Focus Article
Central dopaminergic circuitry controlling food intake and reward: implications for the regulation of obesity
Zivjena Vucetic,
Teresa M. Reyes,
Zivjena Vucetic
Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA, 19104, USA
Search for more papers by this authorCorresponding Author
Teresa M. Reyes
Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA, 19104, USA
Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of Medicine, Philadelphia, PA, 19104, USA
Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA, 19104, USASearch for more papers by this authorZivjena Vucetic,
Teresa M. Reyes,
Zivjena Vucetic
Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA, 19104, USA
Search for more papers by this authorCorresponding Author
Teresa M. Reyes
Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA, 19104, USA
Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of Medicine, Philadelphia, PA, 19104, USA
Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA, 19104, USASearch for more papers by this authorAbstract
Prevalence of obesity in the general population has increased in the past 15 years from 15% to 35%. With increasing obesity, the coincident medical and social consequences are becoming more alarming. Control over food intake is crucial for the maintenance of body weight and represents an important target for the treatment of obesity. Central nervous system mechanisms responsible for control of food intake have evolved to sense the nutrient and energy levels in the organism and to coordinate appropriate responses to adjust energy intake and expenditure. This homeostatic system is crucial for maintenance of stable body weight over long periods of time of uneven energy availability. However, not only the caloric and nutritional value of food but also hedonic and emotional aspects of feeding affect food intake. In modern society, the increased availability of highly palatable and rewarding (fat, sweet) food can significantly affect homeostatic balance, resulting in dysregulated food intake. This review will focus on the role of hypothalamic and mesolimbic/mesocortical dopaminergic (DA) circuitry in coding homeostatic and hedonic signals for the regulation of food intake and maintenance of caloric balance. The interaction of dopamine with peripheral and central indices of nutritional status (e.g., leptin, ghrelin, neuropeptide Y), and the susceptibility of the dopamine system to prenatal insults will be discussed. Additionally, the importance of alterations in dopamine signaling that occur coincidently with obesity will be addressed. Copyright © 2010 John Wiley & Sons, Inc.
This article is categorized under:
- Physiology > Mammalian Physiology in Health and Disease
FURTHER READING
Quorum sensing represents an example of bacterial cell-cell communication. A generally accessible and concise introduction to this topic can be found in the enlightening and visually appealing review [181] by Losick and Kaiser. A systematic account of this field, including quorum sensing, is compiled in the comprehensive collection edited by Dunny and Winans [12]. Since communication is crucial for complex organization, bacterial multicellular morphogenesis is another exciting topic related to quorum sensing [182-184]. Interested in application of mathematical modeling to the analysis of QSN are referred to the clear and accessible paper by Dockery and Keener [117]. Further references on modeling and its role in understanding intracellular decision circuitry can be found in the excellent reviews written by the pioneers of this field [112,113,116,165].
REFERENCES
- 1Flegal KM, Carroll MD, Kuczmarski RJ, Johnson CL. Overweight and obesity in the United States: prevalence and trends, 1960–1994. Int J Obes Relat Metab Disord 1998, 22: 39–47.
- 2Ogden CL, Carroll MD, Curtin LR, McDowell MA, Tabak CJ, et al. Prevalence of overweight and obesity in the United States, 1999–2004. JAMA 2006, 295: 1549–1555.
- 3Ogden CL, Yanovski SZ, Carroll MD, Flegal KM. The epidemiology of obesity. Gastroenterology 2007, 132: 2087–2102.
- 4Ford ES, Mokdad AH. Epidemiology of obesity in the Western Hemisphere. J Clin Endocrinol Metab 2008, 93: S1–S8.
- 5Ogden CL, Carroll MD, Flegal KM. High body mass index for age among US children and adolescents, 2003–2006. JAMA 2008, 299: 2401–2405.
- 6Lawrence VJ, Kopelman PG. Medical consequences of obesity. Clin Dermatol 2004, 22: 296–302.
- 7Kopelman PG. Obesity as a medical problem. Nature 2000, 404: 635–643.
- 8Flegal KM, Graubard BI, Williamson DF, Gail MH. Cause-specific excess deaths associated with underweight, overweight, and obesity. JAMA 2007, 298: 2028–2037.
- 9Kolotkin RL, Meter K, Williams GR. Quality of life and obesity. Obes Rev 2001, 2: 219–229.
- 10Muennig P. The body politic: the relationship between stigma and obesity-associated disease. BMC Public Health 2008, 8: 128.
- 11Sarlio-Lahteenkorva S, Stunkard A, Rissanen A. Psychosocial factors and quality of life in obesity. Int J Obes Relat Metab Disord 1995, 19(suppl 6): S1–S5.
- 12Finkelstein EA, Fiebelkorn IC, Wang G. National medical spending attributable to overweight and obesity: how much, and who's paying? Health Aff (Millwood) 2003. (Suppl Web Exclusives:W3: 219–226).
- 13Sturm R. The effects of obesity, smoking, and drinking on medical problems and costs. Health Aff (Millwood) 2002, 21: 245–253.
- 14Thorpe KE, Florence CS, Howard DH, Joski P. The impact of obesity on rising medical spending. Health Aff (Millwood) 2004. (Suppl Web Exclusives:W4: 480–486).
- 15Finkelstein EA, Trogdon JG, Brown DS, Allaire BT, Dellea PS, et al. The lifetime medical cost burden of overweight and obesity: implications for obesity prevention. Obesity (Silver Spring) 2008, 16: 1843–1848.
- 16Trogdon JG, Finkelstein EA, Hylands T, Dellea PS, Kamal-Bahl SJ. Indirect costs of obesity: a review of the current literature. Obes Rev 2008, 9: 489–500.
- 17Finkelstein EA, Trogdon JG, Cohen JW, Dietz W. Annual medical spending attributable to obesity: payer- and service-specific estimates. Health Aff (Millwood) 2009, W8: 22–83.
- 18Thorleifsson G, Walters GB, Gudbjartsson DF, Steinthorsdottir V, Sulem P, et al. Genome-wide association yields new sequence variants at seven loci that associate with measures of obesity. Nat Genet 2009, 41: 18–24.
