Locomotion is the major determinant of sibutramine-induced increase in energy expenditure.
The anti-obesity effect of the serotonin and noradrenaline reuptake inhibitor sibutramine has been attributed to a dual mechanism involving a reduction of food intake and an increase in energy expenditure. This dual action increases the possibilities for induction of a negative energy balance, the principal goal of an anti-obesity treatment. To elucidate the mechanism behind sibutramine-induced increase in energy expenditure, we applied indirect calorimetry combined with monitoring locomotor activity and body temperature. We confirm that sibutramine has both anorectic and thermogenic effects. In addition, we show here that sibutramine also causes a dose-dependent increase in locomotor activity (LMA) of rats, occurring in parallel with increase in energy expenditure. The dose of sibutramine necessary to induce an effect on locomotion and energy expenditure was only marginally higher than the dose sufficient to induce a significant reduction of food intake. The relation between LMA and energy expenditure was similar to that found with d-amphetamine, which causes both hyper-locomotion and increased energy expenditure, but was different from 2,4-dinitrophenol which causes increase in energy expenditure but not in locomotion. The effect of sibutramine (20 mg/kg) on energy expenditure was not inhibited by the non-selective 5-HT receptor antagonist, metergoline (1 mg/kg), or a high dose (20 mg/kg) of the non-selective beta-blocker propranolol, but was blocked by D1 dopamine receptor inhibitor SCH 23390 (0.3 mg/kg). Therefore, we conclude that the effect of sibutramine on energy expenditure in rats is predominantly due to a dopamine-dependent increase in locomotor activity.
Golozoubova
Valeria
V
Diabetes Pharmacology, Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Måløv, Denmark. vgo@novonordisk.com
Strauss
Frank
F
Malmlöf
Kjell
K
D019297:2,4-Dinitrophenol / Q000494:pharmacology; D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D001067:Appetite Depressants / Q000494:pharmacology*; D001831:Body Temperature / Q000187:drug effects; D003503:Cyclobutanes / Q000494:pharmacology*; D004435:Eating / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects*; D008297:Male; D009043:Motor Activity / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011943:Receptors, Adrenergic, beta / Q000502:physiology; D011985:Receptors, Serotonin / Q000502:physiology
D001067:Appetite Depressants; D003503:Cyclobutanes; D011943:Receptors, Adrenergic, beta; D011985:Receptors, Serotonin; D000661:Amphetamine; D019297:2,4-Dinitrophenol; C058254:sibutramine