Abstract
The role of NMDA receptors in learning, memory and hippocampal function has long been recognized. Post-mortem studies have indicated that the expression or subunit composition of the NMDA glutamate receptor subtype might be related to the impaired cognitive functions found in schizophrenia patients. NMDA receptor antagonists have been used to develop animal models of this disorder. There is accumulating evidence showing that not only the acute but also the chronic application of NMDA receptor antagonists may induce schizophrenia-like alterations in behavior and brain functions. However, limited evidence is available regarding the consequences of NMDA receptor blockage during periods of adolescence and early adulthood. This study tested the hypothesis that a 2-week treatment of male Long-Evans and Wistar rats with dizocilpine (MK-801; 0.5 mg/kg daily) starting at postnatal days (PD) 30 and 60 would cause a long-term cognitive deficit and changes in the levels of NMDA receptor subunits. The working memory version of the Morris water maze (MWM) and active place avoidance with reversal on a rotating arena (Carousel) requiring cognitive coordination and flexibility probed cognitive functions and an elevated-plus maze (EPM) was used to measure anxiety-like behavior. The western blot method was used to determine changes in NMDA receptor subunit levels in the hippocampus. Our results showed no significant changes in behaviors in Wistar rats. Slightly elevated anxiety-like behavior was observed in the EPM in Long-Evans rats with the onset of treatment on PD 30. Furthermore, Long-Evans rats treated from PD 60 displayed impaired working memory in the MWM. There were; however, no significant changes in the levels of NMDA receptor subunits because of MK-801 administration. These findings suggest that a 2-week treatment starting on PD 60 in Long-Evans rats leads to long-term changes in working memory, but this deficit is not paralleled by changes in NMDA receptor subunits. These results support the face validity, but not construct validity of this model. We suggest that chronic treatment of adolescent and adult rats does not constitute a plausible animal model of schizophrenia.
Highlights
Schizophrenia is a devastating neuropsychiatric disease (Owen et al, 2016), affecting all populations worldwide with a lifetime prevalence of approximately 1%
Repeated dizocilpine maleate (MK-801) Led to Mild Long-term Anxiety-Like Behavior in Adolescent Long-Evans Rats Wistar rats Data obtained in the elevated-plus maze (EPM) suggests that MK-801 exerted no effects on anxiety-like behavior in Wistar rats
Long-Evans rats When analyzing behavior of Long-Evans rats, we found significant effect of MK-801 in the time spent in closed arms [F(1,36) = 5.737, P = 0.0219] and significant age vs. treatment interaction in time spent in the center [F(1,36) = 8.259, P = 0.0068]
Summary
Schizophrenia is a devastating neuropsychiatric disease (Owen et al, 2016), affecting all populations worldwide with a lifetime prevalence of approximately 1%. Marked disruptions of behavioral functions similar to those found in schizophrenia can be induced in animal models using acute application of MK-801, a prototypical experimental high-affinity non-competitive antagonist of NMDA receptors. These include social deficits (low doses; Rung et al, 2005), cognitive deficits (low-to-moderate doses; van der Staay et al, 2011; Lobellova et al, 2013, Kubík et al, 2014; Svoboda et al, 2015) and toxic and experimental psychoses (higher doses, Vales et al, 2006; Lobellová et al, 2015). Relatively fewer studies have focused on the chronic effects of NMDA receptor antagonism in subsequent ontogenetic periods such as late adolescence or early adulthood, despite the fact that schizophrenia in human patients manifests itself most commonly in this age range (but see Li et al, 2011)
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