, Volume 204, Issue 1, pp 113–125 | Cite as

A preclinical model of binge eating elicited by yo-yo dieting and stressful exposure to food: effect of sibutramine, fluoxetine, topiramate, and midazolam

  • Carlo Cifani
  • Carlo Polidori
  • Sergio Melotto
  • Roberto Ciccocioppo
  • Maurizio Massi
Original Investigation



Preclinical models are needed to investigate the neurobiology and psychobiology of binge eating and to identify innovative pharmacotherapeutic strategies.


A modification of the model based on the combination of cyclic caloric restrictions and acute stress was developed to further increase its face validity and reliability and, for the first time, to assess its predictive value.

Materials and methods

Four groups of female rats were employed: group 1 was normally fed and not stressed on the test day (25th); group 2 was fed normally but was exposed to an acute stress on day 25; group 3 was exposed to three cycles (4 days 66% of chow intake + 4 days food ad libitum) of yo-yo dieting but not stressed; and group 4 was exposed to cyclic yo-yo dieting and then stressed. All groups were fed highly palatable food (HPF) for 2 h on days 5–6 and 13–14. Acute stress was elicited by exposing rats to HPF, but preventing them from access to it for 15 min.


The combination of cyclic food restriction and stressful exposure to food markedly increased HPF intake. Sibutramine and fluoxetine inhibited food intake in all conditions. Topiramate selectively inhibited compulsive HPF intake in rats submitted to caloric restriction and stress. Midazolam increased HPF intake.


Pharmacological results suggest that this model, in addition to face validity as an isomorphic model of human binge eating, is endowed with good predictive validity.


Binge eating Caloric restriction Environmental stress Palatable food Sibutramine Fluoxetine Topiramate Midazolam Female rats 



This study was supported by the MURST, Rome, Italy (PRIN 2006 to M. Massi).