- 19Willer CJ, Speliotes EK, Loos RJ, Li S, Lindgren CM, et al., Genetic Investigation of ANthropometric Traits Consortium. Six new loci associated with body mass index highlight a neuronal influence on body weight regulation. Nat Genet 2009, 41: 25–34.
- 20Farooqi IS, O'Rahilly S. Monogenic human obesity syndromes. Recent Prog Horm Res 2004, 59: 409–424.
- 21Chung WK, Leibel RL. Considerations regarding the genetics of obesity. Obesity (Silver Spring) 2008, 16(suppl 3): S33–S39.
- 22August GP, Caprio S, Fennoy I, Freemark M, Kaufman FR, et al. Endocrine Society: prevention and treatment of pediatric obesity: an endocrine society clinical practice guideline based on expert opinion. J Clin Endocrinol Metab 2008, 93: 4576–4599.
- 23Cope MB, Allison DB, Critical review of the World Health Organization's (WHO). 2007 report on ‘evidence of the long-term effects of breastfeeding: systematic reviews and meta-analysis’ with respect to obesity. Obes Rev 2008, 9: 594–605.
- 24Qi L, Cho YA. Gene-environment interaction and obesity. Nutr Rev 2008, 66: 684–694.
- 25Marti A, Martinez-Gonzalez MA, Martinez JA. Interaction between genes and lifestyle factors on obesity. Proc Nutr Soc 2008, 67: 1–8.
- 26Levin BE. Epigenetic influences on food intake and physical activity level: review of animal studies. Obesity (Silver Spring) 2008, 16(suppl 3): S51–S54.
- 27Abizaid A, Horvath TL. Brain circuits regulating energy homeostasis. Regul Pept 2008, 149: 3–10.
- 28Berthoud HR, Morrison C. The brain, appetite, and obesity. Annu Rev Psychol 2008, 59: 55–92.
- 29Lenard NR, Berthoud HR. Central and peripheral regulation of food intake and physical activity: pathways and genes. Obesity (Silver Spring) 2008, 16(suppl 3): S11–S22.
- 30Morrison CD, Berthoud HR. Neurobiology of nutrition and obesity. Nutr Rev 2007, 65: 517–534.
- 31Crowley VE. Overview of human obesity and central mechanisms regulating energy homeostasis. Ann Clin Biochem 2008, 45: 245–255.
- 32Woods SC, D'Alessio DA. Central control of body weight and appetite. J Clin Endocrinol Metab 2008, 93(suppl 1): S37–S50.
- 33Meister B. Neurotransmitters in key neurons of the hypothalamus that regulate feeding behavior and body weight. Physiol Behav 2007, 92: 263–271.
- 34Gao Q, Horvath TL. Neurobiology of feeding and energy expenditure. Annu Rev Neurosci 2007, 30: 367–398.
- 35Abizaid A, Gao Q, Horvath TL. Thoughts for food: brain mechanisms and peripheral energy balance. Neuron 2006, 51: 691–702.
- 36Morton GJ, Cummings DE, Baskin DG, Barsh GS, Schwartz MW. Central nervous system control of food intake and body weight. Nature 2006, 443: 289–295.
- 37Schwartz MW, Woods SC, Porte D Jr, Seeley RJ, Baskin DG. Central nervous system control of food intake. Nature 2000, 404: 661–671.
- 38Wang GJ, Volkow ND, Thanos PK, Fowler JS. Similarity between obesity and drug addiction as assessed by neurofunctional imaging: a concept review. J Addict Dis 2004, 23: 39–53.
- 39Rogers PJ, Smit HJ. Food craving and food “addiction”: a critical review of the evidence from a biopsychosocial perspective. Pharmacol Biochem Behav 2000, 66: 3–14.
- 40Lutter M, Nestler EJ. Homeostatic and hedonic signals interact in the regulation of food intake. J Nutr 2009, 139: 629–632.
- 41Moore RY, Bloom FE. Central catecholamine neuron systems: anatomy and physiology of the dopamine systems. Annu Rev Neurosci 1978, 1: 129–169.
- 42Bjorklund A, Dunnett SB. Dopamine neuron systems in the brain: an update. Trends Neurosci 2007, 30: 194–202.
- 43Fibiger HC, Phillips AG. Mesocorticolimbic dopamine systems and reward. Ann N Y Acad Sci 1988, 537: 206–215.
- 44Berridge KC, Kringelbach ML. Affective neuroscience of pleasure: reward in humans and animals. Psychopharmacology (Berl) 2008, 199: 457–480.
- 45Meguid MM, Fetissov SO, Varma M, Sato T, Zhang L, et al. Hypothalamic dopamine and serotonin in the regulation of food intake. Nutrition 2000, 16: 843–857.
- 46Smith GP, Schneider LH. Relationships between mesolimbic dopamine function and eating behavior. Ann N Y Acad Sci 1988, 537: 254–261.
- 47Hoebel BG, Hernandez L, Schwartz DH, Mark GP, Hunter GA. Microdialysis studies of brain norepinephrine, serotonin, and dopamine release during ingestive behavior. Theoretical and clinical implications. Ann N Y Acad Sci 1989, 575: 171–191; discussion 192-3.
- 48Salamone JD, Correa M. Motivational views of reinforcement: implications for understanding the behavioral functions of nucleus accumbens dopamine. Behav Brain Res 2002, 137: 3–25.
- 49Palmiter RD. Is dopamine a physiologically relevant mediator of feeding behavior? Trends Neurosci 2007, 30: 375–381.
- 50Volkow ND, Wang GJ, Fowler JS, Telang F. Overlapping neuronal circuits in addiction and obesity: evidence of systems pathology. Philos Trans R Soc Lond B Biol Sci 2008, 363: 3191–3200.
- 51Palmiter RD. Dopamine signaling in the dorsal striatum is essential for motivated behaviors: lessons from dopamine-deficient mice. Ann N Y Acad Sci 2008, 1129: 35–46.
