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Abstract
Rationale
Performance on the Cambridge Neuropsychological Test Automated Battery touchscreen paired-associates learning (PAL) test is predictive of Alzheimer’s disease and impaired in schizophrenia and chronic drug users. An automated computer touchscreen PAL task for rats has been previously established. A pharmacologically validated PAL task for mice would be a highly valuable tool, which could be useful for a number of experimental aims including drug discovery.
Objectives
This study sought to investigate the effects of systemic administration of cholinergic agents on task performance in C57Bl/6 mice.
Methods
Scopolamine hydrobromide (0.02, 0.2, and 2.0 mg/kg), dicyclomine hydrochloride (M1 receptor antagonist; 2.0, 4.0, and 8.0 mg/kg), and donepezil hydrochloride (cholinesterase inhibitor; 0.03, 0.1, and 0.3 mg/kg) were administered post-acquisition in C57Bl/6 mice performing the PAL task.
Results
Scopolamine (0.2 and 2.0 mg/kg) and dicyclomine (at all administered doses) significantly impaired PAL performance. A significant facilitation in PAL was revealed in mice following donepezil administration (0.3 mg/kg).
Conclusions
The present study shows that mice can acquire the rodent PAL task and that the cholinergic system is important for PAL task performance. M1 receptors in particular are likely implicated in normal performance of PAL. The finding that mouse PAL can detect both impairments and improvements indicates that this task could prove to be a highly valuable tool for a number of experimental aims including drug discovery.
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Barense MD, Bussey TJ, Lee AC, Rogers TT, Davies RR, Saksida LM, Murray EA, Graham KS (2005) Functional specialization in the human medial temporal lobe. J Neurosci 25:10239–10246
Barker GR, Warburton EC (2008) NMDA receptor plasticity in the perirhinal and prefrontal cortices is crucial for the acquisition of long-term object-in-place associative memory. J Neurosci 28:2837–2844
Barnett JH, Sahakian BJ, Werners U, Hill KE, Brazil R, Gallagher O, Bullmore ET, Jones PB (2005) Visuospatial learning and executive function are independently impaired in first-episode psychosis. Psychol Med 35:1031–1041
Bartus RT, Dean RL 3rd, Beer B, Lippa AS (1982) The cholinergic hypothesis of geriatric memory dysfunction. Science 217:408–414
Baxter MG, Browning PG, Mitchell AS (2008) Perseverative interference with object-in-place scene learning in rhesus monkeys with bilateral ablation of ventrolateral prefrontal cortex. Learn Mem 15:126–132
Béracochéa D, Philippin JN, Meunier S, Morain P, Bernard K (2007) Improvement of episodic contextual memory by S 18986 in middle-aged mice: comparison with donepezil. Psychopharmacology (Berl) 193:63–73
Birks J, Harvey RJ (2006) Donepezil for dementia due to Alzheimer’s disease. Cochrane Database Syst Rev: CD001190
Blackwell AD, Sahakian BJ, Vesey R, Semple JM, Robbins TW, Hodges JR (2004) Detecting dementia: novel neuropsychological markers of preclinical Alzheimer’s disease. Dement Geriatr Cogn Disord 17:42–48
Braak H, Braak E (1997) Frequency of stages of Alzheimer-related lesions in different age categories. Neurobiol Aging 18:351–357
Brigman JL, Bussey TJ, Saksida LM, Rothblat LA (2005) Discrimination of multidimensional visual stimuli by mice: intra- and extradimensional shifts. Behav Neurosci 119:839–842
Brigman JL, Feyder M, Saksida LM, Bussey TJ, Mishina M, Holmes A (2008) Impaired discrimination learning in mice lacking the NMDA receptor NR2A subunit. Learn Mem 15:50–54
