Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Dopamine D2 receptors in addiction-like reward dysfunction and compulsive eating in obese rats

A Corrigendum to this article was published on 01 August 2010

This article has been updated

Abstract

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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Weight gain and reward dysfunction in rats with extended access to a cafeteria diet.
Figure 2: Patterns of consumption in rats with extended access to a cafeteria diet.
Figure 3: Persistent reward dysfunction and hypophagia during abstinence in rats with extended access to a cafeteria diet.
Figure 4: Weight gain is inversely related to striatal D2R levels.
Figure 5: Lentivirus-mediated knockdown of striatal D2R expression.
Figure 6: Knockdown of striatal D2R increases vulnerability to reward dysfunction in rats with extended access to a cafeteria diet.
Figure 7: Compulsive-like responding for palatable food.

Change history

  • 09 July 2010

    In the version of this article initially published, two citations were inadvertently omitted. To correct this, the following sentence was inserted after the sixth sentence in the introduction (first paragraph, line 16): "In rats, both susceptibility to obesity and diet-induced obesity have been linked to deficits in mesolimbic dopamine signaling, with obesity-susceptible animals exhibiting reduced levels of D2 receptors50,51." These references have been added to the reference list as follows: 50. Geiger, B.M. et al. Evidence for defective mesolimbic dopamine exocytosis in obesity-prone rats. FASEB J22, 2740–2746 (2008). 51. Geiger, B.M. et al. Deficits of mesolimbic dopamine neurotransmission in rat dietary obesity. Neuroscience 10, 1193–1199 (2009). The error has been corrected in the HTML and PDF versions of the article.

References

  1. Saper, C.B., Chou, T.C. & Elmquist, J.K. The need to feed: homeostatic and hedonic control of eating. Neuron 36, 199–211 (2002).

    Article  CAS  PubMed  Google Scholar 

  2. Zheng, H. & Berthoud, H.R. Eating for pleasure or calories. Curr. Opin. Pharmacol. 7, 607–612 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Farooqi, I.S. et al. Leptin regulates striatal regions and human eating behavior. Science 317, 1355 (2007).

    Article  CAS  PubMed  Google Scholar 

  4. 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).

    Article  CAS  PubMed  Google Scholar 

  5. Noble, E.P. Addiction and its reward process through polymorphisms of the D2 dopamine receptor gene: a review. Eur. Psychiatry 15, 79–89 (2000).

    Article  CAS  PubMed  Google Scholar 

  6. 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).

    Article  CAS  PubMed  Google Scholar 

  7. 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).

    Article  PubMed  Google Scholar 

  8. 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).

    Article  PubMed  Google Scholar 

  9. American Medical Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) (American Psychiatric Association Publishing, Washington, D.C., 1994).

  10. 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).

    Article  CAS  PubMed  Google Scholar 

  11. 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).

    Article  CAS  Google Scholar 

  12. 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).

    Article  CAS  PubMed  Google Scholar 

  13. Markou, A. & Koob, G.F. Postcocaine anhedonia. An animal model of cocaine withdrawal. Neuropsychopharmacology 4, 17–26 (1991).

    CAS  PubMed  Google Scholar 

  14. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. 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).

    Article  CAS  PubMed  Google Scholar 

  16. 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).

    Article  PubMed  Google Scholar 

  17. 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).

    Article  CAS  PubMed  Google Scholar 

  18. Vanderschuren, L.J. & Everitt, B.J. Drug seeking becomes compulsive after prolonged cocaine self-administration. Science 305, 1017–1019 (2004).

    Article  CAS  PubMed  Google Scholar 

  19. Volkow, N.D. & Wise, R.A. How can drug addiction help us understand obesity? Nat. Neurosci. 8, 555–560 (2005).

    Article  CAS  PubMed  Google Scholar 

  20. 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).

    Article  CAS  PubMed  Google Scholar 

  21. Hoebel, B.G. & Teitelbaum, P. Hypothalamic control of feeding and self-stimulation. Science 135, 375–377 (1962).

    Article  CAS  PubMed  Google Scholar 

  22. Mount, G. & Hoebel, B.G. Lateral hypothalamic self-stimulation: self-determined threshold increased by food intake. Psychon. Sci. 9, 265–266 (1967).

