COMMENTS: According to this paper, bingeing rats are a good model for human addictions – both behavioral and chemical. Feeding rats really yummy food on intermittent schedules encourages bingeing behavior. Study on the brains of these bingeing rats reveals the neurobiology of addiction for humans.
Full Study: Bingeing Rats: A Model of Intermittent Excessive Behavior?
Appetite. 2006 Jan; 46(1): 11–15.
Published online 2005 Sep 26. doi: 10.1016/j.appet.2004.09.002
Intermittent excessive behaviors (IEB) characterize a variety human disorders including binge eating, drug abuse, alcoholism, aberrant sexual conduct, and compulsive gambling. Clinical co-morbidity exists among IEB, and limited treatment options are available. The use of behavioral models of bingeing and other feeding protocols is beginning to clarify neural similarities and differences that exist between IEB directed toward obtaining and consuming food and IEB directed toward obtaining and consuming drugs of abuse. Research from this laboratory using a limited access binge-type eating protocol may provide new insight into IEB.
What are intermittent, excessive behaviors?
Intermittent excessive behaviors (IEB) characterize a variety human disorders including binge eating, drug abuse, alcoholism, aberrant sexual conduct, and compulsive gambling. These behaviors are associated with increased morbidity and mortality, but are maintained in spite of the negative consequences associated with them. Over the past few decades, increased attention has been given to understanding the neurobiological basis of intermittent episodes of behavioral excess, with particular effort focused on reducing drug abuse and the overconsumption of food. The hope is that elucidation of the neurobiological underpinnings of one type of behavior (e.g. feeding) will enhance our understanding of other types of behavior (e.g. drug abuse). This would provide a basis for the development of new therapeutic interventions that could be effective in a variety of disorders. Although, recent reports indicate progress in the pharmacological treatment of disorders involving bingeing and certain addictions, treatment options remain limited and relapse rates are high (de Lima, Soares, Reisser, & Farrellde, 2002; Halmi, Agras, Mitchell, Wilson, Crow and Bryson, 2002; Kreek, LaForge, & Butelman, 2002; Safer, Lively, Telch, & Agras, 2002; Zhu & Walsh, 2002).
In humans, IEB directed toward consuming food is perhaps best represented by binge eating. Binge eating involves the intermittent overconsumption of food in brief periods of time in an amount that is more than most individuals would eat under similar circumstances. The binge may or may not be followed by compensatory behaviors such as vomiting (‘purging’), fasting, or excessive exercise. In the bingeing-related eating disorders, binges occur frequently over long periods of time and are associated with a sense of loss of control and emotional distress (DSM-IV, 1994).
Binge eating shares comorbidity with other IEB. For instance, patients seeking treatment for alcohol and cocaine abuse experience high rates of binge eating (Johnson, Spitzer, Williams, Kroenke, Linzer and Brody, 1997; Wilson, 1993), and populations seeking treatment for bingeing-related eating disorders experience high rates of substance abuse, particularly of alcohol and cocaine (Brewerton, Lydiard, Herzog, Brotman, O’Neill and Ballenger, 1995; Bulik, Sullivan, & Kendler, 2002; Bushnell et al., 1994; Herzog et al., 1992; Laessle, Wittchen, Fichter, & Pirke, 1989; Wiederman & Pryor, 1996). A relationship between binge eating and gambling has also been reported (Engwall, Hunter, & Steinberg, 2004).
The comorbidity among IEB suggests that mechanisms mediating these behaviors may overlap. Animal models are needed to examine alterations that occur during IEB development, maintenance, and relapse, and to compare similarities and differences between different IEB classes. Protocols utilizing natural rewards such as food are of particular interest because of their ability to reveal changes that occur when occasional normal behavioral excess (e.g. occasionally bingeing) is transformed into repetitive, intermittent, maladaptive behavioral excess (e.g. repeatedly bingeing). Several behavioral models of binge-type eating have been proposed, which recently have been reviewed (Corwin & Buda-Levin, 2004). The use of these and other protocols is beginning to clarify neural similarities and differences that exist between IEB directed toward food and IEB directed toward drugs of abuse (for example, Bello, Sweigart, Lakoski, Norgren, & Hajnal, 2003; DeSousa, Bush, & Vaccarino, 2000; Di Chiara, 2002; Gosnell, 2000; Grigson, 2002; Hagan & Moss, 1991; Kelley & Berridge, 2002; Schroeder, Binzak, & Kelley, 2001; Spangler, Wittkowski, Goddard, Avena, Hoebel and Leibowitz, 2004).
