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Published in final edited form as: Int J Eat Disord. 2020 Jun 3;53(9):1569–1578. doi: 10.1002/eat.23302

A virtual issue highlighting animal studies of eating disorders as valuable tools for examining neurobiological underpinnings and treatment of eating disorders

Natasha Fowler 1, Kelly L Klump 1
PMCID: PMC7485142  NIHMSID: NIHMS1625212  PMID: 32488869

Abstract

While studies in humans suggest a role for psychosocial factors as well as biological and genetic processes in the development of eating disorders, the specific etiologic mechanisms remain largely unknown. In this virtual issue, we present a collection of 14 archived articles from the International Journal of Eating Disorders to highlight the utility of animal studies of eating disorders to advance our understanding of eating disorder etiology. Selected articles establish animal studies as valid tools to study disordered eating behavior, offer insight into potential neurobiological mechanisms, and highlight novel targets for future pharmacological treatments. Clinical implications of each article’s findings are included to demonstrate the translational value of animal studies for the eating disorders field. We hope that the exciting concepts and findings in this issue inspire future animal studies of eating disorders.

Keywords: animals, eating disorders, binge eating, bulimia nervosa, anorexia nervosa, binge-eating disorder, neurobiology

Studies of eating disorders in humans have significantly increased our understanding of eating disorder development, both in terms of psychosocial risk factors (e.g., interpersonal stressors; Keel & Forney, 2013) as well as biological processes (e.g., genes, neurobiology) that may contribute to the etiology of eating disorders (Frank, Shott, & DeGuzman, 2019b; Hinney & Volckmar, 2013). However, the mechanisms that explain how or why these risk factors contribute to eating pathology remain largely unknown.

Animal studies of disordered eating behaviors are one means to expand our understanding of the specific neurobiological mechanisms underlying etiology of disordered eating. Unlike human studies, animal studies provide a unique opportunity to manipulate specific variables (e.g., stress exposure, hormone levels, neuronal activity, brain circuitry, genes) and control for psychosocial factors that are difficult or impossible to control in human studies. Thus, animal studies are a valuable tool for advancing our understanding of the etiology and maintenance of disordered eating behaviors that are common in eating pathology, with the ultimate goal of being able to inform clinical practice and treatment.

In this virtual issue of the International Journal of Eating Disorders (IJED), we bring together a collection of 14 empirical papers and reviews from past issues of the journal to highlight the utility of using animals to study eating disorders. The selected articles include animal studies of behaviors that are common in anorexia nervosa (AN) and disorders characterized by binge eating (e.g., bulimia nervosa (BN), binge-eating disorder (BED)). Articles were chosen based on their ability to answer the following three questions regarding the validity and utility of using animals to study eating disorders: 1) How can we model key characteristics of eating disorders using animals?; 2) How can we use animal studies to examine mechanisms of eating disorders?; and 3) How can animal studies of eating disorders inform treatment?

To highlight the translational value of the featured studies, each article is accompanied by a brief summary of its clinical implications in the text below and in Table 1. We highly encourage readers to access the full articles for a more in-depth discussion of each study’s findings, conclusions, and clinical implications. In addition to the 14 featured articles, IJED has published 15 additional animal studies of eating disorders that we were unfortunately unable to feature in this virtual issue. Because these additional 15 articles also provide valuable information about eating disorder mechanisms and treatment, we highly encourage readers to access these articles, as well. A full list of all animal studies of eating disorders that have been published in IJED from September 1, 1981 (the first IJED edition) through May 1st, 2020 are listed in Table 2.

Table 1.

