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Investigation of the mechanisms underlying the hypophagic effects of the 5‐HT and noradrenaline reuptake inhibitor, sibutramine, in the rat
Author(s) -
Jackson Helen C.,
Bearham M. Clair,
Hutchins Lisa J.,
Mazurkiewicz Sarah E.,
Needham Andrew M.,
Heal David J.
Publication year - 1997
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0701311
Subject(s) - sibutramine , metergoline , anorectic , antagonist , reuptake inhibitor , endocrinology , ritanserin , medicine , chemistry , pharmacology , serotonin reuptake inhibitor , serotonin , receptor antagonist , 5 ht receptor , receptor , weight loss , food intake , obesity
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 α 1 ‐adrenoceptor antagonist, prazosin (0.3 and 1 mg kg −1 , i.p.), and partially antagonized by the β 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‐HT 2A/2C ; 0.1 and 0.5 mg kg −1 , i.p.) and SB200646 (5‐HT 2B/2C ; 20 and 40 mg kg −1 , p.o.). 4 By contrast, the α 2 ‐adrenoceptor antagonist, RX821002 (0.3 and 1 mg kg −1 , i.p.) and the β 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 β 1 ‐adrenoceptors, 5‐HT 2A/2C ‐receptors and particularly α 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.British Journal of Pharmacology (1997) 121 , 1613–1618; doi: 10.1038/sj.bjp.0701311