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Effects of D- and L-govadine on the disruption of touchscreen object-location paired associates learning in rats by acute MK-801 treatment

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Abstract

Rationale

New pharmacological treatments for the cognitive deficits in schizophrenia are needed. Tetrahydroprotoberberines, such as govadine, are one class of compounds with dopaminergic activities that may be useful in treating some aspects of the cognitive symptoms of the disorder.

Objective

The objective of the present studies was to test the effects of the d- and l-enantiomers of govadine on the impairment in a paired-associate learning (PAL) task produced by acute MK-801 in rats. We also assessed effects of the typical antipsychotic haloperidol as a comparator compound.

Methods

MK-801 (0.05, 0.1, 0.15, and 0.2 mg/kg), d- and l-govadine (0.3, 1.0, and 3.0 mg/kg), and haloperidol (0.05, 0.1, and 0.25 mg/kg) were administered acutely to rats well trained on the PAL task in touchscreen-equipped operant conditioning chambers.

Results

Acute MK-801 impaired performance of PAL in a dose-dependent manner by reducing accuracy and increasing correction trials. l-Govadine (1.0 mg/kg), but not d-govadine, blocked the disruptive effects of MK-801 (0.15 mg/kg) on PAL. Haloperidol failed to affect the MK-801-induced disruption of PAL. Higher doses of l-govadine and haloperidol dramatically impaired performance of the task which confounded interpretation of cognitive outcomes.

Conclusion

l-Govadine appears unique in its ability to improve performance of the MK-801-induced impairment in the PAL task. This behavioral effect may relate the ability of l-govadine to antagonize dopamine D2 receptors while also promoting dopamine efflux. Future research should further characterize the role of the dopamine system in the rodent PAL task to elucidate the mechanisms of its pro-cognitive effects.

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Acknowledgments

This work was supported by an Operating Grant from the Canadian Institutes for Health Research (CIHR) and a Discovery Grant from the Natural Sciences and Engineering Research Council of Canada to JGH. JGH is a CIHR New Investigator. BRL received salary support from the College of Medicine at the University of Saskatchewan.

Conflict of interest

BRL and JGH declare no conflict of interest. AGP who served until July 2013 on the board of directors of Allon Therapeutics declares a patent pending related to the use of d-govadine (PCT/CA2012/050526) and a pending patent (PCT/CA2004/001813) for an IV formulation of the interference peptide Tat-GluA23Y.

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Authors and Affiliations

  1. Department of Physiology, University of Saskatchewan, GB33, Health Sciences Building, 107 Wiggins Rd, Saskatoon, SK, Canada, S7N 5E5

    Brittney R. Lins & John G. Howland

  2. Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada, V6T 2A1

    Anthony G. Phillips

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  1. Brittney R. Lins
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Correspondence to John G. Howland.

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Lins, B.R., Phillips, A.G. & Howland, J.G. Effects of D- and L-govadine on the disruption of touchscreen object-location paired associates learning in rats by acute MK-801 treatment. Psychopharmacology 232, 4371–4382 (2015). https://doi.org/10.1007/s00213-015-4064-1

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