- 52Wellman PJ. Modulation of eating by central catecholamine systems. Curr Drug Targets 2005, 6: 191–199.
- 53Bouthenet ML, Souil E, Martres MP, Sokoloff P, Giros B, Schwartz JC. Localization of dopamine D3 receptor mRNA in the rat brain using in situ hybridization histochemistry: comparison with dopamine D2 receptor mRNA. Brain Res 1991, 564: 203–219.
- 54Cooper SJ, Francis J, Barber DJ. Selective dopamine D-1 receptor agonists, SK&F 38393 and CY 208–243 reduce sucrose sham-feeding in the rat. Neuropharmacology 1993, 32: 101–102.
- 55Fremeau RT Jr, Duncan GE, Fornaretto MG, Dearry A, Gingrich JA, Breese GR, Caron MG. Localization of D1 dopamine receptor mRNA in brain supports a role in cognitive, affective, and neuroendocrine aspects of dopaminergic neurotransmission. Proc Natl Acad Sci U S A 1991, 88: 3772–3776.
- 56Ramos EJ, Meguid MM, Campos AC, Coelho JC. Neuropeptide Y, alpha-melanocyte-stimulating hormone, and monoamines in food intake regulation. Nutrition 2005, 21: 269–279.
- 57Hernandez L, Hoebel BG. Food intake and lateral hypothalamic self-stimulation covary after medial hypothalamic lesions or ventral midbrain 6-hydroxydopamine injections that cause obesity. Behav Neurosci 1989, 103: 412–422.
- 58Meguid MM, Yang ZJ, Montante A. Lateral hypothalamic dopaminergic neural activity in response to total parenteral nutrition. Surgery 1993, 114: 400–405; discussion 405-6.
- 59Meguid MM, Yang ZJ, Koseki M. Eating induced rise in LHA-dopamine correlates with meal size in normal and bulbectomized rats. Brain Res Bull 1995, 36: 487–490.
- 60Yang ZJ, Koseki M, Meguid MM, Laviano A. Eating-related increase of dopamine concentration in the LHA with oronasal stimulation. Am J Physiol 1996, 270: R315–R318.
- 61Najam N. Involvement of dopaminergic systems in the ventromedial hypothalamic hyperphagia. Brain Res Bull 1988, 21: 571–574.
- 62Giannakopoulos G, Galanopoulou P, Daifotis Z, Couvaris C. Effects of mesulergine treatment on diet selection, brain serotonin (5-HT) and dopamine (DA) turnover in free feeding rats. Prog Neuropsychopharmacol Biol Psychiatry 1998, 22: 803–813.
- 63Leibowitz SF, Rossakis C. Pharmacological characterization of perifornical hypothalamic dopamine receptors mediating feeding inhibition in the rat. Brain Res 1979, 172: 115–130.
- 64Leibowitz SF, Rossakis C. Mapping study of brain dopamine- and epinephrine-sensitive sites which cause feeding suppression in the rat. Brain Res 1979, 172: 101–113.
- 65Gilbert DB, Cooper SJ. Analysis of dopamine D1 and D2 receptor involvement in d- and l-amphetamine-induced anorexia in rats. Brain Res Bull 1985, 15: 385–389.
- 66Yang ZJ, Meguid MM, Koseki M, Oler A, Chong C, et al. Increased food intake and body weight gain after lateral hypothalamic dopaminergic cell implantation. Neuroreport 1996, 7: 449–453.
- 67Parada M, Hernandez L, Schwartz D, Hoebel BG. Hypothalamic infusion of amphetamine increases serotonin, dopamine and norepinephrine. Physiol Behav 1988, 44: 607–610.
- 68Baptista T, Parada M, Hernandez L. Long term administration of some antipsychotic drugs increases body weight and feeding in rats. Are D2 dopamine receptors involved? Pharmacol Biochem Behav 1987, 27: 399–405.
- 69Meguid MM, Yang ZJ, Laviano A. Meal size and number: relationship to dopamine levels in the ventromedial hypothalamic nucleus. Am J Physiol 1997, 272: R1925–R1930.
- 70Berridge KC, Robinson TE, Aldridge JW. Dissecting components of reward: ‘liking’, ‘wanting’, and learning. Curr Opin Pharmacol 2009, 9: 65–73.
- 71Ikemoto S. Dopamine reward circuitry: two projection systems from the ventral midbrain to the nucleus accumbens-olfactory tubercle complex. Brain Res Rev 2007, 56: 27–78.
- 72Wise RA. Dopamine and reward: the anhedonia hypothesis 30 years on. Neurotox Res 2008, 14: 169–183.
- 73Cannon CM, Palmiter RD. Reward without dopamine. J Neurosci 2003, 23: 10827–10831.
- 74Salamone JD, Correa M, Mingote SM, Weber SM. Beyond the reward hypothesis: alternative functions of nucleus accumbens dopamine. Curr Opin Pharmacol 2005, 5: 34–41.
- 75Berridge KC. The debate over dopamine's role in reward: the case for incentive salience. Psychopharmacology (Berl) 2007, 191: 391–431.
- 76Baldo BA, Kelley AE. Discrete neurochemical coding of distinguishable motivational processes: insights from nucleus accumbens control of feeding. Psychopharmacology (Berl) 2007, 191: 439–459.
- 77Kelley AE, Baldo BA, Pratt WE, Will MJ. Corticostriatal-hypothalamic circuitry and food motivation: integration of energy, action and reward. Physiol Behav 2005, 86: 773–795.
- 78Hernandez L, Hoebel BG. Food reward and cocaine increase extracellular dopamine in the nucleus accumbens as measured by microdialysis. Life Sci 1988, 42: 1705–1712.
- 79Hoebel BG. Brain neurotransmitters in food and drug reward. Am J Clin Nutr 1985, 42(suppl 5): 1133–1150.
- 80Hernandez L, Lee F, Hoebel BG. Simultaneous microdialysis and amphetamine infusion in the nucleus accumbens and striatum of freely moving rats: increase in extracellular dopamine and serotonin. Brain Res Bull 1987, 19: 623–628.
