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.

Department of Neurology 2nd Faculty of Medicine Charles University and Motol University Hospital 5 Uvalu 84 150 06 Prague Czech Republic International Clinical Research Center St Anne's University Hospital Brno Pekarska 53 656 91 Brno Czech Republic

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

Department of Neurophysiology of Memory Institute of Physiology Academy of Sciences of the Czech Republic Videnska 1083 142 20 Prague Czech Republic National Institute of Mental Health Topolova 748 250 67 Klecany Czech Republic

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

Metis Cognition Ltd Park House Kilmington Common Warminster Wiltshire BA12 6QY UK Imperial College Faculty of Medicine South Kensington Campus London SW7 2AZ UK

NeuroScios GmbH Willersdorferstrasse 6 A 8061 Radegund Graz Austria

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$a Laczó, Jan $u Department of Neurology, Second Faculty of Medicine, Charles University and Motol University Hospital, V Uvalu 84, 150 06, Prague, Czech Republic. JanLaczo@seznam.cz. International Clinical Research Center, St. Anne's University Hospital Brno, Pekarska 53, 656 91, Brno, Czech Republic. JanLaczo@seznam.cz.

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$a 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 / $c J. Laczó, H. Markova, V. Lobellova, I. Gazova, M. Parizkova, J. Cerman, T. Nekovarova, K. Vales, S. Klovrzova, J. Harrison, M. Windisch, K. Vlcek, J. Svoboda, J. Hort, A. Stuchlik,

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$a 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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$a Markova, Hana $u Department of Neurology, Second Faculty of Medicine, Charles University and Motol University Hospital, V Uvalu 84, 150 06, Prague, Czech Republic. International Clinical Research Center, St. Anne's University Hospital Brno, Pekarska 53, 656 91, Brno, Czech Republic.

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$a Lobellova, Veronika $u Department of Neurophysiology of Memory, Institute of Physiology, Academy of Sciences of the Czech Republic, Videnska 1083, 142 20, Prague, Czech Republic.

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$a Gazova, Ivana $u Department of Neurology, Second Faculty of Medicine, Charles University and Motol University Hospital, V Uvalu 84, 150 06, Prague, Czech Republic. International Clinical Research Center, St. Anne's University Hospital Brno, Pekarska 53, 656 91, Brno, Czech Republic.

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$a Parizkova, Martina $u Department of Neurology, Second Faculty of Medicine, Charles University and Motol University Hospital, V Uvalu 84, 150 06, Prague, Czech Republic. International Clinical Research Center, St. Anne's University Hospital Brno, Pekarska 53, 656 91, Brno, Czech Republic.

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$a Cerman, Jiri $u Department of Neurology, Second Faculty of Medicine, Charles University and Motol University Hospital, V Uvalu 84, 150 06, Prague, Czech Republic. International Clinical Research Center, St. Anne's University Hospital Brno, Pekarska 53, 656 91, Brno, Czech Republic.

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$a Nekovarova, Tereza $u Department of Neurophysiology of Memory, Institute of Physiology, Academy of Sciences of the Czech Republic, Videnska 1083, 142 20, Prague, Czech Republic. National Institute of Mental Health, Topolova 748, 250 67, Klecany, Czech Republic.

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$a Vales, Karel $u Department of Neurophysiology of Memory, Institute of Physiology, Academy of Sciences of the Czech Republic, Videnska 1083, 142 20, Prague, Czech Republic. National Institute of Mental Health, Topolova 748, 250 67, Klecany, Czech Republic.

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$a Klovrzova, Sylva $u Department of Pharmaceutical Technology, Faculty of Pharmacy, Charles University in Prague, Akademika Heyrovskeho 1203, 500 05, Hradec Králové, Czech Republic.

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$a Harrison, John $u Metis Cognition Ltd., Park House, Kilmington Common, Warminster, Wiltshire, BA12 6QY, UK. Imperial College Faculty of Medicine, South Kensington Campus, London, SW7 2AZ, UK.

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$a Windisch, Manfred $u NeuroScios GmbH, Willersdorferstrasse 6, A-8061, Radegund/Graz, Austria.

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$a Vlcek, Kamil $u Department of Neurophysiology of Memory, Institute of Physiology, Academy of Sciences of the Czech Republic, Videnska 1083, 142 20, Prague, Czech Republic.

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$a Svoboda, Jan $u Department of Neurophysiology of Memory, Institute of Physiology, Academy of Sciences of the Czech Republic, Videnska 1083, 142 20, Prague, Czech Republic.

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$a Hort, Jakub $u Department of Neurology, Second Faculty of Medicine, Charles University and Motol University Hospital, V Uvalu 84, 150 06, Prague, Czech Republic. International Clinical Research Center, St. Anne's University Hospital Brno, Pekarska 53, 656 91, Brno, Czech Republic.

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$a Stuchlik, Ales $u Department of Neurophysiology of Memory, Institute of Physiology, Academy of Sciences of the Czech Republic, Videnska 1083, 142 20, Prague, Czech Republic. ales.stuchlik@fgu.cas.cz.

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