Is the Acute NMDA Receptor Hypofunction a Valid Model of Schizophrenia?

Abstract

Several genetic, neurodevelopmental, and pharmacological animal models of schizophrenia have been established. This short review examines the validity of one of the most used pharmacological model of the illness, ie, the acute administration of N-methyl-D-aspartate (NMDA) receptor antagonists in rodents. In some cases, data on chronic or prenatal NMDA receptor antagonist exposure have been introduced for comparison. The face validity of acute NMDA receptor blockade is granted inasmuch as hyperlocomotion and stereotypies induced by phencyclidine, ketamine, and MK-801 are regarded as a surrogate for the positive symptoms of schizophrenia. In addition, the loss of parvalbumin-containing cells (which is one of the most compelling finding in postmortem schizophrenia brain) following NMDA receptor blockade adds construct validity to this model. However, the lack of changes in glutamic acid decarboxylase (GAD(67)) is at variance with human studies. It is possible that changes in GAD(67) are more reflective of the neurodevelopmental condition of schizophrenia. Finally, the model also has predictive validity, in that its behavioral and transmitter activation in rodents are responsive to antipsychotic treatment. Overall, although not devoid of drawbacks, the acute administration of NMDA receptor antagonists can be considered as a good model of schizophrenia bearing a satisfactory degree of validity.

MK-801-induced impairments on the trial-unique, delayed nonmatching-to-location task in rats: effects of acute sodium nitroprusside

“…Recently, SNP has demonstrated promise as an adjunct treatment to reduce these symptoms, specifically reducing working memory impairments (Maia-de-Oliveira et al 2015a). In the current experiments, we examined the effects of SNP in (Adell et al 2012;Coyle 2012). In rodents, acute MK-801 treatment demonstrates face validity as a model of schizophrenia as its administration produces behavioral changes similar to those observed in the disease (Nestler and Hyman 2010).…”

“…Unfortunately, no available drugs alleviate the cognitive symptoms of schizophrenia and the lack of a positive control prevents the thorough evaluation of an animal model's predictive validity (Markou et al 2009). Predictive validity of the acute MK-801 model of schizophrenia is inconsistent (Adell et al 2012). However, this may be a consequence of the task translatability in assessing novel treatments in the MK-801 model, rather than the model itself.…”

Effects of ketamine on psychomotor, sensory and cognitive functions relevant for driving ability

“…Further effects may include slurred speech, vomiting, confusion, drowsiness [30], reduced/increased motor activities with stereotypes and mannerisms [58]; lack of coordination; dystonia [59]; and motor paralysis/rigidity/ataxia [56]. Visual acuity may be affected with blurred vision and visual field narrowing having been reported [28,60].…”

40 Hz Auditory Steady-State Response Is a Pharmacodynamic Biomarker for Cortical NMDA Receptors

“…Taking advantage of this important validation, preclinical studies often employ a short-term disruption in NMDA neurotransmission to mimic a psychosis-like state (Adell et al, 2012;Frohlich and Van Horn, 2014;Gunduz-Bruce, 2009). Several groups have used this approach to understand the role of NMDA receptors in the 40 Hz ASSR (Sivarao et al, 2013;Sullivan et al, 2015;Vohs et al, 2012).…”