Psychopharmacology

, Volume 180, Issue 1, pp 177–190

Symptomatic effect of donepezil, rivastigmine, galantamine and memantine on cognitive deficits in the APP23 model

  • Debby Van Dam
  • Dorothee Abramowski
  • Matthias Staufenbiel
  • Peter Paul De Deyn
Original Investigation

Abstract

Rationale

APP23 mice are a promising model of Alzheimer’s disease, expressing several histopathological, cognitive and behavioural hallmarks of the human condition. A valid animal model should respond to therapeutic interventions in an equivalent manner as human patients.

Objectives

To further validate the APP23 model, we examined whether cognitive deficits could be antagonised by donepezil, rivastigmine, galantamine or memantine, which are approved drugs for symptomatic treatment of dementia.

Methods

Animals were tested at an age at which untreated APP23 mice display severe deficits in visual–spatial learning. Four-month-old APP23 mice and control littermates were administered donepezil (0.3 or 0.6 mg kg−1), rivastigmine (0.5 or 1.0 mg kg−1), galantamine (1.25 or 2.5 mg kg−1), memantine (2 or 10 mg kg−1) or saline through daily i.p. injections. After 1 week of treatment, acquisition phase commenced, with daily treatment continuing during cognitive testing.

Results

All cholinesterase inhibitors reduced cognitive deficits with the following optimal daily doses: galantamine 1.25 mg kg−1, rivastigmine 0.5 mg kg−1 and donepezil 0.3 mg kg−1. Higher dosages often did not exert beneficial effects in accordance with inverted U-shaped dose–response curves described for cholinomimetics. Symptomatic efficacy of memantine on cognition was mild, with significant amelioration manifesting during probe trial.

Conclusions

This is the first study to simultaneously evaluate the efficacy of therapeutically relevant doses of these four compounds in one particular learning and memory paradigm, being the Morris water maze. The fact that symptomatic intervention was able to diminish cognitive impairment, substantially adds to the validity of the APP23 model as a valuable tool to evaluate future therapeutic approaches.

Keywords

Transgenic mouse model Alzheimer’s disease Cognition Morris water maze Cholinergic hypothesis Acetylcholinesterase Excitotoxicity Acetylcholinesterase inhibitors NMDA receptor antagonist 