Bingeing rats and IEB
The limited access protocol
Research from this laboratory has been directed toward developing a behavioral model of binge-type eating that does not require energy restriction, in order to minimize potential confounds associated with food-deprivation. Therefore, a nutritionally complete laboratory chow and water are provided at all times in our protocol. To induce binge-type eating, limited access to an optional source of dietary fat (hydrogenated vegetable shortening) is provided. Our research has shown that, as access to the shortening decreases, consumption of the shortening increases during the 2-h limited access period (Corwin, 2004; Corwin, Wojnicki, Fisher, Dimitriou, Rice and Young, 1998; Dimitriou, Rice, & Corwin, 2000; Thomas, Rice, Weinstock, & Corwin, 2002). When rats only have access to the shortening for 2 h three times a week, intake during the 2-h access period is very high, i.e. equivalent to what rats with continuous access to shortening consume in 24 h. Establishing these elevated intakes takes about 4 weeks. However, once established, the behavior is easily maintained. This protocol provides a relatively simple and inexpensive means of establishing IEB that can be maintained for extended periods of time. The phenomenon is robust and reliable, as we have demonstrated it in different strains and ages of rats (Thomas et al., 2002), as well as in males and females (Corwin et al., 1998; Dimitriou et al., 2000).
Rats with access to shortening for 2 h on Mon, Weds, Fri (MWF) each week do not compensate for the excess energy consumed during the binge in the 22 h following the binge episode. That is, the excessive intake during the 2-h binge causes significant 24-h overconsumption on the binge day. On subsequent non-binge days, however, 24-h energy intake is reduced. Thus, a binge/compensate behavior pattern develops in the MWF rats, even though they are never deprived of food; only their access to the shortening is limited. The pattern of food intake in the MWF rats is different from that of rats maintained on the daily 2-h shortening access schedule. Daily 24-h food intake in those rats does not differ from chow-only controls on most days.
The fact that bingeing in the limited access protocol is induced by limiting access to a preferred high-fat food is relevant, because binge foods consumed by humans typically consist of restricted ‘forbidden’ high-fat items such as snacks and desserts (DSM-IV; Guertin, 1999; Hadigan, Kissileff, & Walsh, 1989; Kales, 1990; Rosen, Leitenberg, Gross, & Willmuth, 1986). In addition, limiting access to snack foods increases their subsequent consumption in a controlled laboratory setting (Fisher & Birch, 1999). The fact that rats on the limited access protocol are not food-deprived is also relevant, as eating in the absence of hunger has been associated with bingeing in humans (Marcus & Kalarchian, 2003). The behavior of animals on the limited access protocol, then, has relevance to human food intake, and is similar in some ways to that of humans suffering from bingeing-related eating disorders.
Peptides that regulate fat intake are without effect under limited access conditions
In non-binge protocols, galanin stimulates fatty food intake when administered directly into the paraventricular nucleus of the hypothalamus (Corwin, Robinson, & Crawley, 1993; Kyrkouli, Stanley, Seirafi, & Leibowitz, 1990), and the galanin antagonist M40 reduces fat intake (Leibowitz & Kim, 1992). However, when tested under limited access conditions neither galanin nor M40 affected fat intake (Corwin, Rowe, & Crawley, 1995). Similar results were obtained with enterostatin, a neuropeptide thought to contribute to fat-mediated satiety (Erlanson-Albertsson & York, 1997). That is, under limited access conditions, enterostatin had no effect on fatty food intake (Corwin & Rice, 1998; Rice & Corwin, 1996, 1998). These findings indicate that the neurobiology of fat intake under limited access conditions is different from the neurobiology of fat intake under other conditions.
