Antagonism of Sigma-1 Receptors Blocks Compulsive-Like Eating

Abstract

Binge eating disorder is an addiction-like disorder characterized by episodes of rapid and excessive food consumption within discrete periods of time which occur compulsively despite negative consequences. This study was aimed at determining whether antagonism of Sigma-1 receptors (Sig-1Rs) blocked compulsive-like binge eating. We trained male wistar rats to obtain a sugary, highly palatable diet (Palatable group) or a regular chow diet (Chow control group), for 1 h a day under fixed ratio 1 operant conditioning. Following intake stabilization, we evaluated the effects of the selective Sig-1R antagonist BD-1063 on food responding. Using a light/dark conflict test, we also tested whether BD-1063 could block the time spent and the food eaten in an aversive, open compartment, where the palatable diet was offered. Furthermore, we measured Sig-1R mRNA and protein expression in several brain areas of the two groups, 24 h after the last binge session. Palatable rats rapidly developed binge-like eating, escalating the 1 h intake by four times, and doubling the eating rate and the regularity of food responding, compared to Chow rats. BD-1063 dose-dependently reduced binge-like eating and the regularity of food responding, and blocked the increased eating rate in Palatable rats. In the light/dark conflict test, BD-1063 antagonized the increased time spent in the aversive compartment and the increased intake of the palatable diet, without affecting motor activity. Finally, Palatable rats showed reduced Sig-1R mRNA expression in prefrontal and anterior cingulate cortices, and a two-fold increase in Sig-1R protein expression in anterior cingulate cortex compared to control Chow rats. These findings suggest that the Sig-1R system may contribute to the neurobiological adaptations driving compulsive-like eating, opening new avenues of investigation towards pharmacologically treating binge eating disorder. Neuropsychopharmacology (2012Neuropsychopharmacology ( ) 37, 2593Neuropsychopharmacology ( -2604 doi:10.1038/npp.2012 published online 20 June 2012 Keywords: binge eating disorder; food intake; eating disorders; addiction; palatability; risk-taking behavior INTRODUCTIONBinge eating disorder is a deadly disease that affects approximately 15 million people in the United States (Hudson et al, 2007) and very frequently occurs comorbidly with obesity, diabetes, cardiovascular diseases, and certain psychiatric conditions, such as anxiety and depression (APA, 2000;Javaras et al, 2008;Wilfley et al, 2011;Yanovski, 2003). Binge eating episodes are characterized by excessive, rapid, and compulsive consumption of highly palatable foods (eg, food rich in sugars and/or fats) within short periods of time, and are followed by food restriction (APA, 2000;Avena et al, 2008;Corwin, 2006). The cyclic binge/restriction pattern of consumption of highly palatable foods has raised the question of whether binge eating disorder can be considered an addiction-'like' disorder; however, the debate remains open (Corwin and Grigson, 2009). An effective ...

The Uncompetitive N-methyl-D-Aspartate Antagonist Memantine Reduces Binge-Like Eating, Food-Seeking Behavior, and Compulsive Eating: Role of the Nucleus Accumbens Shell

“…Therefore, data from the food restriction experiment suggest that memantine's effects are specific for palatability induced behavioral processes and independent from high rates of response. More generally, these findings emphasize the difference between hedonic vs energy-homeostatic control of food intake and confirm the hypothesis that although food-related behavioral outcomes induced by palatability can be apparently similar to the ones observed following food restriction/deprivation, the two are governed by dissimilar neuroadaptive mechanisms (Corwin, 2006;Cottone et al, 2009;Cottone et al, 2012). In this study, we used a food-seeking behavior task in ad libitum-fed rats using a second-order schedule of reinforcement, in which responding was maintained by contingent presentation of food-paired stimuli that served as conditioned reinforcers of instrumental behavior (Everitt and Robbins, 2000).…”

“…Rats were habituated to the home-cage AIN-76A-based diet, hereafter referred to as 'Chow A/I' (5TUM diet formulated as 4-5 g extruded pellets, 65.5% (kcal) carbohydrate, 10.4% fat, 24.1% protein, 330 cal/100 g; TestDiet, Richmond, IN). As previously described (Blasio et al, 2014;Cottone et al, 2012;Velazquez-Sanchez et al, 2014), animals were trained to self-administer food pellets (45-mg precision food pellets (Chow A/I)) and water (100 ml) for 1 h a day, under a fixed-ratio 1 (FR1) schedule of reinforcement in the operant chambers. During instrumental training, food pellets were 45-mg precision pellets, identical in composition to the diet that rats received in the home cage as B5 g extruded pellets, to ensure that food intake during operant sessions was not influenced by any hedonic factors, only by homeostatic needs.…”

“…The aim of this study was, therefore, to systematically characterize the neuropsychopharmacological effects of memantine using a battery of tasks developed to evaluate different features of maladaptive feeding behavior induced by limiting access to highly palatable food in rats (Blasio et al, 2014;Cottone et al, 2012;Velazquez-Sanchez et al, 2014). In addition, this study was aimed at evaluating which area of the brain mediates the effects of memantine on excessive intake of palatable food.…”

Pituitary Adenylate Cyclase-Activating Peptide in the Central Amygdala Causes Anorexia and Body Weight Loss via the Melanocortin and the TrkB Systems

“…To identify the effects of PACAP on the rate and regularity of sustained eating within meals, analysis of the ln-transformed duration of consecutive (uninterrupted by drinking) within-meal interfeeding intervals (IFIs) was performed (Cottone et al, 2007a;Cottone et al, 2012). Histograms were constructed from ln-transformed IFI durations that fell from e − 1 to e 3 s (~0.4-20.1 s), with a bin width of e 0.2 (Cottone et al, 2007a;Cottone et al, 2012). The mean, entropy kurtosis, and skewness of the ln-transformed duration of each subject's consecutive IFIs were individually determined and averaged across subjects.…”

CRF Mediates the Anxiogenic and Anti-Rewarding, But Not the Anorectic Effects of PACAP

“…Motor activity of rats was measured as described in Cottone et al (2012) using an Opto-M3 activity system (Columbus Instruments, Columbus, OH); activity was recorded by a computer using the Multi Device Interface software over a 120-min period. White noise was present.…”