References

  1. Albuquerque EX, Alkondon M, Pereira EF, Castro NG, Schrattenholz A, Barbosa CT, Bonfante-Cabarcas R, Aracava Y, Eisenberg HM, Maelicke A (1997) Properties of neuronal nicotinic acetylcholine receptors: pharmacological characterization and modulation of synaptic function. J Pharmacol Exp Ther 280:1117–1136PubMedGoogle Scholar
  2. Anand R, Gharabawi G, Enz A (1996) Efficacy and safety results of the early phase studies with Exelon (ENA-713) in Alzheimer’s disease: an overview. J Drug Dev Clin Pract 8:109–116Google Scholar
  3. Baldi E, Lorenzini CA, Corrado B (2003) Task solving by procedural strategies in the Morris water maze. Physiol Behav 78:785–793CrossRefGoogle Scholar
  4. Ballard TM, McAllister KH (1999) The acetylChE inhibitor, ENA 713 (Exelon), attenuates the working memory impairment induced by scopolamine in an operant DNMTP task in rats. Psychopharmacology 146:10–18CrossRefGoogle Scholar
  5. Barnes CA, Danysz W, Parsons CG (1996) Effects of the uncompetitive NMDA receptor antagonist memantine on hippocampal long-term potentiation, short-term exploratory modulation and spatial memory in awake, freely moving rats. Eur J Neurosci 8:565–571Google Scholar
  6. Bartus RT (2000) On neurodegenerative diseases, models, and treatment strategies: lessons learned and lessons forgotten a generation following the cholinergic hypothesis. Exp Neurol 163:495–529CrossRefGoogle Scholar
  7. Bejar C, Wang RH, Weinstock M (1999) Effect of rivastigmine on scopolamine-induced memory impairment in rats. Eur J Pharmacol 383:231–240CrossRefPubMedGoogle Scholar
  8. Boncristiano S, Calhoun ME, Kelly PH, Pfeifer M, Bondolfi L, Stalder M, Phinney AL, Abramowski D, Sturchler-Pierrat C, Enz A, Sommer B, Staufenbiel M, Jucker M (2002) Cholinergic changes in the APP23 transgenic mouse model of cerebral amyloidosis. J Neurosci 22:3234–3243Google Scholar
  9. Braida D, Sala M (2001) Eptastigmine: ten years of pharmacology, toxicology, pharmacokinetic, and clinical studies. CNS Drug Rev 7:369–386Google Scholar
  10. Braida D, Paladini E, Griffini P, Lamperti M, Maggi A, Sala M (1996) An inverted U-shaped curve for heptylphysostigmine on radial maze performance in rats: comparison with other cholinesterase inhibitors. Eur J Pharmacol 302:13–20CrossRefGoogle Scholar
  11. Cain DP, Saucier D, Hall J, Hargreaves EL, Boon F (1996) Detailed behavioral analysis of water maze acquisition under APV or CNQX: contribution of sensorimotor disturbances to drug-induced acquisition deficits. Behav Neurosci 110:86–102CrossRefGoogle Scholar
  12. Cain DP, Saucier D, Boon F (1997) Testing hypotheses of spatial learning: the role of NMDA receptors and NMDA-mediated long-term potentiation. Behav Brain Res 84:179–193CrossRefGoogle Scholar
  13. Camacho F, Smith CP, Vargas HM, Winslow JT (1996) Alpha 2-adrenoceptor antagonists potentiate acetylChE inhibitor effects on passive avoidance learning in the rat. Psychopharmacology (Berl) 124:347–354Google Scholar
  14. Chen SY, Wright JW, Barnes CD (1996) The neurochemical and behavioral effects of beta-amyloid peptide(25–35). Brain Res 720:54–60CrossRefGoogle Scholar
  15. Chen Z, Xu AJ, Li R, Wei EQ (2002) Reversal of scopolamine-induced spatial memory deficits in rats by TAK-147. Acta Pharmacol Sin 23:355–360PubMedGoogle Scholar
  16. Corey-Bloom J, Anand R, Veach J (1998) A randomised trial evaluating the efficacy and safety of Ena 713 (rivastigmine tartrate), a new acetylChE inhibitor, in patients with mild to moderately severe Alzheimer’s disease. Int J Geriatr Psychopharmacol 1:55–65Google Scholar
  17. Coyle JT, Price DL, DeLong MR (1983) Alzheimer’s disease: a disorder of cortical cholinergic innervation. Science 219:1184–1190Google Scholar
  18. Dajas-Bailador FA, Heimala K, Wonnacott S (2003) The allosteric potentiation of nicotinic acetylcholine receptors by galantamine is transduced into cellular responses in neurons: Ca2+ signals and neurotransmitter release. Mol Pharmacol 64:1217–1226CrossRefGoogle Scholar
  19. Davies P, Maloney AJ (1976) Selective loss of central cholinergic neurons in Alzheimer’s disease. Lancet 2:1403CrossRefGoogle Scholar
