Differential Effects of Olanzapine and Haloperidol on MK-801-induced Memory Impairment in Mice

Abstract

ObjectiveWe investigated the differential effects of the antipsychotic drugs olanzapine and haloperidol on MK-801-induced memory impairment and neurogenesis in mice.MethodsMK-801 (0.1 mg/kg) was administered 20 minutes prior to behavioral testing over 9 days. Beginning on the sixth day of MK-801 treatment, either olanzapine (0.05 mg/kg) or haloperidol (0.05 mg/kg) was administered 40 minutes prior to MK-801 for the final 4 days. Spatial memory performance was measured using a Morris water maze (MWM) test for 9 days (four trials/day). Immunohistochemistry with bromodeoxyuridine (BrdU) was used to identify newborn cells labeled in tissue sections from the dentate gyrus of the hippocampus.ResultsMK-801 administration over 9 days significantly impaired memory performance in the MWM test compared to untreated controls (p<0.05) and these deficits were blocked by treatment with olanzapine (p<0.05) but not haloperidol. The administration of MK-801 also resulted in a decrease in the number of BrdU-labeled cells in the dentate gyrus (28.6%; p<0.01), which was prevented by treatment with olanzapine (p<0.05) but not haloperidol.ConclusionThese results suggest that olanzapine has a protective effect against cognitive impairments induced by MK-801 in mice via the stimulating effects of neurogenesis.

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

“…The results that MK-801-induced cognitive deficits in recognition memory and reversal learning were rescued by olanzapine, but not haloperidol, are in agreement with previous findings that cognitive impairments induced by repeated NMDA receptor blockade can be reversed by SGAs, but not FGAs (Abdul-Monim et al, 2006 ; Grayson et al, 2007 ; Song et al, 2016 ). Our finding of preserved spatial learning performance in MK-801-treated animals does not completely disagree with the study of Song et al ( 2016 ), which reported deficits in spatial learning, because both studies showed the longer, although not significant, escape latency for the MK-801-treated animals compared to animals in the Vehicle group in the first five training days. An inconsistency between the two studies is that as training days extended, the MK-801 effects diminished in our study, but became more pronounced in Song et al’s ( 2016 ) study.…”

“…Our finding of preserved spatial learning performance in MK-801-treated animals does not completely disagree with the study of Song et al ( 2016 ), which reported deficits in spatial learning, because both studies showed the longer, although not significant, escape latency for the MK-801-treated animals compared to animals in the Vehicle group in the first five training days. An inconsistency between the two studies is that as training days extended, the MK-801 effects diminished in our study, but became more pronounced in Song et al’s ( 2016 ) study. This may be attributed to the time interval between MK-801 treatment and behavioral testing: MK-801 was administered about 20 h before behavioral testing in our study, but 20 min before behavioral testing in Song et al’s ( 2016 ) study, in which acute effects of MK-801 treatment cannot be excluded.…”

“…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 thus 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 ).…”

“…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 thus 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 ). These behavioral effects may be associated with differential neurobiological mechanisms of the two types of drugs in various aspects (Lieberman et al, 2008 ), such as the ability to block excessive cortical 5-HT efflux (López-Gil et al, 2007 ) and to prevent decreased neurogenesis following repeated NMDA receptor blockade (Maeda et al, 2007 ; 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 ). These behavioral effects may be associated with differential neurobiological mechanisms of the two types of drugs in various aspects (Lieberman et al, 2008 ), such as the ability to block excessive cortical 5-HT efflux (López-Gil et al, 2007 ) and to prevent decreased neurogenesis following repeated NMDA receptor blockade (Maeda et al, 2007 ; Song et al, 2016 ). With regard to glutamate neurotransmission, previous studies found that SGAs such as olanzapine or clozapine, but not haloperidol, could prevent subchronic PCP-induced electrophysiological alterations of NMDA receptors in vitro (Ninan et al, 2003 ).…”