Clinical implications of featured articles

Article Clinical Implications
Question #1: How can we model key characteristics of eating disorders using animals?
Animal Studies of Anorexia Nervosa Behaviors
Klein, D. & Walsh, B.T. (2005). Translational approaches to understanding anorexia nervosa. International Journal of Eating Disorders, 37 Suppl: S10-4. doi: 10.1002/eat.20108. This review provides an historical and early perspective of the ABA model, including the various studies that contributed to its development. This review also discusses models of overeating to examine binge eating behavior in AN. Interweaved throughout the review is the translational utility of animal studies of AN for understanding AN etiology and informing treatment.
Gutierrez, E. (2013). A rat in the labyrinth of anorexia nervosa: contributions of the activity-based anorexia rodent model to the understanding of anorexia nervosa. International Journal of Eating Disorders, 46(4), 289-301. doi: 10.1002/eat.22095. This review provides an updated overview of the ABA model that covers a large number of studies conducted since 2005, including the use of rats and mice in ABA studies as well as the examination of key factors that contribute to ABA development (e.g., female sex, adolescent age, baseline weight). The paper also emphasizes the translational utility of the ABA model for understanding AN etiology and informing treatment.
Barbarich-Marsteller, N.C. et al. (2013). Identifying novel phenotypes of vulnerability and resistance to activity-based anorexia in adolescent female rats. International Journal of Eating Disorders, 46(7), 737-46. doi: 10.1002/eat.22149. This study outlined an objective set of criteria for defining vulnerable versus resistant ABA phenotypes in female rats during adolescence that can be used to examine why only a small subset of individuals develop AN symptoms despite the high prevalence of dieting and exercise. Results from this study add additional face validity to the ABA model of AN and provide a critical framework for future studies of AN to identify factors that increase risk or resilience for ABA behaviors.
Animal Studies of Binge-Eating Behaviors
Dimitriou, S.G., Rice, H.B., & Corwin, R.L. (2000). Effects of limited access to a fat option on food intake and body composition in female rats. International Journal of Eating Disorders, 28(4), 436-45. doi: 10.1002/1098-108x(200012)28:4<436::aid-eat12>3.0.co;2-p. This study highlighted the importance of intermittent access to PF (as opposed to continuous access) to induce binge-like eating in rats. Findings also showed that rats exhibit similar patterns of binge-like eating as human, where both rats and individuals tend to binge eat on highly palatable food, rather than highly nutritive food, in a short time period (American Psychiatric Association, 2013).
Oswald, K.D., Murdaugh, D.L., King, V.L., & Boggiano, M.M. (2011). Motivation for palatable food despite consequences in an animal model of binge eating. International Journal of Eating Disorders, 44(3), 203-11. doi: 10.1002/eat.20808. This study showed that female rats that are prone to binge eating will endure increasingly high levels of pain (via foot shock) in order to obtain and eat PF, even when they are not hungry. This is opposite to the behavior of female rats that are resistant to binge eating who do not tolerate increased levels of pain to obtain and eat PF. These results suggest a compulsive-like pattern of PF consumption in binge-eating prone rats that mirrors the loss of control over eating that is observed in humans, where despite worsening perceptions of body image, self-esteem, and physical discomfort, individuals continue to engage in binge eating.
Klump, K.L., Racine, S., Hildebrandt, B., & Sisk, C.L. (2013). Sex differences in binge eating patterns in male and female adult rats. International Journal of Eating Disorders, 46(7), 729-36. doi: 10.1002/eat.22139. This study showed that rats exhibit sex differences (rates that are 2-6 higher in female as compared to male rats) in binge eating behavior that is similar to the sex differences observed in humans (2-10 times higher in women versus men; American Psychiatric Association, 2013; Klump, Culbert, & Sisk, 2017). The observed sex differences in binge-eating behavior in rats provides additional face and clinical validity of this model of binge eating.
Hagan, M.M. & Moss, D.E. (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. International Journal of Eating Disorders, 22(4), 411-20. doi: 10.1002/(sici)1098-108x(199712)22:4<411::aid-eat6>3.0.co;2-p. Results from this study suggest that a history of dieting followed by refeeding on PF promotes long-term overeating, even after an individual has stopped dieting and when they are no longer hungry. This pattern of binge-like behavior is consistent with that observed in a range of eating disorders (e.g., BN, BED) where individuals alternate between periods of dieting and bingeing.
Question #2: How can we use animal studies to examine mechanisms of eating disorders?
Animal Study of Anorexia Nervosa Behaviors
D’Addario, C. et al. (2020). Epigenetic regulation of the endocannabinoid receptor CB1 in an activity-based rat model of anorexia nervosa. International Journal of Eating Disorders. doi: 10.1002/eat.23271. Results from this study suggest that changes in the endocannabinoid system in AN may be environmentally/behaviorally driven, and they may be influenced by epigenetic and genetic factors. These results also implicate a potential role for the endocannabinoid receptor Cnr1 in the development of AN.
Animal Studies of Binge-Eating Behaviors
Micioni Di Bonaventura, M.V. et al. (2017). Estrogenic suppression of binge-like eating elicited by cyclic food restriction and frustrative-nonreward stress in female rats. International Journal of Eating Disorders, 50(6), 624-635. doi: 10.1002/eat.22687. Results from this study suggest that estrogen and stress interact at a behavioral and neural level to influence binge eating in rats, and that additional investigations into these processes may increase our understanding of etiology and sex differences in binge eating and highlight new potential areas for intervention.
Hildebrandt, B.A., Sinclair, E.B., Sisk, C.L., & Klump, K.L. (2018). Exploring reward system responsivity in the nucleus accumbens across chronicity of binge eating in female rats. International Journal of Eating Disorders, 51(8), 989-993. doi: 10.1002/eat.22895. Results from this study suggest the presence of brain reward hyper-responsivity in the “early stages” of binge eating, and brain reward hypo-responsivity in the later or more chronic stages (much like what is observed with drug and alcohol use - Lobo & Nestler, 2011; Volkow et al., 2009). The authors propose that early hyper-responsivity may reinforce the development of regular binge eating, which then leads to down-regulation and hypo-responsivity of the reward system with more chronic binge eating.
Question #3: How can animal studies of eating disorders inform treatment?
Animal Studies of Anorexia Nervosa Behaviors
Chen, Y.W., Sherpa, A.D., & Aoki, C. (2018). Single injection of ketamine during mid-adolescence promotes long-lasting resilience to activity-based anorexia of female mice by increasing food intake and attenuating hyperactivity as well as anxiety-like behavior. International Journal of Eating Disorders, 51(8), 1020-1025. doi: 10.1002/eat.22937. Results from this study suggest that ketamine may be a useful treatment for AN during adolescence, particularly for individuals who also experience high levels of anxiety.
Boersma, G.J. et al. (2016). Exposure to activity-based anorexia impairs contextual learning in weight-restored rats without affecting spatial learning, taste, anxiety, or dietary fat preference. International Journal of Eating Disorders, 49(2), 167-79. doi: 10.1002/eat.22489. Results from this study implicate alterations in contextual learning as potential risk factors for relapse in individuals with AN, even after weight has been restored. Such learning alterations may make it more difficult for individuals with AN to adhere to and learn new behavior modification techniques during recovery.
Animal Studies of Binge-Eating Behaviors
Chandler-Laney, P.C., Castañeda, E., Viana, J.B., Oswald, K.D., Maldonado, C.R., & Boggiano, M.M. (2007). A history of human-like dieting alters serotonergic control of feeding and neurochemical balance in a rat model of binge-eating. International Journal of Eating Disorders, 40(2), 136-42. doi: 10.1002/eat.20349. Results from this study suggest that binge eating induced by a history of dieting and refeeding alters serotonergic functioning that is able to be reversed by fluoxetine treatment. Additionally, the authors note that future studies should examine increases in monoamine receptor levels, changes in level of receptor expression, and changes in monoamine release as potential mechanisms underlying fluoxetine’s effects.
Micioni Di Bonaventura, M.V., Ubaldi, M., Giusepponi, M.E., Rice, K.C., Massi, M., Ciccocioppo, R., & Cifani, C. (2017). Hypothalamic CRF1 receptor mechanisms are not sufficient to account for binge-like palatable food consumption in female rats. International Journal of Eating Disorders, 50(10), 1194-1204. doi: 10.1002/eat.22767. This study highlights the stress system, in particular the extra-hypothalamic CRF1 receptor, as a novel target for treatment of binge-related disorders, particularly in individuals experiencing high levels of stress. Because stress impacts various behaviors that often co-occur with or are risk factors for binge eating and other eating disorders (e.g., anxiety, depression; de Kloet, Joëls, & Holsboer, 2005), developing treatments that restore normal functioning in the stress system has the potential to improve symptoms of eating disorders, reduce comorbidity, and lessen symptom severity.
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Note: ABA = activity-based anorexia, AN = anorexia nervosa, BED = binge-eating disorder, BN = bulimia nervosa, Cnr1 = type 1 endocannabinoid receptor, CRF1 = corticotropin-releasing factor receptor 1, PF = palatable food

Table 2.

List of all animal studies of eating disorders that have been published in the International Journal of Eating Disorders from September 1, 1981 through May 1, 2020.

Empirical Papers
Anorexia Nervosa (AN):

  1. Barbarich-Marsteller, N.C. et al. (2013). Identifying novel phenotypes of vulnerability and resistance to activity-based anorexia in adolescent female rats. International Journal of Eating Disorders, 46(7), 737-46. doi: 10.1002/eat.22149.

  2. Boersma, G.J. et al. (2016). Exposure to activity-based anorexia impairs contextual learning in weight-restored rats without affecting spatial learning, taste, anxiety, or dietary fat preference. International Journal of Eating Disorders, 49(2), 167-79. doi: 10.1002/eat.22489.

  3. Brown, A.J., Avena, N.M., & Hoebel, B.G. (2008). A high-fat diet prevents and reverses the development of activity-based anorexia in rats. International Journal of Eating Disorders, 41(5), 383-9. doi: 10.1002/eat.20510.

  4. Cai, W. et al. (2008). Activity-based anorexia during adolescence does not promote binge eating during adulthood in female rats. International Journal of Eating Disorders, 41(8), 681-5. doi: 10.1002/eat.20568.

  5. Cerrato, M., Carrera, O., Vazquez, R., Echevarría, E., & Gutierrez, E. (2012). Heat makes a difference in activity-based anorexia: a translational approach to treatment development in anorexia nervosa. International Journal of Eating Disorders, 45(1), 26-35. doi: 10.1002/eat.20884.

  6. Chen, Y.W., Sherpa, A.D., & Aoki, C. (2018). Single injection of ketamine during mid-adolescence promotes long-lasting resilience to activity-based anorexia of female mice by increasing food intake and attenuating hyperactivity as well as anxiety-like behavior. International Journal of Eating Disorders, 51(8), 1020-1025. doi: 10.1002/eat.22937.

