Mo1996 Cancer-Related Gastrointestinal Dysmotility Is Mediated by the Suppression of Ghrelin-Neuropeptide Y Signaling via Serotonin 2C Receptor in the Hypothalamus

Background & aim: Elderly people often exhibit a lack of appetite, which is known to cause increased morbidity and the progression of physical disorders.Although various factors contribute to decreased appetite, anxiety is the main cause of restricted dietary intake.Activation of the serotonin 2C receptor (5-HT 2C R) induces an anxiety-like response in young animals, causing a restriction of dietary intake.However, the contribution of 5-HT 2C R toward stress-induced anorexia in aged animals remains unclear.In this study, aged mice were exposed to a novel hypophagia paradigm to investigate the effects of a selective 5-HT 2C R antagonist and a traditional Japanese medication, rikkunshito (RKT).Methods: After having group-housed C57BL/6 male mice (young mice, 6 weeks old; aged mice, 79-80 weeks old), the mice were transferred to individual cages to induce novel environmental stress.Changes in the amount of food intake after 6 and 24 h were measured, and blood samples were collected to measure stress hormones using the ELISA method.5-HT 2C R mRNA expression in the hypothalamus was evaluated by real time RT-PCR and in situ hybridization.The 5-HT 2C R antagonist SB242084, RKT or the 5-HT 2C R agonist mCPP were administered to both the mice under stress and the non-stressed mice and the amount of food intake was measured to clarify the role of the 5-HT 2C R on feeding behavior.Results: In the aged mice, exposure to a novel environment reduced the amount of food intake and increased corticosterone secretion.These responses were significant compared with those in the young mice.The administration of SB242084 to control mice increased the amount of food intake of aged mice only over 24 h.In addition, the administration of low-dose mCPP to the control mice induced a greater decrease in appetite in the aged mice than in the young mice.This suggests that there may be a constant hyperfunction or increased 5-HT 2C R sensitivity in aged mice.5-HT 2C R mRNA expression in the hypothalamus (e.g.paraventricular nucleus) was increased in the aged mice following novel environmental stress.In the aged mice placed under novel environment stress, the SB242084 and RKT suppress the increase in stress hormone level as well as the decrease in food intake.Conclusion: These results suggest that the excessive enhancement of 5-HT 2C R function causes an anxiety-like reaction in an aged mouse and greatly contributes to a decrease in food intake.Similar to SB242084, RKT is thought to suppress the decrease in food intake in aged mice under novel environment stress by controlling 5-HT 2C R activity.