INVESTIGATION OF THE MECHANISMS UNDERLYING THE HYPOPHAGIC EFFECTS OF THE 5-HT AND NORADRENALINE REUPTAKE INHIBITOR, SIBUTRAMINE, IN THE RAT

1 Sibutramine is a novel 5-hydroxytryptamine (5-HT) and noradrenaline reuptake inhibitor (serotonin-noradrenaline reuptake inhibitor, SNRI) which is currently being developed as a treatment for obesity. Sibutra mine has been shown to decrease food intake in the rat. In this study we have used a variety of monoamine receptor antagonists to examine th e pharmacological mechanisms underlying sibutramine-induced hypophagia . 2 Individually-housed male Sprague-Dawley rats were maintained on re versed phase lighting with free access to food and water. Drugs were a dministered at 09 h 00 min and food intake was monitored over the foll owing 8 h dark period. 3 Sibutramine (10 mg kg(-1), p.o.) produced a s ignificant decrease in food intake during the 8 h following drug admin istration. This hypophagic response was fully antagonized by the alpha (1)-adrenoceptor antagonist, prazosin (0.3 and 1 mg kg(-1), i.p.), and partially antagonized by the beta(1)-adrenoceptor antagonist, metopro lol (3 and 10 mg kg(-1), i.p.) and the 5-HT receptor antagonists, mete rgoline (nonselective; 0.3 mg kg(-1), i.p.); ritanserin (5-HT2A/2C; 0. 1 and 0.5 mg kg(-1), i.p.) and SB200646 (5-HT2B/2C; 20 and 40 mg kg(-1 ), p.o.).4 By contrast, the alpha(2)-adrenoceptor antagonist, RX821002 (0.3 and 1 mg kg(-1), i.p.) and the beta(2)-adrenoceptor antagonist, ICI 118,551 (3 and 10 mg kg(-1), i.p.) did not reduce the decrease in food intake induced by sibutramine. 5 These results demonstrate that b eta(1)-adrenoceptors, 5-HT2A/2C-receptors and particularly alpha(1)-ad renoceptors, are involved in the effects of sibutramine on food intake and are consistent with the hypothesis that sibutramine-induced hypop hagia is related to its ability to inhibit the reuptake of both noradr enaline and 5-HT, with the subsequent activation of a variety of norad renaline and 5-HT receptor systems.