, Volume 204, Issue 3, pp 431–443 | Cite as

Withdrawal from free-choice high-fat high-sugar diet induces craving only in obesity-prone animals

  • Chris PickeringEmail author
  • Johan Alsiö
  • Anna-Lena Hulting
  • Helgi B. Schiöth
Original Investigation



Vulnerability for weight gain is an individual trait. Obese people undertake dieting, but permanent weight loss is difficult to attain due to repeated phases of relapse to excess consumption.

Materials and methods

In this study, male Wistar rats were trained to operantly self-administer pellets followed by free-choice access in the homecage to high-fat high-sugar (HFHS) diet consisting of 30% sucrose, lard, standard rodent chow and water. Animals were divided into obesity-prone (OP) and obesity-resistant (OR) groups based on relative weight gain compared to normally fed controls despite equal consumption of HFHS.

Results and discussion

After 4 weeks of HFHS access, OP and OR animals did not differ in motivation for food pellets in terms of progressive ratio break point, lever pressing or response rate. However, upon discontinuation of the HFHS diet, differences between the OP and OR groups were noted. OP animals increased their motivation (i.e. craving) during the second withdrawal week and reduced time spent in the centre of an open field (increased anxiety) compared to the OR animals. Both OP and OR animals consumed less of the standard rodent chow during the first week of withdrawal when compared to normally fed controls. But, while the OR animals quickly returned to control levels of food consumption, OP animals continued to consume less standard rodent chow.


The results show for the first time that withdrawal from free-choice HFHS induces craving that is specific to the OP animals and suggests that OP individuals may have withdrawal symptoms that are similar to those induced by addictive drugs.


Diet-induced obesity Operant self-administration Progressive ratio Fixed ratio Whole-animal physiology 



We thank Dr Jonas Lindblom for valuable discussions. The studies were supported by the Swedish Research Council, AFA insurance, Alcohol Research Council of the Swedish Alcohol Retailing Monopoly, Åhlen Foundation and The Novo Nordisk Foundation. CP was supported by the Swedish Brain Foundation (Hjärnfonden).

Supplementary material

213_2009_1474_MOESM1_ESM.doc (16 kb)
Supplementary Table 1 (DOC 20.8 KB)


