes for which the hypothalamus and brainstem have a primary role .
food intake is also regulated by reward pathways that process information about the pleasurable ( hedonic ) and incentive ( motivational ) aspects of food intake .
homeostatic and reward circuits mediating food intake are interrelated :  hunger is the best spice , is a swedish saying acknowledging that all foods have a rewarding value that is influenced by hunger and food availability . from an evolutionary perspective , food reward has a dual role : it not only promotes food seeking and eating when food is scarce , but also promotes overeating when food becomes available , aiming to establish sufficient energy stores for a future famine .
if food is found rewarding , this will motivate animals to go out into the environment to seek it out , ensuring not only an adequate supply of calories , but also that consumed foods are of diverse nutritional composition . in the current obesogenic environment , however , food reward is no longer an evolutionary advantage for modern human beings .
instead , it contributes to the maladaptation to that environment , encouraging people to overeat caloriedense foods to a level far beyond metabolic need .
a key feature of reward processing is the activation of a major dopaminergic cell group located in the vta of the midbrain .
these dopaminergic neurones project to the nac and the prefrontal cortex , as well as to several other brain areas , including the hippocampus and the hypothalamus 61 .
the vta receives projections from many brain nuclei , including the aforementioned areas that receive projections from the vta , cholinergic neurones of the ldtg 55 , as well as taste information via afferent sensory fibres 62 , 63 .
activation of dopaminergic vta neurones occurs in response to both natural rewards ( such as food or sex ) and artificial rewards ( such as alcohol or other addictive drugs of abuse ) .
as is the case for addictive drugs , the consumption of a food reward has been found to trigger dopamine overflow / release in the nac , as measured by microdialysis 64 , and to increase phasic dopamine release in the striatum , as measured by fastscan cyclic voltammetry 65 .
accumbal dopamine overflow is coupled to vta dopamine neurone activity 66 and so it may be inferred that foods , especially palatable foods , have the capacity to activate the vtanac dopamine projection .
indeed , acute consumption of a highfat diet activates the mesolimbic circuit by neuronal pathways that require orosensory stimulation 67 .
the shell part of the nac is particularly important for eating behaviours engaging projections to the lha neurones that control food intake .
orexigenic lha neurones appear to be under a tonic inhibition that can be relieved by activation of reward pathways 69 , 70 .
in addition , lha orexin neurones send projections to the vta , where they activate dopaminergic neurones 71 , 72 .
thus , lha orexin neurones have been proposed as a potential link between homeostatic and reward circuits regulating food intake 73 .
wanting or motivational component of reward that is important for craving behaviour and that is linked to but distinct from the  liking or hedonic component of reward 74 . as reviewed elsewhere 75 , the mechanisms linking dopamine to rewarding aspects of eating are rather sophisticated .
novelty of the reward appears to be critical for achieving a maximal dopamine signal 76 . with repeated exposure to that same reward ( conditioning ) ,
the nac dopamine response lessens ( habituates ) and transfers instead onto a predictive cue associated with its delivery 77 , 78 , 79 .
thus , dopamine signalling is crucially important for the formation of associations between rewards and anticipatory cues 78 , 80 , 81 . as a consequence of conditioning , the dopamine signal takes on a new role : as a predictor of reward ; motivational behaviours are recruited as part of this mechanism ensuring that the expected reward is consumed .
one hypothesis for the role of the dopamine signal in reward is that it serves as a  reward prediction error 82 .
it follows that nac dopamine release could be important for assigning increasing reward value to food cues 83 .
in 2006 , it became apparent that ghrelin activates the dopamine system , triggering nac dopamine release 84 , dopamine turnover and vta dopamine neurone activity 54 .
consistent with this , a subpopulation of vta dopamine neurones was found to express ghsr1a , although the receptor was also found to be located on other cell types within the vta 54 .
