title: Task- and Treatment Length-Dependent Effects of Vortioxetine on Scopolamine-Induced Cognitive Dysfunction and Hippocampal Extracellular Acetylcholine in Rats.
abstract: Major depressive disorder (MDD) is a common psychiatric disorder that often features impairments in cognitive function, and these cognitive symptoms can be important determinants of functional ability. Vortioxetine is a multimodal antidepressant that may improve some aspects of cognitive function in patients with MDD, including attention, processing speed, executive function, and memory. However, the cause of these effects is unclear, and there are several competing theories on the underlying mechanism, notably including regionally-selective downstream enhancement of glutamate neurotransmission and increased acetylcholine (ACh) neurotransmission. The current work sought to evaluate the ACh hypothesis by examining vortioxetine's ability to reverse scopolamine-induced impairments in rodent tests of memory and attention. Additionally, vortioxetine's effects on hippocampal extracellular ACh levels were examined alongside studies of vortioxetine's pharmacokinetic profile. We found that acute vortioxetine reversed scopolamine-induced impairments in social and object recognition memory, but did not alter scopolamine-induced impairments in attention. Acute vortioxetine also induced a modest and short-lived increase in hippocampal ACh levels. However, this short-term effect is at variance with vortioxetine's moderately long brain half life (5.1 hours). Interestingly, subchronic vortioxetine treatment failed to reverse scopolamine-induced social recognition memory deficits and had no effects on basal hippocampal ACh levels. These data suggest that vortioxetine has some effects on memory that could be mediated through cholinergic neurotransmission, however these effects are modest and only seen under acute dosing conditions. These limitations may argue against cholinergic mechanisms being the primary mediator of vortioxetine's cognitive effects, which are observed under chronic dosing conditions in patients with MDD.
authors.affiliation: Lundbeck Research USA, Paramus, New Jersey (A.L.P., G.S., D.S., D.B., M.C., C.S.); Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Risskov, Denmark (C.S.); Department of Pharmacology, University of Michigan, Ann Arbor, Michigan (T.M.H.); Psychology Department, Virginia Commonwealth University, Richmond, Virginia (T.M.H., J.H.P.); Univ Lyon, Université Claude Bernard Lyon 1, Inserm, Stem Cell and Brain Research Institute U1208, 69500 Bron, France (R.R., N.H.); and H. Lundbeck A/S, Copenhagen-Valby, Denmark (A.M.).
authors.forename: Alan L
authors.identifier: 0000-0002-0470-0202
authors.initials: AL
authors.lastname: Pehrson
authors.affiliation: Lundbeck Research USA, Paramus, New Jersey (A.L.P., G.S., D.S., D.B., M.C., C.S.); Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Risskov, Denmark (C.S.); Department of Pharmacology, University of Michigan, Ann Arbor, Michigan (T.M.H.); Psychology Department, Virginia Commonwealth University, Richmond, Virginia (T.M.H., J.H.P.); Univ Lyon, Université Claude Bernard Lyon 1, Inserm, Stem Cell and Brain Research Institute U1208, 69500 Bron, France (R.R., N.H.); and H. Lundbeck A/S, Copenhagen-Valby, Denmark (A.M.).
authors.forename: Todd M
authors.initials: TM
authors.lastname: Hillhouse
authors.affiliation: Lundbeck Research USA, Paramus, New Jersey (A.L.P., G.S., D.S., D.B., M.C., C.S.); Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Risskov, Denmark (C.S.); Department of Pharmacology, University of Michigan, Ann Arbor, Michigan (T.M.H.); Psychology Department, Virginia Commonwealth University, Richmond, Virginia (T.M.H., J.H.P.); Univ Lyon, Université Claude Bernard Lyon 1, Inserm, Stem Cell and Brain Research Institute U1208, 69500 Bron, France (R.R., N.H.); and H. Lundbeck A/S, Copenhagen-Valby, Denmark (A.M.).
authors.forename: Nasser
authors.initials: N
authors.lastname: Haddjeri
authors.affiliation: Lundbeck Research USA, Paramus, New Jersey (A.L.P., G.S., D.S., D.B., M.C., C.S.); Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Risskov, Denmark (C.S.); Department of Pharmacology, University of Michigan, Ann Arbor, Michigan (T.M.H.); Psychology Department, Virginia Commonwealth University, Richmond, Virginia (T.M.H., J.H.P.); Univ Lyon, Université Claude Bernard Lyon 1, Inserm, Stem Cell and Brain Research Institute U1208, 69500 Bron, France (R.R., N.H.); and H. Lundbeck A/S, Copenhagen-Valby, Denmark (A.M.).
authors.forename: Renaud
authors.initials: R
authors.lastname: Rovera
authors.affiliation: Lundbeck Research USA, Paramus, New Jersey (A.L.P., G.S., D.S., D.B., M.C., C.S.); Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Risskov, Denmark (C.S.); Department of Pharmacology, University of Michigan, Ann Arbor, Michigan (T.M.H.); Psychology Department, Virginia Commonwealth University, Richmond, Virginia (T.M.H., J.H.P.); Univ Lyon, Université Claude Bernard Lyon 1, Inserm, Stem Cell and Brain Research Institute U1208, 69500 Bron, France (R.R., N.H.); and H. Lundbeck A/S, Copenhagen-Valby, Denmark (A.M.).
