Understanding of the neural and physiological substrates of hunger and satiety has increased rapidly over the last three decades, and pharmacological targets have already been identified for the treatment of obesity that has moved from pre-clinical screening to therapies approved by regulatory authorities. Initially, this review describes the way in which physiological signals of energy availability interact with hedonic and rewarding properties of food to modulate the neural circuitry that supports eating behaviour. This is followed by a brief account of current and promising targets for drug development and a review of the wide range of preclinical paradigms that model important influences on human eating behaviour, and can be used to guide early stages of the drug development process.
AdamTCEpelES (2007) Stress, eating and the reward system. Physiol Behav91: 449–458.
2.
AdanRAH (2013) Mechanisms underlying current and future anti-obesity drugs. Trends Neurosci36: 133–140.
3.
AllisonDBGaddeKMGarveyWTet al. (2012) Controlled-release phentermine/topiramate in severely obese adults: A randomized controlled trial (EQUIP). Obesity20: 330–342.
4.
American Psychiatric Association (2013) Diagnostic and Statistical Manual of Mental Disorders (DSM-5®). St. Louis, MI: American Psychiatric Association.
5.
AnandBKBrobeckJR (1951) Hypothalamic control of food intake in rats and cats. Yale J Biol Med24: 123–140.
6.
AnderbergRHRichardJEEerolaKet al. (2017) Glucagon-like peptide 1 and its analogs act in the dorsal raphe and modulate central serotonin to reduce appetite and body weight. Diabetes66: 1062–1073.
7.
AntinJGibbsJHoltJet al. (1975) Cholecystokinin elicits the complete behavioral sequence of satiety in rats. J Comp Physiol Psychol89: 784–790.
8.
AponteYAtasoyDSternsonSM (2011) AGRP neurons are sufficient to orchestrate feeding behavior rapidly and without training. Nat Neurosci14: 351–355.
9.
AronneLShanahanWFainRet al. (2014) Safety and efficacy of lorcaserin: A combined analysis of the BLOOM and BLOSSOM trials. Postgrad Med126: 7–18.
10.
AstrupARössnerSVan GaalLet al. (2009) Effects of liraglutide in the treatment of obesity: A randomised, double-blind, placebo-controlled study. Lancet374: 1606–1616.
11.
AtasoyDBetleyJNSuHHet al. (2012) Deconstruction of a neural circuit for hunger. Nature488: 172–177.
12.
BajzerMOlivieriMHaasMKet al. (2011) Cannabinoid receptor 1 (CB1) antagonism enhances glucose utilisation and activates brown adipose tissue in diet-induced obese mice. Diabetologia, 54: 3121–3131.
13.
BaldoBAGual-BonillaLSijapatiKet al. (2004) Activation of a subpopulation of orexin/hypocretin-containing hypothalamic neurons by GABAA receptor-mediated inhibition of the nucleus accumbens shell, but not by exposure to a novel environment. Eur J Neurosci19: 376–386.
14.
BatterhamRLCohenMAEllisSMet al. (2003) Inhibition of food intake in obese subjects by peptide YY3–36. N Engl J Med349: 941–948.
Benite-RibeiroSAPuttDASoares-FilhoMCet al. (2016) The link between hypothalamic epigenetic modifications and long-term feeding control. Appetite107: 445–453.
17.
BerthoudH-R (2002) Multiple neural systems controlling food intake and body weight. Neurosci Biobehav Rev26: 393–428.
18.
BerthoudH-R (2012) The neurobiology of food intake in an obesogenic environment. Proc Nutr Soc71: 478–487.
19.
BirchLLMcPheeLSullivanSet al. (1989) Conditioned meal initiation in young children. Appetite13: 105–113.
20.
BlázquezEVelázquezEHurtado-CarneiroVet al. (2014) Insulin in the brain: Its pathophysiological implications for States related with central insulin resistance, type 2 diabetes and Alzheimer’s disease. Front Endocrinol5: 161.
21.
BlundellJEFinlaysonGGibbonsCet al. (2015a) The biology of appetite control: Do resting metabolic rate and fat-free mass drive energy intake?Physiol Behav152: 473–478.
22.
BlundellJEGibbonsCCaudwellPet al. (2015b) Appetite control and energy balance: Impact of exercise. Obes Rev16(Suppl 1): 67–76.
23.
