Effects of fluoxetine on basal and K(+)-induced tritium release from synaptosomes preloaded with [3H]serotonin

Synaptosomes from rat brain cortex and spinal cord were preloaded with [3H]serotonin ([3H]5-HT), superfused and exposed to fluoxetine and/or 15 mM K+. In both regions 10 microM, but not 1 microM fluoxetine evoked a marked tritium overflow, about 2 min later than the immediate [3H]5-HT release induced by K+, and mainly (73%) due to the efflux of a tritiated metabolite of 5-HT, possibly [3H]5-hydroxy-indoleacetic acid. These findings confirm previous data in the rat hippocampus and are probably due to fluoxetine interacting with the 5-HT storage vesicles. One microM fluoxetine significantly reduced the d-fenfluramine-induced [3H]5-HT overflow, in accordance with its action as 5-HT uptake blocker, but did not affect the K(+)-induced [3H]5-HT overflow. This latter finding does not confirm that fluoxetine inhibits the depolarization-induced Ca(2+)-influx, suggested to involve a drug interaction with the L-type Ca(2+)-channels. Thus, the overflow induced by 10 microM fluoxetine was additive with the depolarization-induced overflow, when the two stimuli were applied together. When 10 microM fluoxetine was added 7 min before 15 mM K+, there was no depolarization-induced overflow. Such inhibition might be only apparent and due either to the fluoxetine-induced loss of vesicular 5-HT or to a fluoxetine-induced alterations of synaptic vesicles. The in vivo relevance of the fluoxetine releasing effect remains to be assessed.