Effects of S-Citalopram, Citalopram, and R-Citalopram on the Firing Patterns of Dopamine Neurons in the Ventral Tegmental Area, N-methyl-D-aspartate Receptor-Mediated Transmission in the Medial Prefrontal Cortex and Cognitive Function in the Rat

Escitalopram, the S-enantiomer of citalopram, possesses superior efficacy compared to other selective serotonin reuptake inhibitors (SSRIs) in the treatment of major depression. Escitalopram binds to an allosteric site on the serotonin transporter, which further enhances the blockade of serotonin reuptake, whereas R-citalopram antagonizes this positive allosteric modulation. Escitalopram's effects on neurotransmitters other than serotonin, for example, dopamine and glutamate, are not well studied. Therefore, we here studied the effects of escitalopram, citalopram, and R-citalopram on dopamine cell firing in the ventral tegmental area, using single-cell recording in vivo and on NMDA receptor-mediated currents in pyramidal neurons in the medial prefrontal cortex using in vitro electrophysiology in rats. The cognitive effects of escitalopram and citalopram were also compared using the novel object recognition test. Escitalopram (40-640 mu g/kg i.v.) increased both firing rate and burst firing of dopaminergic neurons, whereas citalopram (80-1280 mu g/kg) had no effect on firing rate and only increased burst firing at high dosage. R-citalopram (40-640 mu g/kg) had no significant effects. R-citalopram (320 mu g/kg) antagonized the effects of escitalopram (320 mu g/kg). A very low concentration of escitalopram (5 nM), but not citalopram (10 nM) or R-citalopram (5 nM), potentiated NMDA-induced currents in pyramidal neurons. Escitalopram's effect was antagonized by R-citalopram and blocked by the dopamine D-1 receptor antagonist SCH23390. Escitalopram, but not citalopram, improved recognition memory. Our data suggest that the excitatory effect of escitalopram on dopaminergic and NMDA receptor-mediated neurotransmission may have bearing on its cognitive-enhancing effect and superior efficacy compared to other SSRIs in major depression. Synapse 65:357-367, 2011. (C)2010 Wiley-Liss, Inc.