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Effect of cholinergic neurotransmission modulation on visual spatial paired associate learning in healthy human adults

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Abstract

Rationale

Use of cross-species neuropsychological paradigms such as visual–spatial paired associate learning (PAL) may allow for a better understanding of underlying neural substrates of memory. Such paradigms, which are often used to guide models of memory in animals, can then be carried forward into humans to provide a basis for evaluation of pharmacologic compounds designed to ameliorate learning and memory impairments in neurologic and psychiatric morbidities.

Objectives

This double-blind, randomized, crossover trial investigated effects of donepezil, an acetylcholinesterase (AChE) inhibitor, in attenuating scopolamine-induced cognitive impairment using a novel, “process-based” computerized measure of visual–spatial PAL.

Results

In healthy male volunteers, scopolamine (0.6 mg) induced a time-dependent reduction in visual–spatial PAL, with the greatest impairment (Cohen's d = 1.37) observed 2 h after dosing. Cotreatment with donepezil (10 mg) significantly ameliorated scopolamine-induced impairment at the 2-h time point (Cohen's d = 0.66). Process-based analyses revealed a significant impairment in both memory (Cohen's d = 1.37 to 0.50) and executive (Cohen's d = 1 .21 to 0.62) aspects of visual–spatial PAL performance following acute scopolamine challenge, and these reductions were ameliorated by donepezil.

Conclusions

Acute scopolamine challenge can produce large and robust deficits in visual–spatial PAL, which reflect impairments in both memory and executive processes. Coadministration of a single dose of donepezil can ameliorate these deficits. These results provide support for the use of a visual–spatial PAL test as a pharmacodynamic cognitive marker of central nervous system (CNS)-mediating compounds in humans.

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Conflict of interest

Drs. Harel and Maruff are full time employees of CogState, a cognitive test company that provided the test used in this study. Drs. Pietrzak and Snyder are consultants to this company.

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Authors and Affiliations

  1. CogState, Ltd, 195 Church St., 8th Floor, New Haven, CT, 06510, USA

    Brian T. Harel

  2. Yale University School of Medicine, New Haven, CT, 06510, USA

    Robert H. Pietrzak

  3. Lifespan Hospital System, Providence, RI, USA

    Peter J. Snyder

  4. Department of Neurology, Alpert Medical School of Brown University, Providence, RI, USA

    Peter J. Snyder

  5. CogState Ltd, Level 2, 255 Bourke St, Melbourne, 3000, Australia

    Paul Maruff

  6. Centre for Neuroscience, University of Melbourne, Victoria, Australia

    Paul Maruff

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  1. Brian T. Harel
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  2. Robert H. Pietrzak
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  4. Paul Maruff
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Correspondence to Brian T. Harel.

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Harel, B.T., Pietrzak, R.H., Snyder, P.J. et al. Effect of cholinergic neurotransmission modulation on visual spatial paired associate learning in healthy human adults. Psychopharmacology 228, 673–683 (2013). https://doi.org/10.1007/s00213-013-3072-2

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  • DOI: https://doi.org/10.1007/s00213-013-3072-2

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