title: Antidepressant and anxiolytic potential of the multimodal antidepressant vortioxetine (Lu AA21004) assessed by behavioural and neurogenesis outcomes in mice.
abstract: Vortioxetine (Lu AA21004) is an investigational novel antidepressant with multimodal activity that functions as a 5-HT3, 5-HT7 and 5-HT(1D) receptor antagonist, 5-HT(1B) receptor partial agonist, 5-HT(1A) receptor agonist and inhibitor of the 5-HT transporter in vitro. Here we explore its anxiolytic and antidepressant potential in adult mice. Vortioxetine was assessed in BalB/cJ@RJ mice using the open-field and forced-swim tests (acute: p.o. 1 h, repeated: daily p.o. 21 days), and in 129S6/SvEvTac mice using the novelty suppressed feeding paradigm (acute: p.o. 1 h, sustained: daily p.o. 14 or 21 days). Fluoxetine and diazepam were controls. Acute and repeated dosing of vortioxetine produced more pronounced anxiolytic- and antidepressant-like activities than fluoxetine. Vortioxetine significantly increased cell proliferation and cell survival and stimulated maturation of immature granule cells in the subgranular zone of the dentate gyrus of the hippocampus after 21 days of treatment. After 14 days, a high dose of vortioxetine increased dendritic length and the number of dendrite intersections, suggesting that vortioxetine accelerates the maturation of immature neurons. Vortioxetine displays an antidepressant and anxiolytic profile following repeated administration associated with increased neurogenesis at several stages. Vortioxetine effects were observed at low levels of 5-HT transporter occupancy, suggesting an alternative mechanism of action to 5-HT reuptake inhibition.
authors.affiliation: Univ Paris-Sud, EA3544, Faculté de Pharmacie, Châtenay-Malabry F-92296, France. jean-philippe.guilloux@u-psud.fr
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Guilloux
authors.forename: Indira
authors.initials: I
authors.lastname: Mendez-David
authors.forename: Alan
authors.initials: A
authors.lastname: Pehrson
authors.forename: Bruno P
authors.initials: BP
authors.lastname: Guiard
authors.forename: Christelle
authors.initials: C
authors.lastname: Repérant
authors.forename: Sophie
authors.initials: S
authors.lastname: Orvoën
authors.forename: Alain M
authors.initials: AM
authors.lastname: Gardier
authors.forename: René
authors.initials: R
authors.lastname: Hen
authors.forename: Bjarke
authors.initials: B
authors.lastname: Ebert
authors.forename: Silke
authors.initials: S
authors.lastname: Miller
authors.forename: Connie
authors.initials: C
authors.lastname: Sanchez
authors.forename: Denis J
authors.initials: DJ
authors.lastname: David
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D000928:Antidepressive Agents / Q000494:pharmacology*; D018891:Dentate Gyrus / Q000166:cytology / Q000187:drug effects; D003975:Diazepam / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D005106:Exploratory Behavior / Q000187:drug effects; D005473:Fluoxetine / Q000494:pharmacology; D046353:Immobility Response, Tonic / Q000187:drug effects; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D055495:Neurogenesis / Q000187:drug effects*; D010879:Piperazines / Q000494:pharmacology*; D013440:Sulfides / Q000494:pharmacology*; D000078784:Vortioxetine
chemical_list: D014151:Anti-Anxiety Agents; D000928:Antidepressive Agents; D010879:Piperazines; D013440:Sulfides; D005473:Fluoxetine; D000078784:Vortioxetine; D003975:Diazepam
keywords: Antidepressant; Anxiolytic; Behaviour; Mice; Multimodal antidepressant; Neurogenesis