  1. Abraham SF, Beumont PJV (1982) How patients describe bulimia or binge eating. Psychol Med 12:625–635PubMedCrossRefGoogle Scholar
  2. Akana SF, Cascio CS, Du J-Z, Levin N, Dallman MF (1986) Reset of feedback in the adrenocortical system: an apparent shift in sensitivity of adrenocorticotrpin to inhibition of corticosterone in the morning and evening. Endocrinology 119:2325–2332PubMedGoogle Scholar
  3. American Psychiatric Association (2000) Diagnostic and statistic manual of mental disorders, IV-TR. APA, Washington, DCGoogle Scholar
  4. Appolinario JC, Godoy-Matos A, Fontenelle LF, Carraro L, Cabral M, Vieira A, Coutinho W (2002) An open-label trial of sibutramine in obese patients with binge-eating disorder. J Clin Psychiatry 63:28–30PubMedGoogle Scholar
  5. Appolinario JC, McElroy SL (2004) Pharmacological approaches in the treatment of binge eating disorders. Curr Drug Targets 5:301–307PubMedCrossRefGoogle Scholar
  6. Arnold LM, McElroy SL, Hudson JI, Welge JA, Bennett AJ, Keck PE (2002) A placebo-controlled, randomized trial of fluoxetine in the treatment of binge-eating disorder. J Clin Psychiatry 63:1028–1033PubMedGoogle Scholar
  7. Artiga AI, Viana JB, Maldonado CR, Chandler-Laney PC, Oswald KD, Boggiano MM (2007) Body composition and endocrine status of long-term stress-induced binge-eating rats. Physiol Behav 91:424–431PubMedCrossRefGoogle Scholar
  8. Carter WP, Hudson JI, Lalonde JK, Pindyck L, McElroy SL, Pope HG Jr (2003) Pharmacologic treatment of binge eating disorder. Int J Eat Disord 34(suppl):S74–S88PubMedCrossRefGoogle Scholar
  9. Cooper SJ (2005) Palatability-dependent appetite and benzodiazepines: new directions from the pharmacology of GABA(A) receptor subtype. Appetite 44:133–150PubMedCrossRefGoogle Scholar
  10. Cooper SJ, Estall LB (1985) Behavioural pharmacology of food, water and salt intake in relation to drug actions at benzodiazepine receptors. Neurosci Biobehav Rev 9:5–19PubMedCrossRefGoogle Scholar
  11. Corwin RL, Buda-Levin A (2004) Behavioral models of binge-type eating. Physiol Behav 82:123–130PubMedCrossRefGoogle Scholar
  12. Crowther JH, Sanftner J, Bonifazi DZ, Shepherd KL (2001) The role of daily hassles in binge eating. Int J Eat Disord 29:449–454PubMedCrossRefGoogle Scholar
  13. De Bernardi C, Ferraris S, D’Innella P, Do F, Torre E (2005) Topiramate for binge eating disorder. Prog Neuropsychopharmacol Biol Psychiatry 29:339–341PubMedCrossRefGoogle Scholar
  14. Dolengevich Segal H, Rodriguez Salgado B, Conejo Garcia A, San Sebastian Cabases J (2006) Efficacy of topiramate in children and adolescent with problems of impulse control: preliminary results. Actas Esp Psiquiatr 34:280–282PubMedGoogle Scholar
  15. Freeman LM, Gil KM (2004) Daily stress, coping, and dietary restraint in binge eating. Int J Eat Disord 36:204–212PubMedCrossRefGoogle Scholar
  16. Hagan MM, Moss DE (1997) Persistence of binge-eating patterns after a history of restriction with intermittent bouts of refeeding on palatable food in rats: implications for bulimia nervosa. Int J Eat Disord 22:411–420PubMedCrossRefGoogle Scholar
  17. Hagan MM, Wauford PK, Chandler PC, Jarrett LA, Rybak RJ, Blackburn K (2002) A new animal model of binge-eating: key synergistic role of past caloric restriction and stress. Physiol Behav 77:45–54PubMedCrossRefGoogle Scholar
  18. Hagan MM, Chandler PC, Wauford PK, Rybak RJ, Oswald KD (2003) The role of palatable food and hunger as trigger factors in an animal model of stress-induced binge-eating. Int J Eat Disord 34:183–197PubMedCrossRefGoogle Scholar
  19. Han DH, Lyool IK, Sung YH, Lee SH, Renshaw PF (2008) The effect of acamprosate on alcohol and food craving in patients with alcohol dependence. Drug Alcohol Depend 93:279–283PubMedCrossRefGoogle Scholar
