Original article 465 R-citalopram counteracts the antidepressant-like effect of escitalopram in a rat chronic mild stress model C. Sa ´ nchez a , P. Gruca b and M. Papp b The selective serotonin (5-HT) reuptake inhibitor, citalopram, is a racemic mixture of the stereoisomers, S-( + )-citalopram (escitalopram) and R-( – )-citalopram (R-citalopram). R-citalopram has been shown to counteract the 5-HT enhancing properties of escitalopram in acute studies in animals. In the present study we report, for the first time, on an interaction between R-citalopram and escitalopram after repeated dosing in a rat chronic mild stress (CMS) model of depression. The effect of escitalopram (2.0, 3.9 and 7.8mg/kg per day), R-citalopram (7.8mg/kg per day) and escitalopram 3.9 mg/kg per day plus R-citalopram 7.8mg/kg per day were studied and compared to the effect of citalopram (8.0 mg/kg per day), imipramine and R-fluoxetine (8.9 mg/kg per day). Significant effects relative to a vehicle-treated group were achieved from week 1 for escitalopram (3.9 and 7.8mg/kg per day), from week 2 for citalopram (8.0 mg/kg per day), from week 3 for R-fluoxetine (8.9 mg/kg per day) and from week 4 for escitalopram (2.0 mg/kg per day) and imipramine (8.9 mg/ kg per day). R-citalopram (7.8mg/kg per day) and escitalopram (3.9 mg/kg per day) plus R-citalopram (7.8mg/kg per day) did not differ significantly from vehicle. There were no drug-induced effects in non-stressed control groups. In conclusion, escitalopram showed a shorter time to response in the rat CMS model of depression than citalopram, which was faster acting than R-fluoxetine and imipramine. R-citalopram counteracted the effect of escitalopram. The mechanism of action of R-citalopram is, at the moment unclear, but may be relevant to the improved clinical antidepressant activity seen with escitalopram in comparison with citalopram, and may also indicate an earlier response to escitalopram compared to other selective serotonin reuptake inhibitors (SSRIs). Behavioural Pharmacology 14:465–470  c 2003 Lippincott Williams & Wilkins. Behavioural Pharmacology 2003, 14:465–470 Keywords: chronic mild stress, depression, rat, citalopram, escitalopram a Neuropharmacological Research, H. Lundbeck A/S, Copenhagen–Valby, Denmark and b Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland. Correspondence and requests for reprints to Connie Sa ´ nchez, Neuropharmacological Research, H. Lundbeck A/S, Ottiliavej 9, DK 2500 Copenhagen–Valby, Denmark. E-mail: cs@lundbeck.com Received 27 February 2003 Accepted as revised 31 March 2003 Introduction The selective serotonin (5-HT) reuptake inhibitors (SSRIs) have gained extensive clinical use during the past two decades, and are drugs of choice for the treatment of depression and anxiety disorders. The widely used SSRI, citalopram, is a racemic mixture of the S-( + )- and R-( – )-enantiomers, escitalopram and R- citalopram, respectively, in a 1:1 ratio. The 5-HT reuptake inhibitory activity of citalopram has previously been reported to reside in the S-enantiomer (Hyttel et al., 1992). During the past few years, escitalopram has been used successfully to treat major depressive and anxiety disorders (Montgomery et al., 2001; Burke et al., 2002; Wade et al., 2002). The in vitro and in vivo 5-HT reuptake inhibitory activity and the effect of escitalopram and R-citalopram in acute animal models predictive of antidepressant, anxio- lytic, and anti-aggressive activity have recently been characterized and compared with that of citalopram (Sa ´nchez et al., 2003). In line with previous investigations (Hyttel et al., 1992), escitalopram was found to mediate 5-HT uptake inhibitory and antidepressant- and anxiolytic-like and anti-aggressive effects, whereas R-citalopram produced no or minor effects. However, while escitalopram inhibited footshock-induced ultraso- nic vocalization completely, citalopram only produced a partial inhibition in the same dose range. R-citalopram inhibited footshock-induced ultrasonic vocalization par- tially, but was much less potent than escitalopram and citalopram. The partial inhibition produced by citalopram could suggest that R-citalopram attenuates the 5-HT enhancing properties of escitalopram. In line with this hypothesis, a series of recent studies comparing 5-HT levels in frontal cortex of freely moving rats after a single dose of escitalopram, R-citalopram or citalopram racemate has demonstrated that R-citalopram counteracts the 5-HT enhancing properties of escitalopram (Mørk et al., 2003). The chronic mild stress (CMS) procedure is suggested to be an appropriate model to study onset of antidepressant action in animals (reviewed by Willner, 1997). The pharmacological validation of the model is extensive compared to most animal models of depression, and prolonged antidepressant treatment over several weeks is 0955-8810  c 2003 Lippincott Williams & Wilkins DOI: 10.1097/01.fbp.0000087733.21047.60 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.