Fluoxetine prevents stimulation-dependent fatigue of synaptic vesicle exocytosis in hippocampal neurons.

Effects of the antidepressant fluoxetine on stimulation-dependent synaptic vesicle exocytosis were examined in cultured primary hippocampal neurons. Synaptic vesicles were fluorescently labeled in vitro with FM1-43, washed and subsequently destained in two consecutive cycles. Exocytosis was triggered by electric field stimulation and imaged by fluorescence microscopy. In control preparations, the second staining-destaining cycle caused a significant reduction of relative fluorescence loss, number of active synapses and half-decay time (t(50)). These fatigue effects were largely prevented by short-term administration of 1 microM fluoxetine, which was present before and during the second stimulation cycle. Fluoxetine concentrations above 10 microM inhibited exocytosis almost completely but showed no other toxic effects on neurons. Stressed neurons, grown under hyperosmotic conditions, were even more fatigue-protected by fluoxetine. These observations support the idea that therapeutic concentrations of fluoxetine enhance the recovery of neurotransmission from exhausting stimuli in healthy and in hyperosmotically stressed neurons as well.