    Article  Google Scholar 

  23. Hoebel, B.G. Feeding and self-stimulation. Ann. NY Acad. Sci. 157, 758–778 (1969).

    Article  CAS  PubMed  Google Scholar 

  24. Hoebel, B.G. & Balagura, S. Self-stimulation of the lateral hypothalamus modified by insulin and glucagon. Physiol. Behav. 2, 337–340 (1967).

    Article  Google Scholar 

  25. 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).

    Article  CAS  PubMed  Google Scholar 

  26. Wilkinson, H.A. & Peele, T.L. Modification of intracranial self-stimulation by hunger satiety. Am. J. Physiol. 203, 537–540 (1962).

    Article  CAS  PubMed  Google Scholar 

  27. Fulton, S., Woodside, B. & Shizgal, P. Modulation of brain reward circuitry by leptin. Science 287, 125–128 (2000).

    Article  CAS  PubMed  Google Scholar 

  28. Wang, G.J. et al. Gastric distention activates satiety circuitry in the human brain. Neuroimage 39, 1824–1831 (2008).

    Article  PubMed  Google Scholar 

  29. Batterham, R.L. et al. PYY modulation of cortical and hypothalamic brain areas predicts feeding behavior in humans. Nature 450, 106–109 (2007).

    Article  CAS  PubMed  Google Scholar 

  30. Hommel, J.D. et al. Leptin receptor signaling in midbrain dopamine neurons regulates feeding. Neuron 51, 801–810 (2006).

    Article  CAS  PubMed  Google Scholar 

  31. Fulton, S. et al. Leptin regulation of the mesoaccumbens dopamine pathway. Neuron 51, 811–822 (2006).

    Article  CAS  PubMed  Google Scholar 

  32. Koob, G.F. & Le Moal, M. Plasticity of reward neurocircuitry and the 'dark side' of drug addiction. Nat. Neurosci. 8, 1442–1444 (2005).

    Article  CAS  PubMed  Google Scholar 

  33. Kenny, P.J. Brain reward systems and compulsive drug use. Trends Pharmacol. Sci. 28, 135–141 (2007).

    Article  CAS  PubMed  Google Scholar 

  34. Wang, G.J. et al. Brain dopamine and obesity. Lancet 357, 354–357 (2001).

    Article  CAS  PubMed  Google Scholar 

  35. 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).

    Article  CAS  PubMed  Google Scholar 

  36. 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).

    Article  CAS  PubMed  Google Scholar 

  37. 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).

    Article  CAS  PubMed  Google Scholar 

  38. 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).

    Article  CAS  PubMed  Google Scholar 

  39. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. 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).

    Article  PubMed  Google Scholar 

  41. Klein, T.A. et al. Genetically determined differences in learning from errors. Science 318, 1642–1645 (2007).

    Article  CAS  PubMed  Google Scholar 

  42. Teegarden, S.L. & Bale, T.L. Decreases in dietary preference produce increased emotionality and risk for dietary relapse. Biol. Psychiatry 61, 1021–1029 (2007).

    Article  PubMed  Google Scholar 

  43. 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).

    Article  PubMed  Google Scholar 

  44. 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).

    Article  CAS  PubMed  Google Scholar 

  45. 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).

    Article  CAS  PubMed  Google Scholar 

  46. 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).

    Article  PubMed  Google Scholar 

  47. Cottone, P. et al. CRF system recruitment mediates dark side of compulsive eating. Proc. Natl. Acad. Sci. USA 106, 20016–20020 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Pellegrino, L.J., Pellegrino, A.S. & Cushman, A.J. A Stereotaxic Atlas of the Rat Brain (Plenum, New York, 1979).

  49. 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).

    Article  CAS  PubMed  Google Scholar 

  50. Geiger, B.M. et al. Evidence for defective mesolimbic dopamine exocytosis in obesity-prone rats. FASEB J. 22, 2740–2746 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Geiger, B.M. et al. Deficits of mesolimbic dopamine neurotransmission in rat dietary obesity. Neuroscience 10, 1193–1199 (2009).

    Article  Google Scholar 

Download references

Acknowledgements

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.

Author information

Authors and Affiliations

Authors

Contributions

P.M.J. conducted all experiments. P.M.J. and P.J.K. designed the experiments, analyzed the data and wrote the manuscript.

Corresponding author

Correspondence to Paul J Kenny.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–13 (PDF 6630 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nn.2519

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing