We found that development of obesity was coupled with emergence of a progressively worsening deficit in neural reward responses. Similar changes in reward homeostasis induced by cocaine or heroin are considered to be crucial in triggering the transition from casual to compulsive drug-taking. Accordingly, we detected compulsive-like feeding behavior in obese but not lean rats, measured as palatable food consumption that was resistant to disruption by an aversive conditioned stimulus. Striatal dopamine D2 receptors (D2Rs) were downregulated in obese rats, as has been reported in humans addicted to drugs. Moreover, lentivirus-mediated knockdown of striatal D2Rs rapidly accelerated the development of addiction-like reward deficits and the onset of compulsive-like food seeking in rats with extended access to palatable high-fat food. These data demonstrate that overconsumption of palatable food triggers addiction-like neuroadaptive responses in brain reward circuits and drives the development of compulsive eating. Common hedonic mechanisms may therefore underlie obesity and drug addiction.
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Saper, C.B., Chou, T.C. & Elmquist, J.K. The need to feed: homeostatic and hedonic control of eating. Neuron 36, 199–211 (2002).
Zheng, H. & Berthoud, H.R. Eating for pleasure or calories. Curr. Opin. Pharmacol. 7, 607–612 (2007).
Farooqi, I.S. et al. Leptin regulates striatal regions and human eating behavior. Science 317, 1355 (2007).
Stice, E., Spoor, S., Bohon, C. & Small, D.M. Relation between obesity and blunted striatal response to food is moderated by TaqIA A1 allele. Science 322, 449–452 (2008).
Noble, E.P. Addiction and its reward process through polymorphisms of the D2 dopamine receptor gene: a review. Eur. Psychiatry 15, 79–89 (2000).
Wang, G.J., Volkow, N.D. & Fowler, J.S. The role of dopamine in motivation for food in humans: implications for obesity. Expert Opin. Ther. Targets 6, 601–609 (2002).
Booth, M.L., Wilkenfeld, R.L., Pagnini, D.L., Booth, S.L. & King, L.A. Perceptions of adolescents on overweight and obesity: the weight of opinion study. J. Paediatr. Child Health 44, 248–252 (2008).
Puhl, R.M., Moss-Racusin, C.A., Schwartz, M.B. & Brownell, K.D. Weight stigmatization and bias reduction: perspectives of overweight and obese adults. Health Educ. Res. 23, 347–358 (2008).
American Medical Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) (American Psychiatric Association Publishing, Washington, D.C., 1994).
Markou, A. & Koob, G.F. Construct validity of a self-stimulation threshold paradigm: effects of reward and performance manipulations. Physiol. Behav. 51, 111–119 (1992).
Rolls, B.J., Rowe, E.A. & Turner, R.C. Persistent obesity in rats following a period of consumption of a mixed, high energy diet. J. Physiol. (Lond.) 298, 415–427 (1980).
Ahmed, S.H., Kenny, P.J., Koob, G.F. & Markou, A. Neurobiological evidence for hedonic allostasis associated with escalating cocaine use. Nat. Neurosci. 5, 625–626 (2002).
Markou, A. & Koob, G.F. Postcocaine anhedonia. An animal model of cocaine withdrawal. Neuropsychopharmacology 4, 17–26 (1991).
Kenny, P.J., Chen, S.A., Kitamura, O., Markou, A. & Koob, G.F. Conditioned withdrawal drives heroin consumption and decreases reward sensitivity. J. Neurosci. 26, 5894–5900 (2006).
Cottone, P., Sabino, V., Steardo, L. & Zorrilla, E.P. Opioid-dependent anticipatory negative contrast and binge-like eating in rats with limited access to highly preferred food. Neuropsychopharmacology 33, 524–535 (2008).
Lladó, I. et al. Effects of cafeteria diet feeding on beta3-adrenoceptor expression and lipolytic activity in white adipose tissue of male and female rats. Int. J. Obes. Relat. Metab. Disord. 24, 1396–1404 (2000).
Fishburn, C.S., Elazar, Z. & Fuchs, S. Differential glycosylation and intracellular trafficking for the long and short isoforms of the D2 dopamine receptor. J. Biol. Chem. 270, 29819–29824 (1995).
Vanderschuren, L.J. & Everitt, B.J. Drug seeking becomes compulsive after prolonged cocaine self-administration. Science 305, 1017–1019 (2004).
Volkow, N.D. & Wise, R.A. How can drug addiction help us understand obesity? Nat. Neurosci. 8, 555–560 (2005).
Blundell, J.E. & Herberg, L.J. Relative effects of nutritional deficit and deprivation period on rate of electrical self-stimulation of lateral hypothalamus. Nature 219, 627–628 (1968).
Hoebel, B.G. & Teitelbaum, P. Hypothalamic control of feeding and self-stimulation. Science 135, 375–377 (1962).
Mount, G. & Hoebel, B.G. Lateral hypothalamic self-stimulation: self-determined threshold increased by food intake. Psychon. Sci. 9, 265–266 (1967).
Hoebel, B.G. Feeding and self-stimulation. Ann. NY Acad. Sci. 157, 758–778 (1969).
Hoebel, B.G. & Balagura, S. Self-stimulation of the lateral hypothalamus modified by insulin and glucagon. Physiol. Behav. 2, 337–340 (1967).
