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MK-801 and amphetamine result in dissociable profiles of cognitive impairment in a rodent paired associates learning task with relevance for schizophrenia

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Abstract

Rationale

Paired associates learning (PAL) has been suggested to be predictive of functional outcomes in first episode psychosis and of conversion from mild cognitive impairment to Alzheimer’s disease. An automated touch screen-based rodent PAL (rPAL) task has been developed and is sensitive to manipulations of the dopaminergic and glutamatergic system. Accordingly, rPAL when used with pharmacological models of schizophrenia, like NMDA receptor blockade with MK-801 or dopaminergic stimulation with amphetamine, may have utility as a translational model of cognitive impairment in schizophrenia.

Objective

The purpose of this study was to determine if amphetamine- and MK-801-induced impairment represent distinct models of cognitive impairment by testing their sensitivity to common antipsychotics and determine the relative contributions of D1 versus D2 receptors on performance of PAL.

Method

Rats were trained in rPAL and were then treated with MK-801, amphetamine, risperidone, haloperidol, quinpirole, SK-82958, or SCH-23390 alone and in combination.

Results

While both amphetamine and MK-801 caused clear impairments in accuracy, MK-801 induced a profound “perseverative” type behavior that was more pronounced when compared to amphetamine. Moreover, amphetamine-induced impairments, but not the effects of MK-801, could be reversed by antipsychotics as well as the D1 receptor antagonist SCH-23390, suggesting a role for both the D1 and D2 receptor in the amphetamine impairment model.

Conclusions

These data suggest that amphetamine and MK-801 represent dissociable models of impairment in PAL, dependent on different underlying neurobiology. The ability to distinguish dopaminergic versus glutamatergic effects on performance in rPAL makes it a unique and useful tool in the modeling of cognitive impairments in schizophrenia.

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Notes

  1. The amphetamine impairment model has proven to be very consistent. We have employed this challenge in over 20 studies and have only once observed a lack of an amphetamine effect. In contrast, the MK-801 model has been more difficult to employ. 0.05 mg/kg will cause deficits in percent correct with no effects on secondary measures; however, this dose may lack the consistency needed for repeated drug screening. In contrast at 0.075 mg/kg MK-801 did consistently cause a decrease in percent correct, but this same dose will also cause substantial increases in response latencies. Since response latency is preferentially affected by MK-801 over collection latency, this may represent cognitive slowing as opposed to non-specific behavioral changes. However, we cannot rule out the possibility that some of the effects observed on percent correct after an MK-801 challenge are non-cognitive in nature.

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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).

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Authors and Affiliations

  1. Department of Neuroscience, Janssen Research and Development, 30 Turnhoutseweg, 2340, Beerse, Belgium

    John Talpos, Nancy Aerts, Jason Waddell & Thomas Steckler

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  1. John Talpos
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  2. Nancy Aerts
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  3. Jason Waddell
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  4. Thomas Steckler
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Correspondence to John Talpos.

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Talpos, J., Aerts, N., Waddell, J. et al. MK-801 and amphetamine result in dissociable profiles of cognitive impairment in a rodent paired associates learning task with relevance for schizophrenia. Psychopharmacology 232, 3911–3920 (2015). https://doi.org/10.1007/s00213-015-3934-x

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  • DOI: https://doi.org/10.1007/s00213-015-3934-x

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