Sa1461 Serotonin 2C Receptor Antagonism is a Potential New Candidate Treatment for Stress-Related Anorexia

Abstract

Background/Aims: Stress is well known to suppress appetite, ultimately leading to chronic eating disorders that may require medical treatment. However, no treatment exists for stressinduced loss of appetite, because its detailed mechanism remains unknown. Serotonin regulates emotions and food intake, and serotonin 2c receptor (5-HT2cR) is known to control feeding behavior. In this study, we used an urocortin 1 (UCN)-induced stress model to evaluate the effects of central 5-HT2cR and changes in the expression of c-fos mRNA. 5-HT2bR, another serotonin receptor that controls food intake, was also evaluated, and the effects of both receptor antagonists on loss of appetite were compared to investigate the potential of 5-HT2cR antagonist drugs for anorexia treatment. Methods: Intraventricular (ICV) injection of UCN or phosphate-buffered saline was administered to Sprague-Dawley rats, and the brains were collected after perfusion fixation, and fixed whole brains were cut in the coronal plane. The mRNA expression of 5-HT2cR and c-fos was evaluated by in situ hybridization. In addition, double staining of 5-HT2cR was performed for a sample section in which an increased level of c-fos mRNA expression was observed. The selective 5-HT2cR antagonist SB242084, the selective 5-HT2bR antagonist SB215505 (intraperitoneal), or rikkunshito (oral), which shows properties of both 5-HT2cR and 5-HT2bR antagonism, was administered and their respective effects on food intake decreases were evaluated in order to clarify the role of 5-HT2cR activation on stress-induced anorexia. Results: The 5-HT2cR mRNA expression in rats under UCN-induced stress was increased primarily in the solitary tract nucleus (NTS) of the medulla oblongata and in the paraventricular nucleus (PVN) of the hypothalamus. Concurrent enhancement of c-fos mRNA expression was observed. Expression of 5-HT2cR mRNA in the arcuate nucleus was approximately the same in both stress-induced and non-stress-induced groups. Double staining revealed that 5-HT2cR and c-fos were expressed in the same cells in the solitary tract nucleus and PVN. Intraperitoneal administration of 5-HT2cR antagonist SB242084 and oral administration of rikkunshito significantly inhibited food intake decreases in rats exposed to UCN-induced stress; in contrast, administration of the 5-HT2bR antagonist SB215505 did not affect food intake. Conclusion: 5-HT2cR antagonism is a potential candidate for the treatment of stressrelated anorexia. When the corticotrophin-releasing factor (CRF) receptor is activated, stress responses may be enhanced by increased responsiveness of 5-HT2cR on CRF neurons in the PVN. Signals from the vagus nerve may increase responsiveness of 5-HT2cR in the NTS, leading to further negative regulation of food intake.