14 August 1997, Volume 121, Issue 8, Pages 1613 – 1618

Article

Investigation of the mechanisms underlying the hypophagic effects of the 5-HT and noradrenaline reuptake inhibitor, sibutramine, in the rat Helen C. Jackson1, M. Clair Bearham, Lisa J. Hutchins, Sarah E. Mazurkiewicz, Andrew M. Needham & David J. Heal Knoll Pharmaceuticals Research & Development, Pennyfoot Street, Nottingham, NG1 1GF     1Author for correspondence

Keywords

Sibutramine;   food intake;   monoamine reuptake inhibition;   serotonin-noradrenaline reuptake inhibitor (SNRI);   noradrenaline;   5-hydroxytryptamine;   1-adrenoceptors;   1-adrenoceptors;   5-HT receptors

Abstract

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. Sibutramine has been shown to decrease food intake in the rat. In this study we have used a variety of monoamine receptor antagonists to examine the pharmacological mechanisms underlying sibutramine-induced hypophagia. 2   Individually-housed male Sprague-Dawley rats were maintained on reversed phase lighting with free access to food and water. Drugs were administered at 09 h 00 min and food intake was monitored over the following 8 h dark period. 3   Sibutramine (10 mg kg-1, p.o.) produced a significant decrease in food intake during the 8 h following drug administration. This hypophagic response was fully antagonized by the 1-adrenoceptor antagonist, prazosin (0.3 and 1 mg kg-1, i.p.), and partially antagonized by the 1-adrenoceptor antagonist, metoprolol (3 and 10 mg kg-1, i.p.) and the 5-HT receptor antagonists, metergoline (non-selective; 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 2-adrenoceptor antagonist, RX821002 (0.3 and 1 mg kg-1, i.p.) and the 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 1-adrenoceptors, 5-HT2A/2C-receptors and particularly 1-adrenoceptors, are involved in the effects of sibutramine on food intake and are consistent with the hypothesis that sibutramine-induced hypophagia is related to its ability to inhibit the reuptake of both noradrenaline and 5-HT, with the subsequent activation of a variety of noradrenaline and 5-HT receptor systems.

Received 13 February, 97; Revised 9 May, 97; Accepted 14 May, 97

^© Macmillan Publishers Ltd 1997