  1. Alexander J, Chang GQ, Dourmashkin JT, Leibowitz SF (2006) Distinct phenotypes of obesity-prone AKR/J, DBA2J and C57BL/6 J mice compared to control strains. Int J Obes (Lond) 30:50–9CrossRefGoogle Scholar
  2. Anton RF, Moak DH, Latham P, Waid LR, Myrick H, Voronin K, Thevos A, Wang W, Woolson R (2005) Naltrexone combined with either cognitive behavioral or motivational enhancement therapy for alcohol dependence. J Clin Psychopharmacol 25:349–57PubMedCrossRefGoogle Scholar
  3. Avena NM, Bocarsly ME, Rada P, Kim A, Hoebel BG (2008a) After daily bingeing on a sucrose solution, food deprivation induces anxiety and accumbens dopamine/acetylcholine imbalance. Physiol Behav 94:309–15PubMedCrossRefGoogle Scholar
  4. Avena NM, Rada P, Hoebel BG (2008b) Evidence for sugar addiction: behavioral and neurochemical effects of intermittent, excessive sugar intake. Neurosci Biobehav Rev 32:20–39PubMedCrossRefGoogle Scholar
  5. Avena NM, Rada P, Hoebel BG (2008c) Underweight rats have enhanced dopamine release and blunted acetylcholine response in the nucleus accumbens while bingeing on sucrose. Neuroscience 156:865–71PubMedCrossRefGoogle Scholar
  6. Bassareo V, De Luca MA, Di Chiara G (2002) Differential expression of motivational stimulus properties by dopamine in nucleus accumbens shell versus core and prefrontal cortex. J Neurosci 22:4709–19PubMedGoogle Scholar
  7. Bassareo V, Di Chiara G (1997) Differential influence of associative and nonassociative learning mechanisms on the responsiveness of prefrontal and accumbal dopamine transmission to food stimuli in rats fed ad libitum. J Neurosci 17:851–61PubMedGoogle Scholar
  8. Bassareo V, Di Chiara G (1999) Differential responsiveness of dopamine transmission to food-stimuli in nucleus accumbens shell/core compartments. Neuroscience 89:637–41PubMedCrossRefGoogle Scholar
  9. Boggiano MM, Artiga AI, Pritchett CE, Chandler-Laney PC, Smith ML, Eldridge AJ (2007) High intake of palatable food predicts binge-eating independent of susceptibility to obesity: an animal model of lean vs obese binge-eating and obesity with and without binge-eating. Int J Obes (Lond) 31:1357–67CrossRefGoogle Scholar
  10. Buonopane A, Petrakis IL (2005) Pharmacotherapy of alcohol use disorders. Subst Use Misuse 40(2001–20):2043–8Google Scholar
  11. Colantuoni C, Rada P, McCarthy J, Patten C, Avena NM, Chadeayne A, Hoebel BG (2002) Evidence that intermittent, excessive sugar intake causes endogenous opioid dependence. Obes Res 10:478–88PubMedCrossRefGoogle Scholar
  12. Collins S, Martin TL, Surwit RS, Robidoux J (2004) Genetic vulnerability to diet-induced obesity in the C57BL/6 J mouse: physiological and molecular characteristics. Physiol Behav 81:243–8PubMedCrossRefGoogle Scholar
  13. Denenberg VH (1969) Open-field behavior in the rat: what does it mean? Ann N Y Acad Sci 159:852–9PubMedCrossRefGoogle Scholar
  14. Eichler K, Zoller M, Steurer J, Bachmann LM (2007) Cognitive-behavioural treatment for weight loss in primary care: a prospective study. Swiss Med Wkly 137:489–95PubMedGoogle Scholar
  15. Ferster CB, Skinner BF (1957) Schedules of Reinforcement. Appleton-Century-Crofts, Appleton-Century-CroftsCrossRefGoogle Scholar
  16. Galarce EM, Crombag HS, Holland PC (2007) Reinforcer-specificity of appetitive and consummatory behavior of rats after Pavlovian conditioning with food reinforcers. Physiol Behav 91:95–105PubMedCrossRefGoogle Scholar
  17. Heilig M, Egli M (2006) Pharmacological treatment of alcohol dependence: target symptoms and target mechanisms. Pharmacol Ther 111:855–76PubMedCrossRefGoogle Scholar
  18. Heyser CJ, Schulteis G, Koob GF (1997) Increased ethanol self-administration after a period of imposed ethanol deprivation in rats trained in a limited access paradigm. Alcohol Clin Exp Res 21:784–91PubMedGoogle Scholar
  19. Hill AJ (2007) The psychology of food craving. Proc Nutr Soc 66:277–85PubMedCrossRefGoogle Scholar
  20. Holter SM, Linthorst AC, Reul JM, Spanagel R (2000) Withdrawal symptoms in a long-term model of voluntary alcohol drinking in Wistar rats. Pharmacol Biochem Behav 66:143–51PubMedCrossRefGoogle Scholar
  21. Katz RJ, Roth KA, Carroll BJ (1981) Acute and chronic stress effects on open field activity in the rat: implications for a model of depression. Neurosci Biobehav Rev 5:247–51PubMedCrossRefGoogle Scholar
  22. la Fleur SE, Akana SF, Manalo SL, Dallman MF (2004) Interaction between corticosterone and insulin in obesity: regulation of lard intake and fat stores. Endocrinology 145:2174–85PubMedCrossRefGoogle Scholar
  23. la Fleur SE, Vanderschuren LJ, Luijendijk MC, Kloeze BM, Tiesjema B, Adan RA (2007) A reciprocal interaction between food-motivated behavior and diet-induced obesity. Int J Obes (Lond) 31:1286–94CrossRefGoogle Scholar
  24. Leibowitz KL, Chang GQ, Pamy PS, Hill JO, Gayles EC, Leibowitz SF (2007) Weight gain model in prepubertal rats: prediction and phenotyping of obesity-prone animals at normal body weight. Int J Obes (Lond) 31:1210–21CrossRefGoogle Scholar