- 81Liang NC, Hajnal A, Norgren R. Sham feeding corn oil increases accumbens dopamine in the rat. Am J Physiol Regul Integr Comp Physiol 2006, 291: R1236–R1239.
- 82Hajnal A, Smith GP, Norgren R. Oral sucrose stimulation increases accumbens dopamine in the rat. Am J Physiol Regul Integr Comp Physiol 2004, 286: R31–R37.
- 83Hajnal A, Norgren R. Accumbens dopamine mechanisms in sucrose intake. Brain Res 2001, 904: 76–84.
- 84Salamone JD, Cousins MS, Snyder BJ. Behavioral functions of nucleus accumbens dopamine: empirical and conceptual problems with the anhedonia hypothesis. Neurosci Biobehav Rev 1997, 21: 341–359.
- 85Szczypka MS, Rainey MA, Kim DS, Alaynick WA, Marck BT, et al. Feeding behavior in dopamine-deficient mice. Proc Natl Acad Sci USA 1999, 96: 12138–12143.
- 86Szczypka MS, Kwok K, Brot MD, Marck BT, Matsumoto AM, et al. Dopamine production in the caudate putamen restores feeding in dopamine-deficient mice. Neuron 2001, 30: 819–828.
- 87Wang GJ, Volkow ND, Fowler JS. The role of dopamine in motivation for food in humans: implications for obesity. Expert Opin Ther Targets 2002, 6: 601–609.
- 88Zheng H, Berthoud HR. Eating for pleasure or calories. Curr Opin Pharmacol 2007, 7: 607–612.
- 89Zheng H, Berthoud HR. Neural systems controlling the drive to eat: mind versus metabolism. Physiology (Bethesda) 2008, 23: 75–83.
- 90Berridge KC, Robinson TE. Parsing reward. Trends Neurosci 2003, 26: 507–513.
- 91Elman I, Borsook D, Lukas SE. Food intake and reward mechanisms in patients with schizophrenia: implications for metabolic disturbances and treatment with second-generation antipsychotic agents. Neuropsychopharmacology 2006, 31: 2091–2120.
- 92Holtzman SG. Behavioral effects of separate and combined administration of naloxone and d-amphetamine. J Pharmacol Exp Ther 1974, 189: 51–60.
- 93Yeomans MR, Gray RW. Opioid peptides and the control of human ingestive behaviour. Neurosci Biobehav Rev 2002, 26: 713–728.
- 94Erlanson-Albertsson C. How palatable food disrupts appetite regulation. Basic Clin Pharmacol Toxicol 2005, 97: 61–73.
- 95Pecina S. Opioid reward ‘liking’ and ‘wanting’ in the nucleus accumbens. Physiol Behav 2008, 94: 675–680.
- 96Figlewicz DP, Benoit SC. Insulin, leptin, and food reward: update 2008. Am J Physiol Regul Integr Comp Physiol 2009, 296: R9–R19.
- 97DiLeone RJ, Georgescu D, Nestler EJ. Lateral hypothalamic neuropeptides in reward and drug addiction. Life Sci 2003, 73: 759–768.
- 98Hommel JD, Trinko R, Sears RM, Georgescu D, Liu ZW, et al. Leptin receptor signaling in midbrain dopamine neurons regulates feeding. Neuron 2006, 51: 801–810.
- 99Figlewicz DP, Bennett JL, Aliakbari S, Zavosh A, Sipols AJ. Insulin acts at different CNS sites to decrease acute sucrose intake and sucrose self-administration in rats. Am J Physiol Regul Integr Comp Physiol 2008, 295: R388–R394.
- 100Pardini AW, Nguyen HT, Figlewicz DP, Baskin DG, Williams DL, et al. Distribution of insulin receptor substrate-2 in brain areas involved in energy homeostasis. Brain Res 2006, 1112: 169–178.
- 101Malik S, McGlone F, Bedrossian D, Dagher A. Ghrelin modulates brain activity in areas that control appetitive behavior. Cell Metab 2008, 7: 400–409.
- 102Abizaid A, Liu ZW, Andrews ZB, Shanabrough M, Borok E, et al. Ghrelin modulates the activity and synaptic input organization of midbrain dopamine neurons while promoting appetite. J Clin Invest 2006, 116: 3229–3239.
- 103Bassareo V, Di Chiara G. Differential responsiveness of dopamine transmission to food-stimuli in nucleus accumbens shell/core compartments. Neuroscience 1999, 89: 637–641.
- 104Figlewicz DP, Brot MD, McCall AL, Szot P. Diabetes causes differential changes in CNS noradrenergic and dopaminergic neurons in the rat: a molecular study. Brain Res 1996, 736: 54–60.
- 105Figlewicz DP, Szot P, Chavez M, Woods SC, Veith RC. Intraventricular insulin increases dopamine transporter mRNA in rat VTA/substantia nigra. Brain Res 1994, 644: 331–334.
- 106Figlewicz DP. Adiposity signals and food reward: expanding the CNS roles of insulin and leptin. Am J Physiol Regul Integr Comp Physiol 2003, 284: R882–R892.
- 107Olszewski PK, Schioth HB, Levine AS. Ghrelin in the CNS: from hunger to a rewarding and memorable meal? Brain Res Rev 2008, 58: 160–170.
- 108Jerlhag E, Egecioglu E, Dickson SL, Andersson M, Svensson L, Engel JA. Ghrelin stimulates locomotor activity and accumbal dopamine-overflow via central cholinergic systems in mice: implications for its involvement in brain reward. Addict Biol 2006, 11: 45–54.
- 109Naleid AM, Grace MK, Cummings DE, Levine AS. Ghrelin induces feeding in the mesolimbic reward pathway between the ventral tegmental area and the nucleus accumbens. Peptides 2005, 26: 2274–2279.
- 110Quarta D, Di Francesco C, Melotto S, Mangiarini L, Heidbreder C, et al. Systemic administration of ghrelin increases extracellular dopamine in the shell but not the core subdivision of the nucleus accumbens. Neurochem Int 2009, 54: 89–94.
