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

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Abstract
Summary 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.