  7. Collu, R. et al. (2019). Impaired brain endocannabinoid tone in the activity-based model of anorexia. International Journal of Eating Disorders, 52(11), 1251-1262. Doi: 10.1002/eat.23157.

  8. D’Addario, C. et al. (2020). Epigenetic regulation of the endocannabinoid receptor CB1 in an activity-based rat model of anorexia nervosa. International Journal of Eating Disorders. doi: 10.1002/eat.23271.

  9. Gutierrez, E. (2013). A rat in the labyrinth of anorexia nervosa: contributions of the activity-based anorexia rodent model to the understanding of anorexia nervosa. International Journal of Eating Disorders, 46(4), 289-301. doi: 10.1002/eat.22095.

  10. Gutierrez, E., Cerrato, M., Carrera, O., &Vazquez, R. (2008). Heat reversal of activity-based anorexia: implications for the treatment of anorexia nervosa. International Journal of Eating Disorders, 41(7), 594-601. doi: 10.1002/eat.20535.

  11. Wong, M.L., Licinio, J., Gold, P.W., & Glowa, J. (1993). Activity-induced anorexia in rats does not affect hypothalamic neuropeptide gene expression chronically. International Journal of Eating Disorders, 13(4), 399-405. doi: 10.1002/1098–108x(199305)13:4<399::aid-eat2260130408>3.0.co;2-j.

Binge Eating (BE):

  1. Chandler-Laney, P.C., Castañeda, E., Viana, J.B., Oswald, K.D., Maldonado, C.R., & Boggiano, M.M. (2007). A history of human-like dieting alters serotonergic control of feeding and neurochemical balance in a rat model of binge-eating. International Journal of Eating Disorders, 40(2), 136-42. doi: 10.1002/eat.20349.

  2. Consoli, D. Contarino, A., Tabarin, A., & Drago, F. (2009). Binge-like eating in mice. International Journal of Eating Disorders, 42(5), 402-8. doi: 10.1002/eat.20637.

  3. Dimitriou, S.G., Rice, H.B., & Corwin, R.L. (2000). Effects of limited access to a fat option on food intake and body composition in female rats. International Journal of Eating Disorders, 28(4), 436-45. doi: 10.1002/1098-108x(200012)28:4<436::aid-eat12>3.0.co;2-p.

  4. Hagan, M.M. & Moss, D.E. (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. International Journal of Eating Disorders, 22(4), 411-20. doi: 10.1002/(sici)1098-108x(199712)22:4<411::aid-eat6>3.0.co;2-p.

  5. Hagan, M.M., Chandler, P.C., Wauford, P.K., Rybak, R.J., & Oswald, K.D. (2003). The role of palatable food and hunger as trigger factors in an animal model of stress induced binge eating. International Journal of Eating Disorders, 34(2), 183-97. doi: 10.1002/eat.10168.

  6. Hildebrandt, B.A., Sinclair, E.B., Sisk, C.L., & Klump, K.L. (2018). Exploring reward system responsivity in the nucleus accumbens across chronicity of binge eating in female rats. International Journal of Eating Disorders, 51(8), 989-993. doi: 10.1002/eat.22895.

  7. Klump, K.L., Racine, S., Hildebrandt, B., & Sisk, C.L. (2013). Sex differences in binge eating patterns in male and female adult rats. International Journal of Eating Disorders, 46(7), 729-36. doi: 10.1002/eat.22139.

  8. Micioni Di Bonaventura, M.V. et al. (2017). Estrogenic suppression of binge-like eating elicited by cyclic food restriction and frustrative-nonreward stress in female rats. International Journal of Eating Disorders, 50(6), 624-635. doi: 10.1002/eat.22687.

  9. Micioni Di Bonaventura, M.V., Ubaldi, M., Giusepponi, M.E., Rice, K.C., Massi, M., Ciccocioppo, R., & Cifani, C. (2017). Hypothalamic CRF1 receptor mechanisms are not sufficient to account for binge-like palatable food consumption in female rats. International Journal of Eating Disorders, 50(10), 1194-1204. doi: 10.1002/eat.22767.

  10. Oswald, K.D., Murdaugh, D.L., King, V.L., & Boggiano, M.M. (2011). Motivation for palatable food despite consequences in an animal model of binge eating. International Journal of Eating Disorders, 44(3), 203-11. doi: 10.1002/eat.20808.

  11. Placidi, R.J., Chandler, P.C., Oswald, K.D., Maldonado, C., Wauford, P.K., & Boggiano, M.M. (2004). Stress and hunger alter the anorectic efficacy of fluoxetine in binge-eating rats with a history of caloric restriction. International Journal of Eating Disorders, 36(3), 328-41. doi: 10.1002/eat.20044.

  12. Pucci, M. et al. (2018). Transcriptional regulation of the endocannabinoid system in a rat model of binge-eating behavior reveals a selective modulation of the hypothalamic fatty acid amide hydrolase gene. International Journal of Eating Disorders, 52(1), 51-60. doi: 10.1002/eat.22989.
Reviews
AN:

  1. aFessler, D.M.T. (2001). Pseudoparadoxical impulsivity in restrictive anorexia nervosa: a consequence of the logic of scarcity. International Journal of Eating Disorders, 31(4), 376-88. doi: 10.1002/eat.10035.

  2. aKlein, D. & Walsh, B.T. (2005). Translational approaches to understanding anorexia nervosa. International Journal of Eating Disorders, 37 Suppl: S10-4. doi: 10.1002/eat.20108.

  3. aStrober, M., Peris, T., & Steiger, H. (2014). The plasticity of development: how knowledge of epigenetics may advance understanding of eating disorders. International Journal of Eating Disorders, 47(7), 696-704. doi: 10.1002/eat.22322.

  4. Treasure, J.L. & Owen, J.B. (1997). Intriguing links between animal behavior and anorexia nervosa. International Journal of Eating Disorders, 21(4), 307-11. doi: 10.1002/(sici)1098-108x(1997)21:4<307::aid-eat1>3.0.co;2-s.
Commentaries
BE:

  1. Geary, N. (2003). A new animal model of binge eating. International Journal of Eating Disorders, 34(2), 198-9. doi: 10.1002/eat.10226.
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a

Animal and human studies are reviewed in this paper.

How can we model key characteristics of eating disorders using animals?

The value of any animal study lies in the extent to which it reflects the phenomena observed in humans. If animals are unable to model the behaviors observed in humans, then findings from animal studies will be much less useful for informing eating disorder pathology in humans. Clearly, animal studies cannot model all aspects of eating disorders (e.g., over-evaluation of body shape and weight) that are present in humans. However, they can be used to model key traits/behaviors that are characteristic of each disorder. While the following seven featured articles (Barbarich-Marsteller et al., 2013; Dimitriou, Rice, & Corwin, 2000; Gutierrez, 2013; Hagan & Moss, 1997; Klein & Walsh, 2005; Klump, Racine, Hildebrandt, & Sisk, 2013; Oswald, Murdaugh, King, & Boggiano, 2011) highlight key traits/behaviors of AN, BN, and BED that have been studied in rats and mice, other animals (e.g., pigs; Treasure & Owen, 1997) have also been examined in past IJED studies.

