Systematic Review of Binge Eating Rodent Models for Developing Novel or Repurposing Existing Pharmacotherapies

Recent advances in developing and screening candidate pharmacotherapies for psychiatric disorders have depended on rodent models. Eating disorders are a set of psychiatric disorders that have traditionally relied on behavioral therapies for effective long-term treatment. However, the clinical use of Lisdexamfatamine for binge eating disorder (BED) has furthered the notion of using pharmacotherapies for treating binge eating pathologies. While there are several binge eating rodent models, there is not a consensus on how to define pharmacological effectiveness within these models. Our purpose is to provide an overview of the potential pharmacotherapies or compounds tested in established rodent models of binge eating behavior. These findings will help provide guidance for determining pharmacological effectiveness for potential novel or repurposed pharmacotherapies.


Introduction
Advancements in uncovering novel therapeutics for eating disorders have been limited in the past several decades. Treatments for eating disorders have historically depended on cognitive behavioral and psychotherapies [1][2][3]. While these therapies remain effective for specific eating disorders and coping with individualized factors, the long-term effectiveness of these therapies is dependent on the availability of trained clinicians, patient commitment, and other clinically managed outcomes [4][5][6]. In recent years, there has been an interest in developing pharmacotherapies as adjuvant to improve behavioral and psychotherapy outcomes [7,8]. In the US, there are only two FDA-approved pharmacotherapies options for the treatment of eating disorders. Both medications are "repurposed" and were originally approved for other psychiatric illnesses [9]. Fluoxetine (FLX) is available for the clinical management of bulimia nervosa (BN), whereas lisdexamfetamine (LDX) is available for binge eating disorder (BED). To date, there is no pharmacotherapy approved for use in patients with anorexia nervosa (AN). Notably, BN and BED are two separate psychiatric disorders with binge eating as a core pathology but differ in their clinical diagnostic criteria and management [10].
FLX was FDA-approved in 1987 for the treatment of major depressive disorder and then approved for acute management and maintenance of BN in 1994 [11,12]. Efficacy of FLX was determined in two pivotal randomized placebo-controlled multi-center studies [13,14]. In an 8-week study (n = 387, 100% were female; DSM III-R defined BN), FLX (60 mg/day) had a 20% placebo-subtracted reduction of binge eating and a 31% placebosubtracted reduction of vomiting episodes per week. Discontinuation rates were 37.2% for placebo and 30.2% for FLX [13]. Similar reductions in bulimic behaviors were demonstrated in a 16-week study (n = 398, 96.2% were female; DSM III-R defined BN) [14]. FLX (60 mg/d) had a 32% placebo-subtracted reduction in binge eating and a 29% placebo-reduction reduction of vomiting episodes per week. Discontinuation rates were 52% for placebo and 40.5% for FLX [14]. Recent evidence suggest that FLX is still considered effective for the management of BN, but approximately 60% of BN patients do not achieve remission with FLX or available psychotherapies or their combination [15].
The other available pharmacotherapy is LDX, which was initially FDA-approved for the management of attention deficit hyperactivity disorder (ADHD) in 2007 for children (6-12 years old) and 2008 for adults. In 2015, LDX was FDA-approved for the maintenance of moderate to severe BED [16]. Several randomized placebo-controlled phase III studies were conducted to determine the efficacy of LDX for BED. Two 12-week studies (Study 1: n = 379, 86.5% were female; Study 2: n = 366, 85.2% were female; DSM-IV TR defined BED; NCT01718483 and NCT01718509) demonstrated LDX (50 or 70 mg/day) had a 26.3% placebo-subtracted reduction (study 1) and a 37.6% placebo-subtracted reduction (study 2) in binge eating days/per week [17]. Discontinuation rates were 18% and 25.9% for placebo and 17.7% and 26.5% for LDX for each study, respectively [17]. Efficacy of LDX was further established in a 26-week study (n = 418, 87.1% female; DSM-IV TR defined BED; NCT02009163), which demonstrated a reduced relapse risk for BED patients [18]. LDXtreated subjects had a 3.7% relapse rate compared with 32.1% relapse rate in placebo-treated subjects [18]. LDX is also likely to improve the high impulsivity reported in some BED populations [19]. Using a within-subjects design, it was demonstrated that 8-week LDX (50 mg/day or 70 mg/day) decreased binge eating frequency in BED subjects (n = 41, 97.6% female; DSM-V defined BED) [19]. Notably, binge episode frequency was also quantified as binge days per week rather than discrete binge episodes, since self-reporting of when binge episodes start and finish can be difficult to delineate or recall [17]. Additional medications initially approved to treat other psychiatric illnesses have been investigated in BED or BN populations [20][21][22][23][24] and are reviewed in detail elsewhere [25,26].
Concerns for the safety and tolerability of pharmacotherapies for BN and BED arise on several levels. The frequency and severity of treatment emergent adverse events represents a major contributor to the discontinuation rate in efficacy trials [14,27]. Pregnancy risks are major concerns for women of child-bearing age, which represents the predominant age range of women seeking therapeutic assistance for eating disorders. For instance, LDX and FLX has not been systematically tested for their effects on a developing fetus, but there is ample evidence in rodent and non-rodent species to suggest a pregnancy risk (FDA Pregnancy category C) [12,28]. LDX also has an abuse and dependency potential with a long-term risk to elevate cardiovascular endpoints [29]. For the most part, though, FLX and LDX are considered to be well-tolerated medications for the treatment of BN and BED, respectively.
Unlikely other classes of medications [30], to date, there is no guidance for industry on developing pharmacotherapies for the clinical management of binge eating. However, in the FDA application for LDX for moderate to severe BED, there was a stated assertion by the sponsor that a mean reduction of 0.5 or more binge days per week was "clinically meaningful" [31]. Additional endpoints include number of subjects with total remission of binge eating and/or vomiting, improvements in structured diagnostic assessments (i.e., Y-BOCS-BE, BES, EDI, CGI, BDI, etc.), and triglyceride levels in BED patients [13,17,28,31]. As such, the primary endpoint for determining efficacy of a pharmacotherapy for BED or BN is a sustained significant reduction in the frequency of binge (BN/BED) or vomiting (BN) episodes [13,20]. A reduction in binge frequency outcomes could also represent only one component in multi-stage optimization innervation [32]. Nonetheless, reduction in binge frequency represents a measurable behavioral endpoint for determining pharmacotherapeutic effectiveness.
Animal models, specifically rodent models, are used to advance the screening and development of potential pharmacotherapies for psychiatric disorders [33,34]. In addition, animal models can assist in the early identification of some safety and tolerability-related issues. No animal model, however, can fully encompass all the intricacies of a psychiatric disorder. To be relevant and effective, animal models should be developed to ask specific hypothesis-testable questions for particular features of the complex psychiatric disease under investigation [35]. Within the field of eating disorders, binge eating has several core components that can be recapitulated in rodents for assessing the effectiveness of potential pharmacotherapies. While the sense of 'loss of control' of binge eating is a pathological feature that is difficult to objectively assess in animals, two aspects of binge eating that can be recapitulated are excessive ingestion of calories in a short period of time and the episodic pattern of eating. In addition, some rodent binge eating models have incorporated a caloric restriction component to mimic restrictive eating or cycling dieting influencing binge eating behaviors [10]. Rats and mice lack an emetic response [36], so calorie restriction in animal models also serves as a method of assessing the influence of calorie restrictive conditions on eating without vomiting. The purpose of this systematic review is not to further debate on which experimentally controlled factors appropriately recapitulate the core features of a clinical eating disorder. The purpose of this systematic review is to provide an overview of the potential pharmacotherapies or compounds tested in established rodent models of binge eating behavior. This information can be used to develop hypothesis-testable questions on pharmacotherapeutic options, standardized approaches to assess candidate drugs, and to provide guidance on future experimental design approaches building on existing findings in binge eating rodent models.

