title: Pharmacological characterisation of the thermogenic effect of bupropion.
abstract: 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.
authors.affiliation: Department of Physiology, Basic Medical Sciences, St. George's Hospital Medical School, Tooting, London, SW17 0RE, UK. yliu@sghms.ac.uk
authors.forename: Yong-Ling
authors.initials: YL
authors.lastname: Liu
authors.forename: Ian P
authors.initials: IP
authors.lastname: Connoley
authors.forename: David J
authors.initials: DJ
authors.lastname: Heal
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Stock
mesh_terms: 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
chemical_list: 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