- 111Toshinai K, Date Y, Murakami N, Shimada M, Mondal MS, et al. Ghrelin-induced food intake is mediated via the orexin pathway. Endocrinology 2003, 144: 1506–1512.
- 112Chen HY, Trumbauer ME, Chen AS, Weingarth DT, Adams JR, et al. Orexigenic action of peripheral ghrelin is mediated by neuropeptide Y and agouti-related protein. Endocrinology 2004, 145: 2607–2612.
- 113Benoit SC, Tracy AL, Davis JF, Choi D, Clegg DJ. Novel functions of orexigenic hypothalamic peptides: from genes to behavior. Nutrition 2008, 24: 843–847.
- 114Harris GC, Wimmer M, Aston-Jones G. A role for lateral hypothalamic orexin neurons in reward seeking. Nature 2005, 437: 556–559.
- 115Narita M, Nagumo Y, Hashimoto S, Narita M, Khotib J, et al. Direct involvement of orexinergic systems in the activation of the mesolimbic dopamine pathway and related behaviors induced by morphine. J Neurosci 2006, 26: 398–405.
- 116Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, et al. Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 1998, 92: 573–585.
- 117Borgland SL, Taha SA, Sarti F, Fields HL, Bonci A. Orexin A in the VTA is critical for the induction of synaptic plasticity and behavioral sensitization to cocaine. Neuron 2006, 49: 589–601.
- 118Vittoz NM, Schmeichel B, Berridge CW. Hypocretin /orexin preferentially activates caudomedial ventral tegmental area dopamine neurons. Eur J Neurosci 2008, 28: 1629–1640.
- 119Alberto CO, Trask RB, Quinlan ME, Hirasawa M. Bidirectional dopaminergic modulation of excitatory synaptic transmission in orexin neurons. J Neurosci 2006, 26: 10043–10050.
- 120Bubser M, Fadel JR, Jackson LL, Meador-Woodruff JH, Jing D, et al. Dopaminergic regulation of orexin neurons. Eur J Neurosci 2005, 21: 2993–3001.
- 121Pissios P, Bradley RL, Maratos-Flier E. Expanding the scales: The multiple roles of MCH in regulating energy balance and other biological functions. Endocr Rev 2006, 27: 606–620.
- 122Qu D, Ludwig DS, Gammeltoft S, Piper M, Pelleymounter MA, et al. A role for melanin-concentrating hormone in the central regulation of feeding behaviour. Nature 1996, 380: 243–247.
- 123Georgescu D, Sears RM, Hommel JD, Barrot M, Bolanos CA, et al. The hypothalamic neuropeptide melanin-concentrating hormone acts in the nucleus accumbens to modulate feeding behavior and forced-swim performance. J Neurosci 2005, 25: 2933–2940.
- 124Chung S, Hopf FW, Nagasaki H, Li CY, Belluzzi JD, et al. The melanin-concentrating hormone system modulates cocaine reward. Proc Natl Acad Sci U S A 2009, 106: 6772–6777.
- 125Pissios P, Frank L, Kennedy AR, Porter DR, Marino FE, et al. Dysregulation of the mesolimbic dopamine system and reward in MCH-/- mice. Biol Psychiatry 2008, 64: 184–191.
- 126Fetissov SO, Byrne LC, Hassani H, Ernfors P, Hokfelt T. Characterization of neuropeptide Y Y2 and Y5 receptor expression in the mouse hypothalamus. J Comp Neurol 2004, 470: 256–265.
- 127Korotkova TM, Brown RE, Sergeeva OA, Ponomarenko AA, Haas HL. Effects of arousal- and feeding-related neuropeptides on dopaminergic and GABAergic neurons in the ventral tegmental area of the rat. Eur J Neurosci 2006, 23: 2677–2685.
- 128Cao G, Gardner A, Westfall TC. Mechanism of dopamine mediated inhibition of neuropeptide Y release from pheochromocytoma cells (PC12 cells). Biochem Pharmacol 2007, 73: 1446–1454.
- 129Pelletier G, Simard J. Dopaminergic regulation of pre-proNPY mRNA levels in the rat arcuate nucleus. Neurosci Lett 1991, 127: 96–98.
- 130Smialowska M, Bajkowska M, Heilig M, Obuchowicz E, Turchan J, et al. Pharmacological studies on the monoaminergic influence on the synthesis and expression of neuropeptide Y and corticotropin releasing factor in rat brain amygdala. Neuropeptides 2001, 35: 82–91.
- 131Lindefors N, Brene S, Herrera-Marschitz M, Persson H. Neuropeptide gene expression in brain is differentially regulated by midbrain dopamine neurons. Exp Brain Res 1990, 80: 489–500.
- 132Yang SC, Shieh KR. Differential effects of melanin concentrating hormone on the central dopaminergic neurons induced by the cocaine- and amphetamine-regulated transcript peptide. J Neurochem 2005, 92: 637–646.
- 133Lindblom J, Opmane B, Mutulis F, Mutule I, Petrovska R, et al. The MC4 receptor mediates alpha-MSH induced release of nucleus accumbens dopamine. Neuroreport 2001, 12: 2155–2158.
- 134Lindblom J, Kask A, Hagg E, Harmark L, Bergstrom L, Wikberg J. Chronic infusion of a melanocortin receptor agonist modulates dopamine receptor binding in the rat brain. Pharmacol Res 2002, 45: 119–124.
- 135Tiligada E, Wilson JF. D2- but not D1-dopamine receptors are involved in the inhibitory control of alpha-melanocyte-stimulating hormone release from the rat hypothalamus. Exp Brain Res 1989, 74: 645–648.
- 136Alvaro JD, Taylor JR, Duman RS. Molecular and behavioral interactions between central melanocortins and cocaine. J Pharmacol Exp Ther 2003, 304: 391–399.
- 137Nestler EJ, Carlezon WA Jr. The mesolimbic dopamine reward circuit in depression. Biol Psychiatry 2006, 59: 1151–1159.