Animal studies of AN behaviors

One of the most commonly examined models of AN is the activity-based anorexia (ABA) model (Cheney & Epling, 1968; Routtenberg & Kuznesof, 1967). The ABA model focuses on replicating two key features of AN: 1) self-induced starvation; and 2) increased levels of physical activity. In order to examine these features, the ABA initially model limits food access to 60-90 minutes per day (versus the typical 24 hours of food access), but allows animals unlimited access to a running wheel. Under this paradigm, animals engage in increasingly higher levels of wheel running and reliably lose large amounts of weight (e.g., 25% decrease in body weight). While starvation in this model is initially not self-induced, as animals lose weight, they increase their level of wheel running at the expense of eating, even when food is available (akin to self-starvation). This pattern of increased physical activity and self-induced starvation further perpetuates their ABA symptoms (Gutierrez, 2013). Much like some individuals with AN, ABA animals will continue to exercise and self-starve until weight loss becomes lethal (Gutierrez, 2013). ABA animals also exhibit increased levels of anxiety-like behavior following weight recovery (Gutierrez, 2013). Two excellent featured reviews by Gutierrez (2013) and Klein and Walsh (2005) provide in-depth and eloquent overviews of the ABA model, including a historical perspective on the model, its use in rats and mice, as well as a discussion of several key factors that contribute to ABA development (e.g., female sex, adolescent age, baseline weight) with an emphasis on the translational utility of the ABA model for understanding AN etiology and informing effective treatments.

The featured article by Barbarich-Marsteller and colleagues (2013) extended these findings by examining individual differences in the propensity for ABA behaviors to develop under the ABA paradigm. Because adolescence is a critical period of development for AN onset (Dominé, Dadoumont, & Bourguignon, 2012), and ABA behaviors (i.e., self-starvation and increased physical activity) escalate more quickly in adolescence versus adulthood (Boakes & Mills, 1999), the authors focused on identifying female rats who were more or less vulnerable to developing ABA behaviors during the adolescent period. They found that adolescent female rats fall along a spectrum of ABA propensity that ranges from vulnerable to ABA to ABA-resistant. Importantly, this study outlined an objective set of criteria for defining vulnerable versus resistant ABA phenotypes in females that can be used to examine why only a small subset of girls develop AN symptoms despite the high prevalence of dieting and exercise during adolescence. This study adds additional face validity to the ABA model of AN and provides a critical framework for future studies of AN to identify factors that increase risk or resilience.

Animal studies of binge-eating behaviors

A key feature of binge eating is the overconsumption of highly palatable food (PF) (i.e., food high in sugar and/or fat) in a discrete time period (American Psychiatric Association, 2013). In the featured article by Dimitriou and colleagues (2000), they demonstrate the importance of intermittent access to PF (as opposed to continuous access) to induce binge eating in female rats. They found that female rats given 2-hour, intermittent access to PF ate significantly higher amounts of PF compared to rats with continuous access to PF. During the 2-hour feeding period when both PF and chow were available, intermittent access rats ate 40-50% of their total daily caloric intake, of which 90% came from PF. This was significantly more PF than the rats in the continuous access PF and control (i.e., chow intake only - no PF access) conditions consumed during the same time period. This pattern of binge eating mirrors that of binge eating in humans where binge eating is intermittent and focused on highly palatable food rather than nutritive food (Weltzin, Hsu, Pollice, & Kaye, 1991; Woell, Ficher, Pirke, & Wolfram, 1989).

Two additional key aspects of binge eating in humans is loss of control over food intake during a binge and the sex difference in prevalence. While loss of control over eating is a quality unique to humans (Hagan et al., 2002), Oswald and colleagues (2011) showed in their featured article that female rats prone to binge eating will endure increasingly high levels of pain (via foot shock) in order to consume PF, even when they are not hungry. This pattern of PF intake is opposite to what is observed in female rats that are resistant to binge eating who do not tolerate increased levels of pain to consume PF. Importantly, this suggests a compulsive-like pattern of PF consumption in binge-eating prone rats that mirrors the loss of control over eating that is observed in humans, where despite worsening perceptions of body image, self-esteem, and physical discomfort, individuals continue to engage in binge eating (Fairburn & Wilson, 1993; Hagan et al., 2002). There are also sex differences in binge eating in rats. In their featured article, Klump and colleagues (2013) demonstrate that sex differences in binge-eating behaviors in rats (rates that are 2-6 higher in female versus male rats) are similar to the sex differences observed in humans (2-10 times higher in women versus men; American Psychiatric Association, 2013; Klump, Culbert, & Sisk, 2017). This sex difference provides further support for the face validity and translational potential of studying binge eating in female and male rats.

The above papers describe studies that examine key aspects of binge-eating behavior that are present regardless of other factors that may contribute to binge eating (e.g., caloric restriction). However, given that binge eating in humans is often preceded by a history of dieting (Brown, Forney, Klein, Grillot, & Keel, 2020; Liechty & Lee, 2013), it is important to examine the effects of caloric restriction and weight loss on binge eating in animals. In their featured article, Hagan and Moss (1997) compared binge-eating behavior in female rats from three groups: 1) rats that were exposed to 12 cycles of food restriction, and then refed on PF; 2) rats that were exposed to 12 cycles of food restriction, and then refed on chow; and 3) rats that did not experience food restriction or re-feeding. Thirty days after food restriction and refeeding had stopped and body weights were normalized, rats with a history of food restriction/re-feeding on PF consumed significantly more PF (when both chow and PF were available) as compared to the other two groups. This pattern of food consumption in the food restriction/re-feeding on PF group was the same under both sated and food deprived conditions. Results suggest that a history of dieting followed by refeeding on PF promotes binge eating on PF, even after dieting has stopped and rats are no longer hungry. This pattern of dieting followed by binge eating behavior is consistent with that observed in several eating disorders (e.g., BN, BED) where individuals alternate between periods of dieting and binge eating (American Psychiatric Association, 2013; Elran-Barak et al., 2015).

How can we use animal studies to examine mechanisms of eating disorders?

Although additional work is needed, the studies highlighted above provide initial support for studying disordered eating behaviors in animals. Using these and similar models (Consoli, Contarino, Tabarin, & Drago, 2009; Geary, 2003; Treasure & Owen, 1997), it is now possible to examine the mechanistic underpinnings that contribute to each behavior. Three articles are featured in this virtual issue (D’Addario et al., 2020; Hildebrandt, Sinclair, Sisk, & Klump, 2018; Micioni Di Bonaventura, Lutz, et al., 2017) that present findings on potential genetic, environmental, and biological mechanisms underlying the dysregulated appetite, female susceptibility to binge eating, and altered reward processing present in eating disorders. These results have the potential to elucidate mechanisms of effects that will help us better identify at-risk individuals and provide potential targets for future treatment development.

