Exploring New Pharmacological Strategies to Treat Binge-Like Eating Behavior

Binge eating disorder (BED) is the most common eating disorder. It is characterized by recurrent episodes of binge eating, during which individuals consume, in a discrete period of time, amounts of food larger than most people would eat under similar circumstances, while experiencing loss of control towards their eating behavior. BED has a strong negative impact on the functionality and quality of life, and it is associated with negative health consequences, including obesity and other psychiatric disorders. Psychological therapy is generally recommended for the treatment of BED, but unfortunately not all of the patients positively respond to this approach. Thus, pharmacological approaches are strongly required for the management of this pathology. To date, only Lisdexamfetamine dimesylate (LDX) has been approved for the treatment of BED by the Food and Drug Administration (FDA) in 2015, even though its clinical efficacy is limited by the adverse effects associated to this psychostimulant, in particular the increase in heart rate and blood pressure, which might lead to cardiovascular adverse events. The research for innovative pharmacological strategies is necessary, and the development of animal models of binge eating is a useful approach to investigate the neurobiological processes underlying binge eating behavior and to test the efficacy of innovative compounds to block binge eating episodes. Based on this premises, in this experimental thesis I tested the effects of two innovative compounds which might represent useful pharmacological agents for the treatment of binge eating behavior, and I also investigated potential neurobiological alterations underlying compulsive-like eating behavior, using an animal model of binge eating developed by Cifani et al. in 2009. This animal model involves the use of female rats, which develop a compulsive-like eating behavior towards highly palatable food (HPF), after being exposed to cycles of caloric restriction/refeeding plus a frustration stress procedure. This animal model is characterized by a high degree of face, construct and predictive validity. The first target analyzed in this thesis is the Sigma 1 receptor (σ1R), a chaperone-like protein which has been demonstrated to promote binge eating behavior. In particular, I tested the effect of a highly selective σ1R antagonist in the binge eating model of Cifani et al., observing that this compound was able to block the binge eating episode in female rats, without affecting anxiety-like and depressive-like behaviors. Thus, the results of this study evidenced that antagonism of the σ1R is a pharmacological strategy to selectively target and block the neuronal mechanisms that lead to the binge eating episode. The second target of my experimental thesis is orexin-A (OX-A) and the orexin-1 receptor (OX1R), importantly implicated in driving non-homeostatic consumption of HPF. Specifically, I tested the effect of a selective OX1R antagonist (SO1RA) developed by Idorsia Pharmaceuticals Ltd, named ACT-539313, on binge eating behavior. This compound blocked the binge eating episode in female rats under both acute and chronic administration regimens, without sign of tolerance. I also investigated by immunohistochemistry whether binge eating rats might display alterations in Orexin-A (OX-A) and Delta FosB protein expression (marker of long- term neuronal adaptation and plasticity) in multiple brain regions implicated in binge eating behavior. Rats chronically exposed to the binge eating protocol displayed a down-regulation of OX-A protein expression in different extra-hypothalamic sites, such as the central amygdala (CeA), dorsal raphe nucleus (DRN) and paraventricular nucleus of the thalamus (PVT), which could represent a protective mechanism against overconsumption of palatable food. In contrast, no changes in Delta FosB protein expression were found in all brain regions analyzed in binge eating rats. I also investigated whether chronic administration of ACT-539313 might produce changes in the expression of OX-A and delta FosB. Chronic treatment with the SO1RA led to an increase in the number of OX-A positive neurons in the hypothalamus, reflecting a compensatory increase in OX-A expression in response to the SO1RA, and also to an increase in the number of hypothalamic delta-FosB positive cells, suggesting activation of populations of neurons in the hypothalamus. Collectively, these results support the use of SO1RAs in the treatment of binge eating, with efficacy observed even under chronic administration regimen. Furthermore, changes in OX-A protein expression at extra-hypothalamic brain regions appear to represent a marker of binge eating behavior. In conclusion, the data obtained in my experimental thesis provide novel insights about the potential role of the σ1R and OX1R in driving binge eating behavior, and support the clinical evaluation of antagonists of these receptors in humans affected by BED.