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 (7)-pindolol-paroxetine administration, we used genetical and pharmacological approaches in 5-HT 1A knockout mice (5-HT 1A À/À). 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 (7)-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 À/À mice. Similar responses were obtained following local intra-raphe perfusion by reverse microdialysis of either WAY-100635 or (7)-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 À/À mice. In contrast, (7)-pindolol blocked Prx-induced decreases in the immobility time while WAY-100635 had no effect in both genotypes. These findings using 5-HT 1A À/À mice confirm that (7)-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.

VGLUT3 (Vesicular Glutamate Transporter Type 3) Contribution to the Regulation of Serotonergic Transmission and Anxiety

“…Samples were collected at 30 or 15 min intervals for DRN and hippocampus respectively, and analyzed by HPLC with amperometrical detection. The amount of 5-HT in samples was calculated by measurement of peak heights relative to known amounts in external standards (Guilloux et al, 2006). The limit of sensitivity for 5-HT was ϳ0.5 fmol per sample (signal-to-noise ratio ϭ 2).…”

“…Dialysis probes were perfused with artificial CSF (aCSF) containing (in mM): 140 NaCl, 3 KCl, 1.5 CaCl 2 , 1 MgCl 2 , 1.2 NaH 2 PO 4 , 0.27 Na 2 HPO 4 and pH was adjusted to 7.4. The aCSF was infused at 0.5 and 1.5 l/min for DRN and hippocampus respectively, using a microdialysis pump (Phymep) (Guilloux et al, 2006). Infusion was started 3 h before experiments to allow sufficient time for wash-out of 5-HT originating from non-neural sources.…”

“…Microdialysis experiments were performed as previously described (Guilloux et al, 2006). Animals were anesthetized with a combination of ketamine (100 mg/kg, i.p.)…”

Neurokinin1 Antagonists Potentiate Antidepressant Properties of Serotonin Reuptake Inhibitors, Yet Blunt Their Anxiogenic Actions: A Neurochemical, Electrophysiological, and Behavioral Characterization

“…However, GR205171 and RP67580 have no affinity for 5-HT 1B receptors, and this would not explain their abrogation of the inhibitory influence of SSRIs on serotonergic neurones in the DRN (Gardner et al, 1996;Millan et al, 2000). Rather, inhibitory 5-HT 1A autoreceptors are localized on serotonergic perikarya, and 5-HT 1A antagonists likewise enhance increases in FCX levels of 5-HT elicited by SSRIs (Gobert et al, 1997;Millan et al, 2000;Guilloux et al, 2006). Though GR205171 and RP67580 do not behave as 5-HT 1A antagonists (pK i values, o5.0; Gardner et al, 1996; Figure 5), it is important to consider the significance of 5-HT 1A autoreceptors.…”

“…However, changes in firing rate do not invariably translate into alterations in release (Gobert et al, 1995;Millan and Gobert, 1999;Millan et al, 2000;Artigas et al, 2001;Gobbi et al, 2007), and the reduction by S15535 (and 8-OH-DPAT) of 5-HT release in FCX was not modified by GR205171. Moreover, GR205171 did not modify the influence on serotonergic neurones of (À)-pindolol, a low efficacy 5-HT 1A ligand (ca 20%) which only submaximally decreases firing rate (Newman-Tancredi et al, 1998;Millan and Gobert, 1999;Guilloux et al, 2006). Recruitment of postsynaptic 5-HT 1A receptors in FCX triggers long-loop, inhibitory feedback to serotonergic cell bodies in raphe nuclei Celada et al, 2001;Sharp et al, 2007).…”