Buccafusco JJ, Terry AV (2004) Donepezil-induced improvement in delayed matching accuracy by young and old rhesus monkeys. J Mol Neurosci 24:85–91
Buccafusco JJ, Terry AV Jr, Webster SJ, Martin D, Hohnadel EJ, Bouchard KA, Warner SE (2008) The scopolamine-reversal paradigm in rats and monkeys: the importance of computer-assisted operant-conditioning memory tasks for screening drug candidates. Psychopharmacology (Berl) 199:481–494
Burns A, Rossor M, Hecker J, Gauthier S, Petit H, Moller HJ, Rogers SL, Friedhoff LT (1999) The effects of donepezil in Alzheimer’s disease—results from a multinational trial. Dement Geriatr Cogn Disord 10:237–244
Bussey TJ, Muir JL, Robbins TW (1994) A novel automated touchscreen procedure for assessing learning in the rat using computer graphic stimuli. Neurosci Res Commun 15:103–110
Bussey TJ, Muir JL, Everitt BJ, Robbins TW (1997) Triple dissociation of anterior cingulate, posterior cingulate, and medial frontal cortices on visual discrimination tasks using a touchscreen testing procedure for the rat. Behav Neurosci 111:920–936
Bussey TJ, Dias R, Amin E, Muir JL, Aggleton JP (2001a) Perirhinal cortex and place–object conditional learning in the rat. Behav Neurosci 115:776–785
Bussey TJ, Saksida LM, Rothblat LA (2001b) Discrimination of computer-graphic stimuli by mice: a method for the behavioral characterization of transgenic and gene-knockout models. Behav Neurosci 115:957–960
Bussey TJ, Padain TL, Skillings EA, Winters BD, Morton AJ, Saksida LM (2008) The touchscreen cognitive testing method for rodents: how to get the best out of your rat. Learn Mem 15:516–523
Caccamo A, Oddo S, Billings LM, Green KN, Martinez-Coria H, Fisher A, LaFerla FM (2006) M1 receptors play a central role in modulating AD-like pathology in transgenic mice. Neuron 49:671–682
Cachard-Chastel M, Devers S, Sicsic S, Langlois M, Lezoualc’h F, Gardier AM, Belzung C (2008) Prucalopride and donepezil act synergistically to reverse scopolamine-induced memory deficit in C57Bl/6j mice. Behav Brain Res 187:455–461
Chudasama Y, Bussey TJ, Muir JL (2001) Effects of selective thalamic and prelimbic cortex lesions on two types of visual discrimination and reversal learning. Eur J Neurosci 14:1009–1020
Clelland CD, Choi M, Romberg C, Clemenson GD Jr, Fragniere A, Tyers P, Jessberger S, Saksida LM, Barker RA, Gage FH, Bussey TJ (2009) A functional role for adult hippocampal neurogenesis in spatial pattern separation. Science 325:210–213
Csernansky JG, Martin M, Shah R, Bertchume A, Colvin J, Dong H (2005) Cholinesterase inhibitors ameliorate behavioral deficits induced by MK-801 in mice. Neuropsychopharmacology 30:2135–2143
Dodart JC, Mathis C, Ungerer A (1997) Scopolamine-induced deficits in a two-trial object recognition task in mice. NeuroReport 8:1173–1178
Dong H, Csernansky CA, Martin MV, Bertchume A, Vallera D, Csernansky JG (2005) Acetylcholinesterase inhibitors ameliorate behavioral deficits in the Tg2576 mouse model of Alzheimer’s disease. Psychopharmacology (Berl) 181:145–152
Doods HN, Mathy MJ, Davidesko D, van Charldorp KJ, de Jonge A, van Zwieten PA (1987) Selectivity of muscarinic antagonists in radioligand and in vivo experiments for the putative M1, M2 and M3 receptors. J Pharmacol Exp Ther 242:257–262
Ersche KD, Clark L, London M, Robbins TW, Sahakian BJ (2006) Profile of executive and memory function associated with amphetamine and opiate dependence. Neuropsychopharmacology 31:1036–1047
Gaffan D, Parker A (1996) Interaction of perirhinal cortex with the fornix-fimbria: memory for objects and “object-in-place” memory. J Neurosci 16:5864–5869
