title: Sibutramine does not decrease the number of 5-HT re-uptake sites in rat brain and, like fluoxetine, protects against the deficits produced by dexfenfluramine.
abstract: The effect of sibutramine and dexfenfluramine on 5-HT re-uptake sites, labelled with [(3)H]paroxetine, have been determined in various rat brain regions. In addition, the ability of fluoxetine and sibutramine to protect against the changes in [(3)H]paroxetine binding produced by dexfenfluramine was examined. Sibutramine (9 mg/kg, p.o.) and dexfenfluramine (1, 3 and 10 mg/kg, p.o.) were administered twice daily (before 09.00 h and after 16.00 h) for four days, followed by a 14 day drug-free period. In the protection studies, fluoxetine (10 mg/kg, i.p.) and sibutramine (9 mg/kg, p.o.) were given 1 h prior to dexfenfluramine (10 mg/kg, p.o.) using the same dosing regimen as described above. Sibutramine (9 mg/kg, p.o.; three times its ED(50) to inhibit food intake at 2 h) had no significant effect on the number or affinity of 5-HT re-uptake sites the brain regions studied. In contrast, dexfenfluramine at an equivalent dose (3 mg/kg, p.o.) significantly decreased the number of 5-HT re-uptake sites in frontal cortex (by 35%), hippocampus (by 47%) and hypothalamus (by 27%). This effect was dose-dependent with marked decreases (by 58-84%) in the number of sites following 10 mg/kg, p.o. These effects were not associated with changes in binding affinity. Fluoxetine (10 mg/kg, i.p.) completely blocked the effect of dexfenfluramine (10 mg/kg, p.o.) without having any significant effect alone. Sibutramine (9 mg/kg, p.o.) also blocked the effects of dexfenfluramine, although the reversal was only partial in frontal cortex, hippocampus and hypothalamus. Thus sibutramine, unlike dexfenfluramine, does not alter brain 5-HT re-uptake sites. Furthermore, sibutramine and fluoxetine protect against the deficits in 5-HT re-uptake sites produced by dexfenfluramine. These data provide further evidence that sibutramine is a 5-HT re-uptake inhibitor and it does not have neurotoxic potential.
authors.affiliation: BASF Pharma, Research and Development, Nottingham NG1 1GF, UK. sharon.cheetham@basf.pharma.co.uk
authors.forename: S C
authors.initials: SC
authors.lastname: Cheetham
authors.forename: J A
authors.initials: JA
authors.lastname: Viggers
authors.forename: N A
authors.initials: NA
authors.lastname: Slater
authors.forename: D J
authors.initials: DJ
authors.lastname: Heal
mesh_terms: D000818:Animals; D001067:Appetite Depressants / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D003503:Cyclobutanes / Q000494:pharmacology*; D020372:Dexfenfluramine / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D005473:Fluoxetine / Q000494:pharmacology; D008297:Male; D017374:Paroxetine / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology
chemical_list: D001067:Appetite Depressants; D003503:Cyclobutanes; D020372:Dexfenfluramine; D005473:Fluoxetine; D017374:Paroxetine; D017366:Serotonin Receptor Agonists; D017367:Selective Serotonin Reuptake Inhibitors; C058254:sibutramine