Gregory Berger,Joshua D. Corris,Spencer E. Fields,Lihong Hao,Lori L. Scarpa,Nicholas T. Bello
Systematic Review of Binge Eating Rodent Models for Developing Novel or Repurposing Existing Pharmacotherapies
eating pathologies,binge,Vyvanse,fluoxetine,Prozac,rat,mouse,bulimia nervosa
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.
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.

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% placebo-subtracted 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]. LDX-treated 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.

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.

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 Table 1, Table 2, Table 3, Table 4 and Table 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.

As described in Table 1, 16 studies [38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53] were identified that used compounds acting on the biogenic amine systems.

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].

Three compounds (LDX, SCH23390, and raclopride) were used to target the central dopaminergic system [42,46,47,51]. LDX at 1.5 mg/kg reduced operant responding for binge food in female rats [51]. At 0.8 mg/kg, LDX normalized binge eating-induced delay discounting and binge eating-induced avoidance behaviors in female rats [46,47]. In male mice with deep brain stimulation (DBS)-induced binge eating, raclopride (3 mg/kg), a dopamine D2 receptor antagonist, effectively reduced DBS-induced binge eating [42]. In contrast, SCH23390 (0.75 mg/kg), a dopamine D1 receptor antagonist, was not effective in reducing DBS-induced binge eating [42].

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].

The GABAergic system was targeted in two studies using the GABAB 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].

The glutamatergic system was targeted with two compounds (memantine and VU0409106) [45,52]. VU0409106, a negative allosteric modulator of the metabotropic glutamate receptor 5 (mGluR5), reduced binge eating in mice at 7.5 or 15 mg/kg [52]. The uncompetitive N-methyl-D-Aspartate antagonist, memantine, (2.5, 5, or 10 mg/kg), administered peripherally and site-specifically into the nucleus accumbens shell (10 or 20 µg), reduced binge eating in male rats [45].

As described in Table 2, there were a total of five studies [54,55,56,57,58] that targeted the opioid system. The opioid antagonists, naloxone (0.1–1 mg/kg) and naltrexone (1 or 3 mg/kg), showed reductions in binge eating in rats following peripheral administration [54,55,56]. The novel opioid antagonist, GSK1521498 (1 or 3 mg/kg), reduced binge eating in male and female rats [56]. Peripherally administered naloxone (10 or 30 mg/kg) or intra- paraventricular hypothalamic nucleus naloxone (10–100 nmol) reduced intra-accumbens DAMGO-induced binge eating [58]. Two studies demonstrated the binge promoting effects of butorphanol (8 mg/kg), an opioid agonist/antagonist, on binge eating in female rats [55,57].

As described in Table 3, there were a total of 12 studies that targeted hormonal signaling pathways [59,60,61,62,63,64,65,66,67,68,69,70].

The targets of sex steroids were examined in seven studies [59,60,61,62,63,64,65]. Several studies examined the effects of estradiol (E2) on binge eating behavior in ovariectomized (OVX) female mice. Results were mixed with E2 either reducing or not influencing binge eating behaviors [59,62,63,64,65]. E2 treatment combined with progesterone reduced binge food intake compared with the vehicle or progesterone alone [64,65]. However, the estrogen metabolite, 2-hydroxy-estradiol (2OH-E2), increased binge eating behavior in male and female rats [60,61].

Compounds targeting stress-related hormonal and brain signaling were examined in two studies [68,69]. Specifically, CRF receptor antagonists, centrally administered D-Phe-CRF (12–41) 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].

