Olanzapine Reverses MK-801-Induced Cognitive Deficits and Region-Specific Alterations of NMDA Receptor Subunits.

Xiao Liu,Tianmei Si,Yaxin Sun,Chunmei Guo,Jitao Li,Keqing Li,Yun-Ai Su,Hongli Wang,Han Wang

doi:10.3389/fnbeh.2017.00260

Abstract

Cognitive dysfunction constitutes an essential component in schizophrenia for its early presence in the pathophysiology of the disease and close relatedness to life quality of patients. To develop effective treatment of cognitive deficits, it is important to understand their neurobiological causes and to identify potential therapeutic targets. In this study, adopting repeated MK-801 treatment as an animal model of schizophrenia, we investigated whether antipsychotic drugs, olanzapine and haloperidol, can reverse MK-801-induced cognitive deficits and how the reversal processes recruited proteins involved in glutamate neurotransmission in rat medial prefrontal cortex (mPFC) and hippocampus. We found that low-dose chronic MK-801 treatment impaired object-in-context recognition memory and reversal learning in the Morris water maze, leaving reference memory relatively unaffected, and that these cognitive deficits can be partially reversed by olanzapine, not haloperidol, treatment. At the molecular level, chronic MK-801 treatment resulted in the reduction of multiple N-methyl-D-aspartate (NMDA) receptor subunits in rat mPFC and olanzapine, not haloperidol, treatment restored the levels of GluN1 and phosphorylated GluN2B in this region. Taken together, MK-801-induced cognitive deficits may be associated with region-specific changes in NMDA receptor subunits and the reversal of specific NMDA receptor subunits may underlie the cognition-enhancing effects of olanzapine.

Highlights

Schizophrenia is a severe, chronic psychiatric disorder that represents a major burden for patients, their families and the whole society (Howes and Murray, 2014)
One-way analysis of variance (ANOVA) on total distance traveled in the locomotor activity test (Figure 2A) did not reveal significant group differences (F(3,40) = 2.026, P = 0.126), animals in the MK-801 group (MK) and haloperidol + MK-801 group (HPD) groups exhibited noticeable reductions in locomotor activity compared to vehicle animals
MK-801-Induced Deficits in Recognition Memory Were Partially Rescued by Olanzapine, Not Haloperidol

Summary

Introduction

Schizophrenia is a severe, chronic psychiatric disorder that represents a major burden for patients, their families and the whole society (Howes and Murray, 2014). Chronic treatment with the N-methyl-D-aspartate (NMDA) receptor antagonists, such as phencyclidine (PCP) and MK-801, produces wide-range schizophrenia-like behavioral, structural and neurobiological alterations and is a widely used animal model for schizophrenia (Beraki et al, 2008; Elsworth et al, 2011; Song et al, 2016) Adopting this model, several studies demonstrated the superiority of SGAs over FGAs in reversing cognitive deficits in spatial learning, reversal learning and recognition memory induced by NMDA receptor blockade (Abdul-Monim et al, 2006; Amitai et al, 2007; Grayson et al, 2007; Beraki et al, 2008; Goetghebeur and Dias, 2009; Song et al, 2016). The effects of these antipsychotic drugs on the expression of NMDA receptor subunits as well as proteins associated with glutamate release and clearance in vivo remain largely unknown

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Conclusion