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

Abstract

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 μg/kg i.v.) increased both firing rate and burst firing of dopaminergic neurons, whereas citalopram (80-1280 μg/kg) had no effect on firing rate and only increased burst firing at high dosage. R-citalopram (40-640 μg/kg) had no significant effects. R-citalopram (320 μg/kg) antagonized the effects of escitalopram (320 μg/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.

Escitalopram, an antidepressant with an allosteric effect at the serotonin transporter—a review of current understanding of its mechanism of action

“…The potentiation of NMDA currents by escitalopram is also in line with a recent study on long-term potentiation (LTP), in which hippocampal LTP deficits induced by neonatal clomipramine manipulation were restored after 2 weeks of escitalopram treatment (Bhagya et al 2011). Additional studies to confirm these results will be valuable, since a possible excitatory effect of escitalopram on dopaminergic and NMDA receptor-mediated neurotransmission may have bearing on cognition (Schilstrom et al 2011). Further investigations into the contribution of NR2A versus NR2B subtype of NMDA receptors in these effects may also be important, given NR2B is particularly indicated in potential novel treatment strategies for depression (Skolnick et al 2009).…”

“…had only a minimal effect on burst firing. R-citalopram (40-640 μg/kg) did not have an effect by itself, but 320 μg/kg of R-citalopram completely blocked the effect of an equal dose of escitalopram (320 μg/kg) (Schilstrom et al 2011). These results, however, are different from previous reports in which escitalopram and SSRIs such as fluoxetine, citalopram, paroxetine, sertraline, and fluvoxamine seem to inhibit the firing of dopamine neurons in the VTA (Di Mascio et al 1998;Dremencov et al 2009;Prisco and Esposito 1995).…”

“…In this report, transgenic mice that bear the I172M mutation, which abolishes citalopram binding without impacting the recognition of 5-HT, possess normal basal 5-HT levels and transport rates but lack the response to citalopram in 5-HT increase and raphe neuron firing modulation. In addition to the above studies on the firing of 5-HT neurons, the effects of escitalopram and citalopram on dopaminergic and glutamatergic neurons have recently been reported (Schilstrom et al 2011). In this study, Schilstrom and colleagues tested the acute effects of compounds on the firing of dopamine neurons in the ventral tegmental area (VTA) of anesthetized rats.…”

“…Schilstrom and colleagues also tested the effect of escitalopram on N-methyl-D-aspartate (NMDA)-mediated currents in pyramidal neurons in medial prefrontal cortical slices (Schilstrom et al 2011). Escitalopram (5 or 100 nM) potentiated NMDA-induced currents by~40%.…”

Reversal of age-associated cognitive deficits is accompanied by increased plasticity-related gene expression after chronic antidepressant administration in middle-aged mice

“…Decreased plasticity in middle-aged and aged rodents (Kumar, 2011;Rex et al, 2005) may also play a role in cognitive impairment (Balietti et al, 2012). In this context, it is interesting that antidepressants, which have been shown to have pro-cognitive effects in some animal models (Elizalde et al, 2008;Schilstrom et al, 2011), also alter stem cell proliferation (Ibi et al, 2008), growth factor expression (Song et al, 2006) and neuroplasticity-related gene expression (Djordjevic et al, 2012;Freitas et al, 2013), which could underlie the effects of antidepressants on cognitive function as well as mood. This is of particular importance as even sub-threshold depressive symptoms negatively impact cognitive functions in middle-aged and old subjects (Brevik et al, 2013).…”