Three studies used compounds that targeted glucagon-like peptide-1 (GLP-1) and ghrelin signaling [66,67,70]. Intra-accumbens administration of GLP-1 receptor agonist (exendin 4; ex4; 0.05 and 0.1 µg) and antagonist (exendin 9; ex9; 2.5 and 5 µg) reduced and increased, respectively, mu-opioid-stimulated binge eating [70]. Neither intra-accumbens ex4 nor ex9 alone influenced binge food intake [70]. Acute central ghrelin (1 or 2 µg) reduced binge food preference, whereas chronic central ghrelin (0.5 μg/h for 28 days) increased binge food intake in male rats [66]. Central ghrelin signaling was further delineated by using exogenous LEAP2, an antagonist for ghrelin receptor, and K-(D-1-Nal)-FwLL-NH2, a growth hormone secretagogue receptor (GHSR) inverse agonist, to reduce binge eating in male mice [67].

As described in Table 4, there were a total of 17 studies that examined additional compounds individually that were insufficient in the number of studies to justify a single table or category [71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87].

Two studies investigated site-specific injections of PACAP or PACAP1–38 [77,80]. Intra-accumbens PACAP (50 pmol/side) reduced binge eating, whereas ventromedial hypothalamic injections did not influence binge food intake in male rats [77]. Intra-VTA PACAP1–38 (30 pmol/side) reduced binge eating in male mice, but not in female or OVX female mice [80].

Two studies investigated peripheral injections of selective orexin receptor-1 (OX1) or orexin receptor-2 (OX2) or combined (OX1/OX2) antagonists [83,85]. A selective OX1 antagonist, GSK1059865, (10 or 30 mg/kg), and a dual OX1/OX2 receptor antagonist, SB-649868 (3 mg/kg), reduced binge eating in rats with stress exposure [83]. A selective OX2 antagonist, JNJ-10397049 (1 or 3 mg/kg), was not effective in reducing binge food intake [83]. In contrast, the selective OX1 antagonist, SB-334867 (5 mg/kg), only reduced intake for the first binge eating episode, but was not effective at preventing the escalation in binge food intake over time in mice [85]. In one study examining the centrally administered OX1 antagonist, bilateral microinfusions of SB-334867 (500 ng/0.3 μL per side) into the nucleus accumbens shell were ineffective at reducing binge eating in male rats with high or low impulsivity [87].

Two studies examined novel sigma receptor antagonists in female rats with a history of calorie restriction and stress exposure [72,74]. Both the racemic spipethiane analogue (2-(1-Benzylpiperidin-4-yl)thiochroman-4-one) (±)-1 (3 or 7 mg/kg) and 1,3-dioxane derivative, 9-Benzyl-3-phenyl-1,5-dioxa-9-azaspiro[5.5]undecane (3 or 7 mg/kg) were effective in reducing binge eating behaviors [72,74].

Site-specific injections into the PVN of the relaxin-family peptide-3 receptor (RXFP3) antagonist, R3(B1-22)R (1 µg/side), reduced binge eating in female rats [79]. Peripheral administration of oleoylethanolamide (OEA; 10 mg/kg) reduced binge eating in female rats with stress exposure [84]. Peripheral injections of a novel monoamine stabilizer OSU6162 (15 or 30 mg/kg) reduced binge eating in male rats [75]. A selective trace amine-associated receptor 1 (TAAR1) full-agonist RO5256390 (3 or 10 mg/kg) administered peripherally reduced binge food intake in male rats [76]. Peripheral (90 mg/kg) or central administration of N-acetylcysteine (10 µg ICV) reduced binge eating without producing a conditioned taste aversion to the binge food or sodium saccharin solution [78]. Central injections of the cocaine- and amphetamine-regulated transcript peptide (CART; 1.5 or 2 µg; ICV) reduced binge eating, whereas the central injections of the CART antibody (1:500 or 1:250) did not influence binge food intake [71]. In the same study, peripheral injections of the inverse agonist of the cannabinoid receptor 1 (CB1), rimonabant (3 or 10 mg/kg), reduced binge intake [71]. 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 A2A 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 A2A antagonist ANR 94 (1 mg/kg) increased %DNA methylation of the A2A 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].

As described in Table 5, there were 16 studies that were combinational or were designed to be direct comparisons between compounds [89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104].

