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

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Abstract
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. 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. Sibutramine and fluoxetine had no effect on 5‐hydroxytryptophan (5‐HTP) accumulation in either frontal cortex or hypothalamus at doses −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. 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. Only (+)‐fenfluramine (10 mg kg−1) altered 5‐HT2A receptors in rat frontal cortex when given for 14 days, producing a 61% reduction in receptor number and a 18% decrease in radioligand affinity. 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. British Journal of Pharmacology (1998) 125, 301–308; doi:10.1038/sj.bjp.0702067