- 138Patterson TA, Brot MD, Zavosh A, Schenk JO, Szot P, et al. Food deprivation decreases mRNA and activity of the rat dopamine transporter. Neuroendocrinology 1998, 68: 11–20.
- 139Fetissov SO, Meguid MM, Sato T, Zhang LH. Expression of dopaminergic receptors in the hypothalamus of lean and obese Zucker rats and food intake. Am J Physiol Regul Integr Comp Physiol 2002, 283: R905–R910.
- 140Figlewicz DP, Patterson TA, Johnson LB, Zavosh A, Israel PA, Szot P. Dopamine transporter mRNA is increased in the CNS of Zucker fatty (fa/fa) rats. Brain Res Bull 1998, 46: 199–202.
- 141Geiger BM, Behr GG, Frank LE, Caldera-Siu AD, Beinfeld MC. Evidence for defective mesolimbic dopamine exocytosis in obesity-prone rats. FASEB J 2008, 22: 2740–2746.
- 142Meguid MM, Fetissov SO, Miyata G, Torelli GF. Feeding pattern in obese Zucker rats after dopaminergic and serotonergic LHA grafts. Neuroreport 1999, 10: 1049–1053.
- 143Yang ZJ, Meguid MM. LHA dopaminergic activity in obese and lean Zucker rats. Neuroreport 1995, 6: 1191–1194.
- 144Orosco M, Rouch C, Meile MJ, Nicolaidis S. Spontaneous feeding-related monoamine changes in rostromedial hypothalamus of the obese Zucker rat: a microdialysis study. Physiol Behav 1995, 57: 1103–1106.
- 145Orosco M, Rouch C, Nicolaidis S. Rostromedial hypothalamic monoamine changes in response to intravenous infusions of insulin and glucose in freely feeding obese Zucker rats: a microdialysis study. Appetite 1996, 26: 1–20.
- 146Lemierre S, Rouch C, Nicolaidis S, Orosco M. Combined effect of obesity and aging on feeding-induced monoamine release in the rostromedial hypothalamus of the Zucker rat. Int J Obes Relat Metab Disord 1998, 22: 993–999.
- 147Fuemmeler BF, Agurs-Collins TD, McClernon FJ, Kollins SH, Kail ME, et al. Genes implicated in serotonergic and dopaminergic functioning predict BMI categories. Obesity (Silver Spring) 2008, 16: 348–355.
- 148Comings DE, Gade R, MacMurray JP, Muhleman D, Peters WR. Genetic variants of the human obesity (OB) gene: association with body mass index in young women, psychiatric symptoms, and interaction with the dopamine D2 receptor (DRD2) gene. Mol Psychiatry 1996, 1: 325–335.
- 149Noble EP, Noble RE, Ritchie T, Syndulko K, Bohlman MC, et al. D2 dopamine receptor gene and obesity. Int J Eat Disord 1994, 15: 205–217.
- 150Wu X, Hudmon KS, Detry MA, Chamberlain RM, Spitz MR. D2 dopamine receptor gene polymorphisms among African-Americans and Mexican-Americans: a lung cancer case-control study. Cancer Epidemiol Biomarkers Prev 2000, 9: 1021–1026.
- 151Thomas GN, Critchley JA, Tomlinson B, Cockram CS, Chan JC. Relationships between the taqI polymorphism of the dopamine D2 receptor and blood pressure in hyperglycaemic and normoglycaemic Chinese subjects. Clin Endocrinol (Oxf) 2001, 55: 605–611.
- 152Morton LM, Wang SS, Bergen AW, Chatterjee N, Kvale P, et al. DRD2 genetic variation in relation to smoking and obesity in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Pharmacogenet Genomics 2006, 16: 901–910.
- 153Stice E, Spoor S, Bohon C, Small DM. Relation between obesity and blunted striatal response to food is moderated by TaqIA A1 allele. Science 2008, 322: 449–452.
- 154Guo G, North KE, Gorden-Larsen P, Bulik CM, Choi S. Body mass, DRD4, physical activity, sedentary behavior, and family socioeconomic status: the add health study. Obesity (Silver Spring) 2007, 15: 1199–1206.
- 155Kaplan AS, Levitan RD, Yilmaz Z, Davis C, Tharmalingam S, et al. A DRD4/BDNF gene-gene interaction associated with maximum BMI in women with bulimia nervosa. Int J Eat Disord 2008, 41: 22–28.
- 156Need AC, Ahmadi KR, Spector TD, Goldstein DB. Obesity is associated with genetic variants that alter dopamine availability. Ann Hum Genet 2006, 70: 293–303.
- 157Davis CA, Levitan RD, Reid C, Carter JC, Kaplan AS, et al. Dopamine for “wanting” and opioids for “liking”: a comparison of obese adults with and without binge eating. Obesity (Silver Spring) 2009, 17: 1220–1225.
- 158Wang GJ, Volkow ND, Logan J, Pappas NR, Wong CT, et al. Brain dopamine and obesity. Lancet 2001, 357: 354–357.
- 159Wang GJ, Volkow ND, Telang F, Jayne M, Ma J, et al. Exposure to appetitive food stimuli markedly activates the human brain. Neuroimage 2004, 21: 1790–1797.
- 160Volkow ND, Wang GJ, Telang F, Fowler JS, Thanos PK, et al. Low dopamine striatal D2 receptors are associated with prefrontal metabolism in obese subjects: possible contributing factors. Neuroimage 2008, 42: 1537–1543.
- 161Volkow ND, Wise RA. How can drug addiction help us understand obesity? Nat Neurosci 2005, 8: 555–560.
- 162Trinko R, Sears RM, Guarnieri DJ, DiLeone RJ. Neural mechanisms underlying obesity and drug addiction. Physiol Behav 2007, 91: 499–505.
- 163Avena NM, Rada P, Hoebel BG. Sugar and fat bingeing have notable differences in addictive-like behavior. J Nutr 2009, 139: 623–628.
- 164Carr KD. Chronic food restriction: enhancing effects on drug reward and striatal cell signaling. Physiol Behav 2007, 91: 459–472.