BoitardCCavarocASauvantJet al. (2014) Impairment of hippocampal-dependent memory induced by juvenile high-fat diet intake is associated with enhanced hippocampal inflammation in rats. Brain Behav Immun40: 9–17.
24.
BubarMJStutzSJCunninghamKA (2011) 5-HT(2C) receptors localize to dopamine and GABA neurons in the rat mesoaccumbens pathway. PloS One6: e20508.
25.
CambridgeVCZiauddeenHNathanPJet al. (2013) Neural and behavioral effects of a novel mu opioid receptor antagonist in binge-eating obese people. Biol Psychiatry73: 887–894.
26.
CannonWBWashburnAL (1912) An explanation of hunger. Am J Physiol29: 441–454.
27.
CaricilliAMPenteadoEde AbreuLLet al. (2012) Topiramate treatment improves hypothalamic insulin and leptin signaling and action and reduces obesity in mice. Endocrinology153: 4401–4411.
28.
CastroDCBerridgeKC (2014) Opioid hedonic hotspot in nucleus accumbens shell: Mu, delta, and kappa maps for enhancement of sweetness “liking” and “wanting”. J Neurosci34: 4239–4250.
29.
CastroDCColeSLBerridgeKC (2015) Lateral hypothalamus, nucleus accumbens, and ventral pallidum roles in eating and hunger: Interactions between homeostatic and reward circuitry. Front Syst Neurosci9: 90.
30.
ChatzigeorgiouAKandarakiEPapavassiliouAGet al. (2014) Peripheral targets in obesity treatment: A comprehensive update. Obes Rev15: 487–503.
31.
ChowCCHallKD (2014) Short and long-term energy intake patterns and their implications for human body weight regulation. Physiol Behav134: 60–65.
32.
ChristensenRKristensenPKBartelsEMet al. (2007) Efficacy and safety of the weight-loss drug rimonabant: A meta-analysis of randomised trials. Lancet370: 1706–1713.
33.
ChuaSCChungWKWu-PengXSet al. (1996) Phenotypes of mouse diabetes and rat fatty due to mutations in the OB (leptin) receptor. Science271: 994–996.
CliftonPG (2000) Meal patterning in rodents: Psychopharmacological and neuroanatomical studies. Neurosci Biobehav Rev24: 213–222.
36.
CliftonPGLeeMDDourishCT (2000) Similarities in the action of Ro 60–0175, a 5-HT2C# receptor agonist and d-fenfluramine on feeding patterns in the rat. Psychopharmacologia152: 256–267.
37.
CliftonPGRuskINCooperSJ (1991) Effects of dopamine D1 and dopamine D2 antagonists on the free feeding and drinking patterns of rats. Behav Neurosci105: 272–281.
38.
CliftonPGVickersSPSomervilleEM (1998) Little and often: Ingestive behavior patterns following hippocampal lesions in rats. Behav Neurosci112: 502–511.
39.
ClunyNLChambersAPVemuriVKet al. (2011) The neutral cannabinoid CB1 receptor antagonist AM4113 regulates body weight through changes in energy intake in the rat. Pharmacol Biochem Behav97: 537–543.
40.
ConeRD (2005) Anatomy and regulation of the central melanocortin system. Nat Neurosci8: 571–578.
41.
ConnollyHMCraryJLMcGoonMDet al. (1997) Valvular heart disease associated with fenfluramine-phentermine. N Engl J Med337: 581–588.
42.
CooperGDPickavanceLCWildingJPHet al. (2007) Effects of olanzapine in male rats: Enhanced adiposity in the absence of hyperphagia, weight gain or metabolic abnormalities. J Psychopharmacol21: 405–413.
43.
CorwinRLAvenaNMBoggianoMM (2011) Feeding and reward: Perspectives from three rat models of binge eating. Physiol Behav104: 87–97.
44.
CrawleyJN (2000) What’s Wrong With My Mouse?: Behavioral Phenotyping of Transgenic and Knockout Mice. Hoboken, NJ: Wiley.
45.
CrombagHSBossertJMKoyaEet al. (2008) Review. Context-induced relapse to drug seeking: A review. Philos Trans R Soc B Biol Sci363: 3233–3243.
46.
DakinCLGunnISmallCJet al. (2001) Oxyntomodulin inhibits food intake in the rat. Endocrinology142: 4244–4250.
47.
DavidsonTLKanoskiSEChanKet al. (2010) Hippocampal lesions impair retention of discriminative responding based on energy state cues. Behav Neurosci124: 97–105.
48.
