Involvement of 5-HT3 receptors in the action of vortioxetine in rat brain: Focus on glutamatergic and GABAergic neurotransmission.
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.
Department of Neurochemistry and Neuropharmacology, Institut d'Investigacions Biomèdiques de Barcelona, Consejo Superior de Investigaciones Científicas (CSIC), Spain; CIBERSAM (Centro de Investigació Biomédica en Red de Salud Mental), Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Spain.
Maurizio S
MS
Riga
Lundbeck A/S Valby, Denmark.
Connie
C
Sánchez
Department of Neurochemistry and Neuropharmacology, Institut d'Investigacions Biomèdiques de Barcelona, Consejo Superior de Investigaciones Científicas (CSIC), Spain; CIBERSAM (Centro de Investigació Biomédica en Red de Salud Mental), Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Spain.
Pau
P
Celada
Department of Neurochemistry and Neuropharmacology, Institut d'Investigacions Biomèdiques de Barcelona, Consejo Superior de Investigaciones Científicas (CSIC), Spain; CIBERSAM (Centro de Investigació Biomédica en Red de Salud Mental), Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Spain. Electronic address: francesc.artigas@iibb.csic.es.
Francesc
F
Artigas
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D058786:GABA-B Receptor Agonists / Q000494:pharmacology; D059330:GABAergic Neurons / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D010879:Piperazines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D044406:Receptors, Serotonin, 5-HT3 / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism*; D058825:Serotonin 5-HT1 Receptor Agonists / Q000494:pharmacology; D058827:Serotonin 5-HT3 Receptor Agonists / Q000494:pharmacology; D058831:Serotonin 5-HT3 Receptor Antagonists / Q000494:pharmacology; D013440:Sulfides / Q000494:pharmacology*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D000078784:Vortioxetine
D058786:GABA-B Receptor Agonists; D010879:Piperazines; D044406:Receptors, Serotonin, 5-HT3; D058825:Serotonin 5-HT1 Receptor Agonists; D058827:Serotonin 5-HT3 Receptor Agonists; D058831:Serotonin 5-HT3 Receptor Antagonists; D013440:Sulfides; D012701:Serotonin; D000078784:Vortioxetine
5-HT(3) receptors; Medial prefrontal cortex; Pyramidal neurons; Serotonin release; Serotonin transporter; Ventral hippocampus