Reversal of sibutramine-induced anorexia with a selective 5-HT sub(2C) receptor antagonist

Rationale: The monoamine reuptake inhibitor sibutramine reduces food intake but the receptor subtypes mediating the effects of sibutramine on feeding remain to be clearly identified. Objectives: The involvement of the 5-HT sub(2C) receptor subtype in the satiety-enhancing effects of sibutramine was investigated by examining the effects of co-administration of sibutramine with the selective 5-HT sub(2C) receptor antagonist SB 242084 Methods: Microstructural analyses of licking for a glucose solution by non-deprived, male rats were performed over a range of doses of sibutramine to identify a selective satiety-enhancing dose (experiment 1). Similar analyses were performed after administration of a vehicle control, two doses of SB 242084 alone or two doses of SB 242084 in combination with sibutramine (experiment 2). Results: Sibutramine at doses of 1a3ANBmg/kg selectively reduced glucose consumption via a reduction in the number of bouts of licking. Non-selective effects to increase latency to lick were only observed at the higher dose of 6ANBmg/kg. Co-administration of sibutramine (3ANBmg/kg) with SB 242084 (1 or 3ANBmg/kg) reversed the effect of sibutramine on bout number whereas either dose of SB 242084 alone had no significant effect. Conclusions: We confirm behaviourally selective effects of sibutramine on feeding and provide further support for the satiety-enhancing effects of sibutramine. Our data also provide evidence for the involvement of the 5-HT sub(2C) receptor in the satiety-enhancing effects of sibutramine although additional targets may have an impact, and further investigation of the molecular mechanisms underlying the efficacy of sibutramine as an anorectic is warranted.