DavisJDPerezMC (1993) Food deprivation- and palatability-induced microstructural changes in ingestive behavior. Am J Physiol264: R97–R103.
49.
DavoodiNKalinichevMKorneevSAet al. (2009) Hyperphagia and increased meal size are responsible for weight gain in rats treated sub-chronically with olanzapine. Psychopharmacology203: 693–702.
50.
Di MarzoVMatiasI (2005) Endocannabinoid control of food intake and energy balance. Nat Neurosci8: 585–589.
51.
Di MatteoVDe BlasiADi GiulioCet al. (2001) Role of 5-HT(2C) receptors in the control of central dopamine function. Trends Pharmacol Sci22: 229–232.
52.
DiPatrizioNVPiomelliD (2012) The thrifty lipids: Endocannabinoids and the neural control of energy conservation. Trends Neurosci35: 403–411.
53.
DoslikovaBGarfieldASShawJet al. (2013) 5-HT2C receptor agonist anorectic efficacy potentiated by 5-HT1B receptor agonist coapplication: An effect mediated via increased proportion of pro-opiomelanocortin neurons activated. J Neurosci33: 9800–9804.
54.
DruckerDJNauckMA (2006) The incretin system: Glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet368: 1696–1705.
55.
EronduNWaddenTGantzIet al. (2007) Effect of NPY5R antagonist MK-0557 on weight regain after very-low-calorie diet-induced weight loss. Obesity15: 895–905.
56.
EverittBJRobbinsTW (2000) Second-order schedules of drug reinforcement in rats and monkeys: Measurement of reinforcing efficacy and drug-seeking behaviour. Psychopharmacology153: 17–30.
57.
FanWEllacottKLJHalatchevIGet al. (2004) Cholecystokinin-mediated suppression of feeding involves the brainstem melanocortin system. Nat Neurosci7: 335–336.
58.
FaulconbridgeLFWaddenTABerkowitzRIet al. (2009) Changes in symptoms of depression with weight loss: Results of a randomized trial. Obesity17: 1009–1016.
59.
FenselauHCampbellJNVerstegenAMJet al. (2017) A rapidly acting glutamatergic ARC→PVH satiety circuit postsynaptically regulated by α-MSH. Nat Neurosci20: 42–51.
60.
FergusonAVLatchfordKJSamsonWK (2008) The paraventricular nucleus of the hypothalamus - a potential target for integrative treatment of autonomic dysfunction. Expert Opin Ther Targets12: 717–727.
61.
FiglewiczDPBenoitSC (2009) Insulin, leptin, and food reward: Update 2008. Am J Physiol Regul Integr Comp Physiol296: R9–R19.
62.
FosgerauKHoffmannT (2015) Peptide therapeutics: Current status and future directions. Drug Discov Today20: 122–128.
63.
GaddeKMAllisonDBRyanDHet al. (2011) Effects of low-dose, controlled-release, phentermine plus topiramate combination on weight and associated comorbidities in overweight and obese adults (CONQUER): A randomised, placebo-controlled, phase 3 trial. Lancet377: 1341–1352.
64.
GarfieldASLiCMadaraJCet al. (2015) A neural basis for melanocortin-4 receptor-regulated appetite. Nat Neurosci18: 863–871.
65.
GelegenCChandaranaKChoudhuryAIet al. (2012) Regulation of hindbrain Pyy expression by acute food deprivation, prolonged caloric restriction, and weight loss surgery in mice. Am J Physiol Endocrinol Metab303: E659–E668.
66.
GiulianoCRobbinsTWNathanPJet al. (2012) Inhibition of opioid transmission at the μ-opioid receptor prevents both food seeking and binge-like eating. Neuropsychopharmacology37: 2643–2652.
67.
Gomez-SmithMKarthikeyanSJeffersMSet al. (2016) A physiological characterization of the Cafeteria diet model of metabolic syndrome in the rat. Physiol Behav167: 382–391.
68.
GonzálezJAJensenLTIordanidouPet al. (2016) Inhibitory interplay between orexin neurons and eating. Curr Biol26: 2486–2491.
69.
GökeRLarsenPJMikkelsenJDet al. (1995) Distribution of GLP-1 binding sites in the rat brain: Evidence that exendin-4 is a ligand of brain GLP-1 binding sites. Eur J Neurosci7: 2294–2300.
70.
GribbleFMReimannF (2016) Enteroendocrine cells: Chemosensors in the intestinal epithelium. Annu Rev Physiol78: 277–299.
