Antagonism of Sigma-1 Receptors Blocks Compulsive-Like Eating

Laboratory of Addictive Disorders, Departments of Pharmacology and Psychiatry, Boston University School of Medicine, Boston, MA, USA.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology (Impact Factor: 7.05). 06/2012; 37(12):2593-604. DOI: 10.1038/npp.2012.89
Source: PubMed


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.

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    • "The BDZ receptor partial inverse agonist Ro 15-4513 was administered immediately prior to ethanol in order to unmask its motor stimulating effect, previously reported to be hard to observe in C57Bl/6 mice [35] [36]. A locomotor activity test was performed in Plexiglas chambers (27 × 48 × 20 cm) using an Opto-M3 activity system (Columbus Instruments, Columbus, OH), as reported before [37] [38]. The Opto-M3 system consists of a series of 16 sensor beams spaced 2.54 cm apart along the longest side of the cage; motor activity was recorded by a computer over a 20 min period, which began 2 min after mice were pre-treated with Ro 15-4513 (0, 3 mg/kg; i.p.), and 1 min after ethanol (0, 1.5 g/kg; i.p.). "
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    ABSTRACT: Rationale: The Sigma-1 receptor (Sig-1R) is a chaperone protein that has been implicated in drug abuse and addiction. Multiple studies have characterized the role the Sig-1R plays in psychostimulants addiction, but fewer studies have specifically investigated its role in alcohol addiction. We have previously shown that antagonism of the Sig-1R reduces excessive drinking and motivation to drink, whereas agonism induces binge-like drinking in rodents. Objectives: The objectives of these studies were to investigate the impact of Sig-1R gene deletion in C57Bl/6J mice on ethanol drinking and other ethanol-related behaviors. Methods: We used an extensive panel of behavioral tests to examine ethanol actions in male, adult mice lacking Oprs1, the gene encoding the Sig-1R. To compare ethanol drinking behavior, Sig-1 knockout (KO) and wild type (WT) mice were subject to a two-bottle choice, continuous access paradigm with different concentrations of ethanol (3%-20% v/v) vs. water. Consumption of sweet and bitter solutions was also assessed in Sig-1R KO and WT mice. Finally, motor stimulant sensitivity, taste aversion and ataxic effects of ethanol were assessed. Results: Sig-1R KO mice displayed higher ethanol intake compared to WT mice; the two genotypes did not differ in their sweet or bitter taste perception. Sig-1R KO mice showed lower sensitivity to ethanol stimulant effects, but greater sensitivity to its taste aversive effects. Ethanol-induced sedation was unaltered in the mutants. Conclusions: Our results suggest that the deletion of the Sig-1R increases ethanol consumption, likely by decreasing its rewarding effects, and therefore indicating that the Sig-1R is involved in modulation of the reinforcing effects of alcohol.
    Behavioural brain research 10/2015; 297. DOI:10.1016/j.bbr.2015.10.013 · 3.03 Impact Factor
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    • "Next, we determined whether high impulsivity predicted the loss of control over palatable food intake and compulsivelike eating. To test this hypothesis, we tested the rats in a light/dark conflict test, in which the food was offered in the aversive, bright compartment of the apparatus (Cottone et al, 2012; Dore et al, 2013b). Therefore, rats were required to face the aversive context in order to consume the food. "

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    • "On the test day, rats were placed into the light compartment, facing both the food cup and the doorway. Under normal, control conditions, eating behavior is typically suppressed when a rat is in the aversive, bright compartment; a significant increase in food intake in spite of the adverse conditions, as compared with control conditions, was operationalized as a construct of 'compulsive-like eating' (Cottone et al, 2012; Dore et al, 2014; Velazquez-Sanchez et al, 2014). The apparatus was cleaned with a water-dampened cloth after each subject. "
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    ABSTRACT: Binge-eating disorder is characterized by excessive, uncontrollable consumption of palatable food within brief periods of time. The role of the glutamatergic NMDA receptor system in hedonic feeding is poorly understood. The aim of this study was to characterize the effects of the uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist memantine on palatable food-induced behavioral adaptations using a rat model which mimics the characteristic symptomatology observed in binge eating disorder. For this purpose, we allowed male Wistar rats to respond to obtain a highly palatable, sugary diet (Palatable group) or a regular chow diet (Chow control group), for 1 h a day, under a fixed ratio 1 (FR1) schedule of reinforcement. Upon stabilization of food responding, we tested the effects of memantine on Chow and Palatable food groups' intake. Then, we tested the effects of memantine on food seeking behavior, under a second order schedule of reinforcement. Furthermore, we investigated the effects of memantine on the intake of food when it was offered in an aversive, bright compartment of a light/dark conflict test. Finally, we evaluated the effects of memantine on FR1 responding for food, when microinfused into the nucleus accumbens (NAcc) shell or core. Memantine dose-dependently decreased binge-like eating and fully blocked food seeking behavior and compulsive eating, selectively in the Palatable food group. The drug treatment did not affect performance of control Chow food group. Finally, intra-NAcc shell, but not core, microinfusion of memantine decreased binge-like eating. Together, these findings substantiate a role of memantine as a potential pharmacological treatment for binge eating disorder.Neuropsychopharmacology accepted article preview online, 10 November 2014. doi:10.1038/npp.2014.299.
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