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Porter
authors.affiliation: Lundbeck Research USA, Paramus, New Jersey (A.L.P., G.S., D.S., D.B., M.C., C.S.); Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Risskov, Denmark (C.S.); Department of Pharmacology, University of Michigan, Ann Arbor, Michigan (T.M.H.); Psychology Department, Virginia Commonwealth University, Richmond, Virginia (T.M.H., J.H.P.); Univ Lyon, Université Claude Bernard Lyon 1, Inserm, Stem Cell and Brain Research Institute U1208, 69500 Bron, France (R.R., N.H.); and H. Lundbeck A/S, Copenhagen-Valby, Denmark (A.M.).
authors.forename: Arne
authors.initials: A
authors.lastname: Mørk
authors.affiliation: Lundbeck Research USA, Paramus, New Jersey (A.L.P., G.S., D.S., D.B., M.C., C.S.); Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Risskov, Denmark (C.S.); Department of Pharmacology, University of Michigan, Ann Arbor, Michigan (T.M.H.); Psychology Department, Virginia Commonwealth University, Richmond, Virginia (T.M.H., J.H.P.); Univ Lyon, Université Claude Bernard Lyon 1, Inserm, Stem Cell and Brain Research Institute U1208, 69500 Bron, France (R.R., N.H.); and H. Lundbeck A/S, Copenhagen-Valby, Denmark (A.M.).
authors.forename: Gennady
authors.initials: G
authors.lastname: Smagin
authors.affiliation: Lundbeck Research USA, Paramus, New Jersey (A.L.P., G.S., D.S., D.B., M.C., C.S.); Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Risskov, Denmark (C.S.); Department of Pharmacology, University of Michigan, Ann Arbor, Michigan (T.M.H.); Psychology Department, Virginia Commonwealth University, Richmond, Virginia (T.M.H., J.H.P.); Univ Lyon, Université Claude Bernard Lyon 1, Inserm, Stem Cell and Brain Research Institute U1208, 69500 Bron, France (R.R., N.H.); and H. Lundbeck A/S, Copenhagen-Valby, Denmark (A.M.).
authors.forename: Dekun
authors.initials: D
authors.lastname: Song
authors.affiliation: Lundbeck Research USA, Paramus, New Jersey (A.L.P., G.S., D.S., D.B., M.C., C.S.); Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Risskov, Denmark (C.S.); Department of Pharmacology, University of Michigan, Ann Arbor, Michigan (T.M.H.); Psychology Department, Virginia Commonwealth University, Richmond, Virginia (T.M.H., J.H.P.); Univ Lyon, Université Claude Bernard Lyon 1, Inserm, Stem Cell and Brain Research Institute U1208, 69500 Bron, France (R.R., N.H.); and H. Lundbeck A/S, Copenhagen-Valby, Denmark (A.M.).
authors.forename: David
authors.initials: D
authors.lastname: Budac
authors.affiliation: Lundbeck Research USA, Paramus, New Jersey (A.L.P., G.S., D.S., D.B., M.C., C.S.); Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Risskov, Denmark (C.S.); Department of Pharmacology, University of Michigan, Ann Arbor, Michigan (T.M.H.); Psychology Department, Virginia Commonwealth University, Richmond, Virginia (T.M.H., J.H.P.); Univ Lyon, Université Claude Bernard Lyon 1, Inserm, Stem Cell and Brain Research Institute U1208, 69500 Bron, France (R.R., N.H.); and H. Lundbeck A/S, Copenhagen-Valby, Denmark (A.M.).
authors.forename: Manuel
authors.initials: M
authors.lastname: Cajina
authors.affiliation: Lundbeck Research USA, Paramus, New Jersey (A.L.P., G.S., D.S., D.B., M.C., C.S.); Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Risskov, Denmark (C.S.); Department of Pharmacology, University of Michigan, Ann Arbor, Michigan (T.M.H.); Psychology Department, Virginia Commonwealth University, Richmond, Virginia (T.M.H., J.H.P.); Univ Lyon, Université Claude Bernard Lyon 1, Inserm, Stem Cell and Brain Research Institute U1208, 69500 Bron, France (R.R., N.H.); and H. Lundbeck A/S, Copenhagen-Valby, Denmark (A.M.) connie_sanchez@clin.au.dk.
authors.forename: Connie
authors.initials: C
authors.lastname: Sanchez
mesh_terms: D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D060825:Cognitive Dysfunction / Q000139:chemically induced* / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D005110:Extracellular Space / Q000187:drug effects* / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology; D008297:Male; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D021641:Recognition, Psychology / Q000187:drug effects; D012601:Scopolamine / Q000494:pharmacology*; D012919:Social Behavior; D013440:Sulfides / Q000494:pharmacology* / Q000627:therapeutic use; D009435:Synaptic Transmission / Q000187:drug effects; D000078784:Vortioxetine
chemical_list: D010879:Piperazines; D013440:Sulfides; D000078784:Vortioxetine; D012601:Scopolamine; D000109:Acetylcholine