Similarities in the action of Ro 60-0175, a 5-HT2C receptor agonist, and d-fenfluramine on feeding patterns in the rat

Rationale: Activation of 5-HT2C receptors is thought to enhance satiety and to mediate the action of the prototypical anorectic drug d-fenfluramine. O bjective: Four experiments investigated the role of the 5-HT2C receptor in the modulation of feeding by comparison of the effects of the putative sele ctive 5-HT2C receptor agonist Ro 60-0175 and d-fenfluramine on feeding beha viour, Methods: Microstructural analyses of meal patterning and drinking of a palatable solution were made over a range of drug doses administered to male Lister hooded rats. Results: Ro 60-0175 increased the latency to the f irst meal (3 mg/kg) and reduced meal size (1 mg/kg). d-Fenfluramine (1 mg/k g) produced a similar behavioural pattern, but 3 mg/kg produced a more prof ound hypophagia that persisted for 10-12 h. Ro 60-0175 (1, 3 mg/kg) and d-f enfluramine (1. 5 mg/kg) reduced ingestion of a palatable glucose/saccharin solution, by a reduction in the number of bouts of licking, with little ef fect on the size of individual bouts.d-Fenfluramine-induced hypophagia (2.1 mg/kg) was challenged by the administration of the selective 5-HT2C recept or antagonist SE 242084 (1, 3 mg/kg) in the meal patterning paradigm. SE 24 2084 significantly attenuated the decrease in feeding rate and increase in latency to feed produced by n-fenfluramine, but had no effect on the fenflu ramine-induced reduction in meal size. A similar pattern of results was obt ained when Ro 60-0175-induced hvpophagia (3 mg/kg) was challenged by SE 242 084 (1, 3 mg/kg). Conclusions: These results demonstrate that Ro 60-0175 is a useful probe of the importance of 5-HT2C activation in the control of fo od intake and support the hypothesis that activation of 5-HT2C receptors is a critical aspect of the hypophagic action of d-fenfluramine. The 5-HT2C r eceptor may prove to be a useful target in the development of clinically ef fective drugs for the treatment of obesity.