  20. Davies P, Wolozin BL (1987) Recent advances in the neurochemistry of Alzheimer’s disease. J Clin Psychiatry 48:23–30Google Scholar
  21. Dawson GR, Iversen SD (1993) The effects of novel ChE inhibitors and selective muscarinic receptor agonists in tests of reference and working memory. Behav Brain Res 57:143–153CrossRefGoogle Scholar
  22. De Deyn PP, D’Hooge R, van Zutphen LFM (2000) Animal models of human disorders—general aspects. Neurosci Res Commun 26:141–148Google Scholar
  23. D’Hooge R, De Deyn PP (2001) Applications of the Morris water maze in the study of learning and memory. Brain Res Rev 36:60–90CrossRefGoogle Scholar
  24. D’Hooge R, Nagels G, Westland CE, Mucke L, De Deyn PP (1996) Spatial learning deficit in mice expressing human 751-amino acid beta-amyloid precursor protein. NeuroReport 7:2807–2811Google Scholar
  25. D’Hooge R, Franck F, Mucke L, De Deyn PP (1999) Age-related behavioural deficits in transgenic mice expressing the HIV-1 coat protein gp120. Eur J Neurosci 11:4398–4402CrossRefGoogle Scholar
  26. Ditzler K (1991) Efficacy and tolerability of memantine in patients with dementia syndrome. A double-blind, placebo controlled trial. Arzneimittelforschung 41:773–780Google Scholar
  27. Doble A (1999) The role of excitotoxicity in neurodegenerative disease: implications for therapy. Pharmacol Ther 81:163–221CrossRefGoogle Scholar
  28. Enz A, Amstutz R, Hofmann A, Gmelin G, Kelly PH (1989) Pharmacological properties of the preferentially centrally acting acetylcholinesterase inhibitor SDZ ENA 713. In: Kewitz, Thomson, Bickel (eds) Pharmacological interventions on central cholinergic mechanisms in senile dementia (Alzheimer’s disease). Zuckswerdt Verlag, München, pp 271–277Google Scholar
  29. Enz A, Amstutz R, Boddeke H, Gmelin G, Malanowski J (1993) Brain selective inhibition of acetylChE: a novel approach to therapy for Alzheimer’s disease. Prog Brain Res 98:431–438Google Scholar
  30. Fishkin RJ, Ince ES, Carlezon WA Jr, Dunn RW (1993) d-Cycloserine attenuates scopolamine-induced learning and memory deficits in rats. Behav Neural Biol 59:150–157CrossRefGoogle Scholar
  31. Flood JF, Landry DW, Jarvik ME (1981) Cholinergic receptor interactions and their effects on long-term memory processing. Brain Res 215:177–185CrossRefGoogle Scholar
  32. Görtelmeyer R, Erbler H (1992) Memantine in the treatment of mild to moderate dementia syndrome. A double-blind placebo-controlled study. Arzneimittelforschung 42:904–913Google Scholar
  33. Hodges H (1996) Maze procedures: the radial-arm and water maze compared. Brain Res Cogn Brain Res 3:167–181CrossRefGoogle Scholar
  34. Hoh TE, Cain DP (1997) Fractionating the nonspatial pretraining effect in the water maze task. Behav Neurosci 111:1285–1291CrossRefGoogle Scholar
  35. Kelly PH, Hunziker D, Schlecht HP, Carver K, Abramowski D, Sturchler-Pierrat C, Staufenbiel M, Sommer B (1999) Progressive behavioural impairment in amyloid precursor protein transgenic mouse line APP23. Soc Neurosci Abstr 25:1291Google Scholar
  36. Kelly PH, Bondolfi L, Hunziker D, Schlecht HP, Carver K, Maguire E, Abramowski D, Wiederhold KH, Sturchler-Pierrat C, Jucker M, Bergmann R, Staufenbiel M, Sommer B (2003) Progressive age-related impairment of cognitive behavior in APP23 transgenic mice. Neurobiol Aging 24:365–378CrossRefGoogle Scholar
  37. Koob GF (2000) Neurobiology of addiction. Toward the development of new therapies Ann NY Acad Sci 909:170–185PubMedGoogle Scholar
  38. Lalonde R, Dumont M, Staufenbiel M, Sturchler-Pierrat C, Strazielle C (2002) Spatial learning, exploration, anxiety, and motor coordination in female APP23 transgenic mice with the Swedish mutation. Brain Res. 956:36–44CrossRefGoogle Scholar
  39. Levi MS, Borne RF (2002) A review of chemical agents in the pharmacotherapy of addiction. Curr Med Chem 9:1807–1818Google Scholar
  40. Lilienfeld S (2002) Galantamine—a novel cholinergic drug with a unique dual mode of action for the treatment of patients with Alzheimer’s disease. CNS Drug Rev 8:159–176Google Scholar
