Tu1912 Urocortin 1-Induced Anorexia Is Mediated by Activation of Sympathetic Nervous System: The System Involving Serotonin 2C Receptor in Brain

Background: Stress has been known to induce chronic anorexia. However, no curable treatment is available for this condition because the detailed mechanism of decrease in appetite remains unknown. The role of corticotropin-releasing factor (CRF) family in modulating anorexia is well recognized. We have recently shown that intracerebroventricular (ICV) urocortin 1 (UCN1), a CRF receptor agonist, induces a decrease in the food intake with the suppression of gastric ghrelin. However, the details of the mechanisms for anorexia still remain to be elucidated. Aim: We aimed to investigate neuronal mechanism in the brain that regulates appetite in UCN1-induced anorexia model rats. Methods: Adult male Sprague-Dawley rats with chronically implanted ICV cannula were injected ICV with UCN1 (300 pmol/rat). We measured the food intake after ICV UCN1 and mRNA levels of appetiterelated peptides in the hypothalamus by real-time RT-PCR. In another set of experimental, the selective serotonin 2C receptor (5-HT2CR) antagonist (SB242084 3 mg/kg, IP), or ghrelin enhancer "rikkunshito" [RKT; 1000mg/kg, orally (PO)] a Japanese traditional medicine, which contains components that have antagonistic properties to 5-HT2CR were administered for respectively examining the effects to inhibit decrease of food intake and ghrelin in UCN1treated rats. In addition, the rat's brains were processed to determine the expression of cfos 1h after ICV by in situ hybridization. Effects of co-administration of RKT with ICV UCN1 were also determined. Results: UCN1-treated rats exhibited the decreased ghrelin and increased corticosterone in plasma, and suppression of appetite. The gene expression of orexin in the hypothalamus was decreased, while that of pro-opiomelanocortin and αmelanocyte-stimulating hormone showed no change. RKT successfully increased the food intake with increase of plasma ghrelin in UCN1-treated rats. SB242084 successfully increased the food intake. UCN1 elevated c-fos mRNA expression in the brain regions, which are located at the regions with 5-HT2CR, such as arcuate nucleus, paraventricular nucleus, ventromedial hypothalamic nuclei of the hypothalamus as a satiety center ,and locus coeruleus, solitary tract nucleus, and ventrolateral nucleus of medulla oblongata, known as a root of sympathetic outflow. The expression of c-fos in these regions was suppressed by the administration of RKT. Conclusions: These results suggest that the sympathetic neuron from the central nerve to the periphery, and vagal input from the periphery to satiety center relate to decreased feeding in the UCN1-induced stress model. In addition, activation of 5HT2CR in the brain neuron is suggested to be involved in this root. RKT may restore disturbed appetite through the restoration of balance of central autonomic nervous system.