Bingeing induced by limited access may resemble substance abuse
Recent studies have been initiated to investigate potential similarities between fat intake induced by limited access and another IEB, substance abuse. Reports from other groups have shown that the GABA-B agonist baclofen reduces drug self-administration in animals (Fattore, Cossu, Martellotta, & Fratta, 2002; Janak & Gill, 2003; Ranaldi & Poeggel, 2002; see also Brebner, Phelan, & Roberts, 2002; Cousins, Roberts, & de Wit, 2002, for reviews), and has shown promise clinically in the treatment of substance abuse and dependence (Addolorato, Caputo, Capristo, Domenicali, Bernard and Janiri, 2002; Assadi, Radgoodarzi, & Ahmadi-Abhari, 2003; Shoptaw, Yang, Rotheram-Fuller, Hsieh, Kintaudi and Charuvastra, 2003; see also Brebner et al., 2002; Cousins et al., 2002, for reviews). Recent data from this laboratory indicate that baclofen reduces binge-type consumption of fat induced by limited access without reducing consumption of a high-fat diet or chow (Buda-Levin, Wojnicki, & Corwin, 2005). This is interesting because bingeing and substance abuse share clinical comorbidity (Brewerton et al., 1995; Bulik et al., 2002; Bushnell et al., 1994; Herzog et al., 1992; Johnson et al., 1997; Laessle et al., 1989; Wiederman & Pryor, 1996; Wilson, 1993) and baclofen generally has no effect on or increases food intake in non-binge animal protocols (Brebner et al., 2000; Ebenezer, 1995; Echo, Lamonte, Ackerman, & Bodnar, 2002; Higgs & Barber, 2004; Minano, Meneres Sancho, Sancibrian, Salinas, & Myers, 1992; Stratford & Kelley, 1997; Ward, Somerville, & Clifton, 2000; Wirtshafter, Stratford, & Pitzer, 1993; Znamensky, Echo, Lamonte, Christian, Ragnauth and Bodnar, 2001). Taken together, these findings suggest that the neural signaling involved in binge-type eating, as modeled in the limited access protocol, is different from that of non-binge eating. Instead, neural signals relevant to the IEB of bingeing may be more closely aligned with those involved in the IEB of substance abuse.
The neurobiology of repeated, intermittent, episodes of behavioral excess is not well understood. However, converging evidence suggests that common mechanisms may contribute to disorders involving this type of behavior. Research from this laboratory has shown that limited access to shortening can induce repeated, intermittent, excessive consumption of shortening in non-food-deprived rats. The protocol is relatively simple and inexpensive, and the behavior is similar in some ways to human bingeing. Recent data suggest that neural signaling under limited access binge-type conditions is different from non-binge conditions, and may be more closely aligned with substance abuse. There currently are a variety of feeding protocols that can be used to advance our understanding of physiological and neurological alterations that occur as a result of engaging in IEB. Such research is critical if we are to elucidate mechanisms that contribute to development, maintenance, and relapse in these often destructive patterns of behavior.
Presented at Society for the Study of Ingestive Behavior (SSIB) Satellite Symposium, Hueston Woods Resort, Ohio, July 18–20, 2004. Chaired by Allan Geliebter and Harry R. Kissileff. The satellite was supported in part by the New York Obesity Research Center, SSIB, General Mills Foods, McNeil Nutritionals, Ortho-McNeil Pharmaceuticals, Procter & Gamble.