Hoebel, B.G. & Thompson, R.D. Aversion to lateral hypothalamic stimulation caused by intragastric feeding or obesity. J. Comp. Physiol. Psychol. 68, 536–543 (1969).
Wilkinson, H.A. & Peele, T.L. Modification of intracranial self-stimulation by hunger satiety. Am. J. Physiol. 203, 537–540 (1962).
Fulton, S., Woodside, B. & Shizgal, P. Modulation of brain reward circuitry by leptin. Science 287, 125–128 (2000).
Wang, G.J. et al. Gastric distention activates satiety circuitry in the human brain. Neuroimage 39, 1824–1831 (2008).
Batterham, R.L. et al. PYY modulation of cortical and hypothalamic brain areas predicts feeding behavior in humans. Nature 450, 106–109 (2007).
Hommel, J.D. et al. Leptin receptor signaling in midbrain dopamine neurons regulates feeding. Neuron 51, 801–810 (2006).
Fulton, S. et al. Leptin regulation of the mesoaccumbens dopamine pathway. Neuron 51, 811–822 (2006).
Koob, G.F. & Le Moal, M. Plasticity of reward neurocircuitry and the 'dark side' of drug addiction. Nat. Neurosci. 8, 1442–1444 (2005).
Kenny, P.J. Brain reward systems and compulsive drug use. Trends Pharmacol. Sci. 28, 135–141 (2007).
Wang, G.J. et al. Brain dopamine and obesity. Lancet 357, 354–357 (2001).
Huang, X.F. et al. Dopamine transporter and D2 receptor binding densities in mice prone or resistant to chronic high fat diet-induced obesity. Behav. Brain Res. 175, 415–419 (2006).
Thanos, P.K., Michaelides, M., Piyis, Y.K., Wang, G.J. & Volkow, N.D. Food restriction markedly increases dopamine D2 receptor (D2R) in a rat model of obesity as assessed with in vivo muPET imaging ([11C] raclopride) and in vitro ([3H] spiperone) autoradiography. Synapse 62, 50–61 (2008).
Frank, G.K. et al. Increased dopamine D2/D3 receptor binding after recovery from anorexia nervosa measured by positron emission tomography and [11C]raclopride. Biol. Psychiatry 58, 908–912 (2005).
Neville, M.J., Johnstone, E.C. & Walton, R.T. Identification and characterization of ANKK1: a novel kinase gene closely linked to DRD2 on chromosome band 11q23.1. Hum. Mutat. 23, 540–545 (2004).
Mastronardi, C.A., Yu, W.H., Srivastava, V.K., Dees, W.L. & McCann, S.M. Lipopolysaccharide-induced leptin release is neurally controlled. Proc. Natl. Acad. Sci. USA 98, 14720–14725 (2001).
Yin, H.H., Knowlton, B.J. & Balleine, B.W. Inactivation of dorsolateral striatum enhances sensitivity to changes in the action-outcome contingency in instrumental conditioning. Behav. Brain Res. 166, 189–196 (2006).
Klein, T.A. et al. Genetically determined differences in learning from errors. Science 318, 1642–1645 (2007).
Teegarden, S.L. & Bale, T.L. Decreases in dietary preference produce increased emotionality and risk for dietary relapse. Biol. Psychiatry 61, 1021–1029 (2007).
Volkow, N.D. et al. Low dopamine striatal D2 receptors are associated with prefrontal metabolism in obese subjects: possible contributing factors. Neuroimage 42, 1537–1543 (2008).
Clarke, H.F., Dalley, J.W., Crofts, H.S., Robbins, T.W. & Roberts, A.C. Cognitive inflexibility after prefrontal serotonin depletion. Science 304, 878–880 (2004).
Avena, N.M., Rada, P. & Hoebel, B.G. Evidence for sugar addiction: behavioral and neurochemical effects of intermittent, excessive sugar intake. Neurosci. Biobehav. Rev. 32, 20–39 (2008).
Volkow, N.D. & O'Brien, C.P. Issues for DSM-V: should obesity be included as a brain disorder? Am. J. Psychiatry 164, 708–710 (2007).
Cottone, P. et al. CRF system recruitment mediates dark side of compulsive eating. Proc. Natl. Acad. Sci. USA 106, 20016–20020 (2009).
Pellegrino, L.J., Pellegrino, A.S. & Cushman, A.J. A Stereotaxic Atlas of the Rat Brain (Plenum, New York, 1979).
David, C., Fishburn, C.S., Monsma, F.J. Jr., Sibley, D.R. & Fuchs, S. Synthesis and processing of D2 dopamine receptors. Biochemistry 32, 8179–8183 (1993).
Geiger, B.M. et al. Evidence for defective mesolimbic dopamine exocytosis in obesity-prone rats. FASEB J. 22, 2740–2746 (2008).
Geiger, B.M. et al. Deficits of mesolimbic dopamine neurotransmission in rat dietary obesity. Neuroscience 10, 1193–1199 (2009).
This work was supported by a Bank of America Fellowship (P.M.J.), the Landenberger Foundation (P.J.K.) and a grant from the US National Institutes of Health (DA025983; P.J.K.). This is publication number 19,563 from the Scripps Research Institute.
The authors declare no competing financial interests.
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Johnson, P., Kenny, P. Dopamine D2 receptors in addiction-like reward dysfunction and compulsive eating in obese rats. Nat Neurosci 13, 635–641 (2010). https://doi.org/10.1038/nn.2519
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