1. ¹Laboratoire de Neuropharmacologie EA 3544, Faculté de Pharmacie, Université Paris-Sud, Châtenay-Malabry Cedex, France
2. ²Laboratoire Neurobiologie de l'anxiété et de la dépression EA3256, Faculté de Médecine, Université de Nantes, Nantes, France
3. ³Department of Pharmacology, Weill Medical College of Cornell University, New York, NY, USA

Correspondence: Dr AM Gardier, Laboratoire de Neuropharmacologie EA 3544, Tour D1, 2^ème étage, Faculté de Pharmacie, Université Paris-Sud, 5 rue J-B. Clément, 92296 Châtenay-Malabry Cedex, France. Tel: +33 1 46 83 54 16; Fax: +33 1 46 83 53 55; E-mail: alain.gardier@cep.u-psud.fr

Received 28 January 2005; Revised 22 September 2005; Accepted 28 November 2005; Published online 25 January 2006.

Abstract

Selective serotonin reuptake inhibitors like paroxetine (Prx) often requires 4–6 weeks to achieve clinical benefits in depressed patients. Pindolol shortens this delay and it has been suggested that this effect is mediated by somatodendritic 5-hydroxytryptamine (5-HT) 1A autoreceptors. However clinical data on the beneficial effects of pindolol are conflicting. To study the effects of ()-pindolol–paroxetine administration, we used genetical and pharmacological approaches in 5-HT_1A knockout mice (5-HT_1A-/-). Two assays, in vivo intracerebral microdialysis in awake mice and the forced swimming test (FST), were used to assess the antidepressant-like effects of this drug combination. Basal levels of extracellular serotonin, 5-HT ([5-HT]_ext) in the frontal cortex (FCX) and the dorsal raphe nucleus (DRN) did not differ between the two strains of mice, suggesting a lack of tonic control of 5-HT_1A autoreceptors on nerve terminal 5-HT release. Prx (1 and 4 mg/kg) dose-dependently increased cortical [5-HT]_ext in both genotypes, but the effects were greater in mutants. The selective 5-HT_1A receptor antagonist, WAY-100635 (0.5 mg/kg), or ()-pindolol (5 and 10 mg/kg) potentiated the effects of Prx (4 mg/kg) on cortical [5-HT]_ext in 5-HT_1A+/+, but not in 5-HT_1A-/- mice. Similar responses were obtained following local intra-raphe perfusion by reverse microdialysis of either WAY-100635 or ()-pindolol (100 M each). In the FST, Prx administration dose-dependently decreased the immobility time in both strains of mice, but the response was much greater in 5HT_1A-/- mice. In contrast, ()-pindolol blocked Prx-induced decreases in the immobility time while WAY-100635 had no effect in both genotypes. These findings using 5-HT_1A-/- mice confirm that ()-pindolol behaves as an antagonist of 5-HT_1A autoreceptor in mice, but its blockade of paroxetine-induced antidepressant-like effects in the FST may be due to its binding to other neurotransmitter receptors.