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: 7.83). 06/2012; 37(12):2593-604. DOI: 10.1038/npp.2012.89
Source: PubMed

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.

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Available from: Marta Valenza, Aug 28, 2015
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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.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 11/2014; 40(5). DOI:10.1038/npp.2014.299 · 7.83 Impact Factor
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    • "The putative sigma opiate agonist, N-allynormetazocine (+SKF-10,047) (Martin et al., 1984) increases food intakes of rats and Chinese hamsters (Billington et al., 1984; Gosnell et al., 1983a). Cottone et al. (2012) reported the blockade of compulsive like eating following the antagonism of Sig1R. However , biphasic, isomer related and contradictory studies are reported by various research laboratories. "
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    ABSTRACT: The potent orexigenic peptide neuropeptide Y (NPY) has been considered as a possible endogenous ligand for a subpopulation of sigma receptors (SigR). However, their mutual interaction with reference to feeding behavior remains poorly understood. In the present study, we explored the possible interaction between sigma1 receptors (Sig1R) agonist, pentazocine, and NPY on food intake in satiated rats. While pentazocine dose-dependently reduced the food intake, NPY significantly increased it at 2, 4 and 6 h post injection time points. In combination studies, pretreatment with NPY (0.1 nmol/rat, intra-PVN) normalized the inhibitory effect of pentazocine (60 μg/rat, intra-PVN) on food intake. Similarly, pre-treatment with pentazocine (30 μg/rat, intra-PVN) significantly antagonized the orexigenic effect of NPY (0.5 and 1.0 nmol/rat, intra-PVN). Moreover, pentazocine treatment decreased NPY immunoreactivity in arcuate (ARC), paraventricular (PVN), dorsomedial (DMH) and ventromedial (VMH) nuclei of hypothalamus. However, no change was observed in lateral hypothalamus (LH). Study implicates the reduced NPY immunoreactivity for the anorectic effect observed following pentazocine injections. Therefore, the concomitant activation of the NPYergic system along with the Sig1R agonist treatment, during pain management, may serve a useful purpose in the management of the unwanted side effects related to energy homeostasis.
    Neuropeptides 06/2014; DOI:10.1016/j.npep.2014.02.003 · 2.55 Impact Factor
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