71.
GrillHJHayesMR (2012) Hindbrain neurons as an essential hub in the neuroanatomically distributed control of energy balance. Cell Metab16: 296–309.
72.
GrunddalKVRatnerCFSvendsenBet al. (2016) Neurotensin is coexpressed, coreleased, and acts together with GLP-1 and PYY in enteroendocrine control of metabolism. Endocrinology157: 176–194.
73.
HalfordJCBlundellJE (1996) The 5-HT1B receptor agonist CP-94,253 reduces food intake and preserves the behavioural satiety sequence. Physiol Behav60: 933–939.
74.
HalfordJCWanninayakeSCBlundellJE (1998) Behavioral satiety sequence (BSS) for the diagnosis of drug action on food intake. Pharmacol Biochem Behav61: 159–168.
75.
HallKD (2010) Predicting metabolic adaptation, body weight change, and energy intake in humans. Am J Physiol Endocrinol Metab298: E449–E466.
76.
HarrisGCWimmerMAston-JonesG (2005) A role for lateral hypothalamic orexin neurons in reward seeking. Nature437: 556–559.
77.
HartfieldAWMooreNACliftonPG (2003) Effects of clozapine, olanzapine and haloperidol on the microstructure of ingestive behaviour in the rat. Psychopharmacologia167: 115–122.
78.
HerreraCGPonomarenkoAKorotkovaTet al. (2017) Sleep & metabolism: The multitasking ability of lateral hypothalamic inhibitory circuitries. Front Neuroendocrinol44: 27–34.
79.
HetheringtonAWRansonSW (1942) The spontaneous activity and food intake of rats with hypothalamic lesions. Am J Physiol136: 609–617.
80.
HewittKNLeeMDDourishCTet al. (2002) Serotonin 2C receptor agonists and the behavioural satiety sequence in mice. Pharmacol Biochem Behav71: 691–700.
81.
HigginsGASilenieksLBAltherrEBet al. (2016) Lorcaserin and CP-809101 reduce motor impulsivity and reinstatement of food seeking behavior in male rats: Implications for understanding the anti-obesity property of 5-HT2C receptor agonists. Psychopharmacology233: 2841–2856.
82.
HiggsS (2008) Cognitive influences on food intake: The effects of manipulating memory for recent eating. Physiol Behav94: 734–739.
83.
HiggsSCooperSJ (1998) Effects of benzodiazepine receptor ligands on the ingestion of sucrose, intralipid, and maltodextrin: an investigation using a microstructural analysis of licking behavior in a brief contact test. Behav Neurosci112: 447–457.
84.
HiggsSWilliamsCMKirkhamTC (2003) Cannabinoid influences on palatability: Microstructural analysis of sucrose drinking after delta(9)-tetrahydrocannabinol, anandamide, 2-arachidonoyl glycerol and SR141716. Psychopharmacologia165: 370–377.
85.
HoC-YBerridgeKC (2013) An orexin hotspot in ventral pallidum amplifies hedonic ‘liking’ for sweetness. Neuropsychopharmacology38: 1655–1664.
86.
HoebelBG (1971) Feeding: Neural control of intake. Annu Rev Physiol33: 533–568.
JenningsJHRizziGStamatakisAMet al. (2013) The inhibitory circuit architecture of the lateral hypothalamus orchestrates feeding. Science341: 1517–1521.
89.
JordanSDKönnerACBrüningJC (2010) Sensing the fuels: Glucose and lipid signaling in the CNS controlling energy homeostasis. Cell Mol Life Sci67: 3255–3273.
90.
KanoskiSEFortinSMRicksKMet al. (2013) Ghrelin signaling in the ventral hippocampus stimulates learned and motivational aspects of feeding via PI3K-Akt signaling. Biol Psychiatry73: 915–923.
KanoskiSEZhaoSGuarnieriDJet al. (2012) Endogenous leptin receptor signaling in the medial nucleus tractus solitarius affects meal size and potentiates intestinal satiation signals. Am J Physiol Endocrinol Metab303: E496–E503.
93.
KarraEChandaranaKBatterhamRL (2009) The role of peptide YY in appetite regulation and obesity. J Physiol587: 19–25.
94.
KeeferSEPetrovichGD (2017) Distinct recruitment of basolateral amygdala-medial prefrontal cortex pathways across Pavlovian appetitive conditioning. Neurobiol Learn Mem141: 27–32.