Materials and Methods
This systematic review was performed using Pubmed (https://pubmed.ncbi.nlm.nih. gov/; accessed 31 December 2022) and APA PsycInfo (https://psycnet.apa.org/search) web-based databases (accessed 31 December 2022). The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (PRISMA) flowchart was used in the literature selections [37]. The following terms were used: "binge eating", "binge eating disorder", "bulimia nervosa", "animal models", "rodents", "rat", "mouse", "intermittent", "intermittent access", "intermittent palatable food", "dietary binge eating", "stress eating", "stress overeating", "stress-induced binge eating", "binge-like eating", "binge-type eating", and "binge feeding". The searches were performed to include all studies with a full publication date before 1 January 2023 (not epub date). Inclusion criteria were studies published as peer-reviewed articles, written in the English language, and definition of the feeding schedule as "binge" or "binge-like" or "binge-type". Articles were further selected based on pharmacology endpoints to included compounds, agents, drugs, or medication interventions on feeding outcomes. Exclusion criteria were studies that used liquid (i.e., Ensure ® or chocolate drink) or sweetened solutions as binge foods. Our rationale for excluding liquid binge food studies was that while these represent related ingestive behaviors and brain processes, fluid intake is also regulated by osmotic and volumetric factors. These factors are distinguishable from eating. Additional studies were excluded that had alcohol-and/or drugs of abuse-related outcomes. Studies were also excluded if the binge paradigm with regards to binge food composition, access, frequency, or duration were poorly defined.