the idea that ghrelin may provide a physiological signal connecting gut and reward pathways paved the way to studies exploring the effects of ghrelin on behaviours linked to dopamine signalling , including hedonic and motivational aspects of eating . in rodents ,
reward can be assessed in the condition place preference ( cpp ) test in which the animals learn to associate the experience of reward with a particular environment / chamber .
they will return to that chamber , spending more time there , even when the reward is no longer available .
in satiated rats , the peripheral delivery of a ghsr1a antagonist has been shown to abolish cpp for chocolate 85 .
similarly , in mice , the delivery of a ghsr1a antagonist suppresses / abolishes cpp for a highfat diet 35 , and even for alcohol 86 or psychostimulant drugs such as cocaine or amphetamine 87 .
these data using ghsr1a antagonists , together with data from ghrelin receptor knockout mice 35 , 85 , 86 , indicate that central ghrelin signalling is required for the rodents to experience reward from alcohol ( an artificial reward ) or food ( a natural reward ) .
consistent with this , ghrelin appears to enhance cpp for a highfat diet 35 and psychostimulant drugs such as cocaine 88 .
cravinglike behaviour ( i.e.  wanting , motivated , goaldirect behaviour ) for food or other reward reinforcers can be explored in rodents using the 
operant conditioning paradigm in which the animals have to progressively work harder ( e.g. by pressing a lever ) to obtain a reward .
the animals are first trained on a fixed ratio schedule to associate the pressing of the lever a fixed number of times with the delivery of a reward .
subsequently , they are tested using a progressive ratio schedule in which the animal has to work increasingly hard for each reward obtained .
the number of lever presses or the number of reward earned can be used to estimate motivation or goaldirected behaviour .
motivated behaviour for sugar treats has been shown to be increased by ghrelin ( administered peripherally or centrally to satiated rats ) and decreased by a ghsr1a antagonist administered to fasted rats ( also delivered both peripherally and centrally ) 36 .
similarly , operant behaviour for a highfat diet in mice , measured by nose pokes instead of lever presses , was increased by ghrelin 35 . also , goatdeficient mice display an attenuated motivation for a highfat diet in an operant responding model and a decreased rewardlinked feeding response examined in a  dessert effect protocol , in which the intake of a palatable highfat diet pellet  dessert is assessed in caloricallysatiated mice 90 .
ghrelin administration also increases intake of palatable saccharin solution and preference for saccharinflavored foods in mice 92 .
similarly , rats treated with a ghsr1a antagonist consume less peanut butter and the liquid nutritional supplement ensure ( abbott laboratories , chicago , il , usa ) but fail to change intake of regular chow in a free choice protocol 85 . on the other hand , ghrelin also increases food anticipatory activity , which is characterised by increased arousal , increased locomotor activity and an elevated body temperature in anticipation of a predicted meal 21 , 22 .
ghrelin secreted in anticipation of a meal correlates with anticipatory locomotor activity and the administration of ghrelin increases locomotor activity and foraginglike activities in rodents 93 , 94 , 95 .
ghrelin fails to alter the avidity of licking , when lick motor patterns were recorded using lickometry , suggesting that ghrelin does not affect the hedonic valuation ( i.e.  liking ) in rats 89 .
odour also plays a role in conferring information about food availability , and ghrelin may have a beneficial role in to help animals seek out because it has been shown to stimulate sniffing and to increase olfactory sensitivity in mice 96 .
overall , there is a great deal of evidence supporting a role for ghrelin in a variety of food rewardrelated eating behaviours .
it is perhaps not surprising therefore that ghrelinsensitive brain networks overlap considerably with those important for feeding control 97 .
the neurobiological substrates and circuits underpinning the effects of ghrelin on foodmotivated behaviour show some overlap with ( but also divergence from ) those involved in food intake 2 , 97 .
although food intake can be driven by ghrelin delivery to both the vta 26 , 54 , 85 and the nac 26 , 85 , foodmotivated behaviour occurs only after vta ( but not nac ) microinjection of ghrelin 27 .
