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Effects of the T-type calcium channel antagonist Z944 on paired associates learning and locomotor activity in rats treated with the NMDA receptor antagonist MK-801

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Abstract

Rationale

Currently available antipsychotics are unsatisfactory given their side effects and limited efficacy for the cognitive symptoms of schizophrenia. Many currently available drugs, such as haloperidol, are T-type calcium channel antagonists in addition to their well-established antagonism of dopamine D2 receptors. Thus, preclinical research into the effects of T-type calcium channel antagonists/blockers in behavioral assays related to schizophrenia may inform novel therapeutic strategies.

Objectives

We explored the effects of a recently developed highly selective T-type calcium channel antagonist, Z944 (2.5, 5.0, 10.0 mg/kg), on the MK-801 (0.15 mg/kg) model of acute psychosis.

Methods

To examine the effects of Z944 on behaviors relevant to schizophrenia, we tested touchscreen-based paired associates learning given its relevance to the cognitive symptoms of the disorder and locomotor activity given its relevance to the positive symptoms.

Results

Acute treatment with Z944 failed to reverse the visuospatial associative memory impairments caused by MK-801 in paired associates learning. The highest dose of drug (10.0 mg/kg) given alone produced subtle impairments on paired associates learning. In contrast, Z944 (5.0 mg/kg) blocked the expected increase in locomotion following MK-801 treatment in a locomotor assay.

Conclusions

These experiments provide support that Z944 may reduce behaviors relevant to positive symptoms of schizophrenia, although additional study of its effects on cognition is required. These findings and other research suggest T-type calcium channel antagonists may be an alternative to currently available antipsychotics with less serious side effects.

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Acknowledgements

This research was supported by an operating grant from the Canadian Institutes of Health Research (CIHR) to JGH (#125984). Work in the laboratory of TPS is supported by an operating grant from CIHR (#10677), the Canada Research Chair in Biotechnology and Genomics-Neurobiology and the Koerner Foundation. Matching funds for these experiments were provided by the Saskatchewan Health Research Foundation and the University of Saskatchewan. AJR received salary support from the Natural Sciences and Engineering Research Council of Canada Collaborative Research and Training Program (NSERC CREATE). WNM is supported by funding from the Saskatchewan Health Research Foundation. MCL received an award from the Natural Sciences and Engineering Research Council of Canada Undergraduate Student Research Award Program. NBT received salary support from the College of Medicine, University of Saskatchewan.

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Authors and Affiliations

  1. Department of Physiology, University of Saskatchewan, GD30.7, Health Sciences Building, 107 Wiggins Road, Saskatoon, SK, S7N 5E5, Canada

    Andrew J. Roebuck, Wendie N. Marks, Max C. Liu, Nimra B. Tahir, Nadine K. Zabder & John G. Howland

  2. Michael Smith Laboratories and Djavad Mowafaghian Centre for Brain Health, University of British Colombia, Vancouver, BC, Canada

    Terrance P. Snutch

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  1. Andrew J. Roebuck
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  2. Wendie N. Marks
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  3. Max C. Liu
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  4. Nimra B. Tahir
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  5. Nadine K. Zabder
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  6. Terrance P. Snutch
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  7. John G. Howland
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Correspondence to John G. Howland.

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Roebuck, A.J., Marks, W.N., Liu, M.C. et al. Effects of the T-type calcium channel antagonist Z944 on paired associates learning and locomotor activity in rats treated with the NMDA receptor antagonist MK-801. Psychopharmacology 235, 3339–3350 (2018). https://doi.org/10.1007/s00213-018-5040-3

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  • DOI: https://doi.org/10.1007/s00213-018-5040-3

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