title: 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.
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 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.
authors.affiliation: Laboratoire de Neuropharmacologie EA 3544, Faculté de Pharmacie, Université Paris-Sud, Châtenay-Malabry Cedex, France.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Guilloux
authors.forename: Denis J P
authors.initials: DJ
authors.lastname: David
authors.forename: Bruno P
authors.initials: BP
authors.lastname: Guiard
authors.forename: Franck
authors.initials: F
authors.lastname: Chenu
authors.forename: Christelle
authors.initials: C
authors.lastname: Repérant
authors.forename: Miklos
authors.initials: M
authors.lastname: Toth
authors.forename: Michel
authors.initials: M
authors.lastname: Bourin
authors.forename: Alain M
authors.initials: AM
authors.lastname: Gardier
mesh_terms: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D019540:Area Under Curve; D001522:Behavior, Animal / Q000187:drug effects*; D002540:Cerebral Cortex / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D046353:Immobility Response, Tonic / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017551:Microdialysis / Q000379:methods; D017374:Paroxetine / Q000494:pharmacology; D010869:Pindolol / Q000494:pharmacology*; D011903:Raphe Nuclei / Q000187:drug effects; D044282:Receptor, Serotonin, 5-HT1A / Q000172:deficiency*; D012701:Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D013550:Swimming
chemical_list: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D017374:Paroxetine; D010869:Pindolol; D044282:Receptor, Serotonin, 5-HT1A; D012701:Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D017367:Selective Serotonin Reuptake Inhibitors