Sertraline inhibits pre-synaptic Na+ channel-mediated responses in hippocampus-isolated nerve endings

J. Neurochem. (2012) 121, 197–205. 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 μM 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 Ca2+‐free conditions or in the presence of external Ca2+. 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 pre‐synaptic Na+ channels controlling neurotransmitter release. Na+ channels controlling neurotransmitter release, a novel aspect in sertraline mechanism of action. Sertraline is known as a selective 5‐HT transporter (SERT) inhibitor. Here, we found that in addition to its 5‐HT reuptake blocking action, that selectively increases 5‐HT under baseline conditions, sertraline inhibits 5‐HT, Glu and GABA release triggered by the Na+ channel opener veratridine in hippocampal isolated nerve endings. These findings demonstrate that the antidepressant sertraline is an effective inhibitor of cerebral pre‐synaptic Na+ channels.