Involvement of 5-HT 3 receptors in the action of vortioxetine in rat brain: Focus on glutamatergic and GABAergic neurotransmission

Apr 24, 2016Neuropharmacology

Role of 5-HT3 receptors in how vortioxetine affects brain signals controlling excitation and inhibition in rats

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Abstract

Vortioxetine increases glutamatergic and serotonergic neurotransmission in the rat forebrain by blocking 5-HT3 receptors.

Vortioxetine enhances pyramidal neuron activity in the medial prefrontal cortex (mPFC) but escitalopram does not.
The increase in pyramidal neuron discharge caused by vortioxetine is prevented by a 5-HT3 receptor agonist.
A 5-HT3 receptor antagonist mimics the effect of vortioxetine and can enhance the action of escitalopram.
Increased serotonin levels in the mPFC and ventral hippocampus (vHPC) are observed with ondansetron in combination with escitalopram.
Blocking GABAB receptors reverses the increase in serotonin levels driven by vortioxetine and the escitalopram/ondansetron combinations.

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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 GABAB 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.

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Involvement of 5-HT 3 receptors in the action of vortioxetine in rat brain: Focus on glutamatergic and GABAergic neurotransmission

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