  41. Lindner MD (1997) Reliability, distribution, and validity of age-related cognitive deficits in the Morris water maze. Neurobiol Learn Mem 68:203–220CrossRefGoogle Scholar
  42. Maelicke A (2000) Allosteric modulation of nicotinic receptors as a treatment strategy for Alzheimer’s disease. Dement Geriatr Cogn Disord 11:11–18CrossRefGoogle Scholar
  43. Maldonado C, Cauli O, Rodriguez-Arias M, Aguilar MA, Minarro J (2003) Memantine presents different effects from MK-801 in motivational and physical signs of morphine withdrawal. Behav Brain Res 144:25–35CrossRefGoogle Scholar
  44. McKeith I, Truyen L, Lilienfeld S, Mahableshwarkar A, Gal-GBR Study Team (2003) Galantamine demonstrates superior efficacy on attention and MMSE compared with donepezil in patients with Alzheimer’s disease actively treated for 52 weeks: an initial analysis. Neurology 60(Suppl 5):A141Google Scholar
  45. Miguel-Hidalgo JJ, Alvarez XA, Cacabelos R, Quack G (2002) Neuroprotection by memantine against neurodegeneration induced by beta-amyloid(1–40). Brain Res 958:210–221CrossRefGoogle Scholar
  46. Misztal M, Frankiewicz T, Parsons CG, Danysz W (1996) Learning deficits induced by chronic intraventricular infusion of quinolinic acid–protection by MK-801 and memantine. Eur J Pharmacol 296:1–8CrossRefGoogle Scholar
  47. Mohr E, Carter C, Wallin A (1990) Neurochemical substrates of human aging and dementia. Pharmacopsychiatry 23:53–55Google Scholar
  48. Moller HJ (1999) Reappraising neurotransmitter-based strategies. Eur Neuropsychopharmacol 9:S53–S59CrossRefGoogle Scholar
  49. Newhouse PA, Potter A, Levin ED (1997) Nicotinic system involvement in Alzheimer’s and Parkinson’s diseases. Implications for therapeutics. Drugs Aging 11:206–228Google Scholar
  50. Niigawa H, Tanimukai S, Takeda M, Hariguchi S, Nishimura T (1995) Effects of SDZ ENA 713, novel acetylChE inhibitor, on learning in rats with basal forebrain lesions. Prog Neuro-Psychopharmacol Biol Psychiatry 19:171–186CrossRefGoogle Scholar
  51. Ogura H, Kosasa T, Kuriya Y, Yamanishi Y (2000) Donepezil, a centrally acting acetylChE inhibitor, alleviates learning deficits in hypocholinergic models in rats. Methods Find Exp Clin Pharmacol 22:89–95PubMedGoogle Scholar
  52. Ohara T, Fukaya H, Tanaka K, Seno N (1997a) Ameliorating effects of SDZ ENA 713 on age-associated decreases in learning performance and brain choline acetyltransferase activity in rats. Brain Res Bull 43:39–42CrossRefGoogle Scholar
  53. Ohara T, Takeda M, Fukaya H, Demura N, Iimura A, Seno N (1997b) SDZ ENA 713 facilitates central cholinergic function and ameliorates spatial memory impairment in rats. Behav Brain Res 83:229–233CrossRefGoogle Scholar
  54. Parsons CG, Danysz W, Quack G (1999) Memantine is a clinically well tolerated N-methyl-d-aspartate (NMDA) receptor antagonist—a review of preclinical data. Neuropharmacology 38:735–767CrossRefGoogle Scholar
  55. Piasecki J, Koros E, Dyr W, Kostowski W, Danysz W, Bienkowski P (1998) Ethanol-reinforced behaviour in the rat: effects of uncompetitive NMDA receptor antagonist, memantine. Eur J Pharmacol 354:135–143CrossRefGoogle Scholar
  56. Popik P, Danysz W (1997) Inhibition of reinforcing effects of morphine and motivational aspects of naloxone-precipitated opioid withdrawal by N-methyl-d-aspartate receptor antagonist, memantine. J Pharmacol Exp Ther 280:854–865Google Scholar
  57. Rao VL, Dogan A, Todd KG, Bowen KK, Dempsey RJ (2001) Neuroprotection by memantine, a non-competitive NMDA receptor antagonist after traumatic brain injury in rats. Brain Res 911:96–100CrossRefGoogle Scholar
  58. Raskind MA, Peskind ER, Wessel T, Yuan W, Galantamine USA-1 Study Group (2000) Galantamine in AD: a 6-month randomized, placebo-controlled trial with a 6-month extension. Neurology 54:2261–2268Google Scholar
  59. Reisberg B, Doody R, Stoffler A, Schmitt F, Ferris S, Mobius HJ, Memantine Study Group (2003) Memantine in moderate-to-severe Alzheimer’s disease. N Engl J Med 348:1333–1341CrossRefGoogle Scholar