  25. Levin BE, Dunn-Meynell AA, Balkan B, Keesey RE (1997) Selective breeding for diet-induced obesity and resistance in Sprague-Dawley rats. Am J Physiol 273:R725–30PubMedGoogle Scholar
  26. Markou A, Weiss F, Gold LH, Caine SB, Schulteis G, Koob GF (1993) Animal models of drug craving. Psychopharmacology (Berl) 112:163–82CrossRefGoogle Scholar
  27. McTigue KM, Harris R, Hemphill B, Lux L, Sutton S, Bunton AJ, Lohr KN (2003) Screening and interventions for obesity in adults: summary of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med 139:933–49PubMedGoogle Scholar
  28. Mierzejewski P, Koros E, Goldberg SR, Kostowski W, Stefanski R (2003) Intravenous self-administration of morphine and cocaine: a comparative study. Pol J Pharmacol 55:713–26PubMedGoogle Scholar
  29. Moreira T, Cebers G, Cebere A, Wagner A, Liljequist S (2005) Extradural compression of the sensorimotor cortex delays the acquisition but not the recalling of a lever-pressing task in Wistar rats. Behav Brain Res 164:250–65PubMedCrossRefGoogle Scholar
  30. Pecoraro N, Reyes F, Gomez F, Bhargava A, Dallman MF (2004) Chronic stress promotes palatable feeding, which reduces signs of stress: feedforward and feedback effects of chronic stress. Endocrinology 145:3754–62PubMedCrossRefGoogle Scholar
  31. Pelchat ML (2002) Of human bondage: food craving, obsession, compulsion, and addiction. Physiol Behav 76:347–52PubMedCrossRefGoogle Scholar
  32. Pickering C, Avesson L, Lindblom J, Liljequist S, Schioth HB (2007a) Identification of neurotransmitter receptor genes involved in alcohol self-administration in the rat prefrontal cortex, hippocampus and amygdala. Prog Neuropsychopharmacol Biol Psychiatry 31:53–64PubMedCrossRefGoogle Scholar
  33. Pickering C, Liljequist S (2003) Cue-induced behavioural activation: a novel model of alcohol craving? Psychopharmacology (Berl) 168:307–13CrossRefGoogle Scholar
  34. Pickering C, Moreira T, Liljequist S (2007b) Delayed access to alcohol accelerates self-administration of alcohol on a progressive ratio schedule. Basic Clin Pharmacol Toxicol 100:109–14PubMedGoogle Scholar
  35. Prut L, Belzung C (2003) The open field as a paradigm to measure the effects of drugs on anxiety-like behaviors: a review. Eur J Pharmacol 463:3–33PubMedCrossRefGoogle Scholar
  36. Rada P, Avena NM, Hoebel BG (2005) Daily bingeing on sugar repeatedly releases dopamine in the accumbens shell. Neuroscience 134:737–44PubMedCrossRefGoogle Scholar
  37. Richardson NR, Roberts DC (1996) Progressive ratio schedules in drug self-administration studies in rats: a method to evaluate reinforcing efficacy. J Neurosci Methods 66:1–11PubMedCrossRefGoogle Scholar
  38. Schemmel R, Mickelsen O, Gill JL (1970) Dietary obesity in rats: body weight and body fat accretion in seven strains of rats. J Nutr 100:1041–8PubMedGoogle Scholar
  39. Shepherd J, Harden A, Rees R, Brunton G, Garcia J, Oliver S, Oakley A (2006) Young people and healthy eating: a systematic review of research on barriers and facilitators. Health Educ Res 21:239–57PubMedCrossRefGoogle Scholar
  40. Skinner BF (1938) The Behavior of Organisms: An Experimental Analysis. B F Skinner Foundation, B F Skinner FoundationGoogle Scholar
  41. Stafford D, LeSage MG, Glowa JR (1998) Progressive-ratio schedules of drug delivery in the analysis of drug self-administration: a review. Psychopharmacology (Berl) 139:169–84CrossRefGoogle Scholar
  42. Tiffany ST, Carter BL (1998) Is craving the source of compulsive drug use? J Psychopharmacol 12:23–30PubMedCrossRefGoogle Scholar
  43. Tiffany ST, Conklin CA (2000) A cognitive processing model of alcohol craving and compulsive alcohol use. Addiction 95(Suppl 2):S145–53PubMedGoogle Scholar
  44. Vanderschuren LJ, Everitt BJ (2005) Behavioral and neural mechanisms of compulsive drug seeking. Eur J Pharmacol 526:77–88PubMedCrossRefGoogle Scholar
  45. Wang J, Alexander JT, Zheng P, Yu HJ, Dourmashkin J, Leibowitz SF (1998) Behavioral and endocrine traits of obesity-prone and obesity-resistant rats on macronutrient diets. Am J Physiol 274:E1057–66PubMedGoogle Scholar
  46. Weiss F (2005) Neurobiology of craving, conditioned reward and relapse. Curr Opin Pharmacol 5:9–19PubMedCrossRefGoogle Scholar
  47. Volkow ND, Wise RA (2005) How can drug addiction help us understand obesity? Nat Neurosci 8:555–60PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Chris Pickering
    • 1
    Email author
  • Johan Alsiö
    • 1
  • Anna-Lena Hulting
    • 2
  • Helgi B. Schiöth
    • 1
  1. 1.Department of Neuroscience Functional PharmacologyUppsala UniversityUppsalaSweden
  2. 2.Department of Endocrinology, Metabolism and DiabetologyKarolinska Institutet/Karolinska University Hospital-SolnaStockholmSweden

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