Activation of Serotonin 2C Receptors in Dopamine Neurons Inhibits Binge-like Eating in Mice

BACKGROUND: Neural networks that regulate binge eating remain to be identified, and effective treatments for binge eating are limited. METHODS: We combined neuroanatomic, pharmacologic, electrophysiological, Cre-lox, and chemogenetic approaches to investigate the functions of 5-hydroxytryptamine (5-HT) 2C receptor (5-HT(2C)R) expressed by dopamine (DA) neurons in the regulation of binge-like eating behavior in mice. RESULTS: We showed that 5-HT stimulates DA neural activity through a 5-HT(2C)R-mediated mechanism, and activation of this midbrain 5-HT→DA neural circuit effectively inhibits binge-like eating behavior in mice. Notably, 5-HT medications, including fluoxetine, d-fenfluramine, and lorcaserin (a selective 5-HT(2C)R agonist), act on 5-HT(2C)Rs expressed by DA neurons to inhibit binge-like eating in mice. CONCLUSIONS: We identified the 5-HT(2C)R population in DA neurons as one potential target for antibinge therapies, and provided preclinical evidence that 5-HT(2C)R agonists could be used to treat binge eating.