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
| Autor: | Alain M. Gardier, Franck Chenu, Christelle Repérant, Michel Bourin, Miklós Tóth, Jean-Philippe Guilloux, Bruno P. Guiard, Denis J. David |
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| Rok vydání: | 2006 |
| Předmět: |
Male
Serotonin medicine.medical_specialty Microdialysis Mice Dorsal raphe nucleus Internal medicine polycyclic compounds medicine Animals Drug Interactions Pindolol Swimming 5-HT receptor Cerebral Cortex Mice Knockout Pharmacology 8-Hydroxy-2-(di-n-propylamino)tetralin Analysis of Variance Behavior Animal Dose-Response Relationship Drug Chemistry Immobility Response Tonic Serotonin Receptor Agonists Mice Inbred C57BL Paroxetine Psychiatry and Mental health Endocrinology Area Under Curve Receptor Serotonin 5-HT1A Autoreceptor Raphe Nuclei 5-HT1A receptor Serotonin Antagonists Raphe nuclei Selective Serotonin Reuptake Inhibitors medicine.drug |
| Zdroj: | Neuropsychopharmacology. 31:2162-2172 |
| ISSN: | 1740-634X 0893-133X |
| DOI: | 10.1038/sj.npp.1301019 |
| Popis: | 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 microM 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. |
| Databáze: | OpenAIRE |
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