title: Vortioxetine disinhibits pyramidal cell function and enhances synaptic plasticity in the rat hippocampus.
abstract: Vortioxetine, a novel antidepressant with multimodal action, is a serotonin (5-HT)3, 5-HT7 and 5-HT1D receptor antagonist, a 5-HT1B receptor partial agonist, a 5-HT1A receptor agonist and a 5-HT transporter (SERT) inhibitor. Vortioxetine has been shown to improve cognitive performance in several preclinical rat models and in patients with major depressive disorder. Here we investigated the mechanistic basis for these effects by studying the effect of vortioxetine on synaptic transmission, long-term potentiation (LTP), a cellular correlate of learning and memory, and theta oscillations in the rat hippocampus and frontal cortex. Vortioxetine was found to prevent the 5-HT-induced increase in inhibitory post-synaptic potentials recorded from CA1 pyramidal cells, most likely by 5-HT3 receptor antagonism. Vortioxetine also enhanced LTP in the CA1 region of the hippocampus. Finally, vortioxetine increased fronto-cortical theta power during active wake in whole animal electroencephalographic recordings. In comparison, the selective SERT inhibitor escitalopram showed no effect on any of these measures. Taken together, our results indicate that vortioxetine can increase pyramidal cell output, which leads to enhanced synaptic plasticity in the hippocampus. Given the central role of the hippocampus in cognition, these findings may provide a cellular correlate to the observed preclinical and clinical cognition-enhancing effects of vortioxetine.
authors.affiliation: Lundbeck Research USA, Paramus, NJ, USA EDAL@lundbeck.com.
authors.forename: Elena
authors.initials: E
authors.lastname: Dale
authors.affiliation: Lundbeck Research USA, Paramus, NJ, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Lundbeck Research USA, Paramus, NJ, USA.
authors.forename: Steven C
authors.initials: SC
authors.lastname: Leiser
authors.affiliation: Shanghai Chempartner Co. Ltd., Shanghai, China.
authors.forename: Yixin
authors.initials: Y
authors.lastname: Xiao
authors.affiliation: Shanghai Chempartner Co. Ltd., Shanghai, China.
authors.forename: Dunguo
authors.initials: D
authors.lastname: Lu
authors.affiliation: Shanghai Chempartner Co. Ltd., Shanghai, China.
authors.forename: Charles R
authors.initials: CR
authors.lastname: Yang
authors.affiliation: Lundbeck Research DK, Copenhagen, Denmark.
authors.forename: Niels
authors.initials: N
authors.lastname: Plath
authors.affiliation: Lundbeck Research USA, Paramus, NJ, USA.
authors.forename: Connie
authors.initials: C
authors.lastname: Sanchez
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology; D056547:CA1 Region, Hippocampal / Q000187:drug effects* / Q000502:physiology; D015283:Citalopram / Q000494:pharmacology; D005625:Frontal Lobe / Q000187:drug effects / Q000502:physiology; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D009473:Neuronal Plasticity / Q000187:drug effects* / Q000502:physiology; D010879:Piperazines / Q000494:pharmacology*; D017966:Pyramidal Cells / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D012701:Serotonin / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology; D013440:Sulfides / Q000494:pharmacology*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D013826:Theta Rhythm / Q000187:drug effects / Q000502:physiology; D000078784:Vortioxetine
chemical_list: D000928:Antidepressive Agents; D010879:Piperazines; D012702:Serotonin Antagonists; D013440:Sulfides; D015283:Citalopram; D012701:Serotonin; D000078784:Vortioxetine
keywords: 5-hydroxytryptamine 3 receptor; CA1; Serotonin; cognition; electroencephalography; long-term potentiation