Pharmacological characterisation of the thermogenic effect of bupropion.
The pharmacological mechanism of bupropion's thermogenic effect has been investigated in female Wistar rats by measuring oxygen consumption at thermoneutrality (29 degrees C). Bupropion (30 mg/kg) rapidly increased oxygen consumption (VO2) with a maximum effect at 30 min, and VO2 remained elevated throughout the 4-h experimental period. The nonselective 5-hydroxytryptamine (5-HT or serotonin) receptor antagonist, metergoline (1 mg/kg), and the alpha1-adrenoceptor antagonist, prazosin (1 mg/kg), had no effect on the VO2 response to bupropion, whereas the alpha2-adrenoceptor antagonist, RS79948 [(8aR, 12aS, 13aS)-5,8,8a,9,10,11,12,12a,13,13a-decahydro-3-methoxy-12-(ethylsulphonyl)-6H-isoquino[2,1-g][1,6]-naphthyridine hydrochloride] (1 mg/kg), potentiated the response. The VO2 response to bupropion during the first 60 min was significantly inhibited by a high dose of the nonselective beta-adrenoceptor antagonist, propranolol (20 mg/kg), but it had no effect at a low dose (1 mg/kg). Pretreatment with the dopamine D2/D1 receptor antagonist, (+)butaclamol (200 microg/kg), caused a partial, but significant, inhibition (P<0.01) of the VO2 response to bupropion during the first 60 min, and this antagonist abolished the effect of bupropion between 90 and 240 min. Pretreatment with a combination of a high dose of propranolol (20 mg/kg) and (+)butaclamol (200 microg/kg) prevented any increase in VO2 induced by bupropion. It is concluded that the beta3-adrenoceptor subtype, as well as dopamine D2/D1 receptors, is responsible for the increase in oxygen consumption induced by bupropion. We have previously demonstrated that bupropion did not significantly reduce food intake in rats. Hence, in this species, its weight-reducing action predominantly results from thermogenesis mediated via activation of beta3-adrenergic and dopamine D2/D1 receptors. Because bupropion has also been reported not to alter food intake in the clinic, thermogenesis may also contribute to its antiobesity effect in man.
Liu
Yong-Ling
YL
Department of Physiology, Basic Medical Sciences, St. George's Hospital Medical School, Tooting, London, SW17 0RE, UK. yliu@sghms.ac.uk
Connoley
Ian P
IP
Heal
David J
DJ
Stock
Michael J
MJ
D058668:Adrenergic alpha-1 Receptor Antagonists; D058669:Adrenergic alpha-2 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D016642:Bupropion / Q000494:pharmacology*; D002069:Butaclamol / Q000494:pharmacology; D065127:Dopamine D2 Receptor Antagonists; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D004347:Drug Interactions; D005260:Female; D007546:Isoquinolines / Q000494:pharmacology; D008711:Metergoline / Q000494:pharmacology; D009287:Naphthyridines / Q000494:pharmacology; D010101:Oxygen Consumption / Q000187:drug effects; D011224:Prazosin / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors; D012702:Serotonin Antagonists / Q000494:pharmacology; D022722:Thermogenesis / Q000187:drug effects*; D013997:Time Factors
D058668:Adrenergic alpha-1 Receptor Antagonists; D058669:Adrenergic alpha-2 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D000319:Adrenergic beta-Antagonists; D065127:Dopamine D2 Receptor Antagonists; D018765:Dopamine Uptake Inhibitors; D007546:Isoquinolines; D009287:Naphthyridines; C104875:RS 79948-197; D017447:Receptors, Dopamine D1; D012702:Serotonin Antagonists; D016642:Bupropion; D008711:Metergoline; D011433:Propranolol; D002069:Butaclamol; D011224:Prazosin