Animal studies of mechanisms of AN

Both genetic and environmental factors are known to contribute to AN development, however the extent to which genes and the environment interact to influence AN onset has remained largely unexplored (Guarnieri et al., 2012; Mazzeo & Bulik, 2009). It is possible that epigenetic factors may contribute to AN development, whereby the environment changes the expression and/or function of vulnerability or protective genes. Because AN is associated with dysregulated appetite and satiety, D’Addario and colleagues (2020) examined in their featured article possible epigenetic regulation of one system involved in feeding regulation, the endocannabinoid system (Cristino, Becker, & Di Marzo, 2014). The authors first used female rats in the ABA model of AN to investigate endocannabinoid gene expression and epigenetic markers in brain regions involved in food intake, reward, and emotion. They found that following the ABA paradigm, female rats exhibited decreased expression of the gene for the type 1 cannabinoid receptor (Cnr1) in brain regions related to food intake (e.g., hypothalamus) and reward (e.g., nucleus accumbens). Decreased expression of Cnr1 was associated with increased epigenetic markers in the Cnr1 gene promoter region and reduced food intake and body weight in ABA rats. The authors then expanded these findings by showing that genetically modified male and female mice (i.e., mice expressing a mutation that led to hypophagia and emaciation) also exhibited decreased expression of the same receptor gene in brain regions related to emotion and cognitive control (e.g., prefrontal cortex), with no differences in expression in brain regions related to food intake and reward. These results suggest that changes in the endocannabinoid system in AN may be environmentally/behaviorally driven, and they may be influenced by epigenetic and genetic factors. These results also implicate a potential role for the endocannabinoid receptor Cnr1, in the development of AN.

Animal studies of mechanisms of binge eating

Given the higher prevalence of binge eating in females (American Psychiatric Association, 2013; Klump et al., 2017) and interactions between stress and gonadal hormones (Oyola & Handa, 2017), the featured article by Micioni di Bonaventura and colleagues (2017) examined whether estrogen and stress interact to predict increased rates of binge eating in female rats. In the first set of experiments the authors examined binge eating in intact female rats in the following four groups: 1) food restriction-refeeding (i.e., on ad libitum chow with intermittent PF exposure) only; 2) frustrative non-reward stress only (i.e., 15-minute exposure to PF without being able to eat it); 3) the food restriction-refeeding with frustrative non-reward stress paradigms described above; and 4) neither restriction-refeeding nor frustrative non-reward stress (i.e., controls). Rates of binge eating were highest in the rats who experienced both food restriction-refeeding and the frustrative non-reward stress, with the most robust effects observed in rats during nonestrous (i.e., low estradiol) phases of the estrous cycle. In a second set of experiments, the authors used the same restriction-refeeding and stress paradigms to examine binge eating in a group of ovariectomized female rats who received or did not receive exogenous estradiol treatment. Importantly, the highest rates of binge eating were observed in ovariectomized rats without estradiol replacement who were restricted-refed and stressed. The restricted-refed and stressed ovariectomized rats who were given estradiol replacement exhibited lower levels of binge eating as compared to ovariectomized rats who were restricted-refed and stressed, but not given estradiol replacement. Moreover, brain regions that regulate the stress response (e.g., central amygdala, bed nucleus of the stria terminalis) and food intake (e.g., paraventricular nucleus of the hypothalamus) were more active in the restricted-refed and stressed, ovariectomized female rats that did not receive estradiol replacement compared to all other groups. These results suggest that estrogen and stress interact at a behavioral and neural level to influence binge eating in rats, and that additional investigations into these processes may increase our understanding of etiology and sex differences in binge eating and highlight new potential areas for intervention.

In addition to associations with ovarian hormones and the stress response, binge eating is associated with alterations in the reward system, with studies paradoxically reporting both hyper-responsivity (Sinclair, Hildebrandt, Culbert, Klump, & Sisk, 2017) and hypo-responsivity (Bohon & Stice, 2011) of this system in women who binge eat. The featured article by Hildebrandt and colleagues (2018) examined whether mixed results were due to changes in responsivity across chronicity of illness in female rats, whereby hyper-responsivity is observed in the “early stages” of binge eating, whereas hypo-responsivity (via downregulation of c-Fos expression) is observed in “late-stage or chronic” binge eating. These investigators (and others – Bohon & Stice, 2011; Wang et al., 2001) noted that similar patterns of effects have been shown in the addiction literature where acute drug use is associated with hyper-reward response and chronic drug use is associated with hypo-reward response (Lobo & Nestler, 2011; Volkow, Fowler, Wang, Baler, & Telang, 2009). Results confirmed hypotheses that “early stage” binge eating rats showed increased activity in several brain reward regions (e.g., nucleus accumbens shell and core) in response to PF intake. However, activity in these same brain reward regions was significantly attenuated in rats with “long-term/chronic” binge eating. Hildebrandt and colleagues (2018) interpreted their findings as suggestive that hyper-responsivity in the “early stages” of binge eating likely reinforces the development of regular binge eating which then leads to down-regulation and hypo-responsivity of the reward system with more chronic binge eating. This down-regulation/hypo-responsivity may then maintain the behavior, as individuals engage in more binge eating to compensate for the hypoactive reward response (much like what is observed with drug and alcohol use - Lobo & Nestler, 2011; Volkow et al., 2009). This differential biological response to PF across stage of binge eating has the potential to inform etiological models of binge eating regarding potential risk and maintenance factors at both the behavioral and neural level.

How can animal studies of eating disorders help inform eating disorder treatment?

Understanding the mechanisms underlying eating disorders can help us develop more targeted treatment for individuals suffering from these disorders. However, in most cases, the mechanisms underlying specific symptoms of disordered eating are either unknown or poorly understood. Animal studies of eating disorders provide one means to test novel treatment options while simultaneously expanding our knowledge of the mechanistic underpinnings of disordered eating by targeting specific systems implicated in each disorder. The four featured articles (Boersma et al., 2016; Chandler-Laney et al., 2007; Chen, Sherpa, & Aoki, 2018; Micioni Di Bonaventura, Ubaldi, et al., 2017) use animal studies to examine potential treatments for AN and binge eating-related disorders that target systems involved in anxiety, cognition, appetite, and stress. These studies provide valuable insight into potential mechanisms and future drug targets for eating disorders.

Animal studies of treatment of AN

Currently, there are no approved pharmacological treatments for AN (Crow, 2019). Because AN is highly comorbid with anxiety disorders (Marucci et al., 2018), drugs that reduce anxiety may offer potential treatment options for individuals with AN. Ketamine is one potential treatment option that is currently approved for use in depression (Carreno, Lodge, & Frazer, 2020) and anxiety (aan het Rot et al., 2010; Krystal et al., 1994). Animal studies show that ketamine increases food intake, specifically under periods of food restriction (Sarrau, Jourdan, Dupuis-Soyris, & Verwaerde, 2007; Treece, Ritter, & Burns, 2000). However, it is unknown whether ketamine is an effective treatment for AN. The featured article by Chen and colleagues (2018) examined this possibility by testing the effects of a single-dose ketamine injection in mid-adolescence on vulnerability to ABA behaviors in female mice. Of note, mice underwent the ABA paradigm during mid- and late-adolescence, and ketamine was administered on the second day of the first ABA induction. They found that the single dose of ketamine in mid-adolescence attenuated all three measures of ABA vulnerability (i.e., food restriction-induced increases in wheel running activity, weight loss, and stress-induced anxiety-like behavior) in mid-adolescence and promoted prolonged increases in food intake and suppression of body weight loss that lasted until late-adolescence. The authors propose that reductions in anxiety-like behavior in mid-adolescence contributed to the prolonged attenuation of ABA symptoms throughout late-adolescence. These results suggest that ketamine may be a useful treatment for AN during adolescence, particularly for individuals who also experience high levels of anxiety.