Study Charactersitics and Selection
As detailed in Figure 1, there were a total of 434 studies screened, and 67 studies were used for systematic review. Studies were further classified based on targeted systems, combinations, or comparisons between compounds. These studies are summarized in Tables 1-5. Given the differences in study design, approach, binge food, and major pharmacological outcomes, the summary of these studies is best represented in a table  format. omolecules 2022, 12, x FOR PEER REVIEW 4 of 45 combinations, or comparisons between compounds. These studies are summarized in Tables 1-5. Given the differences in study design, approach, binge food, and major pharmacological outcomes, the summary of these studies is best represented in a table format. In accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a total of 67 studies were retained for the examination of pharmacological or compound assessment of binge-like eating behavior in rodents.
• 3 mg/kg dose of FLX suppressed intake of rats with a history of caloric restriction, normalizing the intake of calorie restricted/stressed rats, but had no effect on groups without a history of caloric restriction. • Neurochemical differences were not evident in the hypothalamus or tegmentum across groups. Female Sprague Dawley rats were exposed to binge paradigm with or without stress (i.e., acute foot shock; 0.6 mA). The role of serotonergic function in binge eating behaviors was investigated, specifically the influence of FLX (2 mg/kg; IP).
• History of caloric restriction alone produced binge-like eating • FLX produced binge intake, feeding suppression in rats with a history of caloric restriction and acute stress exposure.

•
The FLX binge intake suppression was abolished when rats were undergoing (i.e., active vs. history) the caloric restriction and had lower body weights. • With non-bingeing rats, baclofen generally had no effect on increased food intake. • Baclofen (1.0, 1.8 mg/kg IP) reduced binge food intake regardless of access condition.

•
Baclofen had no effect on FM or regular chow intake. • Reduction of feeding, body weight, and adipose tissue inflammation was seen in mice treated with high-fat diet after chronic treatment with VU0409106. • VU0409106 (7.5 or 15 mg/kg) reduced binge-like eating. • Memantine (2.5-10 mg/kg IP) reduced binge intake; there was no effect on standard diet. • Intra-accumbens injections of 10 and 20 µg reduced binge intake in animals targeting NAcc shell, but no effect was found with injections targeting the NAcc core.

Noradrenergic/Adrenergic-Acting Compounds
Three compounds (prazosin, guanfacine, and nisoxetine) were used to target the central noradrenergic system in binge eating rodents [43,44,50]. Prazosin, an α-1 adrenergic receptor antagonist, increased the progressive ratio break point for binge food at all doses tested (0.5-2 mg/kg) in male rats [50]. Chronic guanfacine, an α2A-adrenergic receptor agonist (0.5 mg/kg/daily), increased binge eating in female rats exposed to limited binge food access without intermittent calorie restriction [43]. The selective norepinephrine reuptake inhibitor, nisoxetine (3 mg/kg), produced a feeding suppression in all groups, except the binge group with a history of intermittent calorie restriction [44].

Serotonergic-Acting Compounds
Four compounds (FLX, fenfluramine, lorcaserin, and WAY163909) were used to target the central serotonergic system [38,41,48,49,53]. A selective serotonin reuptake inhibitor (SSRI), FLX was administered a single peripheral dose (30 mg/kg) or chronic dose (150 mg/L in drinking water for 21 days) to assess binge eating in mice with a knock-in of tryptophan hydroxylase 2 (Tph2) [53]. Peripherally administered FLX at 3 mg/kg reduced binge eating in female rats with a history of caloric restriction [41], whereas FLX at 2 mg/kg reduced binge eating in female rats exposed to acute foot shock stress [38]. Peripherally administered serotonergic drugs, such as fenfluramine (3 mg/kg), and lorcaserin (1 mg/kg), were used to assess intra-accumbens DAMGO-induced binge eating [48]. In addition, a novel 5HT2c receptor agonist, WAY163909, was effective at reducing binge eating at 1 mg/kg and at 2 mg/kg in male rats [49].

γ-Aminobutyric Acid (GABA)-Ergic Compounds
The GABAergic system was targeted in two studies using the GABA B agonist, baclofen, on binge eating in male rats [39,40]. Baclofen at 1 mg/kg reduced lever responding for binge food [40], whereas at 1.8 mg/kg baclofen reduced binge food intake under all access conditions [39].

