FENFLURAMINE RELEASES SEROTONIN FROM HUMAN BRAIN NERVE-ENDINGS BY A DUAL MECHANISM

Fenfluramine is the most widely used anorexigenic drug in humans. In a nimal experiments d-fenfluramine has been shown to act as a potent rel easer of brain serotonin [5-hydroxy-tryptamine (5-HT)]. Here we have i nvestigated the effects of d-fenfluramine on the release of [H-3]5-HT from isolated nerve endings of human neocortex. The drug elicited rele ase of unmetabolized [H-3]5-HT, and this effect was concentration depe ndent. However, the mechanism of release seems to differ profoundly de pending on the concentrations of d-fenfluramine used. At 5 mu M, the r elease of [H-3]5-HT was blocked by the 5-HT transporter inhibitor fluo xetine and was Ca2+ independent and insensitive to the human autorecep tor 5-HT1D agonist sumatriptan. The release of [H-3]5-HT elicited by 0 .5 mu M 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 diffu ses into serotonergic terminals and causes release of 5-HT through the 5-HT carrier working in the inside-outside direction; at relatively l ow concentrations d-fenfluramine enters the terminals through the 5-HT transporter but elicits release of 5-HT by an exocytotic-like mechani sm.