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.

Vortioxetine Differentially Modulates MK-801-Induced Changes in Visual Signal Detection Task Performance and Locomotor Activity

“…However, a recent paper from this laboratory investigated the effects of vortioxetine in another model of attention, visual signal detection task (VSDT) impairments induced by the muscarinic acetylcholinergic receptor antagonist scopolamine. This study demonstrated that, although acute vortioxetine treatment was able to reverse scopolamine-induced deficits in memory performance at clinically relevant doses, it was unable to alter scopolamine-induced impairments in the VSDT ( Pehrson et al, 2016a ). Importantly, acute administration of the acetylcholinesterase inhibitor donepezil was able to significantly attenuate scopolamine-induced VSDT impairments in this study ( Pehrson et al, 2016a ).…”

“…This study demonstrated that, although acute vortioxetine treatment was able to reverse scopolamine-induced deficits in memory performance at clinically relevant doses, it was unable to alter scopolamine-induced impairments in the VSDT ( Pehrson et al, 2016a ). Importantly, acute administration of the acetylcholinesterase inhibitor donepezil was able to significantly attenuate scopolamine-induced VSDT impairments in this study ( Pehrson et al, 2016a ). As an assessment of vortioxetine’s general effects on attention function, this study could be questioned based on the use of scopolamine as a platform for inducing attention impairment.…”

“…As an assessment of vortioxetine’s general effects on attention function, this study could be questioned based on the use of scopolamine as a platform for inducing attention impairment. Although previous research has consistently demonstrated that acute vortioxetine treatment can modulate cholinergic neurotransmission by increasing acetylcholine efflux ( Mork et al, 2013 ; Pehrson et al, 2016a ), this increase is also consistently small and short-lived. Thus, vortioxetine’s lack of an effect on scopolamine-induced VSDT impairments may be related to its limited influence on cholinergic neurotransmission.…”

“…The rats were trained and tested according to procedures consistent with previously published experiments ( Hillhouse and Prus, 2013 ; Hillhouse et al, 2015 ; Pehrson et al, 2016a ). Each trial started with both the house light and a variable-intensity signal light on.…”

“…Drug doses and pretreatment times were based on published literature. In the case of MK-801, the doses and injection timing have previously demonstrated robust behavioral effects in the VSDT without producing pronounced motor suppression ( Rezvani et al, 2008 ; Levin et al, 2011 ; Hillhouse and Porter, 2014 ; Leiser et al, 2014 ; Hillhouse et al, 2015 ; Pehrson et al, 2016a ). Preliminary experiments demonstrated that lower doses of MK-801failed to produce reliable behavioral impairments.…”