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

Abstract

Attention impairment is a common feature of Major Depressive Disorder (MDD), and MDD-associated cognitive dysfunction may play an important role in determining functional status among this patient population. Vortioxetine is a multimodal antidepressant that may improve some aspects of cognitive function in MDD patients, and may indirectly increase glutamate neurotransmission in brain regions classically associated with attention function. Previous non-clinical research suggests that vortioxetine has limited effects on attention. This laboratory previously found that vortioxetine did not improve attention function in animals impaired by acute scopolamine administration, using the visual signal detection task (VSDT). However, vortioxetine has limited effects on acetylcholinergic neurotransmission, and thus it is possible that attention impaired by other mechanisms would be attenuated by vortioxetine. This study sought to investigate whether acute vortioxetine administration can attenuate VSDT impairments and hyperlocomotion induced by the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist MK-801. We found that acute vortioxetine administration had no effect on VSDT performance on its own, but potentiated MK-801-induced VSDT impairments. Furthermore, vortioxetine had no effect on locomotor activity on its own, and did not alter MK-801-induced hyperlocomotion. We further investigated whether vortioxetine’s effect on MK-801 could be driven by a kinetic interaction, but found that plasma and brain exposure for vortioxetine and MK-801 were similar whether administered alone or in combination. Thus, it appears that vortioxetine selectively potentiates MK-801-induced impairments in attention without altering its effects on locomotion, and further that this interaction must be pharmacodynamic in nature. A theoretical mechanism for this interaction is discussed.

Quetiapine Attenuates Schizophrenia-Like Behaviors and Demyelination in a MK-801–Induced Mouse Model of Schizophrenia

“…To elucidate the etiology and pathogenesis of schizophrenia, NMDA receptor antagonists including MK-801 and phencyclidine have been used to induce pharmacological animal models of schizophrenia ( 33 ). Consistent with previous studies that presented schizophrenia-like behaviors in the MK-801 injected animals ( 12 , 13 , 34 ), MK-801 administrated mice demonstrated the increase of locomotor activity, spatial working memory impairment and sensorimotor gating deficit. Quetiapine, an atypical antipsychotic drug, has been widely used in the treatment of schizophrenia and has shown its efficacy in treating positive and negative symptoms, as well as cognitive impairment in schizophrenia patients ( 14 – 16 ).…”

Antidepressant-like effect of acute dose of Naringin involves suppression of NR1 and activation of protein kinase A/cyclic adenosine monophosphate response element-binding protein/brain-derived neurotrophic factor signaling in hippocampus

“…In this study, MK-801 did not affect locomotion although it may increase locomotor activity, which appeared to be dose-related. Many studies have shown that the increased locomotor activity induced by MK-801 needs to be produced at a higher dose, whereas the dose in our study was too low to cause changes in locomotion (Hillhouse et al, 2018;Ueno et al, 2019). The potential involvement of AMPA receptors in the rapid antidepressant effect, which has been shown relevant for ketamine as well as other fast-acting drugs (Aleksandrova et al, 2017), was not tested in rapid antidepressant-like effects of Nr.…”