Corticotropin-Releasing Factor (CRF) and Stress-Related Compounds
Compounds targeting stress-related hormonal and brain signaling were examined in two studies [68,69]. Specifically, CRF receptor antagonists, centrally administered D-Phe-CRF  or peripherally administered R121919 (20 mg/kg), reduced binge eating in rats with a history of calorie restriction and stress exposure [68,69]. Neither exogenous corticosterone nor metyrapone influenced binge eating [69].
The effects of the novel mu-opioid receptor antagonists, GSK1521498 (0.1, 1, and 3 mg/kg; SC) or Naltrexone (NTX, 0.1, 1, and 3 mg/kg; SC), on food seeking behavior (measured in rats trained to respond for reward under a second-order schedule of reinforcement) and binge-like eating were assessed.
• Both GSK1521498 (1 or 3 mg/kg) and NTK (1 or 3 mg/kg) reduced binge-like eating. • GSK1521498 reduced the anticipatory chow hypophagia. • GSK1521498 (1 or 3 mg/kg) reduced food seeking both before and after binge food ingestion. • NTX reduced food seeking only after binge food ingestion. Male Sprague Dawley rats were implanted bilaterally with guide cannula in the PVN. The effects of the mu-opioid agonist DAMGO (0, 0.025, 0.25, and 2.5 nm, injected unilaterally to stimulate feeding) and the general opioid antagonist NTX (0, 10, 30, and 100 nmol, injected bilaterally) to inhibit feeding in consumption of fat and sucrose diets were assessed. The effect of peripheral subcutaneous injections of NTX (SQ; 0, 0.03, 0.1, and 0.3 mg/kg) was also assessed.
• DAMGO increased intake of fat in the fat-preferring group but had no effect on intake of either diet in the sucrose-preferring group. • History of DEP was highly significant on the amount eaten. • Butorphanol increased food intake in rats with a history of caloric restriction/refeeding, but not in control rats.  • Males consumed significantly less fat/kg of body weight than did females after 5 weeks. • Binge intake was significantly stimulated by 2OHE2 at 3 µg/kg only in the INT group. • 2ME2 had no effect on binge food intake.

•
There was no effect of 2OHE2 and 2ME2 on binge food intake in D access groups.   at 1000 ng effectively reduced binge intake at 15 min.        Female rats were exposed to a restricting(R)/refeeding binge eating paradigm with or without stress (S). The effect of the A 2 A adenosine receptor (AR) agonists, CGS 21680 and VT 7 (0.1 and 0.05 mg/kg IP), on intake of highly palatable food (HPF) on sated rats, and low-palatability food (LPF) intake in food-deprived rats was assessed.
• Rats in the R + S group had a higher intake of binge food than the NR + NS controls. Two studies investigated site-specific injections of PACAP or PACAP 1-38 [77,80]. Intraaccumbens PACAP (50 pmol/side) reduced binge eating, whereas ventromedial hypothalamic injections did not influence binge food intake in male rats [77]. Intra-VTA PACAP 1-38 (30 pmol/side) reduced binge eating in male mice, but not in female or OVX female mice [80].
Peripheral administration of the tricyclic antidepressant clomipramine twice daily (15 mg/kg) prior to weaning resulted in adult binge eating phenotype in male and female rats [86]. Examination of nociception/orphanin FQ (N/OFQ) on binge eating indicated a differential dose-dependent effect [82]. Central injection of N/OFQ peptide (0.5 nmol; ICV) decreased binge intake at 30 min in rats with a history of calorie restriction and stress, but higher doses (1.0 nmol ICV) increased binge eating in rats with a history of calorie restriction without stress [82].
Peripheral administration of two of the A 2A adenosine receptor agonists, CGS 21680 (0.1 mg/kg) and VT 7 (0.1 mg/kg), reduced binge food and non-binge food intake [81]. VT7 (0.1 mg/kg) also increased A2A receptor gene expression in the amygdaloid complex, whereas the A 2A antagonist ANR 94 (1 mg/kg) increased %DNA methylation of the A 2A gene promoter [88]. ANR94 combined with VT 7 had higher %DNA methylation than VT 7 alone [88]. Peripheral administration of extracts of the botanical Rhodiola rosea (10 or 20 mg/kg) reduced binge eating in female rats exposed to a history of calorie restriction and stress [73]. Additional experiments indicated salidroside (312-936 µg/kg), a bioactive component of R. rosea, reduced binge eating [73].