95.
KelleyAEBaldoBAPrattWE (2005) A proposed hypothalamic-thalamic-striatal axis for the integration of energy balance, arousal, and food reward. J Comp Neurol493: 72–85.
96.
KennettGACliftonPG (2010) New approaches to the pharmacological treatment of obesity: Can they break through the efficacy barrier?Pharmacol Biochem Behav97: 63–83.
97.
KennyPJ (2011) Reward mechanisms in obesity: New insights and future directions. Neuron69: 664–679.
KissileffHR (1970) Free feeding in normal and ‘recovered lateral’ rats monitored by a pellet-detecting eatometer. Physiol Behav5: 163–173.
100.
KurtzTWMorrisRCPershadsinghHA (1989) The Zucker fatty rat as a genetic model of obesity and hypertension. Hypertension13: 896–901.
101.
LabouèbeGLiuSDiasCet al. (2013) Insulin induces long-term depression of ventral tegmental area dopamine neurons via endocannabinoids. Nat Neurosci16: 300–308.
102.
LarsenPJTang-ChristensenMHolstJJet al. (1997) Distribution of glucagon-like peptide-1 and other preproglucagon-derived peptides in the rat hypothalamus and brainstem. Neuroscience77: 257–270.
103.
LeeMDAloyoVJFluhartySJet al. (1998) Infusion of the serotonin1B (5-HT1B) agonist CP-93,129 into the parabrachial nucleus potently and selectively reduces food intake in rats. Psychopharmacologia136: 304–307.
104.
LeeMDKennettGADourishCTet al. (2002) 5-HT1B receptors modulate components of satiety in the rat: Behavioural and pharmacological analyses of the selective serotonin1B agonist CP-94,253. Psychopharmacologia164: 49–60.
105.
LeeMDSimanskyKJ (1997) CP-94, 253: A selective serotonin1B (5-HT1B) agonist that promotes satiety. Psychopharmacologia131: 264–270.
106.
LeehrEJKrohmerKSchagKet al. (2015) Emotion regulation model in binge eating disorder and obesity–a systematic review. Neurosci Biobehav Rev49: 125–134.
107.
LevittDRTeitelbaumP (1975) Somnolence, akinesia, and sensory activation of motivated behavior in the lateral hypothalamic syndrome. Proc Natl Acad Sci USA72: 2819–2823.
108.
LjungbergTUngerstedtU (1976) Reinstatement of eating by dopamine agonists in aphagic dopamine denervated rats. Physiol Behav16: 277–283.
109.
LongYCZierathJR (2006) AMP-activated protein kinase signaling in metabolic regulation. J Clin Invest116: 1776–1783.
110.
LutzTA (2013) The interaction of amylin with other hormones in the control of eating. Diabetes Obes Metab15: 99–111.
111.
MacLeanMRDempsieY (2009) Serotonin and pulmonary hypertension–from bench to bedside?Current Opinion in Pharmacology9: 281–286.
112.
ManiBKOsborne-LawrenceSMequinionMet al. (2017) The role of ghrelin-responsive mediobasal hypothalamic neurons in mediating feeding responses to fasting. Molecular Metabolism6: 882–896.
113.
MarshallJFRichardsonJSTeitelbaumP (1974) Nigrostriatal bundle damage and the lateral hypothalamic syndrome. J Comp Physiol Psychol87: 808–830.
114.
MiceliMOPostCAder Kooy vanD (1987) Catecholamine and serotonin colocalization in projection neurons of the area postrema. Brain Res412: 381–385.
115.
MoleTBIrvineMAWorbeYet al. (2015) Impulsivity in disorders of food and drug misuse. Psychol Med45: 771–782.
116.
MolletAGilgSRiedigerTet al. (2004) Infusion of the amylin antagonist AC 187 into the area postrema increases food intake in rats. Physiol Behav81: 149–155.
117.
MoranTHKinzigKP (2004) Gastrointestinal satiety signals II. Cholecystokinin. Am J Physiol Gastrointest Liver Physiol286: G183–G188.
118.
MorganePJ (1961) Medial forebrain bundle and ‘feeding centers’ of the hypothalamus. J Comp Neurol117: 1–25.
119.
MurrayEBrouwerSMcCutcheonRet al. (2014) Opposing neural effects of naltrexone on food reward and aversion: Implications for the treatment of obesity. Psychopharmacology231: 4323–4335.
120.
