A comparison of the effects on central 5-HT function of sibutramine hydrochloride and other weight-modifying agents

Abstract

1. Effects on 5-HT function of sibutramine and its active metabolites, BTS 54 354 and BTS 54 505, were compared with fluoxetine, (+)-fenfluramine and (+)-amphetamine.

2. In vitro sibutramine weakly inhibited [³H]-5-HT uptake into brain synaptosomes. BTS 54 354, BTS 54 505 and fluoxetine were powerful [³H]-5-HT uptake inhibitors, whereas (+)-fenfluramine and (+)-amphetamine were very much weaker. Conversely, whilst sibutramine, its metabolites and fluoxetine did not release [³H]-5-HT from brain slices at ⩽10⁻⁵M, (+)-fenfluramine and (+)-amphetamine concentration-dependently increased [³H]-5-HT release.

3. Sibutramine and fluoxetine had no effect on 5-hydroxytryptophan (5-HTP) accumulation in either frontal cortex or hypothalamus at doses <10 mg kg⁻¹. In contrast, (+)-amphetamine (⩾3 mg kg⁻¹) reduced 5-HTP in hypothalamus, whilst (+)-fenfluramine (⩾1 mg kg⁻¹) decreased 5-HTP in both regions.

4. Sibutramine (10 mg kg⁻¹ i.p.) and fluoxetine (10 mg kg⁻¹ i.p.) produced slow, prolonged increases of extracellular 5-HT in the anterior hypothalamus. In contrast, (+)-fenfluramine (3 mg kg⁻¹ i.p.) and (+)-amphetamine (4 mg kg⁻¹ i.p.) induced rapid, short-lasting increases in extracellular 5-HT.

5. Only (+)-fenfluramine (10 mg kg⁻¹) altered 5-HT_2A receptors in rat frontal cortex when given for 14 days, producing a 61% reduction in receptor number and a 18% decrease in radioligand affinity.

6. These results show that sibutramine powerfully enhances central 5-HT function via its secondary and primary amine metabolites; this effect, like that of fluoxetine, is almost certainly mediated through 5-HT uptake inhibition. By contrast, (+)-fenfluramine enhances 5-HT function predominantly by increasing 5-HT release. (+)-Amphetamine, though weaker than (+)-fenfluramine, also enhances 5-HT function by release.

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