  60. Rogers SL, Doody RS, Pratt RD, Ieni JR (2000) Long-term efficacy and safety of donepezil in the treatment of Alzheimer’s disease: final analysis of a US multicentre open-label study. Eur Neuropsychopharmacol 10:195–203CrossRefGoogle Scholar
  61. Rösler M, Anand R, Cicin-Sain A, Gauthier S, Agid Y, Dal-Bianco P, Stahelin HB, Hartman R, Gharabawi M (1999) Efficacy and safety of rivastigmine in patients with Alzheimer’s disease: international randomised controlled trial. Br Med J 318:633–638Google Scholar
  62. Samochocki M, Hoffle A, Fehrenbacher A, Jostock R, Ludwig J, Christner C, Radina M, Zerlin M, Ullmer C, Pereira EF, Lubbert H, Albuquerque EX, Maelicke A (2003) Galantamine is an allosterically potentiating ligand of neuronal nicotinic but not of muscarinic acetylcholine receptors. J Pharmacol Exp Ther 305:1024–1036CrossRefGoogle Scholar
  63. Schrattenholz A, Pereira EF, Roth U, Weber KH, Albuquerque EX, Maelicke A (1996) Agonist responses of neuronal nicotinic acetylcholine receptors are potentiated by a novel class of allosterically acting ligands. Mol Pharmacol 49:1–6Google Scholar
  64. Selkoe DJ (2001) Alzheimer’s disease: genes, proteins, and therapy. Physiol Rev 81:741–766PubMedGoogle Scholar
  65. Strong R (1998) Neurochemical changes in the aging human brain: implications for behavioral impairment and neurodegenerative disease. Geriatrics 53:S9–S12Google Scholar
  66. Sturchler-Pierrat C, Staufenbiel M (2000) Pathogenic mechanisms of Alzheimer’s disease analyzed in the APP23 transgenic mouse model. Ann NY Acad Sci 920:134–139Google Scholar
  67. Sturchler-Pierrat C, Abramowski D, Duke M, Wiederhold KH, Mistl C, Rothacher S, Ledermann B, Burki K, Frey P, Paganetti PA, Waridel C, Calhoun ME, Jucker M, Probst A, Staufenbiel M, Sommer B (1997) Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology. Proc Natl Acad Sci U S A 94:13287–13292CrossRefGoogle Scholar
  68. Sugimoto H, Ogura H, Arai Y, Limura Y, Yamanishi Y (2002) Research and development of donepezil hydrochloride, a new type of acetylChE inhibitor. Jpn J Pharmacol 89:7–20CrossRefGoogle Scholar
  69. Sutherland RJ, Hamilton DA (2004) Rodent spatial navigation: at the crossroads of cognition and movement. Neurosci Biobehav Rev 28:687–697CrossRefGoogle Scholar
  70. Suzuki M, Yamaguchi T, Ozawa Y, Iwai A, Yamamoto M (1995) Effect of YM796, a novel muscarinic agonist, on the impairment of passive avoidance response in senescence-accelerated mice. Pharmacol Biochem Behav 51:623–626CrossRefGoogle Scholar
  71. Sweeney JE, Bachman ES, Coyle JT (1990) Effects of different doses of galantamine, a long-acting acetylChE inhibitor, on memory in mice. Psychopharmacology 102:191–200Google Scholar
  72. Tariot PN, Solomon PR, Morris JC, Kershaw P, Lilienfeld S, Ding CA (2000) 5-Month, randomized, placebo-controlled trial of galantamine in AD. The Galantamine USA-10 Study Group. Neurology 54:2269–2276PubMedGoogle Scholar
  73. Tariot PN, Farlow MR, Grossberg GT, Graham SM, McDonald S, Gergel I, Memantine Study Group (2004) Memantine treatment in patients with moderate to severe Alzheimer disease already receiving donepezil: a randomized controlled trial. JAMA 291:317–324CrossRefGoogle Scholar
  74. Thomsen T, Kewitz H (1990) Selective inhibition of human acetylChE by galantamine in vitro and in vivo. Life Sci 46:1553–1558CrossRefGoogle Scholar
  75. Tohda C, Tamura T, Komatsu K (2003) Repair of amyloid beta(25–35)-induced memory impairment and synaptic loss by a Kampo formula, Zokumei-to. Brain Res 990:141–147CrossRefGoogle Scholar
  76. Ueki A, Miyoshi K (1991) Reversal of learning impairment in ventral globus pallidus-lesioned rats by combination of continuous intracerebroventricular choline infusion and oral cholinergic drug administration. Brain Res 547:99–109CrossRefGoogle Scholar
  77. Van Dam D, D’Hooge R, Staufenbiel M, Van Ginneken C, Van Meir F, De Deyn PP (2003) Age-dependent cognitive decline in the APP23 model precedes amyloid deposition. Eur J Neurosci 17:388–396CrossRefGoogle Scholar
  78. Van Dam D, Marescau B, Engelborghs S, Cremers T, Mulder J, Staufenbiel M, De Deyn PP. Analysis of cholinergic markers, biogenec amines, and amino acids in the CNS of two APP overexpression mouse models. Neurochem Int (in press a)Google Scholar