vtalesioned rats spend less time than control rats exploring tubes containing peanut butter in response to centrallyadministered ghrelin 85 .
similar effects are observed in foodrestricted rats in which chronic intravta administration of ghrelin enhances , whereas chronic intravta delivery of a ghsr1a antagonist blunts , operant responding for chocolateflavored pellets 98 .
collectively , these findings identify the vta as a key target brain area for the effects of ghrelin on foodmotivated behaviour and suggest that direct action of ghrelin at the level of the vta is sufficient to drive foodmotivated behaviour .
moreover , the uncoupling between food intake and food motivated behaviour elicited by intravta ghrelin resonates with the collective findings that nac dopamine signalling is not coupled to normal feeding 99 , 100 but rather in motivated behaviour towards palatable foods , independent of the calories consumed 101 , 102 .
importantly , only the effect of intravta ghrelin on foodmotivated behaviour was found to require nac dopamine receptor 1 and 2 signalling , whereas food intake driven by vta ghrelin was dopamineindependent in this paradigm 103 .
pretreatment of rats with a dopamine receptor 1 antagonist eliminates ghrelininduced increases in bar pressing , without compromising generalised licking motor control , supporting a role for dopamine receptor 1 signalling mainly in the motivational feeding effects of ghrelin 89 .
it has been shown that mice expressing ghsr1a selectively in tyrosine hydroxylasecontaining cells , including a subset of vta dopaminergic neurones , display a significant , albeit reduced , response to the orexigenic effects of ghrelin and a full cpp for a highfat diet when treated with exogenous ghrelin or exposed to a chronic social defeat stress ( csds ) protocol . in the study
, a nontraditional mouse model was used in which ghsr1a gene expression is disrupted by a transcriptional blocking cassette flanked by loxp sites that enable cre recombinasemediated ghsr1a gene reexpression 53 .
thus , a variety of studies in rodents suggest that the action of ghrelin at the level of the dopaminergic neurones of the vta is essential for the actions of ghrelin on both food intake and food reward .
apart from the vtanac dopamine system , the rest of the neuronal circuitry engaged by ghrelin to modulate food rewardrelated behaviours is quite unclear .
for example , it has been suggested that ghrelin can regulate mesolimbic circuits indirectly via the cholinergic neurones of the ldtg , which express ghsr1a 55 , 56 .
also , the action of ghrelin on food reward appears to require intact orexin signalling , as indicated by the finding that the effects of ghrelin with respect to conditioning food cpp or operant conditioning for a food reward were blocked in orexindeficient mice and wildtype mice given an orexin 1 receptor antagonist 35 .
a potential pathway would involve direct binding of ghrelin to ghsr1a present on orexin neurones of the lha .
this is supported by the finding that ghsr1a is expressed within the lha of the rat 8 , as well as by studies showing that ghrelin can induce action potentials and depolarisation in isolated orexin neurones 104 .
the ghrelinengaged orexin neurones would then project to the vta , where orexin signalling is critical in the activation of mesolimbic dopaminergic circuit and rewardseeking behaviours 105 , 106 .
a recent study using fastscan cyclic voltammetry in awake rats to record dopamine spikes in the nac core showed that the central infusion of ghrelin increases , whereas a ghsr1a antagonist suppresses , the magnitude of dopamine spikes evoked by food , respectively .
in addition , potentiation of foodevoked dopamine spikes was increased by intralha ghrelin and intravta blockade of orexin receptors attenuated food intake induced by central ghrelin 107 .
thus , orexin signalling also appears as a key mediator of the actions of ghrelin on food reward .
additionally , ghrelin might indirectly regulate food rewardrelated behaviours by engaging central npy / agrp neurones of the arc . in this regard
, studies using dreadd technology ( designer receptors exclusively activated by designer drugs ) have revealed that selective activation of agrp neurones is sufficient to drive food motivated behaviour in mice 108 .
npy has been shown to be able to induce cpp when administered to the nac 109 .
