The nucleus accumbens 5-HTR₄-CART pathway ties anorexia to hyperactivity.

Area of Science:

• Neuroscience
• Psychiatry
• Molecular Biology

Background:

• Mental illnesses often disrupt the balance between motor activity and feeding behaviors.
• Anorexia nervosa frequently presents with a paradoxical association between hyperactivity and anorexia, yet its neural basis remains unclear.
• The reward system is implicated in both anorexia and hyperactivity, suggesting shared neural pathways.

Purpose of the Study:

• To investigate the neural mechanisms linking anorexia and hyperactivity, focusing on the reward system.
• To determine if the previously identified 5-HTR(4)/CART pathway in the nucleus accumbens (NAc) contributes to both anorexia and hyperactivity.
• To explore the role of serotonin receptor 4 (5-HTR(4)) and cocaine- and amphetamine-regulated transcript (CART) in mediating these behaviors.

Main Methods:

• Utilized genetically modified mice lacking serotonin receptor 1B (5-HTR(1B)) to study self-imposed food restriction and hyperactivity.
• Investigated the effects of ecstasy (MDMA) on food intake and activity levels in these models.
• Employed molecular techniques including NAc-5-HTR(4) overexpression, knockdown, and blockade, as well as NAc-CART knockdown to assess behavioral outcomes.

Main Results:

• Mice lacking 5-HTR(1B) exhibited self-imposed food restriction and displayed anorexia and hyperactivity after ecstasy administration.
• A gain-of-function in NAc-5-HTR(4) in the absence of 5-HTR(1B) led to increased NAc-CART, causing anorexia and hyperactivity.
• Modulating NAc-5-HTR(4) and NAc-CART levels directly impacted hyperactivity and ecstasy preference, suggesting a causal role in the observed behaviors.

Conclusions:

• The NAc-5-HTR(4)/CART pathway forms a critical link between anorexia and hyperactivity, potentially representing a core functional unit.
• This pathway's involvement in reward mechanisms suggests it plays a role in limiting overeating and maintaining homeostasis.
• Targeting the NAc-5-HTR(4)/CART pathway offers a potential therapeutic strategy for eating disorders characterized by anorexia and hyperactivity.