Fluoxetine (FLX) Compared with Other Compounds
Six studies [89][90][91][92]94,98] compared FLX with other compounds. In all studies, FLX was administered peripherally (IP) at dose ranges of 2.5 to 10 mg/kg in rats and 3 to 30 mg/kg in mice. FLX (30 mg/kg) reduced binge eating, whereas peripherally administered psilocybin (3 mg/kg) was ineffective on reducing binge eating in male mice [90]. In male and female mice, the peripherally administered nociceptin receptor antagonist, SB612111(10 mg/kg), reduced binge food intake in rats with the intermittent access schedule, whereas FLX (30 mg/kg) had a feeding reduction not specific to the binge paradigm [89]. FLX (10 mg/kg), lorcaserin (6 mg/kg), and fenfluramine (3 mg/kg) reduced binge eating in wild-type (WT) mice, but all serotonin-acting compounds were ineffective in mice lacking the serotonin (5HT) 2C receptor (5HT 2C null) [94]. In another study, FLX was compared with topiramate and baclofen in binge eating male mice [89]. In this study, two doses of FLX (10 or 30 mg/kg), while only one dose of baclofen (3 mg/kg), were effective at reducing binge eating [89]. In female rats with a history calorie restriction and stress, FLX (3 mg/kg) and topiramate (60 mg/kg) reduced binge food intake, whereas sibutramine (1 or 3 mg/kg) reduced binge food intake in all groups [98]. In contrast, the benzodiazepine, midazolam (5 or 10 mg/kg), increased binge food intake, except in those rats with a history of calorie restriction and stress exposure [89]. In a study in male rats with either a fat-rich or carbohydrate-rich binge food, FLX (2.5-10 mg/kg) preferentially suppressed carbohydrate-rich binge food, whereas as naloxone (1 mg/kg) suppressed fat-rich binge food [91]. Naloxone (1 mg/kg) increased FLX-induced suppression of both types of binge foods [91].

Discussion
The purpose of this systematic review was to provide an overview of the existing literature on candidate pharmacotherapies or drug targets in rodent models of binge eating behaviors. Based on exclusionary/inclusionary criteria, we identified 67 peer-reviewed studies that used novel compounds or agents to influence binge eating behaviors in rats and mice. Not all studies were designed to test candidate pharmacotherapies. However, there were some similarities in the experimental design among the studies. For all studies, binge food was a highly palatable (e.g., sugar, fat, or combination) optional food item or diet. Each study employed an intermittent or limited access schedule of the binge food. In this sense, binge eating was related to the overconsumption of the highly palatable food, rather than overconsumption of standard (non-binge) diet. Binge eating behaviors in rodents are dependent on increasing the eating rate and amount of binge food consumed in a defined episode. As such, the episodic reduction in the amount of binge food is the major criterion used to determine the effectiveness of the potential pharmacotherapeutic agent. Using the amount of binge food consumed presents an inherent challenge when interpreting the findings from binge eating animal studies to potential therapeutic strategies for BED or BN, since clinical binge eating studies use a reduction in the number of binge days or binge episode frequency as one of the primary efficacy endpoints [22,105]. One way to address this challenge in rodent studies is to incorporate another dimension to binge eating measurements. For instance, binge occurrence (i.e., episodes of increase intake above baseline) or binge propensity (i.e., above the quartile of intake over episodes) are two measurements that could be incorporated into some binge eating paradigms to determine effectiveness of treatment [86,96,106]. Nonetheless, the measurements of binge amount, binge occurrence, and binge propensity do not fully encompass the interoceptive drive initiating binge eating bouts in persons with eating disorders.
Because FLX and LDX are FDA-approved medications for BN or BED [9,25], the incorporation of these medications in rodent binge eating studies assessing candidate pharmacotherapies should be given consideration. Of course, having a FLX or LDX treatment arm incorporated as a comparator is not feasible for all study designs, but would add relevance to findings. Indeed, 15 of the 67 studies included in this systematic review had used FLX or LDX. These studies represent a strong foundation for future studies of drug comparisons using rodent models.

Conclusions
Binge eating rodent models have provided valuable preclinical assessments for the screening and development of candidate pharmacotherapies. As with any animal model for a psychiatric condition, there are limitations in the data interpretation and extrapolation of the findings. Two ways to reduce the limitations and advance the development of future pharmacotherapies are to incorporate more binge eating dimension measurements, such as binge proneness and binge occurrence, and to use existing comparator treatments, such as LDX and FLX, in the study design.