npy also induces sucrosemotivated behaviour when administered to the vta or nac , although it only increased sucrose consumption when administered to the nac 110 .
crosstalk between these npy and ghrelinsensitive networks at the level of the vta for food intake has been suggested by studies showing that the feeding effects , but not foodmotivated effects , of ghrelin were abolished by vta pretreatment with a npy receptor 1 antagonist .
interestingly , the converse was true for the vta delivery of a mupreferring opioid receptor antagonist , which suppressed the effects of vta ghrelin on food motivation but not food intake 111 .
kappa opioid receptor pathways at the hypothalamic level also appear to be a component of the ghrelin sensitive circuitry that is important for feeding control 112 .
collectively , these studies outline the divergence of behaviours ( food motivation and food intake ) , involving overlapping but also distinct neurochemical pathways .
fifteen years after its discovery , the physiological relevance of the ghrelin signalling on food intake regulation , in general , and food reward pathways , in particular , is still a matter of discussion .
notably , some evidence strongly supports a role for ghrelin in shortterm food intake regulation .
as described above , human plasma ghrelin levels decrease rapidly in response to nutrient ingestion , and 24h plasma profiles display marked preprandial increases and postprandial decreases associated with every meal 3 . in rodents , ghrelin levels are suppressed within minutes by refeeding or enteral infusions of nutrients 113 .
interestingly , blockade of ghrelin signalling in adult animals using antighrelin antibodies , ghsr1a antagonists or antisense oligonucleotides report decreases in spontaneous food intake and body weight 114 , 115 , 116 . by contrast , genetically modified mouse models , including mice overexpressing ghrelin or mice with genetic deletion of ghrelin , ghsr1a or goat , are almost indistinguishable from wildtype mice in terms of ad  lib .
the argument invariably put forward for the lack of a robust phenotype in these mutant mice is that compensatory physiological mechanisms arise during development . however , a recent study has reported that genetic ablation of ghrelinproducing cells in adult mice fails to lead to a loss of appetite or body weight , or resistance to a highfat diet 118 .
even a physiological role for plasma ghrelin concentrations in the regulation of basal food intake was questioned because the study found that only doses of ghrelin resulting in supraphysiological plasma levels of the hormone are able to increase food intake . in line with this possibility
, no increase in appetite was observed in normalweight volunteers when plasma ghrelin is raised fourfold above basal levels 119 .
by contrast to these data , ghrelin has been shown to increase hunger scores and food intake in a buffet test meal in both normal weight and obese subjects 120 , 121 .
thus , further studies are required to better clarify the role of basal ghrelin signalling on food intake and food rewardlinked behaviours .
the significance of ghrelin signalling likely becomes more evident in situations in which ghrelin signalling is physiologically more relevant , such as fasting , caloric restriction or stress 122 . in this
regard , ghsr1a deficient mice show important eating behaviour alterations under specific experimental conditions . for example , wildtype mice subjected to prolonged caloric restriction show enhanced cpp for a highfat diet , whereas ghsr1a deficient mice lack such response 35 , 92 .
moreover , ghsr1a deficient mice in response to scheduled meals have both attenuated anticipatory hyperlocomotion and reduced expression of the marker of cellular activation cfos in the mesolimbic pathway 93 , 123 .
similarly , ghsr1a deficient mice do not anticipate food when exposed to an activitybased anorexia model , in which mice are given free access to a running wheel and fed once per day for 2  h 21 .
most humans change in their eating habits in response to stress , and an emerging literature has started to support the existence of a strong association between the ghrelin / ghsr1a system and stress .
for example , the csds procedure , which subjects mice to daily bouts of social defeat by aggressive male mice , has been used to study the physiological effect of ghrelin on feeding behaviours 39 , 53 , 124 .
wildtype mice exposed to csds increase their plasma ghrelin levels and regular chow intake during and for at least 1  month after the defeat period .