  79. Van Dam D, Vloeberghs E, Abramowski D, Staufenbiel M, De Deyn PP (accepted) APP23 mice as a model of Alzheimer’s Disease—an example of a transgenic breeding approach to modeling a CNS disorder. CNS Spectr (in press b)Google Scholar
  80. Vloeberghs E, Van Dam D, Engelborghs S, Nagels G, Staufenbiel M, De Deyn PP (2004) Altered circadian locomotor activity in APP23 mice: a model for BPSD disturbances. Eur J Neurosci 20:2757–2766CrossRefGoogle Scholar
  81. Waite JJ, Thal LJ (1995) The behavioral effects of heptylphysostigmine on rats lesioned in the nucleus basalis. Neurosci Res 21: 251–259CrossRefGoogle Scholar
  82. Wang T, Tang XC (1998) Reversal of scopolamine-induced deficits in radial maze performance by (−)-huperzine A: comparison with E2020 and tacrine. Eur J Pharmacol 349:137–142CrossRefGoogle Scholar
  83. Wanibuchi F, Nishida T, Yamashita H, Hidaka K, Koshiya K, Tsukamoto S, Usuda S (1994) Characterization of a novel muscarinic receptor agonist, YM796: comparison with cholinesterase inhibitors in in vivo pharmacological studies. Eur J Pharmacol 265:151–158CrossRefGoogle Scholar
  84. Wehner JM, Balogh SA (2003) Phenotyping mice for learning and memory: traditional tasks, modifications of traditional tasks, and the application of new tasks. In: Crawley J (ed) Mouse behavioral phenotyping. Society for Neuroscience, Washington, DC, pp 13–23Google Scholar
  85. Weinstock M, Razin M, Chorev M, Enz A (1994) Pharmacological evaluation of phenyl-carbamates as CNS-selective acetylChE inhibitors. J Neural Transm Suppl 43:219–225Google Scholar
  86. Wenk GL, Danysz W, Mobley SL (1995) MK-801, memantine and amantadine show neuroprotective activity in the nucleus basalis magnocellularis. Eur J Pharmacol 293:267–270Google Scholar
  87. Westerman MA, Cooper-Blacketer D, Mariash A, Kotilinek L, Kawarabayashi T, Younkin LH, Carlson GA, Younkin SG, Ashe KH (2002) The relationship between Abeta and memory in the Tg2576 mouse model of Alzheimer’s disease. J Neurosci 22:1858–1867Google Scholar
  88. Wilcock GK, Lilienfeld S, Gaens E (2000) Efficacy and safety of galantamine in patients with mild to moderate Alzheimer’s disease: multicentre randomised controlled trial. Galantamine International-1 Study Group Br Med J 321:1445–1449Google Scholar
  89. Wilcock G, Howe I, Coles H, Lilienfeld S, Truyen L, Zhu Y, Bullock R, Kershaw P, GAL-GBR-2 Study Group (2003) A long-term comparison of galantamine and donepezil in the treatment of Alzheimer’s disease. Drugs Aging 20:777–789Google Scholar
  90. Wilkinson DG, Passmore AP, Bullock R, Hopker SW, Smith R, Potocnik FC, Maud CM, Engelbrecht I, Hock C, Ieni JR, Bahra RS (2002) A multinational, randomised, 12-week, comparative study of donepezil and rivastigmine in patients with mild to moderate Alzheimer’s disease. Int J Clin Pract 56:441–446Google Scholar
  91. Winblad B, Poritis N (1999) Memantine in severe dementia: results of the 9M-Best Study (benefit and efficacy in severely demented patients during treatment with memantine). Int J Geriatr Psychiatry 14:135–146CrossRefGoogle Scholar
  92. Wright JW, Alt JA, Turner GD, Krueger JM (2004) Differences in spatial learning comparing transgenic p75 knockout, New Zealand Black, C57BL/6, and Swiss Webster mice. Behav Brain Res 153:453–458CrossRefGoogle Scholar
  93. Yoshida S, Suzuki N (1993) Antiamnesic and cholinomimetic side-effects of the cholinesterase inhibitors, physostigmine, tacrine and NIK-247 in rats. Eur J Pharmacol 250:117–124CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Debby Van Dam
    • 1
  • Dorothee Abramowski
    • 2
  • Matthias Staufenbiel
    • 2
  • Peter Paul De Deyn
    • 1
    • 3
  1. 1.Laboratory of Neurochemistry and Behaviour, Born-Bunge Institute, Department of Biomedical SciencesUniversity of AntwerpWilrijkBelgium
  2. 2.Novartis Institutes of Biomedical Research BaselBaselSwitzerland
  3. 3.Department of Neurology/Memory clinicMiddelheim General HospitalAntwerpBelgium

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