- Addolorato G, Caputo F, Capristo E, Domenicali M, Bernard M, Janiri L, et al. Baclofen efficacy in reducing alcohol craving and intake: A preliminary double blind randomized controlled study. Alcohol and Alcoholism. 2002;37:504–508. [PubMed]
- Assadi SM, Radgoodarzi R, Ahmadi-Abhari SA. Baclofen for maintenance treatment of opioid dependence: A randomized double-blind placebo-controlled clinical trial. BMC Psychiatry. 2003;3:16. [PMC free article] [PubMed]
- Bello NT, Sweigart KL, Lakoski JM, Norgren R, Hajnal A. Restricted feeding with scheduled sucrose access results in an upregulation of the rat dopamine transporter. American Journal of Physiology (Regulatory Integrative and Comparative Physiology) 2003;284:R1260–R1268. [PubMed]
- Brebner K, Childress AR, Roberts DCS. A potential role for GABAB agonists in the treatment of psychostimulant addiction. Alcohol and Alcoholism. 2002;37:478–484. [PubMed]
- Brebner K, Phelan R, Roberts DCS. Intra-VTA baclofen attenuates cocaine self-administration on a progressive ratio schedule of reinforcement. Pharmacology Biochemistry and Behavior. 2000;66:857–862. [PubMed]
- Brewerton TD, Lydiard RB, Herzog DB, Brotman AW, O’Neill PM, Ballenger JC. Comorbidity of axis I psychiatric disorders in bulimia nervosa. Journal of Clinical Psychiatry. 1995;56:77–80. [PubMed]
- Buda-Levin A, Wojnicki FH, Corwin RL. Baclofen reduces fat intake under binge-type conditions. Physiology and behavior. 2005 Sep 1; [Epub ahead of print]. [PMC free article] [PubMed]
- Bulik CM, Sullivan PF, Kendler KS. Medical and psychiatric morbidity in obese women with and without binge eating. International Journal of Eating Disorders. 2002;32:72–78. [PubMed]
- Bushnell JA, Wells JE, McKenzie JM, Hornblow AR, Oakley-Browne MA, Joyce PR. Bulimia comorbidity in the general population and in the clinic. Psychological Medicine. 1994;24:605–611. [PubMed]
- Corwin RL. Binge-type eating induced by limited access in rats does not require energy restriction on the previous day. Appetite. 2004;42:139–142. [PubMed]
- Corwin RL, Buda-Levin A. Behavioral models of binge-type eating. Physiology and Behavior. 2004;82:123–130. [PubMed]
- Corwin RL, Rice HB. Effects of enterostatin on optional oil or sucrose consumption in non-food-deprived rats. Physiology and Behavior. 1998;65:1–10. [PubMed]
- Corwin RL, Robinson JK, Crawley JN. Galanin antagonists block galanin-induced feeding in the hypothalamus and amygdala of the rat. European Journal of Neuroscience. 1993;5:1528–1533. [PubMed]
- Corwin RL, Rowe PM, Crawley JN. Galanin and the galanin antagonist M40 do not change fat intake in a fat–chow choice paradigm in rats. American Journal of Physiology (Regulatory Integrative and Comparative Physiology) 1995;269:R511–R518. [PubMed]
- Corwin RL, Wojnicki FHE, Fisher JO, Dimitriou SG, Rice HB, Young MA. Limited access to a dietary fat option affects ingestive behavior but not body composition in male rats. Physiology and Behavior. 1998;65:545–553. [PubMed]
- Cousins MS, Roberts DCS, de Wit H. GABAB receptor agonists for the treatment of drug addiction: A review of recent findings. Drug and Alcohol Dependence. 2002;65:209–220. [PubMed]
- de Lima MS, Soares BGDO, Reisser AAP, Farrell M. Pharmacological treatment of cocaine dependence: A systematic review. Addiction. 2002;97:931–949. [PubMed]
- DeSousa NJ, Bush DEA, Vaccarino FJ. Self-administration of intravenous amphetamine is predicted by individual differences in sucrose feeding in rats. Psychopharmacology. 2000;148:52–58. [PubMed]
- Di Chiara G. Nucleus accumbens shell and core dopamine: Differential role in behavior and addiction. Behavioural Brain Research. 2002;137:75–114. [PubMed]
- Dimitriou SG, Rice HB, Corwin RL. Effects of limited access to a fat option on food intake and body composition in female rats. International Journal of Eating Disorders. 2000;28:436–445. [PubMed]
- DSM-IV™ Diagnostic and statistical manual of mental disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994.
