Reversal of sibutramine-induced anorexia with a selective 5-HT2C receptor antagonist

The monoamine reuptake inhibitor sibutramine reduces food intake but the receptor subtypes mediating the effects of sibutramine on feeding remain to be clearly identified. The involvement of the 5-HT2C receptor subtype in the satiety-enhancing effects of sibutramine was investigated by examining the effects of co-administration of sibutramine with the selective 5-HT2C receptor antagonist SB 242084 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). Sibutramine at doses of 1-3 mg/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 6 mg/kg. Co-administration of sibutramine (3 mg/kg) with SB 242084 (1 or 3 mg/kg) reversed the effect of sibutramine on bout number whereas either dose of SB 242084 alone had no significant effect. 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-HT2C 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.