sb-215505 and 1-(3-chlorophenyl)piperazine

Chemotherapy with an anticancer agent generally causes gastrointestinal tract disorders such as vomiting and anorexia, but the mechanism remains unclear. Rikkunshito, a kampo preparation, is known to alleviate such adverse reactions. In this study, we attempted to clarify the mechanism.. We investigated the decreases of plasma acylated-ghrelin level and food intake caused by cisplatin, serotonin (5-HT), 5-HT agonists, and vagotomy as well as the decrease-suppressing effects of rikkunshito and 5-HT antagonists. In addition, binding affinities of rikkunshito components were determined in receptor-binding assays using 5-HT2B and 5-HT2C receptors.. Cisplatin, 5-HT, BW723C86 (5-HT2B-receptor agonist), and m-chlorophenylpiperazine HCl (5-HT2C agonist) markedly decreased plasma acylated-ghrelin levels, although 5-HT3 and 5-HT4 agonists had no effect. In contrast, 5-HT2B and 5-HT2C antagonists suppressed the cisplatin-induced decrease of plasma acylated-ghrelin level and food intake. Administration of rat ghrelin improved the cisplatin-induced decrease in food intake. Vagotomy decreased the plasma acylated-ghrelin level, which was decreased further by cisplatin. Rikkunshito suppressed such cisplatin-induced decreases of plasma acylated-ghrelin level and food intake. The suppressive effect of rikkunshito was blocked by a ghrelin antagonist. Components of rikkunshito, 3,3',4',5,6,7,8-heptamethoxyflavone, hesperidin, and iso-liquiritigenin showed a 5-HT2B-antagonistic effect in vitro, and oral administration of rikkunshito suppressed the cisplatin-induced decrease in the plasma acylated-ghrelin level.. The cisplatin-induced decreases of the plasma acylated-ghrelin level and food intake are mediated by 5-HT2B/2C receptors and suppressed by flavonoids in rikkunshito.

Topics: Acylation; Aminopyridines; Animals; Anorexia; Antineoplastic Agents; Body Weight; Chalcones; Cisplatin; Disease Models, Animal; Dopamine Antagonists; Dose-Response Relationship, Drug; Drugs, Chinese Herbal; Eating; Flavones; Gastric Mucosa; Gastrointestinal Agents; Ghrelin; Hesperidin; Indoles; Male; Oligopeptides; Piperazines; Protein Binding; Quinolines; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT2B; Receptor, Serotonin, 5-HT2C; Receptors, Ghrelin; Serotonin; Serotonin 5-HT2 Receptor Antagonists; Serotonin Receptor Agonists; Stomach; Thiophenes; Vagotomy

Excessive self-grooming in animal models of obsessive-compulsive disorder (OCD) is regarded as an equivalent of compulsive behaviour in OCD patients. Previous studies have suggested a key modulatory role of certain serotonin2 receptor subtypes both in grooming behaviour and OCD. Certain 5-HT2 receptor agonists were reported to exacerbate symptoms in OCD patients. Here we report that activation of the serotonin2c (5-HT2c) receptor induces self-grooming in rats, which result supports the hypothesis that selective stimulation of central 5-HT2c receptors exacerbates symptoms also in OCD. The present findings may help to understand serotonergic mechanisms underlying psychiatric disorders of the obsessive-compulsive spectrum and may progress the development of novel anxiolytic and anti-OCD medications.

Topics: Aminopyridines; Animals; Grooming; Indoles; Male; Obsessive-Compulsive Disorder; Piperazines; Quinolines; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT2C; Serotonin 5-HT2 Receptor Agonists; Serotonin 5-HT2 Receptor Antagonists; Serotonin Antagonists; Serotonin Receptor Agonists