Giachetti A, Giraldo E, Ladinsky H, Montagna E (1986) Binding and functional profiles of the selective M1 muscarinic receptor antagonists trihexyphenidyl and dicyclomine. Br J Pharmacol 89:83–90
Greig NH, Sambamurti K, Yu QS, Brossi A, Bruinsma GB, Lahiri DK (2005) An overview of phenserine tartrate, a novel acetylcholinesterase inhibitor for the treatment of Alzheimer’s disease. Curr Alzheimer Res 2:281–290
Howell D (2002) Statistical methods for psychology, 5th edn. Duxbury, Duxbury
Humby T, Laird FM, Davies W, Wilkinson LS (1999) Visuospatial attentional functioning in mice: interactions between cholinergic manipulations and genotype. Eur J Neurosci 11:2813–2823
Izquierdo A, Wiedholz LM, Millstein RA, Yang RJ, Bussey TJ, Saksida LM, Holmes A (2006) Genetic and dopaminergic modulation of reversal learning in a touchscreen-based operant procedure for mice. Behav Brain Res 171:181–188
Kemp PM, Holmes C, Hoffmann S, Wilkinson S, Zivanovic M, Thom J, Bolt L, Fleming J, Wilkinson DG (2003) A randomised placebo controlled study to assess the effects of cholinergic treatment on muscarinic receptors in Alzheimer’s disease. J Neurol Neurosurg Psychiatry 74:1567–1570
Lleo A, Greenberg SM, Growdon JH (2006) Current pharmacotherapy for Alzheimer’s disease. Annu Rev Med 57:513–533
Marighetto A, Valerio S, Desmedt A, Philippin JN, Trocmé-Thibierge C, Morain P (2008) Comparative effects of the alpha7 nicotinic partial agonist S 24795, and the cholinesterase inhibitor, donepezil, against aging-related deficits in declarative and working memory in mice. Psychopharmacology (Berl) 197:499–508
McTighe SM, Mar AC, Romberg C, Bussey TJ, Saksida LM (2009) A new touchscreen test of pattern separation: effect of hippocampal lesions. Neuroreport 20:881–885
Morton AJ, Skillings E, Bussey TJ, Saksida LM (2006) Measuring cognitive deficits in disabled mice using an automated interactive touchscreen system. Nat Meth 3:767
Piper DW (1995) A comparative overview of the effects of antinuclear drugs. Drug Saf 12:120–138
Raedler TJ, Bymaster FP, Tandon R, Copolov D, Dean B (2007) Towards a muscarinic hypothesis of schizophrenia. Mol Psychiatry 12:232–246
Riedel G, Kang SH, Choi DY, Platt B (2009) Scopolamine-induced deficits in social memory in mice: reversal by donepezil. Behav Brain Res 204:217–225
Robbins TW, James M, Owen AM, Sahakian BJ, McInnes LPR (1994) Cambridge Neuropsychological Test Automated Battery (CANTAB): a factor analytic study of a large sample of normal elderly volunteers. Dementia 5:266–281
Robbins TW, Semple J, Kumar R, Truman MI, Shorter J, Ferraro A, Fox B, McKay G, Matthews K (1997) Effects of scopolamine on delayed-matching-to-sample and paired associates tests of visual memory and learning in human subjects: comparison with diazepam and implications for dementia. Psychopharmacology (Berl) 134:95–106
Rogers SL, Doody RS, Mohs RC, Friedhoff LT (1998) Donepezil improves cognition and global function in Alzheimer disease: a 15-week, double-blind, placebo-controlled study. Donepezil Study Group. Arch Intern Med 158:1021–1031
Rusted JM, Warburton DM (1988) The effects of scopolamine on working memory in healthy young volunteers. Psychopharmacology (Berl) 96(2):145–152
Sahakian BJ, Morris RG, Evenden JL, Heald A, Levy R, Philpot M, Robbins TW (1988) A comparative study of visuospatial memory and learning in Alzheimer-type dementia and Parkinson’s disease. Brain 111(Pt 3):695–718
Scarr E, Dean B (2009) Role of the cholinergic system in the pathology and treatment of schizophrenia. Expert Rev Neurother 9:73–86
