1. ¹Laboratory of Neuropharmacology and Neurochemistry, Faculty of Pharmacy, University of Claude Bernard Lyon I, Lyon Cedex, France
2. ²Neuropharmacological Research, H Lundbeck A/S, Valby, Denmark

Correspondence: Dr N Haddjeri, Laboratory of Neuropharmacology and Neurochemistry, Faculty of Pharmacy, Claude Bernard University, INSERM U-512, 8, Avenue Rockefeller, 69373 Lyon Cedex 08, France. Tel: +33 4 78 77 75 54; Fax: +33 4 78 77 72 09; E-mail: nhaddj@rockefeller.univ-lyon1.fr

³Present address: Institute of Mental Health Research, University of Ottawa, Lady Grey Bldg, 1145 Carling Avenue, Ottawa, Ontario, Canada K17 7K4.

Received 20 August 2004; Revised 20 December 2004; Accepted 21 December 2004; Published online 9 February 2005.

Abstract

The present study was undertaken to compare the acute and long-term effects of escitalopram and citalopram on rat brain 5-HT neurotransmission, using electrophysiological techniques. In hippocampus, after 2 weeks of treatment with escitalopram (10 mg/kg/day, s.c.) or citalopram (20 mg/kg/day, s.c.), the administration of the selective 5-HT_1A receptor antagonist WAY-100,635 (20–100 g/kg, i.v.) dose-dependently induced a similar increase in the firing activity of dorsal hippocampus CA₃ pyramidal neurons, thus revealing direct functional evidence of an enhanced tonic activation of postsynaptic 5-HT_1A receptors. In dorsal raphe nucleus, escitalopram was four times more potent than citalopram in suppressing the firing activity of presumed 5-HT neurons (ED₅₀=58 and 254 g/kg, i.v., respectively). Interestingly, the suppressant effect of escitalopram (100 g/kg, i.v.) was significantly prevented, but not reversed by R-citalopram (250 g/kg, i.v.). Sustained administration of escitalopram and citalopram significantly decreased the spontaneous firing activity of presumed 5-HT neurons. This firing activity returned to control rate after 2 weeks in rats treated with escitalopram, but only after 3 weeks using citalopram, and was associated with a desensitization of somatodendritic 5-HT_1A autoreceptors. These results suggest that the time course of the gradual return of presumed 5-HT neuronal firing activity, which was reported to account for the delayed effect of SSRI on 5-HT transmission, is congruent with the earlier onset of action of escitalopram vs citalopram in validated animal models of depression and anxiety.