NMDA Receptors in the Nucleus Accumbens Shell Mediate Compulsive Eating of Palatable Food

Background: Binge-eating disorder affects nearly 15 million people in the U.S.A. and is characterized by excessive consumption of palatable food within brief periods of time, and loss of control over eating. 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. Theglutamatergic NMDA receptor system is highly involved in reward-related processes, but its role in hedonic food intake and binge eating is poorly understood. This study is aimed at investigating the effects of uncompetitive NMDA receptor blockade in a rat model of binge-like eating. Methods: We trained male Wistar rats to consume either a highly palatable diet (Palatable group) or a standard chow diet (Chow group) in operant sessions (1 h/day) on a fixed ratio 1 (FR1) schedule of reinforcement. We tested the effects of the uncompetitive NMDA receptor antagonists, ketamine and memantine on binge-like eating. Moreover, we tested the effects of memantine on palatablefood seeking behavior using a second order schedule of reinforcement. In addition, using a light/dark conflict test, we also investigated whether memantine could block the time spent and the food eaten in an aversive, open compartment, where the palatable diet was offered. Furthermore, we examined the effects of memantine on excessive chow intake induced by food restriction. Finally, we investigated the role of NMDA receptors in binge-like eating by microinfusing memantine into either the Nucleus Accumbens Shell (NAccShell) and Core (NAccCore). Results: The palatable-fed rats quickly developed binge-like eating behavior and exhibited compulsive eating and risktaking behavior when palatable food was presented in an aversive environment. Palatable fed rats also showed heightened food seeking behavior compared to control rats. Memantine dose-dependently decreased binge-like eating without affecting water intake, and blocked compulsive eating of palatable food. Conversely, ketamine did not affect food and water responding in neither Chow nor Palatable rats. Furthermore, memantine treatment reduced food seeking behavior, compulsive eating and risk-taking behavior without affecting restriction-induced excessive chow intake. Memantine treatment did not affect any of the variables in control chow-fed rats. Intra-NAccShell injections of memantine dosedependently decreased binge-like eating selectively in the bingeing rats, without affecting water responding. Intra- NAccShell injections of memantine did not affect food or water intake in control Chow rats. No effects were observed when memantine was microinfused into the NAccCore. Conclusions: Overall, these findings confirm the hypothesis that dyregulation of glutamatergic NMDA receptor system within the NAccShell is a key component of neuroadaptive mechanisms that lead to the development of binge-like eating. Our findings propose a novel potential pharmacological strategy to combat binge eating disorder.