Because a large portion of AN patients relapse within the first year of treatment termination (Berends, Boonstra, & van Elburg, 2018), it is possible that AN induces long-lasting changes in parameters relevant to taste, food preference, anxiety, or cognition (all potentially important for relapse) that persist following weight restoration. In their featured paper, Boersma and colleagues (2016) tested this hypothesis by comparing indices of learning and memory, anxiety, food preference, and taste across four groups of adolescent female rats: 1) rats exposed to the full ABA paradigm; 2) sedentary rats (i.e., rats that were not food restricted and did not have access to running wheels); 3) rats with running wheel access, but no food restriction; and 4) rats with food restriction, but no access to running wheels (i.e., this a body-weight matched control group). All behavioral tests were conducted once weights were restored to baseline levels in all rat groups. The authors found that rats exposed to the full ABA paradigm did not show significant impairments in taste, anxiety, fat preference, or spatial learning, as compared to the other rat groups. However, the ABA rats did exhibit impairments in contextual learning (via reduced performance in a novel object recognition task) as compared to the other rat groups that persisted after weight had been restored. Results from this study implicate alterations in contextual learning as potential risk factors for relapse in individuals with AN, even after weight recovery. Such learning alterations may make it more difficult for individuals with AN to adhere to and learn new behavior modification techniques during recovery (see Frank, Shott, & DeGuzman, 2019a).

Animal studies of treatment of binge eating

Fluoxetine is a selective serotonin reuptake inhibitor (SSRI) that is currently approved to treat the binge eating that is present in BN and BED (Crow, 2019). However, the mechanisms underlying fluoxetine’s ability to decrease binge eating remain unclear. In their featured article, Chandler-Laney and colleagues (2007) sought to explore potential mechanisms by examining changes in binge eating and brain monoamines (e.g., serotonin, dopamine, and norepinephrine) and their metabolites following fluoxetine treatment in four groups of female rats: 1) rats exposed to cyclic food restriction-refeeding (i.e., on ad libitum chow with intermittent PF exposure) and stress (foot shock); 2) rats exposed to the same cyclic food restriction-refeeding, but without stress; 3) rats exposed to stress without the food restriction-refeeding; and 4) rats with no food restriction-refeeding and no stress (i.e., controls). They found that all rats with a history of caloric restriction-refeeding engaged in binge eating, regardless of exposure to stress. Fluoxetine was also able to decrease binge eating in all rats with a history of restriction-refeeding, but had the strongest effects in restricted-refed rats who had also been exposed to stress. Fluoxetine had no effect on binge eating in rats who were not exposed to restriction-refeeding or who had only been exposed to stress. Interestingly, the authors did not find any significant differences in levels of brain monoamines or their metabolites across any of the rat groups, which they attribute to a potential recovery of monoamine levels following cessation of restriction-refeeding. Overall, the authors conclude that binge eating induced by a history of dieting and refeeding alters serotonergic functioning that is able to be reversed by fluoxetine treatment. Additionally, the authors conclude that while changes in brain monoamine or monoamine metabolite levels do not seem to underlie fluoxetine’s effects on binge eating, studies should examine alternative mechanisms, including increases in monoamine receptor levels, changes in level of receptor expression, and changes in monoamine release.

In addition to the serotonergic system, there has been some interest in examining the stress system itself as a potential treatment target for binge-related disorders, given evidence that stress is a strong risk factor for binge eating (Larsen et al., 2017; Naish, Laliberte, MacKillop, & Balodis, 2019) and abnormal hypothalamic-pituitary-adrenal (HPA)-axis activity is present in individuals who binge eat (Lo Sauro, Ravaldi, Cabras, Faravelli, & Ricca, 2008; Oyola & Handa, 2017). In the featured article by Micioni di Bonaventura and colleagues (2017), the effects of systemic (in the body) and central (in the brain) blockade of stress receptor (corticotropin-releasing factor receptor 1) activity and stress hormone (corticosterone) synthesis on binge-eating behavior in female rats was examined following either cyclic food restriction-refeeding (i.e., on ad libitum chow with intermittent PF exposure) only, frustrative non-reward stress (15-minute interaction with PF without being able to eat it) only, both restriction-refeeding and stress, or neither restriction-refeeding nor stress (i.e., controls). They found that rats with a history of restriction-refeeding and stress ate significantly more PF than rats in the other groups. Systemic blockade of stress receptor activity reversed these effects in the group that was restricted-refed and stressed (i.e., their rates of binge eating decreased to the levels in other groups), while systemically inhibiting stress hormone synthesis had no effect on PF intake in any rat group. Importantly, rats who were both restricted-refed and stressed displayed significantly higher levels of stress hormone receptor expression in brain regions involved in stress (e.g., bed nucleus of the stria terminalis, central amygdala) as compared to the other rat groups. Finally, blocking stress hormone receptor activity in the bed nucleus of the stria terminalis, but not the central amygdala, significantly reduced PF intake in the rats that were restricted and stressed, but not the other rat groups. These results highlight the stress system, in particular the extra-hypothalamic CRF1 receptor, as a novel target for treatment of binge-related disorders, particularly in individuals experiencing high levels of stress. Because stress impacts various behaviors that often co-occur with or are risk factors for binge eating and other eating disorders (e.g., anxiety, depression; de Kloet, Joëls, & Holsboer, 2005), developing treatments that restore normal functioning in the stress system has the potential to improve symptoms of eating disorders, reduce comorbidity, and lessen symptom severity.

Conclusions

It was a pleasure to curate this virtual issue on animal studies of eating disorders for IJED. Given our limited understanding of the etiology of eating disorders, we hope that the concepts and findings presented in this focused collection will encourage more animal studies of eating disorders. Because we were unable to feature the important findings from all of the animal studies that have been published in IJED, we highly recommend that readers access all of the articles in Table 2 to appreciate the breadth of work that has been conducted using animal studies of eating disorders and their significant contributions to our understanding of the disorders and their component behaviors. We look forward to continued growth in this important area of research.