- Ebenezer IS. Intraperitoneal administration of baclofen increases consumption of both solid and liquid diets in rats. European Journal of Pharmacology. 1995;273:183–185. [PubMed]
- Echo JA, Lamonte N, Ackerman TF, Bodnar RJ. Alterations in food intake elicited by GABA and opioid agonists and antagonists administered into the ventral tegmental region of rats. Physiology and Behavior. 2002;76:107–116. [PubMed]
- Engwall D, Hunter R, Steinberg M. Gambling and other risk behaviors on university campuses. Journal of American College Health. 2004;52:245–255. [PubMed]
- Erlanson-Albertsson C, York D. Enterostatin—a peptide regulating fat intake. Obesity Research. 1997;5:360–372. [PubMed]
- Fattore L, Cossu G, Martellotta MC, Fratta W. Baclofen antagonizes intravenous self-administration of nicotine in mice and rats. Alcohol and Alcoholism. 2002;37:495–498. [PubMed]
- Fisher JO, Birch LL. Restricting access to palatable foods affects children’s behavioral response, food selection, and intake. The American Journal of Clinical Nutrition. 1999;69:1264–1272. [PubMed]
- Gosnell BA. Sucrose intake predicts rate of acquisition of cocaine self-administration. Psychopharmacology. 2000;149:286–292. [PubMed]
- Grigson PS. Like drugs for chocolate: Separate rewards modulated by common mechanisms? Physiology and Behavior. 2002;76:389–395. [PubMed]
- Guertin TL. Eating behavior of bulimics, self-identified binge eaters, and non-eating-disordered individuals: What differentiates these populations? Clinical Psychology Review. 1999;19:1–23. [PubMed]
- Hadigan CM, Kissileff HR, Walsh BT. Patterns of food selection during meals in women with bulimia. The American Journal of Clinical Nutrition. 1989;50:759–766. [PubMed]
- Hagan MM, Moss DE. An animal model of bulimia nervosa: Opioid sensitivity to fasting episodes. Pharmacology Biochemistry and Behavior. 1991;39:421–422. [PubMed]
- Halmi KA, Agras WS, Mitchell J, Wilson GT, Crow S, Bryson SW, et al. Relapse predictors of patients with bulimia nervosa who achieved abstinence through cognitive behavioral therapy. Archives of General Psychiatry. 2002;59:1105–1109. [PubMed]
- Herzog DB, Keller MB, Sacks NR, Yeh CJ, Lavori PW. Psychiatric comorbidity in treatment-seeking anorexics and bulimics. Journal of the American Academy of Child and Adolescent Psychiatry. 1992;31:810–818. [PubMed]
- Higgs S, Barber DJ. Effects of baclofen on feeding behavior examined in the runway. Progress in Neuropsychopharmacology and Biological Psychiatry. 2004;28:405–408. [PubMed]
- Janak PH, Gill TM. Comparison of the effects of allopregnanolone with direct GABAergic agonists on ethanol self-administration with and without concurrently available sucrose. Alcohol. 2003;30:1–7. [PubMed]
- Johnson JG, Spitzer RL, Williams JBW, Kroenke K, Linzer M, Brody D, et al. Psychiatric comorbidity, health status, and functional impairment associated with alcohol abuse and dependence in primary care patients: Findings of the Prime MD-1000 study. In: Marlatt GA, VandenBos GR, editors. Addictive behaviors. Washington, DC: American Psychological Association; 1997.
- Kales EF. Macronutrient analysis of binge eating in bulimia. Physiology and Behavior. 1990;48:837–840. [PubMed]
- Kelley AE, Berridge KC. The neuroscience of natural rewards: Relevance to addictive drugs. Journal of Neuroscience. 2002;22:3306–3311. [PubMed]
- Kreek MJ, LaForge SK, Butelman E. Pharmacotherapy of addictions. Nature reviews. Drug Discovery. 2002;1:710–726. [PubMed]
- Kyrkouli S, Stanley BG, Seirafi RD, Leibowitz SF. Stimulation of feeding by galanin: Anatomical localization and behavioral specificity of this peptide’s effects in the brain. Peptides. 1990;11:995–1001. [PubMed]
- Laessle RG, Wittchen HU, Fichter MM, Pirke KM. The significant subgroups of bulimia and anorexia nervosa: Lifetime frequency of psychiatric disorders. International Journal of Eating Disorders. 1989;8:569–574.