by contrast , ghsr1a deficient mice fail to show csdsinduced hyperphagia 39 , 124 . in wildtype mice
, csds also increases cpp for a highfat diet , whereas such a stressinduced food reward response is not observed in csdsexposed ghsr1a deficient mice 53 .
thus , ghrelin signalling appears to be required for stressinduced change in rewarding aspects of eating in mice , under these particular conditions .
by contrast to these findings , wildtype mice exposed to a chronic unpredictable stress procedure , which also elevates plasma ghrelin levels , decrease food intake and body weight gain , whereas similarlytreated ghsr1a deficient mice lack these changes 124 .
notably , elevations of plasma ghrelin are observed in several stress models and ghrelin administration to either humans or rodents has been shown to induce a strong activation of the hypothalamuspituitaryadrenal neuroendocrine axis 125 , 126 .
the physiological implications of ghrelininduced activation of stress responses or , conversely , the impact of stress on ghrelin responsiveness are currently unknown .
thus , further work is needed to clarify the interrelationship between of ghrelin , stress and food intake .
the ability of ghrelin to act in the brain to regulate food intake depends on the accessibility of circulating ghrelin to the above mentioned brain areas .
brain barrier and it is currently unclear how this hormone enters the brain 127 . in mice , ghrelin can be transported from the brain to the circulation via a saturable transport system ; however , no such system has been identified for blood to brain transport 128 .
a recent study using ghrelinfluorescent tracer has shown that peripheral increases of plasma ghrelin mainly access to the arc 127 , 129 .
the arc is a hypothalamic nucleus located in close apposition to the median eminence , a circumventricular organ with fenestrated capillaries that allows plasma ghrelin to diffuse to the brain parenchyma 130 .
the area postrema is another circumventricular organ also known to participate in food intake regulation and to express ghsr1a 8 , 127 .
early studies using ghsr1a agonists showed that these compounds activate cells in the area postrema and in some closelyadjacent structures 131 . in the study using the fluorescent ghrelin tracer
, it was also found that high levels of circulating ghrelin can directly act on area postrema neurones , which then innervate several hypothalamic and brainstem feeding centres 127 , 129 . in line with this possibility
, there are indications that longterm effects of ghrelin on feeding depend on intact signalling at the area postrema 132 , 133 .
the study using the fluorescent ghrelin tracer could not provide direct evidence for increases of plasma ghrelin reaching centres of the mesolimbic pathway , at least in an acute fashion .
however , an acute effect of peripheral ghrelin on the mesolimbic pathways is supported by a study showing that intravta delivery of a selective ghsr1a antagonist blocked the orexigenic effect of peripherallyadministrated ghrelin 54 .
also , it has been shown that peripheral administration of ghrelin in mice increases the extracellular concentration of dopamine in the nac measured by in vivo microdialysis 134 . however , the extent to which implantation of permanent cannulas in the brain affects the blood 
interestingly , mice expressing ghsr1a selectively in tyrosine hydroxylasecontaining cells partially respond to ghrelininduced food intake and fully develop cpp for a highfat diet in response to either peripheral ghrelin administration during the conditioning sessions or after csds 53 .
thus , future studies are required to clarify the physiological relevance of the action of peripheral ghrelin on the mesolimbic pathway .
the relevance of the expression of ghsr1a in brain areas without obvious access to circulating ghrelin is , in general , unclear .
although earlier studies suggested that ghrelin could be produced in the brain , more recent studies have clearly shown that ghrelin is not synthesised in the central nervous system 135 , 136 , 137 .
ghsr1a mainly signals through gq/11 , phospholipase c , inositol phosphate and calcium mobilisation from intracellular stores ; although it also activates other signalling pathways 138 .
an interesting feature of ghsr1a is its strong constitutive activity that makes it capable to signal in a ghrelinindependent manner 139 , 140 .
thus , the increase of ghsr1a expression would accordingly increase activation of the downstream signalling pathways affecting , as a consequence , food intake and body weight regulation 124 .
