5-HT1B receptors modulate components of satiety in the rat:: behavioural and pharmacological analyses of the selective serotonin1B agonist CP-94,253

Rationale: 5-HT1B receptors are thought to be one of the receptor subtypes that mediate the inhibitory control of serotonin on food intake and satiety. Objective: To use the selective 5-HT1B receptor agonist, CP-94,253 as a probe of 5-HT1B receptor function in feeding behaviour, and to confirm the pharmacological selectivity of CP-94,253-induced hypophagia with a range of antagonists. Methods: Dose-response functions for CP-94,253 (0, 1.25, 2.5, 5.0 mg/kg; IP) were determined in animals consuming wet mash in a 40-min test session during which time-sampled behavioural observations were collected to evaluate satiety sequences. A meal patterning study was carried out in a separate group of rats. The 5-HT1A antagonist WAY 100,635 (0, 1.0, 3.0 mg/kg; SC), the 5-HT1B/1D antagonist GR 127,935 (0, 3 mg/kg; IP), and the 5-HT1B antagonist SB 224289 (0, 2.5, 5.0 mg/kg; IP) were used to confirm that 5-HT1B receptor subtypes were responsible for the action of CP94,253 on feeding behaviour. Results: CP-94,253 (2.5 mg/kg) reduced food intake and preserved the satiety sequence in animals consuming a diet of mash. GR 127,935 (3.0 mg/k) and SB 224289 (2.5 mg/kg), but not WAY 100,635, attenuated the hypophagic effect of the 5-HT1B agonist, and returned the changes in satiety sequence to control patterns. Meal patterning analyses indicated that CP-94,253 (2.5 mg/kg) reduced food intake through a decrease in meal size and duration in the absence of any alteration in the rate of eating. A hypodipsic action of CP-94,253 was also observed (2.5 and 5.0 mg/kg). Conclusion: These findings imply that 5-HT1B receptors regulate discrete elements of satiety. We discuss the potential role of 5-HT1B agonists for the treatment of obesity.