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. 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 alpha 1-adrenoceptor antagonist, prazosin (0.3 and 1 mg kg-1, i.p.), and partially antagonized by the beta 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 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 beta 1-adrenoceptors, 5-HT2A/2C-receptors and particularly alpha 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.
Jackson
H C
HC
Knoll Pharmaceuticals Research & Development, Nottingham.
Bearham
M C
MC
Hutchins
L J
LJ
Mazurkiewicz
S E
SE
Needham
A M
AM
Heal
D J
DJ
D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology*; D000818:Animals; D003503:Cyclobutanes / Q000494:pharmacology*; D004435:Eating / Q000187:drug effects*; D019329:Idazoxan / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D008790:Metoprolol / Q000494:pharmacology; D011224:Prazosin / Q000494:pharmacology; D011412:Propanolamines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011943:Receptors, Adrenergic, beta / Q000187:drug effects; D011985:Receptors, Serotonin / Q000187:drug effects; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*
D018759:Adrenergic Uptake Inhibitors; D003503:Cyclobutanes; D019329:Idazoxan; D008790:Metoprolol; D011224:Prazosin; D011412:Propanolamines; D011943:Receptors, Adrenergic, beta; D011985:Receptors, Serotonin; D017367:Selective Serotonin Reuptake Inhibitors; C026777:ICI 118551; C058525:2-methoxyidazoxan; C058254:sibutramine