Similarities in the action of Ro 60-0175, a 5-HT2C receptor agonist and d-fenfluramine on feeding patterns in the rat.
BACKGROUND
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.
Clifton
P G
PG
Laboratory of Experimental Psychology, University of Sussex, Brighton, UK. pete@biols.susx.ac.uk
Lee
M D
MD
Dourish
C T
CT
D000631:Aminopyridines / Q000494:pharmacology; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005021:Ethylamines / Q000494:pharmacology*; D005247:Feeding Behavior / Q000187:drug effects*; D005277:Fenfluramine / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D051381:Rats; D044405:Receptor, Serotonin, 5-HT2C; D011985:Receptors, Serotonin / Q000187:drug effects*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*
C107820:6-chloro-5-methyl-1-((2-(2-methylpyrid-3-yloxy)pyrid-5-yl)carbamoyl)indoline; D000631:Aminopyridines; D005021:Ethylamines; D007211:Indoles; D044405:Receptor, Serotonin, 5-HT2C; D011985:Receptors, Serotonin; C103848:Ro 60-0175; D017366:Serotonin Receptor Agonists; D005277:Fenfluramine