In vitro and in vivo effects of the anorectic agent dexfenfluramine on the central serotoninergic neuronal systems of non-human primates. A comparison with the rat

Tiziana Mennini, Claudia Fracasso, Alfredo Cagnotto, Alessandra Bergami, Emanuela Frittoli, Marco Gobbi, Silvio Caccia, Silvio Garattini

Research output: Contribution to journalArticlepeer-review

Abstract

The effects of repeated subcutaneous (s.c) injections of dexfenfluramine (d-F; 10 mg/kg, twice daily, for 4 days) on the contents of serotonin (5-HT) and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the brain were assessed in primates (cynomolgus and rhesus monkeys) and compared with the regional brain concentrations of unchanged drug and its active metabolite, dexnorfenfluramine (d-NF). This four-day, high-dose, regimen caused a large depletion of 5-HT (more than 95%) and of 5-HIAA (80-90%) in all brain areas studied (cortex, hippocampus, putamen, caudate nucleus and hypothalamus) 2 h after the last injection of d-F. Analysis of the plasma and brain contents of d-F and d-NF confirmed that both compounds were concentrated as in other species, in regions of the primate brain. However, d-NF was concentrated to a greater extent than d-F, and there were differences between the two primate species. Unlike in the rat brain, concentrations of d-NF greatly exceeded those of d-F in the primate brain suggesting that in these primates the d-NF may play a major role in the overall neurochemical response. The effects of d-F and d-NF on different: in vitro parameters of serotoninergic neuronal function did not show appreciable differences between cynomolgus or rhesus monkeys when compared to rats, the ability of the two compounds to inhibit 5-HT reuptake, to enhance its release, and to affect the binding of [3H]-d-F or of [3H]-mesulergine (a ligand for 5-HT(2C) receptors) being similar. Kinetic differences in the disposition of d-F appear to have more relevance than biochemical effects in providing an explanation for the more marked brain depletion induced by d-F in primates than in rodents.

Original languageEnglish
Pages (from-to)641-647
Number of pages7
JournalNaunyn-Schmiedeberg's Archives of Pharmacology
Volume353
Issue number6
DOIs
Publication statusPublished - 1996

Keywords

  • 5-HT uptake and release
  • 5HT(2C) receptor
  • Brain indoles
  • Brain uptake and distribution
  • Dexfenfluramine
  • Dexnorfenfluramine
  • Primate

ASJC Scopus subject areas

  • Pharmacology

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