References

  1. aan het Rot M, Collins KA, Murrough JW, Perez AM, Reich DL, Charney DS, & Mathew SJ (2010). Safety and efficacy of repeated-dose intravenous ketamine for treatment-resistant depression. Biological Psychiatry, 67(2), 139–145. 10.1016/j.biopsych.2009.08.038. [DOI] [PubMed] [Google Scholar]
  2. American Psychiatric Association. (2013). Diagnostic and Statistical Manual of Mental Disorders (5th ed.). Arlington, VA: American Psychiatric Publishing. [Google Scholar]
  3. Barbarich-Marsteller NC, Underwood MD, Foltin RW, Myers MM, Walsh T, Barrett JS, & Martseller DA (2013). Identifying novel phenotypes of vulnerability and resistance to activity-based anorexia in adolescent female rats. International Journal of Eating Disorders, 46(7), 737–746. 10.1002/eat.22149. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Berends T, Boonstra N, & van Elburg A (2018). Relapse in anorexia nervosa: A systematic review and meta-analysis. Current Opinion in Psychiatry, 31(6), 445–455. 10.1097/YCO.0000000000000453 [DOI] [PubMed] [Google Scholar]
  5. Boakes R ., & Mills KJ (1999). Sex differences in the relationship between activity and weight loss in the rat. Behavioral Neuroscience, 113, 1080–1089. [PubMed] [Google Scholar]
  6. Boersma GJ, Treesukosol Y, Cordner ZA, Kastelein A, Choi P, Moran TH, & Tamashiro KL (2016). Exposure to activity-based anorexia impairs contextual learning in weight-restored rats without affecting spatial learning, taste, anxiety, or dietary fat preference. International Journal of Eating Disorders, 49(2), 167–179. 10.1002/eat.22489. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Bohon C, & Stice E (2011). Reward abnormalities among women with full and subthreshold bulimia nervosa: a functional magnetic resonance imaging study. International Journal of Eating Disorders, 44(7), 585–595. 10.1002/eat.20869 [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Brown TA, Forney KJ, Klein KM, Grillot C, & Keel PK (2020). A 30-year longitudinal study of body weight, dieting, and eating pathology across women and men from late adolescence to later midlife. Journal of Abnormal Psychology, 129(4), 376–386. https://doi.org/doi: 10.1037/abn0000519 [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Carreno FR, Lodge DJ, & Frazer A (2020). Ketamine: Leading us into the future for development of antidepressants. Behavioural Brain Research, 383, 112532 10.1016/j.bbr.2020.112532. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Chandler-Laney PC, Castañeda E, Viana JB, Oswald KD, Maldonado CR, & Boggiano MM (2007). A history of human-like dieting alters serotonergic control of feeding and neurochemical balance in a rat model of binge-eating. International Journal of Eating Disorders, 40(2), 136–142. 10.1002/eat.20349. [DOI] [PubMed] [Google Scholar]
  11. Chen YW, Sherpa AD, & Aoki C (2018). Single injection of ketamine during mid-adolescence promotes long-lasting resilience to activity-based anorexia of female mice by increasing food intake and attenuating hyperactivity as well as anxiety-like behavior. International Journal of Eating Disorders, 51(8), 1020–1025. 10.1002/eat.22937. [DOI] [PubMed] [Google Scholar]
  12. Cheney CD, & Epling WF (1968). Running wheel activity and self starvation in the white rat. (Pierce WD & Cheney CD, Eds.). [Google Scholar]
  13. Consoli D, Contarino A, Tabarin A, & Drago F (2009). Binge-like eating in mice. International Journal of Eating Disorders, 42(5), 402–408. 10.1002/eat.20637 [DOI] [PubMed] [Google Scholar]
  14. Cristino L, Becker T, & Di Marzo V (2014). Endocannabinoids and energy homeostasis: An update. BioFactors, 40(4), 389–397. 10.1002/biof.1168 [DOI] [PubMed] [Google Scholar]
  15. Crow S (2019). Pharmacologic treatment of eating disorders. The Psychiatric Clinics of North America, 42(2), 253–262. 10.1016/j.psc.2019.01.007. [DOI] [PubMed] [Google Scholar]
  16. D’Addario C, Zaplatic E, Giunti E, Pucci M, Micioni Di Bonaventura MV, Scherma M, … Fadda P (2020). Epigenetic regulation of the endocannabinoid receptor CB1 in an activity-based rat model of anorexia nervosa. International Journal of Eating Disorders. 10.1002/eat.23271 [DOI] [PubMed] [Google Scholar]
  17. de Kloet ER, Joëls M, & Holsboer F (2005). Stress and the brain: from adaptation to disease. Nature Reviews Neuroscience, 6(6), 463–475. 10.1038/nrn1683 [DOI] [PubMed] [Google Scholar]
  18. Dimitriou SG, Rice HB, & Corwin RL (2000). Effects of limited access to a fat option on food intake and body composition in female rats. International Journal of Eating Disorders, 28(4), 436–445. . [DOI] [PubMed] [Google Scholar]
  19. Dominé F, Dadoumont C, & Bourguignon J-P (2012). Eating disorders throughout female adolescence. Endocrine Development, 22, 271–286. 10.1159/000326697. [DOI] [PubMed] [Google Scholar]
  20. Elran-Barak R, Sztainer M, Goldschmidt AB, Crow SJ, Peterson CB, Hill LL, … Le Grange D (2015). Dietary restriction behaviors and binge eating in anorexia nervosa, bulimia nervosa and binge eating disorder: Trans-diagnostic examination of the restraint model. Eating Behaviors, 18, 192–196. 10.1016/j.eatbeh.2015.05.012. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Fairburn CG, & Wilson GT (1993). Binge Eating: Nature, Assessment, and Treatment. New York City: The Guilford Press. [Google Scholar]
  22. Frank GKW, Shott ME, & DeGuzman MC (2019a). Recent advances in understanding anorexia nervosa. F1000 Research, 8(F100 Faculty Rev), 504 10.12688/f1000research.17789.1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Frank GKW, Shott ME, & DeGuzman MC (2019b). The neurobiology of eating disorders. Child and Adolescent Psychiatric Clinics of North America, 28(4), 629–640. 10.1016/j.chc.2019.05.007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Geary N (2003). A new animal model of binge eating. International Journal of Eating Disorders, 34(2), 198–199. 10.1002/eat.10226. [DOI] [PubMed] [Google Scholar]
  25. Guarnieri DJ, Brayton CE, Richards SM, Maldonado-Aviles J, Trinko JR, Nelson J, … DiLeone RJ (2012). Gene profiling reveals a role for stress hormones in the molecular and behavioral response to food restriction. Biological Psychiatry, 71(4), 358–365. 10.1016/j.biopsych.2011.06.028. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Gutierrez E (2013). A rat in the labyrinth of anorexia nervosa: contributions of the activity-based anorexia rodent model to the understanding of anorexia nervosa. International Journal of Eating Disorders, 46(4), 289–301. 10.1002/eat.22095. [DOI] [PubMed] [Google Scholar]
  27. 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. International Journal of Eating Disorders, 22(4), 411–420. . [DOI] [PubMed] [Google Scholar]
  28. Hagan MM, Shuman ES, Oswald KD, Corcoran KJ, Profitt JH, Blackburn K, … Birbaum MC (2002). Incidence of chaotic eating behaviors in binge-eating disorder: contributing factors. Behavioral Medicine, 28(3), 99–105. 10.1080/08964280209596048 [DOI] [PubMed] [Google Scholar]
