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Scopolamine disrupts place navigation in rats and humans: a translational validation of the Hidden Goal Task in the Morris water maze and a real maze for humans

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Abstract

Rationale

Development of new drugs for treatment of Alzheimer’s disease (AD) requires valid paradigms for testing their efficacy and sensitive tests validated in translational research.

Objectives

We present validation of a place-navigation task, a Hidden Goal Task (HGT) based on the Morris water maze (MWM), in comparable animal and human protocols.

Methods

We used scopolamine to model cognitive dysfunction similar to that seen in AD and donepezil, a symptomatic medication for AD, to assess its potential reversible effect on this scopolamine-induced cognitive dysfunction. We tested the effects of scopolamine and the combination of scopolamine and donepezil on place navigation and compared their effects in human and rat versions of the HGT. Place navigation testing consisted of 4 sessions of HGT performed at baseline, 2, 4, and 8 h after dosing in humans or 1, 2.5, and 5 h in rats.

Results

Scopolamine worsened performance in both animals and humans. In the animal experiment, co-administration of donepezil alleviated the negative effect of scopolamine. In the human experiment, subjects co-administered with scopolamine and donepezil performed similarly to subjects on placebo and scopolamine, indicating a partial ameliorative effect of donepezil.

Conclusions

In the task based on the MWM, scopolamine impaired place navigation, while co-administration of donepezil alleviated this effect in comparable animal and human protocols. Using scopolamine and donepezil to challenge place navigation testing can be studied concurrently in animals and humans and may be a valid and reliable model for translational research, as well as for preclinical and clinical phases of drug trials.

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Abbreviations

AD:

Alzheimer’s disease

MWM:

Morris water maze

HGT:

Hidden Goal Task

GLM:

General linear model

RM:

Repeated measures

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Acknowledgments

Scientists from the Institute of Physiology CAS were supported by GAČR Center of Excellence P304/12/G069. Tereza Nekovarova and Ales Stuchlik were supported also by MSMT project LH14053 KONTAKT ll.

Scientists from Motol University Hospital were supported by the Grant Agency of Charles University in Prague, grant nos. 624012, 546113, 1108214, and 135215. Ministry of Health, Czech Republic—conceptual development of research organization, University Hospital Motol, Prague, Czech Republic 00064203 provided additional support of scientists from Motol University Hospital.

Scientists from the National Institute of Mental Health were also supported by the project “National Institute of Mental Health (NIMH-CZ),” grant number ED2.1.00/03.0078, and the European Regional Development Fund through the project “Sustainability for the National Institute of Mental Health,” under grant number LO1611, with additional financial support from the Ministry of Education, Youth and Sports of the Czech Republic under the NPU I program.

Other support included the European Regional Development Fund—Project FNUSA-ICRC (No. CZ.1.05/1.1.00/02.0123) and project ICRC-ERA-HumanBridge (No. 316345), and project no. LQ1605 from the National Program of Sustainability II (MEYS CR).

Institutional support was provided by Laboratory Research Grant No. 2/2012 (699002), Excellence Grant and research project RVO: 67985823. We would like to thank Mr. F. Safar, Dr. D. Pechackova, Dr. O. Lerch, Ms. B. Zemlickova, Mr. R. Martinko, Mr. A. Chadima, and Dr. E. Hyncicova for help with data collection and Dr. M. Petrzelova for drug preparation.

All authors have read the journal’s authorship agreement and policy on disclosure of potential conflicts of interest. Dr. Harrison has received consultancy from Abbvie, Astra-Zeneca, Avraham, Boehringer Ingelheim, Bracket (Clinical), CRF Health, EnVivo Pharma, ePharmaSolutions, Eisai, Eli Lilly, Heptares, Janssen AI, Kyowa Hakko Kirin, Lundbeck, MedAvante, Merck, MyCognition, Novartis, Nutricia, Orion Pharma, Pharmanet/i3, Pfizer, Prana Biotech, ProStrakan, Reviva, Servier, Shire, TCG and TransTech Pharma & Velacor. Dr. Windisch is owner and CEO at NeuroScios GmbH. Dr. Hort has consulted for Pfizer, Janssen, Merck, Axon, Sotio, Novartis, Elan, Zentiva and Ipsen. Other authors declare no conflict of interest.

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Authors and Affiliations

  1. Department of Neurology, Second Faculty of Medicine, Charles University and Motol University Hospital, V Uvalu 84, 150 06, Prague, Czech Republic

    Jan Laczó, Hana Markova, Ivana Gazova, Martina Parizkova, Jiri Cerman & Jakub Hort

  2. International Clinical Research Center, St. Anne’s University Hospital Brno, Pekarska 53, 656 91, Brno, Czech Republic

    Jan Laczó, Hana Markova, Ivana Gazova, Martina Parizkova, Jiri Cerman & Jakub Hort

  3. Department of Neurophysiology of Memory, Institute of Physiology, Academy of Sciences of the Czech Republic, Videnska 1083, 142 20, Prague, Czech Republic

    Veronika Lobellova, Tereza Nekovarova, Karel Vales, Kamil Vlcek, Jan Svoboda & Ales Stuchlik

  4. National Institute of Mental Health, Topolova 748, 250 67, Klecany, Czech Republic

    Tereza Nekovarova & Karel Vales

  5. Department of Pharmaceutical Technology, Faculty of Pharmacy, Charles University in Prague, Akademika Heyrovskeho 1203, 500 05, Hradec Králové, Czech Republic

    Sylva Klovrzova

  6. Metis Cognition Ltd., Park House, Kilmington Common, Warminster, Wiltshire, BA12 6QY, UK

    John Harrison

  7. Imperial College Faculty of Medicine, South Kensington Campus, London, SW7 2AZ, UK

    John Harrison

  8. NeuroScios GmbH, Willersdorferstrasse 6, A-8061, Radegund/Graz, Austria

    Manfred Windisch

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  1. Jan Laczó
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  2. Hana Markova
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  3. Veronika Lobellova
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  7. Tereza Nekovarova
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  9. Sylva Klovrzova
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  10. John Harrison
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  11. Manfred Windisch
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  12. Kamil Vlcek
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  14. Jakub Hort
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  15. Ales Stuchlik
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Corresponding authors

Correspondence to Jan Laczó or Ales Stuchlik.

Additional information

Jan Laczó, Hana Markova, and Veronika Lobellova contributed equally to this study.

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Laczó, J., Markova, H., Lobellova, V. et al. Scopolamine disrupts place navigation in rats and humans: a translational validation of the Hidden Goal Task in the Morris water maze and a real maze for humans. Psychopharmacology 234, 535–547 (2017). https://doi.org/10.1007/s00213-016-4488-2

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