In the present study, a possible sertraline action on cerebral pre-synaptic Na ⁺ channels was investigated. For this purpose, the effect of sertraline on responses induced by the Na ⁺channel opener, veratridine, namely the increase in Na ⁺ and in neurotransmitter release in hippocampus-isolated nerve endings was investigated. Results show that sertraline in the low lM range (1.5-25 μM) progressively inhibits the rise in Na ⁺and the release of pre-loaded [ ³H]Glu as well as the release of endogenous 5-HT, Glu and GABA (detected by HPLC) induced by veratridine depolarization either under external Ca ²⁺-free conditions or in the presence of external Ca ²⁺. In addition, under non-depolarized conditions, sertraline (25 μM) increased the external concentration of 5-HT at expense of its internal concentration, and unchanged the external and internal concentrations of the amino acid neurotransmitters and of the 5-HT main metabolite, 5-HIAA. This result is consistent with the sertraline inhibitory action of the serotonin transporter. However, sertraline is unlikely to inhibit pre-synaptic Na ⁺ channels permeability by increasing external 5-HT. Because 5-HT in a wide concentration range (1-1000 μM) did not change the veratridine-induced increase in Na ⁺. In summary, present findings demonstrate that besides the inhibition of 5-HT reuptake, sertraline is an effective inhibitor of presynaptic Na ⁺ channels controlling neurotransmitter release.