Releasing activities of d-fenfluramine and fluoxetine and fluoxetine on rat hippocampal synaptosomes preloaded with [3H]serotonin

Marco Gobbi, Emanuela Frittoli, Tiziana Mennini, Silvio Garattini

Research output: Contribution to journalArticle

Abstract

Rat hippocampal synaptosomes preloaded with [3H]serotonin and maintained in a superfusion apparatus were exposed for 3 min to d-fenfluramine or fluoxetine. Both drugs evoked a tritium overflow which was reserpine-sensitive requiring the presence of intact synaptic vesicles. However the two drugs displayed different characteristics: 1) the overflow was immediate with dfenfluramine whereas the releasing activity of fluoxetine showed a delay of about 2 min; 2) d-fenfluramine-induced overflow was already apparent at 0.15 μmol/l whereas the minimal effective concentration of fluoxetine was 2.5 μmol/l. Their concentration-effect curves were differently shaped, the effect of d-fenfluramine being saturable at 5-20 μmol/l (EC50 about 1 gmol/l) while no saturation was observed with fluoxetine up to 10 μmol/l; 3) only 1907o of the tritium overflow evoked by fluoxetine (2.5-10 μmol/l) consisted of true [3H]serotonin, compared with 7001o when 0.5 μmol/l d-fenfluramine was used; 4) the releasing action of 0.5 μmol/l d-fenfluramine was completely Ca++-dependent, while at higher dfenfluramine concentrations the Ca++-independent overflow became more important. The fluoxetine induced overflow was mainly. (70010) Ca++-independent; 5) the releasing acitvity of d-fenfluramine was mainly (80%) blocked by the serotonin uptake blockers indalpine, midalcipram and also fluoxetine whereas fluoxetine-induced overflow was insensitive to inhibition of the serotonin carrier. In conclusion, the releasing activity of d-fenfluramine is already present at a very low concentration (0.5 μmol/l) and at this concentration its mechanism of action was Ca++-dependent, together with the requirement of a functional serotonin carrier. These data therefore do not support the hypothesis of a simple. "displacement" of 5-HT from its storage vesicles but suggest an exocytotic release possibly triggered by interaction of d-fenfluramine with intracellular receptors. A direct releasing activity is also shown for fluoxetine, very marked at 5-10 μmol/l; such effect is different from that of d-fenfluramine and is probably due to the overflow of 5-hydroxyindoleacetic acid, formed in the synaptosomes after the fluoxetine-induced "displacement" of serotonin from its storage vesicles. The active concentrations of fluoxetine on serotonin release are compatible with those found in rat brain at doses inducing an anorectic activity.

Original languageEnglish
Pages (from-to)1-6
Number of pages6
JournalNaunyn-Schmiedeberg's Archives of Pharmacology
Volume345
Issue number1
DOIs
Publication statusPublished - Jan 1992

Keywords

  • [H]serotonin release
  • d-Fenfluramine
  • Fluoxetine
  • Synaptosomes

ASJC Scopus subject areas

  • Pharmacology

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