Le citalopram (Séropram^®) est un antidépresseur de type inhibiteur sélectif de la recapture de la sérotonine (ISRS) composé, à part égale, d’énantiomère S (escitalopram) et d’énantiomère R (R-citalopram). Il a été démontré que l’escitalopram présente une efficacité supérieure et un délai d’action plus court que la forme racémique (le citalopram). À l’inverse, le R-citalopram, non seulement dépourvu de propriété inhibitrice de la recapture de la sérotonine, contrecarre les effets du escitalopram observés aussi bien in vitro qu’in vivo. Le mécanisme par lequel le R-citalopram exerce son action n’est pas encore pleinement connu, cependant, l’hypothèse d’une interaction allostérique entre les énantiomères et le transporteur membranaire de la sérotonine (SERT) a été proposée. En effet, des études in vitro ont révélé l’existence d’au moins deux sites de liaison distincts sur le SERT : (1) un site primaire à haute affinité ou site orthostérique, responsable de l’inhibition de la recapture de la sérotonine (5-HT) et (2) un site allostérique à basse affinité qui module la liaison des ligands au site primaire. En présence de escitalopram seul, sa liaison au site allostérique renforce sa propre fixation au site primaire et augmente l’efficacité de l’inhibition de la recapture de la 5-HT. En revanche, en présence des deux énantiomères, la liaison du R-citalopram au site allostérique diminue l’action du escitalopram sur le SERT. L’hypothèse d’un tel mécanisme d’action ouvre un large champ de recherche ayant pour objectif de développer des antidépresseurs allostériques susceptibles de résoudre les problèmes d’efficacité et de délai d’action rencontrés avec les molécules actuellement utilisées en clinique.

Citalopram (Séropram^®) is an antidepressant of the selective serotonin (5-HT) reuptake inhibitor (SSRI) class, composed of equal amounts of S-enantiomer, escitalopram, and R-enantiomer, R-citalopram. Both clinical and preclinical studies have reported that escitalopram is a potent SSRI that possesses a faster onset of antidepressant activity in comparison with citalopram. Conversely, R-citalopram, although devoid of 5-HT reuptake inhibition property, was reported to counteract the effect of the S-enantiomer in several in vitro and in vivo experiments. For instance, microdialysis studies have shown that escitalopram increased the extracellular 5-HT levels in the frontal cortex and the ventral hippocampus, and this effect was prevented by concomitant injection of R-citalopram. The in vivo relevance of the antagonistic effect of R-citalopram on escitalopram efficacy was confirmed in dorsal raphe nucleus, a brain region known to be a target for SSRIs. In the later region, escitalopram was four times more potent than citalopram in suppressing the firing activity of 5-HT neurons and this effect of escitalopram was significantly prevented by R-citalopram. The antagonizing effect of R-citalopram on escitalopram efficacy was also observed in behavioural tests predictive of anxiolytic or antidepressant properties. In adult rats, R-citalopram reduced the anxiolytic-like effect of escitalopram obtained in the footshock-induced ultrasonic vocalization model, the conditioned fear model or the Vogel conflict and elevated plus maze tests. In validated chronic models with high predictive value for antidepressant activity, when escitalopram was administered for five weeks, either alone or with twice as much R-citalopram, the effect of the treatment regimens on reversal of hedonic deficit was significantly different. Importantly, chronic treatment with escitalopram reversed the decrease in cytogenesis in the rat dentate gyrus, induced by chronic mild stress. However, in naïve rats, while chronic treatment with R-citalopram did not modify the basal proliferation rate in the dentate gyrus, it blocked the increase induced by escitalopram when coadministered. This suggests that neuronal adaptive changes, which are essential for antidepressant response, are rapidly induced by escitalopram but prevented by R-citalopram coadministration. The attenuating effect of R-citalopram was suggested to underlie the delayed recovery of 5-HT neuronal activity following long-term treatment with citalopram versus escitalopram. This is confirmed since a treatment with R-citalopram antagonized the recovery of firing observed in escitalopram-treated rats. The exact mechanism by which R-citalopram exerts its action is not yet fully defined; however, an allosteric interaction between the enantiomers and the 5-HT transporter (SERT) has been proposed. In this context, in vitro studies have revealed the existence of at least two binding sites on SERT: (1) a primary high-affinity binding site or orthosteric site that mediates the inhibition of 5-HT reuptake and (2) an allosteric low-affinity binding site that modulates the binding of ligands at the primary site. In presence of escitalopram alone, both the primary and the allosteric sites are occupied. Thus, escitalopram exerts a stabilizing effect on this association to SERT, resulting in an effective inhibition of 5-HT reuptake activity. On the other hand, in the presence of the two enantiomers, R-citalopram binds to the allosteric site and decreases the escitalopram action on SERT. Such an innovative mechanism of action can constitute a basis for development of new allosteric antidepressants that demonstrate higher efficacy and earlier onset of therapeutic effect.