- 165Di Chiara G, Bassareo V, Fenu S, De Luca MA, Spina L, et al. Dopamine and drug addiction: the nucleus accumbens shell connection. Neuropharmacology 2004, 47(suppl 1): 227–241.
- 166Di Chiara G, Tanda G, Cadoni C, Acquas E, Bassareo V, Carboni E. Homologies and differences in the action of drugs of abuse and a conventional reinforcer (food) on dopamine transmission: an interpretative framework of the mechanism of drug dependence. Adv Pharmacol 1998, 42: 983–987.
- 167Davis JF, Tracy AL, Schurdak JD, Tschop MH, Lipton JW, et al. Exposure to elevated levels of dietary fat attenuates psychostimulant reward and mesolimbic dopamine turnover in the rat. Behav Neurosci 2008, 122: 1257–1263.
- 168Huang XF, Yu Y, Zavitsanou K, Han M, Storlien L. Differential expression of dopamine D2 and D4 receptor and tyrosine hydroxylase mRNA in mice prone, or resistant, to chronic high-fat diet-induced obesity. Brain Res Mol Brain Res 2005, 135: 150–161.
- 169Huang XF, Zavitsanou K, Huang X, Yu Y, Wang H, et al. Dopamine transporter and D2 receptor binding densities in mice prone or resistant to chronic high fat diet-induced obesity. Behav Brain Res 2006, 175: 415–419.
- 170South T, Huang XF. High-fat diet exposure increases dopamine D2 receptor and decreases dopamine transporter receptor binding density in the nucleus accumbens and caudate putamen of mice. Neurochem Res 2008, 33: 598–605.
- 171Li Y, South T, Han M, Chen J, Wang R, et al. High-fat diet decreases tyrosine hydroxylase mRNA expression irrespective of obesity susceptibility in mice. Brain Res 2009, 1268: 181–189.
- 172Teegarden SL, Nestler EJ, Bale TL. Delta FosB-mediated alterations in dopamine signaling are normalized by a palatable high-fat diet. Biol Psychiatry 2008, 64: 941–950.
- 173Avena NM, Hoebel BG. A diet promoting sugar dependency causes behavioral cross-sensitization to a low dose of amphetamine. Neuroscience 2003, 122: 17–20.
- 174Gosnell BA. Sucrose intake enhances behavioral sensitization produced by cocaine. Brain Res 2005, 1031: 194–201.
- 175Avena NM, Carrillo CA, Needham L, Leibowitz SF, Hoebel BG. Sugar-dependent rats show enhanced intake of unsweetened ethanol. Alcohol 2004, 34: 203–209.
- 176Muhlhausler BS. Programming of the appetite-regulating neural network: a link between maternal overnutrition and the programming of obesity? J Neuroendocrinol 2007, 19: 67–72.
- 177Huang JS, Lee TA, Lu MC. Prenatal programming of childhood overweight and obesity. Matern Child Health J 2007, 11: 461–473.
- 178Junien C, Nathanielsz P. Report on the IASO Stock Conference 2006: early and lifelong environmental epigenomic programming of metabolic syndrome, obesity and type II diabetes. Obes Rev 2007, 8: 487–502.
- 179Hebebrand J, Hinney A. Environmental and genetic risk factors in obesity. Child Adolesc Psychiatr Clin N Am 2009, 18: 83–94.
- 180Gluckman PD, Hanson MA, Pinal C. The developmental origins of adult disease. Matern Child Nutr 2005, 1: 130–141.
- 181Michels KB. Early life predictors of chronic disease. J Womens Health (Larchmt) 2003, 12: 157–161.
- 182Nicolaidis S. Prenatal imprinting of postnatal specific appetites and feeding behavior. Metabolism 2008, 57(suppl 2): S22–S26.
- 183Djiane J, Attig L. Role of leptin during perinatal metabolic programming and obesity. J Physiol Pharmacol 2008, 59(suppl 1): 55–63.
- 184Symonds ME, Gardner DS. Experimental evidence for early nutritional programming of later health in animals. Curr Opin Clin Nutr Metab Care 2006, 9: 278–283.
- 185Tang WY, Ho SM. Epigenetic reprogramming and imprinting in origins of disease. Rev Endocr Metab Disord 2007, 8: 173–182.
- 186Oliveira E, Moura EG, Santos-Silva AP, Fagundes AT, Rios AS, et al. Short- and long-term effects of maternal nicotine exposure during lactation on body adiposity, lipid profile, and thyroid function of rat offspring. J Endocrinol 2009, 202: 397–405.
- 187Fernandez-Twinn DS, Ozanne SE. Mechanisms by which poor early growth programs type-2 diabetes, obesity and the metabolic syndrome. Physiol Behav 2006, 88: 234–243.
- 188Kirk SL, Samuelsson AM, Argenton M, Dhonye H, Kalamatianos T, et al. Maternal obesity induced by diet in rats permanently influences central processes regulating food intake in offspring. PLoS ONE 2009, 4(N): e5870.
- 189Tamashiro KL, Terrillion CE, Hyun J, Koenig JI, Moran TH. Prenatal stress or high-fat diet increases susceptibility to diet-induced obesity in rat offspring. Diabetes 2009, 58: 1116–1125.
- 190Nilsson C, Larsson BM, Jennische E, Eriksson E, Bjorntorp P, et al. Maternal endotoxemia results in obesity and insulin resistance in adult male offspring. Endocrinology 2001, 142: 2622–2630.
- 191Ptak C, Petronis A. Epigenetics and complex disease: from etiology to new therapeutics. Annu Rev Pharmacol Toxicol 2008, 48: 257–276.
- 192Mehler MF: Epigenetics and the nervous system. Ann Neurol 2008, 64: 602–617.
- 193Jiang Y, Langley B, Lubin FD, Renthal W, Wood MA, et al. Epigenetics in the nervous system. J Neurosci 2008, 28: 11753–11759.