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].

Three studies [93,95,97] compared LDX with other compounds. In all studies, LDX was administered orally at dose ranges of 0.15–1.5 mg/kg in mice and 0.1–100 mg/kg rats. Acute dosing with sibutramine (1 or 3 mg/kg) reduced binge eating; however, binge eating was not reduced at the 0.15–1.5 mg/kg dose range of LDX in female mice [93]. In female rats, oral dosing of a nootropic agent, piracetam (200 mg/kg), reduced binge eating to a similar extent as LDX (100 mg/kg) [95]. In a study comparing several compounds in female rats, nalmefene (0.1–1.0 mg/kg), SB-334867 (3–30 mg/kg), R-baclofen (1–10 mg/kg), sibutramine (1–5 mg/kg), rolipram (1–10 mg/kg), amphetamine (0.5–1.0 mg/kg), and LDX (0.3–1.5 mg/kg) reduced binge food intake. Sibutramine (0.3–5 mg/kg), rolipram (1–10 mg/kg), and baclofen (10 mg/kg) also reduced standard chow intake [97]. Prazosin (0.3 and 1.0 mg/kg) and SCH-23390 (0.1 mg/kg) attenuated LDX suppression of binge food intake [97].

Seven studies [96,99,100,101,102,103,104] compared or examined the combinational effects with additional compound or agents. In female rats, two serotonergic compounds peripherally administered, lorcaserin (5HT 2c R agonist) or pimavanserin (5HT 2a antagonist/inverse agonist), were examined alone or combination in a binge paradigm to assess binge intake and binge episode occurrence (>binge food intake during intermittent vs. continuous access) [96]. Lorcaserin alone at 1.0 mg/kg and primavanserin alone at 1 or 3 mg/kg reduced binge intake, whereas the combination of lorcaserin (1 mg/kg) + primavanserin (0.3 mg/kg) reduced binge intake, binge occurrence, and weight gain [96]. Regional differences in the prefrontal cortex (PFC) of male rats to dopamine agonist/antagonists (SKF 81297, SCH 23390, quinpirole, or eticlopride) or GABA receptor-combined agonists (muscimol/baclofen) were assessed in male rats [100]. Intra-PFC (either pre-limbic or dorsomedial region) of the combined GABA agonists and dopamine (D2) receptor antagonist eticloprde (0.3 µg) into the intra-PFC dorsomedial region increased binge eating behavior [100]. In female OVX mice, combinations of GLP-4 and E2 reduced binge food intake; this effect was abolished in mice lacking estrogen receptor alpha (ER-α) on 5 HT neurons [99]. Peripheral administration of memantine (5 mg/kg) reduced binge food intake to a similar level as sibutramine (7.5 mg/kg) in male rats; however, memantine feeding suppression persisted post-treatment [102]. Peripheral administration of the MCH receptor-1 antagonist, GSK-856464 (30 mg/kg), suppressed binge intake compared with peripherally administered citalopram (20 mg/kg) in mice with a history of caloric restriction [101]. In male rats with intermittent access to a binge food of a fat mixture with different levels of sucrose sweetening (3.2–32%), peripheral administration of naltrexone (0.03–1 mg/kg), baclofen (0.6–3.2 mg/kg), and raclopride (0.03–0.3 mg/kg) were assessed [104]. All naltrexone doses tested reduced the fat/sugar mixtures (3.3–32%), whereas all baclofen doses reduced only 3.2% and 10% sugar/fat mixtures. Raclopride at 0.3 mg/kg reduced 3.2% and 10% sugar/fat mixtures; in contrast, at 0.1 mg/kg, raclopride increased 3.2% sugar/fat binge food intake [104]. In male rats, intra-accumbens DAMGO binge eating was blocked by microinjections of muscimol (20 ng/bilaterally) in either the basolateral or central nucleus of the amygdala [103].

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.

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.