OertelWSchulzJB (2016) Current and experimental treatments of Parkinson disease: A guide for neuroscientists. J Neurochem139(Suppl 1): 325–337.
121.
PangalosMNSchechterLEHurkoO (2007) Drug development for CNS disorders: Strategies for balancing risk and reducing attrition. Nat Rev Drug Discov6: 521–532.
122.
PariseEMLillyNKayKet al. (2011) Evidence for the role of hindbrain orexin-1 receptors in the control of meal size. Am J Physiol Regul Integr Comp Physiol301: R1692–R1699.
123.
PerellóMScottMMSakataIet al. (2012) Functional implications of limited leptin receptor and ghrelin receptor coexpression in the brain. J Comp Neurol520: 281–294.
124.
PerryMLAndrzejewskiMEBushekSMet al. (2010) Intra-accumbens infusion of a muscarinic antagonist reduces food intake without altering the incentive properties of food-associated cues. Behav Neurosci124: 44–54.
125.
PerryJLCarrollME (2008) The role of impulsive behavior in drug abuse. Psychopharmacologia200: 1–26.
126.
PetrovichGDGallagherM (2003) Amygdala subsystems and control of feeding behavior by learned cues. Ann N Y Acad Sci985: 251–262.
127.
PetrovichGDHobinMPReppucciCJ (2012) Selective Fos induction in hypothalamic orexin/hypocretin, but not melanin-concentrating hormone neurons, by a learned food-cue that stimulates feeding in sated rats. Neuroscience224: 70–80.
PetrovichGDRossCAHollandPCet al. (2007b) Medial prefrontal cortex is necessary for an appetitive contextual conditioned stimulus to promote eating in sated rats. J Neurosci27: 6436–6441.
130.
PicardFDeshaiesYLalondeJet al. (2000) Topiramate reduces energy and fat gains in lean (Fa/?) and obese (fa/fa) Zucker rats. Obes Res8: 656–663.
131.
Pi-SunyerXAstrupAFujiokaKet al. (2015) A randomized, controlled trial of 3.0 mg of liraglutide in weight management. N Engl J Med373: 11–22.
132.
PlojKBenthemLKakol-PalmDet al. (2016) Effects of a novel potent melanin-concentrating hormone receptor 1 antagonist, AZD1979, on body weight homeostasis in mice and dogs. Br J Pharmacol173: 2739–2751.
133.
PrenticeAMJebbSA (1995) Obesity in Britain: Gluttony or sloth?Br Med J311: 437–439.
134.
PrenticeAMJebbSA (2003) Fast foods, energy density and obesity: A possible mechanistic link. Obes Rev4: 187–194.
135.
PucciAFinerN (2015) New medications for treatment of obesity: Metabolic and cardiovascular effects. Can J Cardiol31: 142–152.
136.
PulmanKGTSomervilleEMCliftonPG (2012) Intra-accumbens baclofen, but not muscimol, increases second order instrumental responding for food reward in rats. PloS One7: e40057.
ReynoldsGPKirkSL (2010) Metabolic side effects of antipsychotic drug treatment–pharmacological mechanisms. Pharmacol Ther125: 169–179.
139.
RidauraVKFaithJJReyFEet al. (2013) Gut microbiota from twins discordant for obesity modulate metabolism in mice. Science341: 1241214.
140.
RodgersRJ (2016) Bench to bedside in appetite research: Lost in translation?Neurosci Biobehav Rev76: 163–173.
141.
RodgersRJHolchPTallettAJ (2010) Behavioural satiety sequence (BSS): Separating wheat from chaff in the behavioural pharmacology of appetite. Pharmacol Biochem Behav97: 3–14.
142.
RollsET (2006) Brain mechanisms underlying flavour and appetite. Philos Trans R Soc Lond B Biol Sci361: 1123–1136.
143.
RomanCWSloatSRPalmiterRD (2017) A tale of two circuits: CCK(NTS) neuron stimulation controls appetite and induces opposing motivational states by projections to distinct brain regions. Neuroscience358: 316–324.
144.
RuiL (2013) Brain regulation of energy balance and body weight. Rev Endocr Metab Disord14: 387–407.
145.
RussellJCProctorSDKellySEet al. (2008) Pair feeding-mediated changes in metabolism: Stress response and pathophysiology in insulin-resistant, atherosclerosis-prone JCR:LA-cp rats. Am J Physiol Endocrinol Metab294: E1078–E1087.
