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

Abstract

Background Neural networks that regulate binge eating remain to be identified, and effective treatments for binge eating are limited. Methods We combined neuroanatomical, pharmacological, electrophysiological, Cre-lox, and chemogenetic approaches to investigate the functions of 5-HT 2C receptor (5-HT2CR) 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-HT2CR-mediated mechansim, 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-HT2CR agonist), act upon 5-HT2CRs expressed by DA neurons to inhibit binge-like eating in mice. Conclusions We identified the 5-HT2CR population in DA neurons as one potential target for anti-binge therapies, and provided pre-clinical evidence that 5-HT2CR agonists could be used to treat binge eating.

Lorcaserin Suppresses Oxycodone Self-Administration and Relapse Vulnerability in Rats

“…88, 95 The 5-HT 2C R is also expressed on a subset of dopamine VTA neurons 89–90 and functions as a key regulator of their physiology in mice. 97 These findings suggest the possibility that lorcaserin may directly regulate oxycodone self-administration via actions at the 5-HT 2C R localized to the VTA, 98 although further experimentation is required to explore the functional mechanisms through which the VTA μ-opioid receptor and the 5-HT 2C R interact. This site of action for the 5-HT 2C R may also control oxycodone cue reactivity as suggested for cocaine, 99 although corticostriatal involvement should be considered given that the functional status of the 5-HT 2C R system in the medial prefrontal cortex is a key contributor to cocaine cue reactivity.…”

Cognitive impairment and gene expression alterations in a rodent model of binge eating disorder

“…Although discrepancies in these studies can be attributed to the use of different learning paradigms, the involvement of OFC 5-HT 2C receptor in the aspect of reversal learning remains consistent. Recent evidence for the involvement of 5-HT 2C in the context of bingeing comes from studies employing a 5HT reuptake inhibitor, fluoxetine, as well as a 5HT agonist, lorcaserin, which suppressed high fat binge eating in wild type mice but failed to inhibit binge eating in 5-HT 2C null mice indicating its potential role in bingeing [105]. Thus, OFC 5-HT 2C receptors maybe an important target for high fat bingeing associated reversal learning deficits.…”

“…Some insight on this issue was provided by a clinical study suggesting that serotonin and dopamine systems are doubly dissociable in a reversal learning task [49]. Recently, it was shown that the activation of midbrain 5-HT→DA neural circuit via a 5-HT 2C receptor mediated mechanism suppressed intermittent high fat binge eating in mice [105]. Several clinical studies have indicated the involvement of both serotonergic and dopaminergic genes polymorphism in BED patients [120–123].…”

A randomized controlled trial of lorcaserin and lifestyle counselling for weight loss maintenance: changes in emotion‐ and stress‐related eating, food cravings and appetite

“…Serotonin (5‐Hydroxytryptamine; 5‐HT) is a monoamine neurotransmitter that has several known functions, including appetite regulation and energy balance . Low levels of serotonin are associated with: preference for carbohydrates , emotion‐ and stress‐related eating , binge eating and increased appetite . Decreased levels of serotonin have also been implicated in carbohydrate cravings and obesity .…”