  20. Hansson AC, Cippitelli A, Sommer WH, Fedeli A, Bjork K, Soverchia L, Terasmaa A, Massi M, Heilig M, Ciccocioppo R (2006) Variation at the rat Crhr1 locus and sensitivity to relapse into alcohol seeking induced by environmental stress. Proc Natl Acad Sci U S A 103:15236–15241PubMedCrossRefGoogle Scholar
  21. Hudson JI, Hiripi E, Pope HG Jr., Kessler RC (2007) The prevalence and correlates of eating disorders in the National Comorbidity Survey Replication. Biol Psychiatry 61:348–358PubMedCrossRefGoogle Scholar
  22. Jackson HC, Needham AM, Hutchins LJ, Mazurkiewicz SE, Heal DJ (1997) Comparison of the effects of sibutramine and other monoamine reuptake inhibitors on food intake in the rat. Br J Pharmacol 121:1758–1762PubMedCrossRefGoogle Scholar
  23. Johannessen Landmark C (2007) Targets for antiepileptic drugs in the synase. Med Sci Monit 13:RA1–RA7Google Scholar
  24. Johnson BA, Ait-Daoud N, Bowden CL, DiClemente CC, Roache JD, Lawson K et al (2003) Oral topiramate for treatment of alcohol dependence: a randomised controlled trial. Lancet 361:1677–1685PubMedCrossRefGoogle Scholar
  25. Kampman KM, Pettinati H, Lynch KG, Dackis C, Sparkman T, Weigley C, O’Brien CP (2004) A pilot trial of topiramate for the treatment of cocaine dependence. Drug Alcohol Depend 75:233–240PubMedCrossRefGoogle Scholar
  26. Kjelsas E, Bjornstrom C, Gotestam KG (2004) Prevalence of eating disorders in female and male adolescents (14–15 years). Eat Behav 5:13–25PubMedCrossRefGoogle Scholar
  27. LeBlanc M, Thibault L (2003) Effect of sibutramine on macronutrient selection in male and female rats. Physiol Behav 80:243–252PubMedCrossRefGoogle Scholar
  28. Leigh AJ, Stock MJ, Lacey JH, Wilson CA (1998) Diet-induced loss of cyclic ovarian function at normal body weight in a rodent model for bulimia nervosa. J Reprod Fertil 112:217–223PubMedCrossRefGoogle Scholar
  29. Leombruni P, Pierò A, Lavagnino L, Brustolin A, Campisi S, Fassino S (2008) A randomized, double-blind trial comparing sertraline and fluoxetine 6-month treatment in obese patients with binge eating disorder. Progr Neuropsychopharmacol Biol Psychiatry 32:1599–1605CrossRefGoogle Scholar
  30. Martin-Fardon R, Ciccocioppo R, Massi M, Weiss F (2000) Nociceptin/orphanin FQ prevents stress induced ethanol- but not cocaine-seeking behavior in rats. NeuroReport 11:1939–1943PubMedCrossRefGoogle Scholar
  31. McElroy SL, Shapira NA, Arnold LM, Keck PE, Rosenthal NR, Wu SC et al (2004) Topiramate in the long-term treatment of binge eating disorder associated with obesity. J Clin Psychiatry 65:1453–1469Google Scholar
  32. McElroy SL, Hudson JI, Capece JA, Beyers K, Fisher AC, Rosenthal NR et al (2007) Topiramate for the treatment of binge eating disorder associated with obesity: a placebo-controlled study. Biol Psychiatry 61:1039–1048PubMedCrossRefGoogle Scholar
  33. Milano W, Petrella C, Casella A, Capasso A, Carrino S, Milano L (2005) Use of sibutramine, an inhibitor of the reuptake or serotonin and noradrenaline, in the treatment of binge eating disorder: a placebo-controlled study. Adv Ther 22:25–31PubMedCrossRefGoogle Scholar
  34. National Institute for Clinical Excellence (2004) Eating disorders—core interventions in the treatment and management of anorexia nervosa, bulimia nervosa, and related eating disorders. National Institute for Clinical Excellence, LondonGoogle Scholar
  35. Padwal RS, Majumdar SR (2007) Drug treatments for obesity: orlistat, sibutramine and rimonabant. Lancet 369:71–77PubMedCrossRefGoogle Scholar
  36. Polivy J, Zeitlin SB, Herman CP, Beal AL (1994) Food restriction and binge eating: a study of former prisoner of war. J Abnorm Psychol 103:409–411PubMedCrossRefGoogle Scholar
  37. Reid MS, Palamar J, Raghavan S, Flammino F (2007) Effects of topiramate on cue-induced cigarette craving and the response to a smoked cigarette in briefly abstinent smokers. Psychopharmacology (Berl) 192:147–158CrossRefGoogle Scholar