- Leibowitz SF, Kim T. Impact of a galanin antagonist on exogenous galanin and natural patters of fat ingestion. Brain Research. 1992;599:148–152. [PubMed]
- Marcus MD, Kalarchian MA. Binge eating in children and adolescents. International Journal of Eating Disorders. 2003;34(Suppl):S47–S57. [PubMed]
- Minano FJ, Meneres Sancho MS, Sancibrian M, Salinas P, Myers RD. GABAA receptors in the amygdala: Role in feeding in fasted and satiated rats. Brain Research. 1992;586:104–110. [PubMed]
- Ranaldi R, Poeggel K. Baclofen decreases methamphetamine self-administration in rats. Neuroreport. 2002;13:1107–1110. [PubMed]
- Rice HB, Corwin RL. Intracerebroventricular enterostatin stimulates food intake in non-food deprived rats. Peptides. 1996;17:885–888. [PubMed]
- Rice HB, Corwin RL. Effects of enterostatin on consumption of optional foods in non-food-deprived rats. Obesity Research. 1998;6:54–61. [PubMed]
- Rosen JC, Leitenberg H, Gross J, Willmuth M. Binge-eating episodes in bulimia nervosa: The amount and type of food consumed. International Journal of Eating Disorders. 1986;5:255–267.
- Safer DL, Lively TJ, Telch CF, Agras WS. Predictors of relapse following successful dialectical behavior therapy for binge eating disorder. International Journal of Eating Disorders. 2002;32:155–163. [PubMed]
- Schroeder BE, Binzak JM, Kelley AE. A common profile of prefrontal cortical activation following exposure to nicotine- or chocolate-associated contextual cues. Neuroscience. 2001;105:535–545. [PubMed]
- Shoptaw A, Yang X, Rotheram-Fuller EJ, Hsieh YC, Kintaudi PC, Charuvastra VC, et al. Randomized placebo-controlled trial of baclofen for cocaine dependence: Preliminary effects for individuals with chronic patterns of cocaine use. Journal of Clinical Psychiatry. 2003;64:1440–1448. [PubMed]
- Spangler R, Wittkowski KM, Goddard NL, Avena NM, Hoebel BG, Leibowitz SF. Opiate-like effects of sugar on gene expression in reward areas of the rat brain. Brain Research. Molecular Brain Research. 2004;124:134–142. [PubMed]
- Stratford TR, Kelley AE. GABA in the nucleus accumbens shell participates in the central regulation of feeding behavior. Journal of Neuroscience. 1997;17:4434–4440. [PubMed]
- Thomas MA, Rice HB, Weinstock D, Corwin RL. Effects of aging on food intake and body composition in rats. Physiology and Behavior. 2002;76:487–500. [PubMed]
- Ward BO, Somerville EM, Clifton PG. Intraaccumbens baclofen selectively enhances feeding behavior in the rat. Physiology and Behavior. 2000;68:463–468. [PubMed]
- Wiederman MW, Pryor T. Substance abuse and impulsive behaviors among adolescents with eating disorders. Addictive Behaviors. 1996;21:269–272. [PubMed]
- Wilson GT. Binge eating and addictive disorders. In: Fairburn CG, Wilson GT, editors. Binge eating: Nature, assessment, and treatment. New York: The Guilford Press; 1993. pp. 97–120.
- Wirtshafter D, Stratford TR, Pitzer MR. Studies on the behavioral activation produced by stimulation of GABA-B receptors in the median raphe nucleus. Behavioral Brain Research. 1993;59:83–93. [PubMed]
- Zhu AJ, Walsh BT. Pharmacologic treatment of eating disorders. Canadian Journal of Psychiatry. 2002;47:227–234. [PubMed]
- Znamensky V, Echo JA, Lamonte N, Christian G, Ragnauth A, Bodnar RJ. Gamma-aminobutyric acid receptor subtype antagonists differentially alter opioid-induced feeding in the shell region of the nucleus accumbens in rats. Brain Research. 2001;906:84–91. [PubMed]