Involvement of 5-HT3 receptors in the action of vortioxetine in rat brain: Focus on glutamatergic and GABAergic neurotransmission

NEUROPHARMACOLOGY

卷:108

Article

Riga, Maurizio S.^1,2,3  Sanchez, Connie⁴  Celada, Pau^1,2,3  Artigas, Francesc^1,2,3 

[1] CSIC, Inst Invest Biomed Barcelona, Dept Neurochem & Neuropharmacol, Barcelona, Spain

[2] CIBERSAM Ctr Invest Biomed Red Salud Mental, Madrid, Spain

[3] Inst Invest Biomed August Pi & Sunyer IDIBAPS, Barcelona, Spain

[4] Lundbeck AS Valby, Valby, Denmark

关键词: 5-HT3 receptors;    Medial prefrontal cortex;    Pyramidal neurons;    Serotonin transporter;    Ventral hippocampus;    Serotonin release;   

DOI  :  10.1016/j.neuropharm.2016.04.023

来源: Elsevier

【 摘 要 】

The antidepressant vortioxetine is a 5-HT3-R, 5-HT7-R and 5-HT1D-R antagonist, 5-HT1B-R partial agonist, 5-HT1A-R agonist, and serotonin (5-HT) transporter (SERT) inhibitor. Vortioxetine occupies all targets at high therapeutic doses and only SERT and 5-HT3-R at low doses. Vortioxetine increases extracellular monoamine concentrations in rat forebrain more than selective serotonin reuptake inhibitors (SSRI) and shows pro-cognitive activity in preclinical models. Given its high affinity for 5-HT3-R (Ki = 3.7 nM), selectively expressed in GABA interneurons, we hypothesized that vortioxetine may disinhibit glutamatergic and monoaminergic neurotransmission following 5-HT3-R blockade. Here we assessed vortioxetine effect on pyramidal neuron activity and extracellular 5-HT concentration using in vivo extracellular recordings of rat medial prefrontal cortex (mPFC) pyramidal neurons and microdialysis in mPFC and ventral hippocampus (vHPC). Vortioxetine, but not escitalopram, increased pyramidal neuron discharge in mPFC. This effect was prevented by SR57227A (5-HT3-R agonist) and was mimicked by ondansetron (5-HT3-R antagonist) and by escitalopram/ondansetron combinations. In microdialysis experiments, ondansetron augmented the 5-HT-enhancing effect of escitalopram in mPFC and vHPC. Local ondansetron in vHPC augmented escitalopram effect, indicating the participation of intrinsic mechanisms. Since 5-HT neurons express GABA(B) receptors, we examined their putative involvement in controlling 5-HT release after 5-HT3-R blockade. Co-perfusion of baclofen (but not muscimol) reversed the increased 5-HT levels produced by vortioxetine and escitalopram/ondansetron combinations in vHPC. The present results suggest that vortioxetine increases glutamatergic and serotonergic neurotransmission in rat forebrain by blocking 5-HT3 receptors in GABA interneurons. (C) 2016 Published by Elsevier Ltd.

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