  29. Hildebrandt BA, Sinclair EB, Sisk CL, & Klump KL (2018). Exploring reward system responsivity in the nucleus accumbens across chronicity of binge eating in female rats. International Journal of Eating Disorders, 51(8), 989–993. 10.1002/eat.22895 [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Hinney A, & Volckmar AL (2013). Genetics of eating disorders. Current Psychiatry Reports. 10.1007/s11920-013-0423-y [DOI] [PubMed] [Google Scholar]
  31. Keel PK, & Forney KJ (2013). Psychosocial risk factors for eating disorders. International Journal of Eating Disorders, 46(5), 433–439. 10.1002/eat.22094. [DOI] [PubMed] [Google Scholar]
  32. Klein D, & Walsh BT (2005). Translational approaches to understanding anorexia nervosa. International Journal of Eating Disorders, 37 Suppl, S10–4. 10.1002/eat.20108. [DOI] [PubMed] [Google Scholar]
  33. Klump KL, Culbert KM, & Sisk CL (2017). Sex differences in binge eating: Gonadal hormone effects across development. Annu. Rev. Clin. Psychol, 13, 183–207. 10.1146/annurev-clinpsy-032816 [DOI] [PubMed] [Google Scholar]
  34. Klump KL, Racine S, Hildebrandt B, & Sisk CL (2013). Sex differences in binge eating patterns in male and female adult rats. International Journal of Eating Disorders, 46(7), 729–736. 10.1002/eat.22139. Epub 2013 Apr 29 [DOI] [PubMed] [Google Scholar]
  35. Krystal JH, Karper LP, Seibyl JP, Freeman GK, Delaney R, Bremner JD, … Charney DS (1994). Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans: Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Archives of General Psychiatry, 52(3), 199–214. 10.1001/archpsyc.1994.03950030035004. [DOI] [PubMed] [Google Scholar]
  36. Larsen JT, Munk-Olsen T, Bulik CM, Thornton LM, Koch SV, Mortensen PB, & Petersen L (2017). Early childhood adversities and risk of eating disorders in women: A Danish register‐based cohort study. International Journal of Eating Disorders, 50(12), 1404–1412. 10.1002/eat.22798 [DOI] [PubMed] [Google Scholar]
  37. Liechty JM, & Lee MJ (2013). Longitudinal predictors of dieting and disordered eating among young adults in the U.S. International Journal of Eating Disorders, 46(8), 790–800. 10.1002/eat.22174 [DOI] [PubMed] [Google Scholar]
  38. Lo Sauro C, Ravaldi C, Cabras PL, Faravelli C, & Ricca V (2008). Stress, hypothalamic-pituitary-adrenal axis and eating disorders. Neuropsychobiology, 57, 95–115. 10.1159/000138912 [DOI] [PubMed] [Google Scholar]
  39. Lobo MK, & Nestler EJ (2011). The striatal balancing act in drug addiction: distinct roles of direct and indirect pathway medium spiny neurons. Frontiers in Neuroanatomy, 5(41). 10.3389/fnana.2011.00041 [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Marucci S, Ragione LD, De Iaco G, Mococci T, Vicini M, Guastamacchia E, & Triggiani V (2018). Anorexia nervosa and comorbid psychopathology. Endocrine, Metabolic, & Immune Disorders Drug Targets, 18(4), 316–324. 10.2174/1871530318666180213111637. [DOI] [PubMed] [Google Scholar]
  41. Mazzeo SE, & Bulik CM (2009). Environmental and genetic risk factors for eating disorders: What the clinician needs to know. Child and Adolescent Psychiatric Clinics of North America, 18(1), 67–82. 10.1016/j.chc.2008.07.003 [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Micioni Di Bonaventura MV, Lutz TA, Romano A, Pucci M, Geary N, Asarian L, & Cifani C (2017). Estrogenic suppression of binge-like eating elicited by cyclic food restriction and frustrative-nonreward stress in female rats. International Journal of Eating Disorders, 50(6), 624–635. 10.1002/eat.22687 [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Micioni Di Bonaventura MV, Ubaldi M, Giusepponi ME, Rice KC, Massi M, Ciccocioppo R, & Cifani C (2017). Hypothalamic CRF1 receptor mechanisms are not sufficient to account for binge-like palatable food consumption in female rats. International Journal of Eating Disorders. 10.1002/eat.22767 [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Naish KR, Laliberte M, MacKillop J, & Balodis IM (2019). Systematic review of the effects of acute stress in binge eating disorder. European Journal of Neuroscience, 50(3), 2415–2429. 10.1111/ejn.14110 [DOI] [PubMed] [Google Scholar]
  45. Oswald KD, Murdaugh DL, King VL, & Boggiano MM (2011). Motivation for palatable food despite consequences in an animal model of binge eating. International Journal of Eating Disorders, 44(3), 203–211. 10.1002/eat.20808. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Oyola MG, & Handa RJ (2017). Hypothalamic-pituitary-adrenal and hypothalamic-pituitary-gonadal axes: sex differences in regulation of stress responsivity. Stress, 20(5), 476–494. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Pucci M, Micioni Di Bonaventura MV, Zaplatic E, Bellia F, Maccarrone M, Cifani C, & D’Addario C (2018). Transcriptional regulation of the endocannabinoid system in a rat model of binge-eating behavior reveals a selective modulation of the hypothalamic fatty acid amide hydrolase gene. International Journal of Eating Disorders, 52(1), 51–60. 10.1002/eat.22989. [DOI] [PubMed] [Google Scholar]
  48. Routtenberg A, & Kuznesof AA (1967). Self-starvation of rats living in activity wheels on a restricted feeding schedule. Journal of Comparative and Physiological Psychology, 64, 414421. [DOI] [PubMed] [Google Scholar]
  49. Sarrau S, Jourdan J, Dupuis-Soyris F, & Verwaerde P (2007). Effects of postoperative ketamine infusion on pain control and feeding behaviour in bitches undergoing mastectomy. The Journal of Small Animal Practice, 48, 670–676. 10.1111/j.1748-5827.2007.00362.x [DOI] [PubMed] [Google Scholar]
  50. Sinclair EB, Hildebrandt BA, Culbert KM, Klump KL, & Sisk CL (2017). Preliminary evidence of sex differences in behavioral and neural responses to palatable food reward in rats. Physiology and Behavior, 176, 165–173. 10.1016/j.physbeh.2017.03.042 [DOI] [PubMed] [Google Scholar]
  51. Treasure JL, & Owen JB (1997). Intriguing links between animal behavior and anorexia nervosa. International Journal of Eating Disorders, 21(4), 307–311. . [DOI] [PubMed] [Google Scholar]
  52. Treece BR, Ritter RC, & Burns GA (2000). Lesions of the dorsal vagal complex abolish increases in meal size induced by NMDA receptor blockade. Brain Research, 872(1–2), 37–43. 10.1016/s0006-8993(00)02432-x. [DOI] [PubMed] [Google Scholar]
  53. Volkow ND, Fowler JS, Wang GJ, Baler R, & Telang F. (2009). Imaging dopamine’s role in drug abuse and addiction. Neuropharmacology, 56(Suppl 1), 3–8. 10.1016/j.neuropharm.2008.05.022 [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Wang GJ, Volkow ND, Logan J, Pappas NR, Wong CT, Zhu W, … Fowler JS (2001). Brain dopamine and obesity. Lancet, 357(9253), 354–357. 10.1016/s0140-6736(00)03643-6. [DOI] [PubMed] [Google Scholar]
  55. Weltzin TE, Hsu LKG, Pollice C, & Kaye WH (1991). Feeding pattern in bulimia nervosa. Biological Psychiatry, 30, 1093–1110. 10.1016/0006-3223(91)90180-t. [DOI] [PubMed] [Google Scholar]
  56. Woell C, Ficher MM, Pirke KM, & Wolfram G (1989). Eating behavior of patients with bulimia nervosa. International Journal of Eating Disorders, 8(5), 557–568. [Google Scholar]

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