Blockade of 5-HT(1A) Receptors by (+/-)-Pindolol Potentiates Cortical 5-HT Outflow, but not Antidepressant-Like Activity of Paroxetine: Microdialysis and Behavioral Approaches in 5-HT(1A) Receptor Knockout Mice.
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 muM 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.Neuropsychopharmacology (2006) 31, 2162-2172. doi:10.1038/sj.npp.1301019; published online 25 January 2006.[1]References
- Blockade of 5-HT(1A) Receptors by (+/-)-Pindolol Potentiates Cortical 5-HT Outflow, but not Antidepressant-Like Activity of Paroxetine: Microdialysis and Behavioral Approaches in 5-HT(1A) Receptor Knockout Mice. Guilloux, J.P., David, D.J., Guiard, B.P., Chenu, F., Repérant, C., Toth, M., Bourin, M., Gardier, A.M. Neuropsychopharmacology (2006) [Pubmed]
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