- 194Sinclair KD, Allegrucci C, Singh R, Gardner DS, Sebastian S, et al. DNA methylation, insulin resistance, and blood pressure in offspring determined by maternal periconceptional B vitamin and methionine status. Proc Natl Acad Sci USA 2007, 104: 19351–19356.
- 195Bogdarina I, Murphy HC, Burns SP, Clark AJ. Investigation of the role of epigenetic modification of the rat glucokinase gene in fetal programming. Life Sci 2004, 74: 1407–1415.
- 196Bogdarina I, Welham S, King PJ, Burns SP, Clark AJ. Epigenetic modification of the renin-angiotensin system in the fetal programming of hypertension. Circ Res 2007, 100: 520–526.
- 197Stoger R. Epigenetics and obesity. Pharmacogenomics 2008, 9: 1851–1860.
- 198Honma K, Mochizuki K, Goda T. Carbohydrate/fat ratio in the diet alters histone acetylation on the sucrase-isomaltase gene and its expression in mouse small intestine. Biochem Biophys Res Commun 2007, 357: 1124–1129.
- 199Simerly RB. Hypothalamic substrates of metabolic imprinting. Physiol Behav 2008, 94: 79–89.
- 200Mokler DJ, Torres OI, Galler JR, Morgane PJ. Stress-induced changes in extracellular dopamine and serotonin in the medial prefrontal cortex and dorsal hippocampus of prenatally malnourished rats. Brain Res 2007, 1148: 226–233.
- 201Valdomero A, Isoardi NA, Orsingher OA, Cuadra GR. Pharmacological reactivity to cocaine in adult rats undernourished at perinatal age: behavioral and neurochemical correlates. Neuropharmacology 2005, 48: 538–546.
- 202Valdomero A, Bussolino DF, Orsingher OA, Cuadra GR. Perinatal protein malnutrition enhances rewarding cocaine properties in adult rats. Neuroscience 2006, 137: 221–229.
- 203Kehoe P, Mallinson K, Bronzino J, McCormick CM. Effects of prenatal protein malnutrition and neonatal stress on CNS responsiveness. Brain Res Dev Brain Res 2001, 132: 23–31.
- 204Naef L, Srivastava L, Gratton A, Hendrickson H, Owens SM, et al. Maternal high fat diet during the perinatal period alters mesocorticolimbic dopamine in the adult rat offspring: reduction in the behavioral responses to repeated amphetamine administration. Psychopharmacology (Berl) 2008, 197: 83–94.
- 205Kuperstein F, Eilam R, Yavin E. Altered expression of key dopaminergic regulatory proteins in the postnatal brain following perinatal n-3 fatty acid dietary deficiency. J Neurochem 2008, 106: 662–671.
- 206Unger EL, Paul T, Murray-Kolb LE, Felt B, Jones BC, et al. Early iron deficiency alters sensorimotor development and brain monoamines in rats. J Nutr 2007, 137: 118–124.
- 207Szczerbak G, Nowak P, Kostrzewa RM, Brus R. Maternal lead exposure produces long-term enhancement of dopaminergic reactivity in rat offspring. Neurochem Res 2007, 32: 1791–1798.
- 208Zhou R, Zhang Z, Zhu Y, Chen L, Sokabe M, et al. Deficits in development of synaptic plasticity in rat dorsal striatum following prenatal and neonatal exposure to low-dose bisphenol A. Neuroscience 2009, 159: 161–171.
- 209Narita M, Miyagawa K, Mizuo K, Yoshida T, Suzuki T. Changes in central dopaminergic systems and morphine reward by prenatal and neonatal exposure to bisphenol-A in mice: evidence for the importance of exposure period. Addict Biol 2007, 12: 167–172.
- 210Yokota S, Mizuo K, Moriya N, Oshio S, Sugawara I, et al. Effect of prenatal exposure to diesel exhaust on dopaminergic system in mice. Neurosci Lett 2009, 449: 38–41.
- 211Stanwood GD, Levitt P. Prenatal exposure to cocaine produces unique developmental and long-term adaptive changes in dopamine D1 receptor activity and subcellular distribution. J Neurosci 2007, 27: 152–157.
- 212Tropea TF, Guerriero RM, Willuhn I, Unterwald EM, Ehrlich ME, et al. Augmented D1 dopamine receptor signaling and immediate-early gene induction in adult striatum after prenatal cocaine. Biol Psychiatry 2008, 63: 1066–1074.
- 213Strackx E, Van den Hove DL, Steinbusch HP, Steinbusch HW, Vles JS, et al. A combined behavioral and morphological study on the effects of fetal asphyxia on the nigrostriatal dopaminergic system in adult rats. Exp Neurol 2008, 211: 413–422.
- 214Son GH, Chung S, Geum D, Kang SS, Choi WS, et al. Hyperactivity and alteration of the midbrain dopaminergic system in maternally stressed male mice offspring. Biochem Biophys Res Commun 2007, 352: 823–829.
- 215Silvagni A, Barros VG, Mura C, Antonelli MC, Carboni E. Prenatal restraint stress differentially modifies basal and stimulated dopamine and noradrenaline release in the nucleus accumbens shell: an ‘in vivo’ microdialysis study in adolescent and young adult rats. Eur J Neurosci 2008, 28: 744–758.
- 216Kippin TE, Szumlinski KK, Kapasova Z, Rezner B, See RE. Prenatal stress enhances responsiveness to cocaine. Neuropsychopharmacology 2008, 33: 769–782.
- 217McArthur S, McHale E, Gillies GE. The size and distribution of midbrain dopaminergic populations are permanently altered by perinatal glucocorticoid exposure in a sex- region- and time-specific manner. Neuropsychopharmacology 2007, 32: 1462–1476.
- 218Wang S, Yan JY, Lo YK, Carvey PM, Ling Z. Dopaminergic and serotoninergic deficiencies in young adult rats prenatally exposed to the bacterial lipopolysaccharide. Brain Res 2009, 1265: 196–204.
- 219Stice E, Spoor S, Ng J, Zald DH. Relation of obesity to consummatory and anticipatory food reward. Physiol Behav 2009, 97: 551–560.
