Task-and treatment length-dependent effects of vortioxetine on scopolamine-induced cognitive dysfunction and hippocampal extracellular acetylcholine in rats

Alan L. Pehrson, Todd M. Hillhouse, Nasser Haddjeri, Renaud Rovera, Joseph H. Porter, Arne Mørk, Gennady Smagin, Dekun Song, David Budac, Manuel Cajina, Connie Sanchez

Research output: Contribution to journalArticle

11 Citations (Scopus)

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 vortioxetine9s cognitive effects, which are observed under chronic dosing conditions in patients with MDD.

Original languageEnglish
Pages (from-to)472-482
Number of pages11
JournalJournal of Pharmacology and Experimental Therapeutics
Volume358
Issue number3
DOIs
StatePublished - Sep 2016

Fingerprint

Scopolamine Hydrobromide
Acetylcholine
Major Depressive Disorder
Synaptic Transmission
Aptitude
Therapeutics
Cognition
Cholinergic Agents
vortioxetine
Cognitive Dysfunction
Neurobehavioral Manifestations
Executive Function
Memory Disorders
Antidepressive Agents
Psychiatry
Half-Life
Glutamic Acid
Rodentia
Pharmacokinetics
Brain

Cite this

Pehrson, Alan L. ; Hillhouse, Todd M. ; Haddjeri, Nasser ; Rovera, Renaud ; Porter, Joseph H. ; Mørk, Arne ; Smagin, Gennady ; Song, Dekun ; Budac, David ; Cajina, Manuel ; Sanchez, Connie. / Task-and treatment length-dependent effects of vortioxetine on scopolamine-induced cognitive dysfunction and hippocampal extracellular acetylcholine in rats. In: Journal of Pharmacology and Experimental Therapeutics. 2016 ; Vol. 358, No. 3. pp. 472-482.
@article{684ca537256844a891e0350aad9cfb51,
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 vortioxetine9s cognitive effects, which are observed under chronic dosing conditions in patients with MDD.",
author = "Pehrson, {Alan L.} and Hillhouse, {Todd M.} and Nasser Haddjeri and Renaud Rovera and Porter, {Joseph H.} and Arne M{\o}rk and Gennady Smagin and Dekun Song and David Budac and Manuel Cajina and Connie Sanchez",
year = "2016",
month = "9",
doi = "10.1124/jpet.116.233924",
language = "English",
volume = "358",
pages = "472--482",
journal = "Journal of Pharmacology and Experimental Therapeutics",
issn = "0022-3565",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
number = "3",

}

Task-and treatment length-dependent effects of vortioxetine on scopolamine-induced cognitive dysfunction and hippocampal extracellular acetylcholine in rats. / Pehrson, Alan L.; Hillhouse, Todd M.; Haddjeri, Nasser; Rovera, Renaud; Porter, Joseph H.; Mørk, Arne; Smagin, Gennady; Song, Dekun; Budac, David; Cajina, Manuel; Sanchez, Connie.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 358, No. 3, 09.2016, p. 472-482.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Task-and treatment length-dependent effects of vortioxetine on scopolamine-induced cognitive dysfunction and hippocampal extracellular acetylcholine in rats

AU - Pehrson, Alan L.

AU - Hillhouse, Todd M.

AU - Haddjeri, Nasser

AU - Rovera, Renaud

AU - Porter, Joseph H.

AU - Mørk, Arne

AU - Smagin, Gennady

AU - Song, Dekun

AU - Budac, David

AU - Cajina, Manuel

AU - Sanchez, Connie

PY - 2016/9

Y1 - 2016/9

N2 - 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 vortioxetine9s cognitive effects, which are observed under chronic dosing conditions in patients with MDD.

AB - 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 vortioxetine9s cognitive effects, which are observed under chronic dosing conditions in patients with MDD.

UR - http://www.scopus.com/inward/record.url?scp=84983805401&partnerID=8YFLogxK

U2 - 10.1124/jpet.116.233924

DO - 10.1124/jpet.116.233924

M3 - Article

C2 - 27402279

AN - SCOPUS:84983805401

VL - 358

SP - 472

EP - 482

JO - Journal of Pharmacology and Experimental Therapeutics

JF - Journal of Pharmacology and Experimental Therapeutics

SN - 0022-3565

IS - 3

ER -