FURTHER EVIDENCE OF CA2-DEPENDENT, EXOCYTOTIC-LIKE SEROTONIN RELEASE INDUCED BY D-FENFLURAMINE()

The effect of polymyxin B and KN-62 on the [H-3]5-HT release induced b y depolarization and by 0.5 mu M D-fenfluramine (dF) from superfused r at hippocampal synaptosomes was examined. Polymyxin B and KN-62 were i nitially characterized as inhibitors, respectively, of calmodulin (CaM ) and of Ca2+/CaM-dependent protein kinase II (Ca/CaM-KII), although b oth compounds were subsequently described as inhibitors of the depolar ization-induced Ca2+ influx through voltage-operated Ca2+ channels, at concentrations similar to those interacting with the CaM systems. Thr ee micromolar KN-62 significantly inhibited the dF- and the depolariza tion-induced [H-3]5-HT release, by 25% and 33%. Polymyxin B, tested at concentrations from 30 to 1000 IU ml(-1), dose-dependently inhibited both the dF- and the depolarization-induced [H-3]5-HT release with sim ilar potency, with complete inhibition at the highest concentration te sted. These compounds did not significantly alter 5-HT transporter fun ction. Moreover dF had no direct effect on Ca/CaM-KII activity. These results further support the suggestion that the [H-3]5-HT release indu ced by low concentrations of dF (0.5 mu M), previously found to be Ca2 +-dependent, actually involves a dF-induced Ca2+ influx into the nerve terminal and the subsequent exocytosis. (C) 1997 The Italian Pharmaco logical Society.