SargentBJMooreNA (2009) New central targets for the treatment of obesity. Br J Clin Pharmacol68: 852–860.
148.
ScannellJWBosleyJ (2016) When quality beats quantity: Decision theory, drug discovery, and the reproducibility crisis. PloS One11: e0147215.
149.
SchagKSchönleberJTeufelMet al. (2013) Food-related impulsivity in obesity and binge eating disorder–a systematic review. Obes Rev14: 477–495.
150.
SelleckRABaldoBA (2017) Feeding-modulatory effects of mu-opioids in the medial prefrontal cortex: a review of recent findings and comparison to opioid actions in the nucleus accumbens. Psychopharmacology234: 1439–1449.
151.
SmietanaKSiatkowskiMMøllerM (2016) Trends in clinical success rates. Nat Rev Drug Discov15: 379–380.
152.
SmithDGRobbinsTW (2013) The neurobiological underpinnings of obesity and binge eating: A rationale for adopting the food addiction model. Biol Psychiatry73: 804–810.
153.
SmithSRProsserWADonahueDJet al. (2009) Lorcaserin (APD356), a selective 5-HT(2C) agonist, reduces body weight in obese men and women. Obesity17: 494–503.
154.
SomervilleEMHorwoodJMLeeMDet al. (2007) 5-HT(2C) receptor activation inhibits appetitive and consummatory components of feeding and increases brain c-fos immunoreactivity in mice. Eur J Neurosci25: 3115–3124.
155.
StanleyBGMagdalinWSeirafiAet al. (1993) The perifornical area: The major focus of (a) patchily distributed hypothalamic neuropeptide Y-sensitive feeding system(s). Brain Res604: 304–317.
156.
StarkRAshleySEAndrewsZB (2013) AMPK and the neuroendocrine regulation of appetite and energy expenditure. Mol Cell Endocrinol366: 215–223.
157.
SticeEFiglewiczDPGosnellBAet al. (2012) The contribution of brain reward circuits to the obesity epidemic. Neurosci Biobehav Rev37: 2047–2058.
158.
StratfordTRKelleyAE (1997) GABA in the nucleus accumbens shell participates in the central regulation of feeding behavior. J Neurosci17: 4434–4440.
159.
SturisJGotfredsenCFRømerJet al. (2003) GLP-1 derivative liraglutide in rats with beta-cell deficiencies: Influence of metabolic state on beta-cell mass dynamics. Br J Pharmacol140: 123–132.
160.
TallettAJBlundellJERodgersRJ (2008) Behaviourally-selective hypophagic effects of naloxone in non-deprived male rats presented with palatable food. Behav Brain Res187: 417–427.
161.
TanTBloomS (2013) Gut hormones as therapeutic agents in treatment of diabetes and obesity. Curr Opin Pharmacol13: 996–1001.
162.
TecottLHSunLMAkanaSFet al. (1995) Eating disorder and epilepsy in mice lacking 5-HT2C serotonin receptors. Nature374: 542–546.
163.
TeitelbaumP (1955) Sensory control of hypothalamic hyperphagia. J Comp Physiol Psychol48: 156–163.
164.
TeitelbaumP (1957) Random and food-directed activity in hyperphagic and normal rats. J Comp Physiol Psychol50: 486–490.
165.
ThaissCAItavSRothschildDet al. (2016) Persistent microbiome alterations modulate the rate of post-dieting weight regain. Nature540: 544–551.
166.
ThomasJMDourishCTTomlinsonJWet al. (2014) Effects of the 5-HT2C receptor agonist meta-chlorophenylpiperazine on appetite, food intake and emotional processing in healthy volunteers. Psychopharmacology231: 2449–2459.
Thornton-JonesZDKennettGAVickersSPet al. (2007) A comparison of the effects of the CB(1) receptor antagonist SR141716A, pre-feeding and changed palatability on the microstructure of ingestive behaviour. Psychopharmacologia193: 1–9.
169.
Thornton-JonesZDVickersSPCliftonPG (2005) The cannabinoid CB1 receptor antagonist SR141716A reduces appetitive and consummatory responses for food. Psychopharmacologia179: 452–460.
TschöpMCastañedaTRJoostHGet al. (2004) Physiology: Does gut hormone PYY3-36 decrease food intake in rodents?Nature430: 1–2.
172.
TurtonMDO’SheaDGunnIet al. (1996) A role for glucagon-like peptide-1 in the central regulation of feeding. Nature379: 69–72.
