Fluoxetine-induced inhibition of synaptosomal [ 3H] 5-HT release: Possible CA 2+-channel inhibition

Abstract

Fluoxetine, a selective 5-HT uptake inhibitor, inhibited 15 mM K +-induced [ 3H] 5-HT release from rat spinal cord and cortical synaptosomes at concentrations > 0.5 uM. This effect reflected a property shared by another selective 5-HT uptake inhibitor paroxetine but not by less selective uptake inhibitors such as amitriptyline, desipramine, imipramine or nortriptyline. Inhibition of release by fluoxetine was inversely related to both the concentration of K + used to depolarize the synaptosomes and the concentration of external Ca 2+. Experiments aimed at determining a mechanism of action revealed that fluoxetine did not inhibit voltage-independent release of [ 3H] 5-HT release induced by the Ca 2+-ionophore A 23187 or Ca 2+-independent release induced by fenfluramine. Moreover the 5-HT autoreceptor antagonist methiothepin did not reverse the inhibitory actions of fluoxetine on K +-induced release. Further studies examined the effects of fluoxetine on voltage-dependent Ca 2+ channels and Ca 2+ entry. Whereas fluoxetine and paroxetine inhibited binding of [ 3H] nitrendipine to the dihydropyridine-sensitive L-type Ca 2+ channel, the less selective uptake inhibitors did not alter binding. The dihydropyridine antagonist nimodipine partially blocked fluoxetine-induced inhibition of release. Moreover enhanced K +-stimulated release due to the dihydropyridine agonist Bay K 8644 was reversed by fluoxetine. Fluoxetine also inhibited the K +-induced increase in intracellular free Ca 2+ in fura-2 loaded synaptosomes. These data are consistent with the suggestion that fluoxetine inhibits K +-induced [ 3H] 5-HT release by antagonizing voltage-dependent Ca 2+ entry into nerve terminals.