Modulation of Ca2+ currents and long-term synaptic plasticity by SSRIs

Selective serotonin reuptake inhibitors are frequently used in the treatment of major depression. Their efficacy is thought to be related to the inhibition of the presynaptic 5-HT transporter which results in an elevation of extracellular 5-HT. In rat hippocampal pyramidal cells, we show that all marketed SSRIs are potent blockers of different Ca²⁺ channel populations suggesting a group effect. High-voltage activated channels (N-, L-, P/Q-type) are inhibited by low drug concentrations. The mode of action of this effect has been further examined for fluvoxamine. The effect of fluvoxamine is independent from 5-HT receptors, G-protein or tyrosine kinase activation and suggest a direct channel blockade. Low-voltage activated currents (T-type channels) are also inhibited. The amount of HVA-inhibition is comparable to that of 5-HT itself.

A functional implication of the Ca²⁺ channel inhibition by SSRIs might be the inhibition of long-term synaptic depression (LTD) which depends on HVA Ca²⁺ influx. These findings further support a role for long-term synaptic plasticity in the pathophysiology of affective disorders.