Releasing activities of d-fenfluramine and fluoxetine on rat hippocampal synaptosomes preloaded with [3H]serotonin.
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 d-fenfluramine whereas the releasing activity of fluoxetine showed a delay of about 2 min; 2) d-fenfluramine-induced overflow was already apparent at 0.15 mumol/l whereas the minimal effective concentration of fluoxetine was 2.5 mumol/l. Their concentration-effect curves were differently shaped, the effect of d-fenfluramine being saturable at 5-20 mumol/l (EC50 about 1 mumol/l) while no saturation was observed with fluoxetine up to 10 mumol/l; 3) only 19% of the tritium overflow evoked by fluoxetine (2.5-10 mumol/l) consisted of true [3H]serotonin, compared with 70% when 0.5 mumol/l d-fenfluramine was used; 4) the releasing action of 0.5 mumol/l d-fenfluramine was completely Ca(++)-dependent, while at higher d-fenfluramine concentrations the Ca(++)-independent overflow became more important. The fluoxetine induced overflow was mainly (70%) Ca(++)-independent; 5) the releasing activity 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 mumol/l) and at this concentration its mechanism of action was Ca(++)-dependent, together with the requirement of a functional serotonin carrier.(ABSTRACT TRUNCATED AT 250 WORDS)
Gobbi
M
M
Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy.
Frittoli
E
E
Mennini
T
T
Garattini
S
S
D000818:Animals; D002118:Calcium / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D005277:Fenfluramine / Q000494:pharmacology*; D005473:Fluoxetine / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051381:Rats; D012110:Reserpine / Q000494:pharmacology; D012701:Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology; D013574:Synaptosomes / Q000187:drug effects* / Q000378:metabolism
D012702:Serotonin Antagonists; D005473:Fluoxetine; D005277:Fenfluramine; D012701:Serotonin; D012110:Reserpine; D002118:Calcium