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

Abstract

RATIONALE:

Activation of 5-HT2C 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-HT2C receptor in the modulation of feeding by comparison of the effects of the putative selective 5-HT2C 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-HT2C 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-HT2C activation in the control of food 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 receptor may prove to be a useful target in the development of clinically effective drugs for the treatment of obesity.

• Authors: P G Clifton, M D Lee, C T Dourish
• Journal: Psychopharmacology (Psychopharmacology (Berl)) Vol. 152 Issue 3 Pg. 256-67 (Oct 2000) ISSN: 0033-3158 [Print] Germany
• PMID: 11105935 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 6-chloro-5-methyl-1-((2-(2-methylpyrid-3-yloxy)pyrid-5-yl)carbamoyl)indoline
• Aminopyridines
• Ethylamines
• Indoles
• Receptor, Serotonin, 5-HT2C
• Receptors, Serotonin
• Ro 60-0175
• Serotonin Receptor Agonists
• Fenfluramine

Topics

• Aminopyridines (pharmacology)
• Animals
• Dose-Response Relationship, Drug
• Ethylamines (pharmacology)
• Feeding Behavior (drug effects)
• Fenfluramine (pharmacology)
• Indoles (pharmacology)
• Male
• Rats
• Receptor, Serotonin, 5-HT2C
• Receptors, Serotonin (drug effects)
• Serotonin Receptor Agonists (pharmacology)