Similarities in the action of Ro 60-0175, a 5-HT_2C receptor agonist, and d-fenfluramine on feeding patterns in the rat

Abstract.

Rationale: Activation of 5-HT_2C receptors is thought to enhance satiety and to mediate the action of the prototypical anorectic drug d-fenfluramine. Objective: Four experiments investigated the role of the 5-HT_2C receptor in the modulation of feeding by comparison of the effects of the putative selective 5-HT_2C receptor agonist Ro 60-0175 and d-fenfluramine on feeding behaviour. 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 first meal (3 mg/kg) and reduced meal size (1 mg/kg). d-Fenfluramine (1 mg/kg) produced a similar behavioural pattern, but 3 mg/kg produced a more profound hypophagia that persisted for 10–12 h. Ro 60-0175 (1, 3 mg/kg) and d-fenfluramine (1. 5 mg/kg) reduced ingestion of a palatable glucose/saccharin solution, by a reduction in the number of bouts of licking, with little effect on the size of individual bouts. d-Fenfluramine-induced hypophagia (2.1 mg/kg) was challenged by the administration of the selective 5-HT_2C receptor antagonist SB 242084 (1, 3 mg/kg) in the meal patterning paradigm. SB 242084 significantly attenuated the decrease in feeding rate and increase in latency to feed produced by d-fenfluramine, but had no effect on the fenfluramine-induced reduction in meal size. A similar pattern of results was obtained when Ro 60-0175-induced hypophagia (3 mg/kg) was challenged by SB 242084 (1, 3 mg/kg). Conclusions: These results demonstrate that Ro 60-0175 is a useful probe of the importance of 5-HT_2C activation in the control of food intake and support the hypothesis that activation of 5-HT_2C receptors is a critical aspect of the hypophagic action of d-fenfluramine. The 5-HT_2C receptor may prove to be a useful target in the development of clinically effective drugs for the treatment of obesity.