Soares JC, Fornari RV, Oliveira MG (2006) Role of muscarinic M1 receptors in inhibitory avoidance and contextual fear conditioning. Neurobiol Learn Mem 86:188–196
Spowart-Manning L, van der Staay FJ (2004) The T-maze continuous alternation task for assessing the effects of putative cognitive enhancers in the mouse. Behav Brain Res 151:37–46
Swainson R, Hodges JR, Galton CJ, Semple J, Michael A, Dunn BD, Iddon JL, Robbins TW, Sahakian BJ (2001) Early detection and differential diagnosis of Alzheimer’s disease and depression with neuropsychological tasks. Dement Geriatr Cogn Disord 12:265–280
Taffe MA, Weed MR, Gutierrez T, Davis SA, Gold LH (2002) Differential muscarinic and NMDA contributions to visuo-spatial paired-associate learning in rhesus monkeys. Psychopharmacology (Berl) 160:253–262
Talpos JC, Winters BD, Dias R, Saksida LM, Bussey TJ (2009) A novel touchscreen-automated paired-associate learning (PAL) task sensitive to pharmacological manipulation of the hippocampus: a translational rodent model of cognitive impairments in neurodegenerative disease. Psychopharmacology (Berl) 205:157–168
Turchi J, Saunders RC, Mishkin M (2005) Effects of cholinergic deafferentation of the rhinal cortex on visual recognition memory in monkeys. Proc Natl Acad Sci USA 102:2158–2161
Van Dam D, Abramowski D, Staufenbiel M, De Deyn PP (2005) Symptomatic effect of donepezil, rivastigmine, galantamine, and memantine on cognitive deficits in the APP23 model. Psychopharmacology (Berl) 180:177–190
Van Dam D, Coen K, De Deyn PP (2008) Cognitive evaluation of disease-modifying efficacy of donepezil in the APP23 mouse model for Alzheimer’s disease. Psychopharmacology (Berl) 197:37–43
Winblad B, Engedal K, Soininen H, Verhey F, Waldemar G, Wimo A, Wetterholm AL, Zhang R, Haglund A, Subbiah P (2001) A 1-year, randomized, placebo-controlled study of donepezil in patients with mild to moderate AD. Neurology 57:489–495
Winters BD, Bartko SJ, Saksida LM, Bussey TJ (2007) Scopolamine infused into perirhinal cortex improves object recognition memory by blocking the acquisition of interfering object information. Learn Mem 14:590–596
Wood SJ, Proffitt T, Mahony K, Smith DJ, Buchanan JA, Brewer W, Stuart GW, Velakoulis D, McGorry PD, Pantelis C (2002) Visuospatial memory and learning in first-episode schizophreniform psychosis and established schizophrenia: a functional correlate of hippocampal pathology? Psychol Med 32:429–438
Acknowledgments
This work was supported by a grant from the Alzheimer’s Research Trust. S.J.B. was additionally supported by a Ruth L. Kirschstein Predoctoral Fellowship from the National Institutes of Mental Health. We also thank Jamie Simon for assistance with Figure1.
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Department of Experimental Psychology, University of Cambridge, Downing St., Cambridge, CB2 3EB, UK
Susan J. Bartko, Ignasi Vendrell, Lisa M. Saksida & Timothy J. Bussey
MRC and Wellcome Trust Behavioural and Clinical Neuroscience Institute, University of Cambridge, Downing St., Cambridge, CB2 3EB, UK
Susan J. Bartko, Ignasi Vendrell, Lisa M. Saksida & Timothy J. Bussey
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Correspondence toSusan J. Bartko.
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Bartko, S.J., Vendrell, I., Saksida, L.M.et al. A computer-automated touchscreen paired-associates learning (PAL) task for mice: impairments following administration of scopolamine or dicyclomine and improvements following donepezil.Psychopharmacology214, 537–548 (2011). https://doi.org/10.1007/s00213-010-2050-1
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