Allosteric modulation of the effects of the 5-HT reuptake inhibitor escitalopram on the rat hippocampal synaptic plasticity

The present in vivo electrophysiological studies in anesthetized rat were undertaken to assess the effects of the selective serotonin (5-HT) reuptake inhibitor (SSRI) escitalopram alone or in combination with the R-citalopram (the S- and R-enantiomers of citalopram), on both long-term potentiation (LTP) in the CA1 region of dorsal hippocampus and spontaneous firing activity of dorsal raphe (DR) 5-HT neurons. At the postsynaptic level, neither escitalopram (10 mg/kg, i.p.) nor R-citalopram (20 mg/kg, i.p.) modified basal synaptic transmission but only escitalopram impaired LTP expression. Importantly, R-citalopram counteracted significantly the escitalopram-induced decrease of LTP. At the pre-synaptic level, escitalopram (25-75 μg/kg, i.v.) dose-dependently suppressed the spontaneous firing activity of DR 5-HT neurons and this suppressant effect was significantly prevented by a prior injection of R-citalopram (10 mg/kg, i.p.). These results support a role of allosteric binding sites of 5-HT transporter in the regulation of long-lasting CA1 synaptic plasticity and DR 5-HT neuronal firing activity.