Anorectic effect and brain concentrations of D-fenfluramine in the marmoset: relationship to the in vivo and in vitro effects on serotonergic mechanisms

Silvio Caccia, Marina Anelli, Claudia Fracasso, Emanuela Frittoli, Paolo Giorcelli, Marco Gobbi, Carlo Taddei, Silvio Garattini, Tiziana Mennini

Research output: Contribution to journalArticle

Abstract

The present study investigated the anorectic activity of d-fenfluramine (d-F) and the relationship with brain levels of unchanged drug and its metabolite d-norfenfluramine (d-NF) in marmosets, relating them to neurochemical effects on the serotoninergic system. d-F and d-NF were equally active in reducing food intake (ED50 about 3 mg/kg, p.o.). However, the brain concentrations of the metabolite required to reduce food intake after synthetic d-NF were more than twice those after d-F, indicating that d-NF contributes to but does not completely explain the anorectic effect of d-F. At this dose d-F did not appreciably modify the serotonin (5-HT) and 5-hydroxyindoleacetic (5-HIAA) contents of the brain regions examined, except for a slight enhancement of 5-HIAA in hippocampus. In vitro in brain cortical synaptosomes d-F inhibited [3H]5-HT uptake more potently than d-NF, as in other species. d-F and d-NF showed similar potency in stimulating [3H]5-HT release, in a Ca++ dependent manner. The tritium released by d-F and d-NF appeared to be mainly unmetabolized [3H]5-HT. Like in other species the marmoset too has saturable and specific [3H]d-F binding sites, for which d-NF has lower affinity. d-F and d-NF have low affinities for 5-HT receptor subtypes, except that d-NF has appreciable affinity for 5-HT1Cand 5-HT1Dreceptors. Unlike in rodents but similarly to primates in the striatum the pharmacology of 5-HT receptors seems to correspond to the 5-HT1D subtype. Brain concentrations of d-F and d-NF at anorectic doses exceeded the concentrations required in vitro to influence the serotoninergic system. Therefore the effect of d-F on food intake might possibly be explained by an interaction with the 5-HT system, particularly uptake and release mechanisms, and that of d-NF by an action on 5-HT1C and 5-HT1D receptor subtypes.

Original languageEnglish
Pages (from-to)306-312
Number of pages7
JournalNaunyn-Schmiedeberg's Archives of Pharmacology
Volume347
Issue number3
DOIs
Publication statusPublished - 1993

Keywords

  • Anorectic ED
  • d-Fenfluramine
  • d-Norfenfluramine
  • Effects on serotoninergic mechanisms
  • Marmoset

ASJC Scopus subject areas

  • Pharmacology

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