, Volume 182, Issue 1, pp 170–179 | Cite as

Cholinergic enhancement of episodic memory in healthy young adults

  • Georg Grön
  • Matthias Kirstein
  • Axel Thielscher
  • Matthias W. Riepe
  • Manfred Spitzer
Original Investigation



Acetylcholine esterase (AchE) inhibitors are known to remediate symptoms of Alzheimer's disease. However, only few systematic data exist on the effects of cholinergic treatment on cognitive functions in normal subjects.


This study evaluated the effects of donepezil, an inhibitor of AchE, on cognitive performance in young and healthy subjects.


We used a randomised double-blind parallel group placebo-controlled repeated measures design to investigate changes of cognitive functions in a group of 30 young healthy male subjects (mean age 23.9 years±2.24 SD) upon application of donepezil or placebo for 30 days. Attentional and executive functions, visual and verbal short-term and working memory, semantic memory, as well as verbal and visual episodic memory were investigated using an extensive neuropsychological test battery.


Time-by-group interactions demonstrated significant drug effects that were specific to episodic memory in both the verbal and visual domain. Additionally, donezepil significantly improved long-term visual episodic recall. In none of the other functions under investigation any significant treatment effects were observed.


Given this specific drug effect and the well-known relevance of the hippocampal region for episodic memory, we conclude that this region appears to be the major target of cholinergic enhancement in healthy subjects due to long-term inhibition of AchE.


Acetylcholinesterase Attention Cognition Learning and memory Hippocampus Human 



We thank Roman Seidl, Markus Kiefer, Lutz Wendland, Jo Grothe, Bärbel Herrnberger for technical assistance. We also wish to thank Gisbert Farger, Clinic–Chemical Laboratory, University Clinic of Psychiatry and Psychotherapy, Tübingen, Germany, for analysis of the blood samples. This study was in part funded by Eisai, Frankfurt, Germany, and Pfizer, Karlsruhe, Germany. Each author has nothing to disclose as regards any involvement, financial or otherwise.