additionally , it has been proposed that an alternative mechanism by which ghsr1a regulates food intake involves its dimerisation with other g proteincoupled receptors .
ghsr1a has been shown to heterodimerise with the melanocortin 3 receptor , the serotonin 2c receptor and the dopamine receptors , which are all involved in food intake and food reward regulation .
heterodimerisation could serve to modulate specific functions of ghsr1a , such as signalling pathways , or to act as an allosteric mechanism to regulate signalling pathways of the other receptors , independently of ghrelin binding 141 , 142 , 143 , 144 .
the evidence reviewed here suggests that ghrelin / ghsr1a system is strongly linked to food rewardrelated pathways in addition to and partially separate from those which drive food intake .
notably , the mechanisms by which ghrelin / ghsr1a system promotes food intake are multifaceted and are summarised in fig .  1 .
the mesoaccumbal dopamine pathway appears to be a key target for ghrelin / ghsr1a system , opening the possibility that a primary role for ghrelin is to regulate rewarding aspects of eating .
the ghrelin / ghsr1a system is not only upregulated by hunger and in anticipation to food , orchestrating a feeding response , but also by negative energy balance conditions , or psychological stress when the activation of the mesoaccumbal dopamine pathway helps animals cope with these detrimental conditions .
thus , the action of the ghrelin / ghsr1a system on the mesolimbic pathway is very advantageous for the survival of the animal in times of food scarcity . the constant abundance of palatable foods together to the excessive stress levels that we suffer in modern societies places the ghrelin / ghsr1a system in a new role in which it likely cause adverse consequences , including overeating beyond metabolic need and body weight gain .
great spice from an evolutionary perspective , although it no longer represents an advantage for modern human beings .
our knowledge of the neuronal circuits and molecular mechanisms mediating the actions of the ghrelin / ghsr1a system on the mesolimbic pathways has progressed considerably in recent years , yet still many novel and exciting aspects of this endocrine gut 
brain reward axis likely remain to be discovered and will deserve intense research in the near future .
endocrine gut  brain reward axis : a model of the effects of ghrelin on eating behaviour .
some specific conditions are known to influence eating regulation by affecting homeostatic brain circuits , which drive food intake depending on energy store levels , and/or reward brain circuits , which drive consumption based on the rewarding properties of foods .
several lines of evidence suggest a key role for the ghrelin / growth hormone secretagogue receptor type 1a system in mediating these eating behaviours .
these specific conditions increase ghrelin , which in turn reaches the brain where , upon interaction with its receptor on dopaminergic neurones in the ventral tegmental area and likely in other brain nuclei , mediates an integrated and complex eating behavioural response .
  hunger is the best spice is an old and wise saying that acknowledges the fact that almost any food tastes better when we are hungry . the neurobiological underpinnings of this lore include activation of the brain 's reward system and the stimulation of this system by the hungerpromoting hormone ghrelin . 
 ghrelin is produced largely from the stomach and levels are higher preprandially . 
 the ghrelin receptor is expressed in many brain areas important for feeding control , including not only the hypothalamic nuclei involved in energy balance regulation , but also rewardlinked areas such as the ventral tegmental area . by targeting the mesoaccumbal dopamine neurones of the ventral tegmental area , 
 ghrelin recruits pathways important for food rewardrelated behaviours that show overlap with but are also distinct from those important for food intake . 
 we review a variety of studies that support the notion that ghrelin signalling at the level of the mesolimbic system is one of the key molecular substrates that provides a physiological signal connecting gut and reward pathways . 
Introduction
The ghrelin/growth hormone secretagogue receptor type 1A (GHSR1A) system
Food reward: motivational and hedonic aspects of eating
Neuronal circuits involved in food reward
Multifaceted actions of ghrelin signalling on food reward
Neuronal circuits mediating the effects of ghrelin on food reward
Physiological role of the ghrelin signalling system on food reward
Concluding remarks