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

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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 ≤ 10-5 M, (+)-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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Heal, D. J., Cheetham, S. C., Prow, M. R., Martin, K. F., & Buckett, W. R. (1998). A comparison of the effects on central 5-HT function of sibutramine hydrochloride and other weight-modifying agents. British Journal of Pharmacology, 125(2), 301–308. https://doi.org/10.1038/sj.bjp.0702067

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