  1. Aigner TG (1995) Pharmacology of memory: cholinergic–glutamatergic interactions. Curr Opin Neurobiol 5:155–160CrossRefPubMedGoogle Scholar
  2. Allgaier C, Warnke P, Stangl AP, Feuerstein TJ (1995) Effects of 5-HT receptor agonists on depolarization-induced [3H]-noradrenaline release in rabbit hippocampus and human neocortex. Br J Pharmacol 116:1769–1774PubMedGoogle Scholar
  3. Baddeley A (2000) The episodic buffer: a new component of working memory? Trends Cogn Sci 4:417–423CrossRefPubMedGoogle Scholar
  4. Bartus RT, Dean RL III, Beer B, Lippa AS (1982) The cholinergic hypothesis of geriatric memory dysfunction. Science 217:408–414PubMedCrossRefGoogle Scholar
  5. Beglinger LJ, Gaydos BL, Kareken DA, Tangphao-Daniels O, Siemers ER, Mohs RC (2004) Neuropsychological test performance in healthy volunteers before and after donepezil administration. J Psychopharmacol 18:102–108CrossRefPubMedGoogle Scholar
  6. Blokland A (1995) Acetylcholine: a neurotransmitter for learning and memory? Brain Res Brain Res Rev 21:285–300CrossRefPubMedGoogle Scholar
  7. Cohen NJ, Ryan J, Hunt C, Romine L, Wszalek T, Nash C (1999) Hippocampal system and declarative (relational) memory: summarizing the data from functional neuroimaging studies. Hippocampus 9:83–98CrossRefPubMedGoogle Scholar
  8. Davis KL, Mohs RC, Tinklenberg JR, Pfefferbaum A, Hollister LE, Kopell BS (1978) Physostigmine: improvement of long-term memory processes in normal humans. Science 201:272–274PubMedCrossRefGoogle Scholar
  9. De Lacalle S, Lim C, Sobreviela T, Mufson EJ, Hersh LB, Saper CB (1994) Cholinergic innervation in the human hippocampal formation including the entorhinal cortex. J Comp Neurol 345:321–344CrossRefPubMedGoogle Scholar
  10. Derrington A (1996) Vision: filling in and pop out. Curr Biol 6:141–143CrossRefPubMedGoogle Scholar
  11. Dooley M, Lamb HM (2000) Donepezil: a review of its use in Alzheimer's disease. Drugs Aging 16:199–226PubMedCrossRefGoogle Scholar
  12. Eichenbaum H (2002) The cognitive neuroscience of memory. Oxford University Press, New YorkGoogle Scholar
  13. Everitt BJ, Robbins TW (1997) Central cholinergic systems and cognition. Annu Rev Psychol 48:649–684CrossRefPubMedGoogle Scholar
  14. Feuerstein TJ, Lehmann J, Sauermann W, van Velthoven V, Jackisch R (1992) The autoinhibitory feedback control of acetylcholine release in human neocortex tissue. Brain Res 572:64–71CrossRefPubMedGoogle Scholar
  15. Furey ML, Pietrini P, Haxby JV, Alexander GE, Lee HC, VanMeter J, Grady CL, Shetty U, Rapoport SI, Schapiro MB, Freo U (1997) Cholinergic stimulation alters performance and task-specific regional cerebral blood flow during working memory. Proc Natl Acad Sci U S A 94:6512–6516CrossRefPubMedGoogle Scholar
  16. Furey ML, Pietrini P, Alexander GE, Mentis MJ, Szczepanik J, Shetty U, Greig NH, Holloway HW, Schapiro MB, Freo U (2000a) Time course of pharmacodynamic and pharmacokinetic effects of physostigmine assessed by functional brain imaging in humans. Pharmacol Biochem Behav 66:475–481CrossRefPubMedGoogle Scholar
  17. Furey ML, Pietrini P, Alexander GE, Shapiro MB, Horwitz B (2000b) Cholinergic enhancement improves performance on working memory by modulating the functional activity in distinct brain regions: a positron emission tomography regional cerebral blood flow study in healthy humans. Brain Res Bull 51:213–218CrossRefPubMedGoogle Scholar
  18. Furey ML, Pietrini P, Haxby JV (2000c) Cholinergic enhancement and increased selectivity of perceptual processing during working memory. Science 290:2315–2319CrossRefPubMedGoogle Scholar
  19. Gill TM, Sarter M, Givens B (2000) Sustained visual attention performance-associated prefrontal neuronal activity: evidence for cholinergic modulation. J Neurosci 20:4745–4757PubMedGoogle Scholar
  20. Goekoop R, Rombouts SA, Jonker C, Hibbel A, Knol DL, Truyen L, Barkhof F, Scheltens P (2004) Challenging the cholinergic system in mild cognitive impairment: a pharmacological fMRI study. NeuroImage 23:1450–1459CrossRefPubMedGoogle Scholar
  21. Gold PE (2003) Acetylcholine modulation of neural systems involved in learning and memory. Neurobiol Learn Mem 80:194–210PubMedCrossRefGoogle Scholar
  22. Gron G, Bittner D, Schmitz B, Wunderlich AP, Tomczak R, Riepe MW (2001) Hippocampal activations during repetitive learning and recall of geometric patterns. Learn Mem 8:336–345CrossRefPubMedGoogle Scholar
  23. Gron G, Bittner D, Schmitz B, Wunderlich AP, Riepe MW (2002) Subjective memory complaints: objective neural markers in patients with Alzheimer's disease and major depressive disorder. Ann Neurol 51:491–498CrossRefPubMedGoogle Scholar
  24. Gron G, Bittner D, Schmitz B, Wunderlich AP, Tomczak R, Riepe MW (2003a) Variability in memory performance in aged healthy individuals: an fMRI study. Neurobiol Aging 24:453–462CrossRefPubMedGoogle Scholar
  25. Gron G, Schul D, Bretschneider V, Wunderlich AP, Riepe MW (2003b) Alike performance during nonverbal episodic learning from diversely imprinted neural networks. Eur J Neurosci 18:3112–3120CrossRefPubMedGoogle Scholar
  26. Horn W (1983) Leistungsprüfsystem (LPS). Hogrefe, GoettingenGoogle Scholar
