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

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 mM each). In the FST, Prx administration dosedependently 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-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.