title: Monoamine reuptake site occupancy of sibutramine: Relationship to antidepressant-like and thermogenic effects in rats.
abstract: Sibutramine was formerly marketed as an anti-obesity agent. The current study investigated the relationships between monoamine reuptake site occupancy for sibutramine and both its antidepressant-like efficacy and thermogenic effects. Sibutramine's effects on locomotor activity (LMA) and food intake were also evaluated. Sibutramine occupied monoamine reuptake binding sites with the rank order of potency of NET>SERT>DAT; at 10mg/kg, po, occupancy was 95% NET, 81% SERT and 73% DAT. Sibutramine produced antidepressant-like behavior in the forced swim test; at the lowest effective dose (3mg/kg, po) occupancy was 61%, 90% and 23% at SERT, NET and DAT sites, respectively. Sibutramine also increased body core temperature in a dose- and time-dependent manner; at the lowest effective dose (30mg/kg) SERT, NET and DAT occupancies were respectively 78%, 86% and 59%. A significant decrease in food consumption was observed at 3 and 10mg/kg, po. LMA was increased at ≥10mg/kg, sc. The relationship between efficacy in the FST and occupancy was also determined for citalopram, fluoxetine and reboxetine. Similarly, the relationship between thermogenesis and target occupancy for several single or double/triple reuptake inhibitors was measured and showed that >40-50% DAT binding was required for thermogenesis. Thermogenesis was blocked by the D1 antagonist SCH39166 (3mg/kg, sc). Our findings indicate that the antidepressant-like effect of sibutramine may result from additive or synergistic actions on the three reuptake binding targets. At higher doses, sibutramine produces thermogenesis; DAT inhibition and activation of dopamine D1 receptors are required for this effect.
authors.affiliation: Department of Neuroscience Biology, Research and Development, 5 Research Parkway, Bristol-Myers Squibb, Wallingford, CT 06492-7660, USA. Electronic address: yu-wen.li@bms.com.
authors.forename: Yu-Wen
authors.initials: YW
authors.lastname: Li
authors.affiliation: Department of Neuroscience Biology, Research and Development, 5 Research Parkway, Bristol-Myers Squibb, Wallingford, CT 06492-7660, USA.
authors.forename: Shaun
authors.initials: S
authors.lastname: Langdon
authors.affiliation: Department of Neuroscience Biology, Research and Development, 5 Research Parkway, Bristol-Myers Squibb, Wallingford, CT 06492-7660, USA.
authors.forename: Rick
authors.initials: R
authors.lastname: Pieschl
authors.affiliation: Department of Neuroscience Biology, Research and Development, 5 Research Parkway, Bristol-Myers Squibb, Wallingford, CT 06492-7660, USA.
authors.forename: Todd
authors.initials: T
authors.lastname: Strong
authors.affiliation: Department of Neuroscience Biology, Research and Development, 5 Research Parkway, Bristol-Myers Squibb, Wallingford, CT 06492-7660, USA.
authors.forename: Robert N
authors.initials: RN
authors.lastname: Wright
authors.affiliation: Department of Metabolic Diseases, Research and Development, Bristol-Myers Squibb, Wallingford, CT 06492-7660, USA.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Rohrbach
authors.affiliation: Department of Neuroscience Biology, Research and Development, 5 Research Parkway, Bristol-Myers Squibb, Wallingford, CT 06492-7660, USA.
authors.forename: Snjezana
authors.initials: S
authors.lastname: Lelas
authors.affiliation: Department of Neuroscience Biology, Research and Development, 5 Research Parkway, Bristol-Myers Squibb, Wallingford, CT 06492-7660, USA.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Lodge
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001665:Binding Sites; D015306:Biogenic Monoamines / Q000378:metabolism*; D001692:Biological Transport / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects*; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D003503:Cyclobutanes / Q000494:pharmacology*; D004435:Eating / Q000187:drug effects; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D050479:Neurotransmitter Transport Proteins / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000928:Antidepressive Agents; D015306:Biogenic Monoamines; D003503:Cyclobutanes; D050479:Neurotransmitter Transport Proteins; C058254:sibutramine
keywords: Depression; Monoamine; Occupancy; Sibutramine; Thermogenesis; Transporter