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-HT1A knockout mice (5-HT1A−/−). 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-HT1A 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-HT1A 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-HT1A+/+, but not in 5-HT1A−/− mice. Similar responses were obtained following local intra-raphe perfusion by reverse microdialysis of either WAY-100635 or (±)-pindolol (100 μM each). In the FST, Prx administration dose-dependently decreased the immobility time in both strains of mice, but the response was much greater in 5HT1A−/− 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-HT1A−/− mice confirm that (±)-pindolol behaves as an antagonist of 5-HT1A 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.
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Acknowledgements
We thank the participation of Isabelle Seif for the genotyping of animals and for her scientific support. This work has been supported by the technical assistance of the Animal Care Facility of the ‘Institut Fédératif de Recherche—IFR75’ of the Paris XI University.
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Guilloux, JP., David, D., Guiard, B. et al. Blockade of 5-HT1A Receptors by (±)-Pindolol Potentiates Cortical 5-HT Outflow, but not Antidepressant-Like Activity of Paroxetine: Microdialysis and Behavioral Approaches in 5-HT1A Receptor Knockout Mice. Neuropsychopharmacol 31, 2162–2172 (2006). https://doi.org/10.1038/sj.npp.1301019
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