  38. Resis AD, Castro LA, Faria R, Laranjeira R (2008) Craving decrease with topiramate in outpatient treatment for cocaine dependence: an open label trial. Rev Bras Psiquiatr 30:132–135Google Scholar
  39. Robbins TW, Fray PJ (1980) Stress-induced eating: fact, fiction or misunderstanding. Appetite 1:103–133Google Scholar
  40. Schneiderman JH (1998) Topiramate: pharmacokinetics and pharmacodynamics. Can J Neurol Sci 25:S3–S5PubMedGoogle Scholar
  41. Shapiro JR, Berkman ND, Brownley KA, Sedway JA, Lohr KN, Bulik CM (2007) Bulimia nervosa treatment: a systematic review of randomized controlled trials. Int J Eat Disord 40:321–336PubMedCrossRefGoogle Scholar
  42. Simeone TA, Wilcox KS, White HS (2006) Subunit selectivity of topiramate modulation of heteromeric GABA(A) receptors. Neuropharmacology 50:845–857PubMedCrossRefGoogle Scholar
  43. Smith GP (1989) Animal models of human eating disorders. Ann N Y Acad Sci 575:63–72PubMedCrossRefGoogle Scholar
  44. Spitzer RL, Stunkard A, Yanovski S, Marcus MD, Wadden T, Wing R, Mitchell J, Hasin D (1993) Binge eating disorder should be included in DSM-IV: a reply to Fairburn et al.’s “the classification of recurrent overeating: the binge eating disorder proposal”. Int J Eat Disord 13:161–169PubMedCrossRefGoogle Scholar
  45. Spitzer RL, Yanovski S, Wadden T, Wing R, Marcus MD, Stunkard A, Devlin M, Mitchell J, Hasin D, Horne RL (1993a) Binge eating disorder: its further validation in a multisite study. Int J Eat Disord 13:137–153PubMedCrossRefGoogle Scholar
  46. Sterritt GM (1962) Inhibition and facilitation of eating by electric shock. J Comp Physiol Psychol 55:226–229PubMedCrossRefGoogle Scholar
  47. Stice E, Agras WS, Telch FC, Halmi KA, Mitchell JE, Wilson T (2001) Subtyping binge eating-disordered women along dieting and negative affect dimensions. Int J Eat Disord 30:11–27PubMedCrossRefGoogle Scholar
  48. Vitale G, Arletti R, Ruggieri V, Cifani C, Massi M (2006) Anxiolytic-like effects of nociceptin/orphanin FQ in the elevated plus maze and in the conditioned defensive burying test in rats. Peptides 27:2193–2200PubMedCrossRefGoogle Scholar
  49. Wardle J, Steptoe A, Oliver G, Lipsey Z (2000) Stress, dietary restraint and food intake. J Psychosom Res 48:195–202PubMedCrossRefGoogle Scholar
  50. Waters A, Hill A, Waller G (2001) Internal and external antecedents of binge eating episodes in a group of women with bulimia nervosa. Int J Eat Disord 29:17–22PubMedCrossRefGoogle Scholar
  51. Weltzin TE, Hsu LKG, Pollice C, Kaye WH (1991) Feeding pattern in bulimia nervosa. Biol Psychiatry 30:1093–1110PubMedCrossRefGoogle Scholar
  52. White HS, Smith MD, Wilcox KS (2007) Mechanism of action of antiepileptic drugs. Int Rev Neurobiol 81:85–110PubMedCrossRefGoogle Scholar
  53. Wilfley DE, Crow SJ, Hudson JI, Mitchell JE, Berkowitz RI, Blakesley V, Walsh BT (2008) Sibutramine eating disorder research Group. Efficacy of sibutramine for the treatment of binge eating disorder: a randomized multicenter placebo-controlled double-blind study. Am J Psychiatry 165:51–58PubMedCrossRefGoogle Scholar
  54. Willner P (1991) Behavioural models in psychopharmacology. In: Willner P (ed) Behavioural models in psychopharmacology. Cambridge University Press, Cambridge, pp 3–18Google Scholar
  55. Wolff GE, Crosby RD, Roberts JA, Wittrock DA (2000) Differences in daily stress, mood, coping, and eating behavior in binge eating and nonbinge eating college women. Addict Behav 25:205–16PubMedCrossRefGoogle Scholar
  56. Yanovski SZ (1993) Binge eating disorder: current knowledge and future directions. Obes Res 1:4163–4169Google Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Carlo Cifani
    • 1
  • Carlo Polidori
    • 1
  • Sergio Melotto
    • 1
  • Roberto Ciccocioppo
    • 1
  • Maurizio Massi
    • 1
  1. 1.Department of Experimental Medicine and Public HealthUniversity of CamerinoCamerinoItaly

Personalised recommendations