Fenfluramine releases serotonin from human brain nerve endings by a dual mechanism

Fenfluramine is the most widely used anorexigenic drug in humans. In animal experiments d-fenfluramine has been shown to act as a potent releaser of brain serotonin [5-hydroxytryptamine (5-HT)]. Here we have investigated the effects of d-fenfluramine on the release of [3H]5-HT from isolated nerve endings of human neocortex. The drug elicited release of unmetabolized [3H]5-HT, and this effect was concentration dependent. However, the mechanism of release seems to differ profoundly depending on the concentrations of d-fenfluramine used. At 5 microM, the release of [3H]5-HT was blocked by the 5-HT transporter inhibitor fluoxetine and was Ca2+ independent and insensitive to the human autoreceptor 5-HT1D agonist sumatriptan. The release of [3H]5-HT elicited by 0.5 microM d-fenfluramine was similarly blocked by fluoxetine, but it was strongly Ca2+ dependent and sensitive to sumatriptan. It is suggested that, at relatively high concentrations, d-fenfluramine largely diffuses into serotonergic terminals and causes release of 5-HT through the 5-HT carrier working in the inside-outside direction; at relatively low concentrations d-fenfluramine enters the terminals through the 5-HT transporter but elicits release of 5-HT by an exocytotic-like mechanism.