A new ghrelin receptor antagonist, agrelax, reduces emotional overeating caused by the stimulation of the lateral hypothalamus reward zone in well-fed rats

Abstract

BACKGROUND: Ghrelin receptor antagonists hold promise for the treatment of eating disorders. The reward zone of the lateral hypothalamus has been proposed as a target for mediating the effects of the ghrelin system in emotional overeating.

AIM: This study aimed to evaluate the effects of a new ghrelin receptor antagonist, agrelax, on emotional overeating induced by the stimulation of the reward zone of the lateral hypothalamus in well-fed rats.

MATERIALS AND METHODS: Male Wistar rats were trained to self-stimulate in a Skinner box. After training, a feeder was placed in the Skinner box, and a food-conditioned reflex was developed in the rats for 5 days. Then, the reaction of food self-deprivation, i.e., behavior under conditions of choice of self-stimulation or food intake, was assessed.

RESULTS: The reaction of food self-deprivation when the animals did not approach the feeder was >10% of the threshold current. Self-stimulation of the lateral hypothalamus with a threshold current caused numerous approaches to the feeder and food intake. Sulpiride, a dopamine D2/D3 antagonist (5 and 20 mg/kg ip), administered to well-fed rats reduced both feeding behavior and the intensity of self-stimulation in the food self-deprivation test at threshold currents. The ghrelin receptor antagonists [D-LYS3]-GHRP-6 and the novel antagonist agrelax (1 µg/µL, 20 µL intranasally) also reduced both feeding behavior and the intensity of self-stimulation under these conditions.

CONCLUSIONS: Ghrelin and dopamine receptors are involved in emotional overeating. Agrelax, a novel ghrelin receptor antagonist, reduces emotional overeating induced by the activation of the lateral hypothalamic reward system. Because emotional overeating is strongly associated with clinical eating disorders such as bulimia and binge-eating disorder, the use of ghrelin antagonists to treat and prevent this problem is promising.

Keywords

emotional overeating / [D-LYS3]-GHRP-6 / agrelax / ghrelin / self-stimulation / lateral hypothalamus

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