173.
UngerstedtU (1971) Adipsia and aphagia after 6-hydroxydopamine induced degeneration of the nigro-striatal dopamine system. Acta Physiol Scand Suppl367: 95–122.
174.
Valencia-TorresLOlarte-SánchezCMLyonsDJet al. (2016) Activation of ventral tegmental area 5-HT2C receptors reduces incentive motivation. Neuropsychopharmacology42: 1511–1521.
175.
VickersSPCliftonPG (2012) Animal models to explore the effects of CNS drugs on food intake and energy expenditure. Neuropharmacology63: 124–131.
176.
VickersSPCliftonPGDourishCTet al. (1999) Reduced satiating effect of d-fenfluramine in serotonin 5-HT(2C) receptor mutant mice. Psychopharmacologia143: 309–314.
177.
VickersSPHackettDMurrayFet al. (2015) Effects of lisdexamfetamine in a rat model of binge-eating. J Psychopharmacol29: 1290–1307.
von EconomoC (1930) Sleep as a problem of localization. J Nerv Ment Dis71: 249–259.
180.
WeingartenHPMartinGM (1989) Mechanisms of conditioned meal initiation. Physiol Behav45: 735–740.
181.
WhishawIQKolbB (2005) The behavior of the laboratory rat: A handbook with tests. Oxford, UK: Oxford University Press.
182.
WhitingLMcCutcheonJEBoyleCNet al. (2017) The area postrema (AP) and the parabrachial nucleus (PBN) are important sites for salmon calcitonin (sCT) to decrease evoked phasic dopamine release in the nucleus accumbens (NAc). Physiol Behav176: 9–16.
183.
WilliamsCMKirkhamTC (2002) Observational analysis of feeding induced by Delta9-THC and anandamide. Physiol Behav76: 241–250.
184.
WilliamsDL (2014) Neural integration of satiation and food reward: Role of GLP-1 and orexin pathways. Physiol Behav136: 194–199.
185.
WillnerP (1984) The validity of animal models of depression. Psychopharmacologia83: 1–16.
186.
WiseRAYokelRADeWitH (1976) Both positive reinforcement and conditioned aversion from amphetamine and from apomorphine in rats. Science191: 1273–1275.
187.
WrightFLRodgersRJ (2013) Acute behavioural effects of bupropion and naltrexone, alone and in combination, in non-deprived male rats presented with palatable mash. Psychopharmacology228: 291–307.
188.
WuZKimERSunHet al. (2015) GABAergic projections from lateral hypothalamus to paraventricular hypothalamic nucleus promote feeding. J Neurosci35: 3312–3318.
189.
WynneKParkAJSmallCJet al. (2006) Oxyntomodulin increases energy expenditure in addition to decreasing energy intake in overweight and obese humans: A randomised controlled trial. Int J Obes30: 1729–1736.
190.
XuPHeYCaoXet al. (2017) Activation of serotonin 2C receptors in dopamine neurons inhibits binge-like eating in mice. Biol Psychiatry81: 737–747.
191.
XuYJonesJEKohnoDet al. (2008) 5-HT2CRs expressed by pro-opiomelanocortin neurons regulate energy homeostasis. Neuron60: 582–589.
192.
YangYAtasoyDSuHHet al. (2011) Hunger states switch a flip-flop memory circuit via a synaptic AMPK-dependent positive feedback loop. Cell146: 992–1003.
193.
YeoGSHHeislerLK (2012) Unraveling the brain regulation of appetite: Lessons from genetics. Nat Neurosci15: 1343–1349.
194.
YeomansMRWrightPMacleodHAet al. (1990) Effects of nalmefene on feeding in humans. Dissociation of hunger and palatability. Psychopharmacologia100: 426–432.
195.
ZhanCZhouJFengQet al. (2013) Acute and long-term suppression of feeding behavior by POMC neurons in the brainstem and hypothalamus, respectively. J Neurosci33: 3624–3632.
196.
ZhangQDengCHuangX-F (2013) The role of ghrelin signalling in second-generation antipsychotic-induced weight gain. Psychoneuroendocrinology38: 2423–2438.
197.
ZiauddeenHFarooqiISFletcherPC (2012) Obesity and the brain: How convincing is the addiction model?Nat Rev Neurosci13: 279–286.
198.
ZiauddeenHFletcherPC (2013) Is food addiction a valid and useful concept?Obes Rev14: 19–28.
