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

Abstract

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.

Task- and Treatment Length-Dependent Effects of Vortioxetine on Scopolamine-Induced Cognitive Dysfunction and Hippocampal Extracellular Acetylcholine in Rats

“…Vortioxetine is a 5-HT transporter protein (SERT) inhibitor, a 5-HT 1A receptor agonist, 5-HT 1B receptor partial agonist, and 5-HT 1D , 5-HT 3 , and 5-HT 7 receptor antagonist (Sanchez et al, 2015). Interestingly, vortioxetine’s 5-HT receptor activity may confer the ability to indirectly modulate signaling through several other neurotransmitter systems, including norepinephrine, dopamine (Pehrson et al, 2013), acetylcholine (ACh) and histamine (Mørk et al, 2013), γ-aminobutyric acid (Pehrson and Sanchez, 2015; Dale et al, 2016), and glutamate (Dale et al, 2014; Pehrson and Sanchez, 2014; Riga et al, 2016). Several of these neurotransmitter systems have known relationships to cognitive function, and we have hypothesized that vortioxetine’s cognitive effects may be specifically related to indirect modulation of γ-aminobutyric acid and glutamate neurotransmission (Pehrson and Sanchez, 2014), ACh, or histamine neurotransmission (Mørk et al, 2013).…”

Randomized, 8‐week, double‐blind, placebo‐controlled trial of vortioxetine in Japanese adults with major depressive disorder, followed by a 52‐week open‐label extension trial

“…Vortioxetine is a 5‐HT 3 , 5‐HT 7 , and 5‐HT 1D receptor antagonist, 5‐HT 1B receptor partial agonist, and 5‐HT 1A receptor agonist, in addition to a 5‐HT transporter inhibitor . Nonclinical data suggest that vortioxetine modulates direct and indirect multiple neurotransmitters in the brain, including serotonin, norepinephrine, dopamine, histamine, acetylcholine, γ‐aminobutyric acid (GABA), and glutamate . Vortioxetine's multimodal mechanism of action implies a differentiated profile from conventional antidepressants .…”

“…8,9 Nonclinical data suggest that vortioxetine modulates direct and indirect multiple neurotransmitters in the brain, including serotonin, norepinephrine, dopamine, histamine, acetylcholine, γ-aminobutyric acid (GABA), and glutamate. 8,[10][11][12] Vortioxetine's multimodal mechanism of action implies a differentiated profile from conventional antidepressants. 8 Phase 2 and 3 clinical trials conducted in the USA and Europe have demonstrated the antidepressant efficacy of vortioxetine in MDD patients at doses of up to 20 mg/day.…”

Can we increase speed and efficacy of antidepressant treatments? Part I: General aspects and monoamine-based strategies

“…Conversely, blockade of 5-HT3 receptors by vortioxetine reduces the GABAergic tone on GABAA and GABAB receptors, which then translates into a disinhibition of the activity of midbrainprojecting pyramidal neurons in the mPFC (Riga et al, 2016) (Fig. 4).…”

“…This prefrontalbrainstem connectivity may account for the rapid recovery of serotonergic activity after repeated vortioxetine treatment (Bétry et al, 2013). In addition, 5-HT3 receptor blockade potentiates the increase in extracellular 5-HT produced by SERT blockade, an effect likely involving the removal of a GABAB tone on 5-HT axon terminals (Riga et al, 2016). These effects may account for the greater enhancement of forebrain monoamine release produced by vortioxetine, as compared with SSRI (Mork et al, 2012).…”