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Dissociable effects of NR2A and NR2B NMDA receptor antagonism on cognitive flexibility but not pattern separation

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Abstract

Rationale

N-methyl-d-aspartate (NMDA) receptors play crucial roles in learning and memory, but the role of each NMDA receptor subtype in a specific cognitive process is unclear. Non-selective blockers of NMDA receptor are used to model the cognitive impairment in schizophrenia and Alzheimer’s disease. Counter-intuitively selective NR2A and 2B NMDA receptor antagonists are thought to have pro-cognitive properties. These seemingly contrasting findings might in part be the result of different compounds and behavioral measures used across studies.

Objective

We compared the effect of NVP-AAM077 (NR2A antagonist), CP 101-606 (NR2B antagonist), and MK-801 (non-selective antagonist) in a series of touch screen tasks that can be used to measure spatial cognition and cognitive flexibility.

Methods

NVP-AAM077, CP 101-606, and MK-801 were administered prior to testing, in adult male Lister-hooded rats trained in tasks of location discrimination, paired associate learning (PAL), and trial unique non-match to location (TUNL).

Results

Results showed that MK-801 impaired performance on all the tasks. In contrast, CP 101-606 only impaired reversal learning in location discrimination and had minimal effect on working memory in TUNL and caused a modest improvement in accuracy in PAL and acquisition of a spatial discrimination. NVP-AAM077 had little effect on performance across tasks, although these data allude to a potential enhancement of acquisition of a spatial location and impairments in spatial reversal learning in a separation-dependent manner.

Conclusions

These data demonstrated that non-selective NMDA antagonism will disrupt numerous aspects of cognitive function. However, selective antagonism is capable of impairing or enhancing cognitive function in a task-dependent fashion.

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Acknowledgments

NEWMEDS—The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under Grant agreement no.115008 of which resources are composed of EFPIA in-kind contribution and financial contribution from the European Union’s Seventh Framework Programme (FP7/2007–2013).

Conflicts of interests

Authors declare no conflicts of interests financial or otherwise, however all authors are current or former employees of Janssen Research & Development.

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Authors and Affiliations

  1. Janssen Research & Development, Turnhoutseweg 30, 2340, Beerse, Belgium

    Gaurav Kumar, Joseph Olley, Thomas Steckler & John Talpos

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  1. Gaurav Kumar
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  2. Joseph Olley
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Correspondence to Gaurav Kumar.

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Kumar, G., Olley, J., Steckler, T. et al. Dissociable effects of NR2A and NR2B NMDA receptor antagonism on cognitive flexibility but not pattern separation. Psychopharmacology 232, 3991–4003 (2015). https://doi.org/10.1007/s00213-015-4008-9

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  • DOI: https://doi.org/10.1007/s00213-015-4008-9

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