  27. Kasa P, Rakonczay Z, Guly K (1997) The cholinergic system in Alzheimer's disease. Prog Neurobiol 52:511–535CrossRefPubMedGoogle Scholar
  28. Kilgard MP, Merzenich MM (1998) Cortical map reorganization enabled by nucleus basalis activity. Science 279:1714–1718PubMedCrossRefGoogle Scholar
  29. Kuhl DE, Koeppe RA, Minoshima S, Snyder SE, Ficaro EP, Foster NL, Frey KA, Kilbourn MR (1999) In vivo mapping of cerebral acetylcholinesterase activity in aging and Alzheimer's disease. Neurology 52:691–699PubMedGoogle Scholar
  30. Lezak M (1995) Neuropsychological assessment, 3rd edn. Oxford University Press, New YorkGoogle Scholar
  31. Liljenstrom H, Hasselmo ME (1995) Cholinergic modulation of cortical oscillatory dynamics. J Neurophysiol 74:288–297PubMedGoogle Scholar
  32. McClelland JL, McNaughton BL, O'Reilly RC (1995) Why there are complementary learning systems in the hippocampus and neocortex: insights from the successes and failures of connectionist models of learning and memory. Psychol Rev 102:419–457CrossRefPubMedGoogle Scholar
  33. Mesulam M (2004) The cholinergic lesion of Alzheimer's disease: pivotal factor or side show? Learn Mem 11:43–49CrossRefPubMedGoogle Scholar
  34. Mihara M, Ohnishi A, Tomono Y, Hasegawa J, Shimamura Y, Yamazaki K, Morishita N (1993) Pharmacokinetics of E2020, a new compound for Alzheimer's disease, in healthy male volunteers. Int J Clin Pharmacol Ther Toxicol 31:223–229PubMedGoogle Scholar
  35. Mumenthaler MS, Yesavage JA, Taylor JL, O'Hara R, Friedman L, Lee H, Kraemer HC (2003) Psychoactive drugs and pilot performance: a comparison of nicotine, donepezil, and alcohol effects. Neuropsychopharmacology 28:1366–1373CrossRefPubMedGoogle Scholar
  36. Nadel L, Moscovitch M (1997) Memory consolidation, retrograde amnesia and the hippocampal complex. Curr Opin Neurobiol 7:217–227CrossRefPubMedGoogle Scholar
  37. Nelson HE (1976) A modified card sorting test sensitive to frontal lobe defects. Cortex 12:313–324PubMedGoogle Scholar
  38. Oldfield RC (1971) The assessment and analysis of handedness: the Edinburgh inventory. Neuropsychologia 9:97–113CrossRefPubMedGoogle Scholar
  39. Oswald WD, Roth E (1978) Der Zahlen-Verbindungs-Test (ZVT). Hogrefe, Goettingen, GermanyGoogle Scholar
  40. Parent MB, Baxter MG (2004) Septohippocampal acetylcholine: involved in but not necessary for learning and memory? Learn Mem 11:9–20CrossRefPubMedGoogle Scholar
  41. Rogers SL, Friedhoff LT (1996) The efficacy and safety of donepezil in patients with Alzheimer's disease: results of a US Multicentre, randomized, double-blind, placebo-controlled trial. The Donepezil Study Group. Dementia 7:293–303PubMedCrossRefGoogle Scholar
  42. 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 158:1021–1031CrossRefPubMedGoogle Scholar
  43. Rombouts SA, Barkhof F, Van Meel CS, Scheltens P (2002) Alterations in brain activation during cholinergic enhancement with rivastigmine in Alzheimer's disease. J Neurol Neurosurg Psychiatry 73:665–671CrossRefPubMedGoogle Scholar
  44. Sarter M, Bruno JP, Givens B (2003) Attentional functions of cortical cholinergic inputs: what does it mean for learning and memory? Neurobiol Learn Mem 80:245–256CrossRefPubMedGoogle Scholar
  45. Schacter DL, Wagner AD (1999) Medial temporal lobe activations in fMRI and PET studies of episodic encoding and retrieval. Hippocampus 9:7–24CrossRefPubMedGoogle Scholar
  46. Schmidt KH, Metzler P (1992) WST-Wortschatztest. Beltz Verlag, WeinheimGoogle Scholar
  47. Selden NR, Gitelman DR, Salamon-Murayama N, Parrish TB, Mesulam MM (1998) Trajectories of cholinergic pathways within the cerebral hemispheres of the human brain. Brain 121:2249–2257CrossRefPubMedGoogle Scholar
  48. Simard M, van Reekum R (1999) Memory assessment in studies of cognition-enhancing drugs for Alzheimer's disease. Drugs Aging 14:197–230PubMedCrossRefGoogle Scholar
  49. Sitaram N, Weingartner H, Gillin JC (1978) Human serial learning: enhancement with arecholine and choline impairment with scopolamine. Science 201:274–276PubMedCrossRefGoogle Scholar
  50. Small SA, Perera GM, DeLaPaz R, Mayeux R, Stern Y (1999) Differential regional dysfunction of the hippocampal formation among elderly with memory decline and Alzheimer's disease. Ann Neurol 45:466–472CrossRefPubMedGoogle Scholar
  51. Sperling R, Greve D, Dale A, Killiany R, Holmes J, Rosas HD, Cocchiarella A, Firth P, Rosen B, Lake S, Lange N, Routledge C, Albert M (2001) Functional MRI detection of pharmacologically induced memory impairment. Proc Natl Acad Sci U S A 99:455–460CrossRefPubMedGoogle Scholar
  52. Sperling R, Chua E, Cocchiarella A, Rand-Giovannetti E, Poldrack R, Schacter DL, Albert M (2003) Putting names to faces: successful encoding of associative memories activates the anterior hippocampal formation. NeuroImage 20:1400–1410CrossRefPubMedGoogle Scholar
  53. Spitzer M, Braun U, Hermle L, Maier S (1993) Associative semantic network dysfunction in thought-disordered schizophrenic patients: direct evidence from indirect semantic priming. Biol Psychiatry 34:864–877CrossRefPubMedGoogle Scholar
  54. Spitzer M, Franke B, Walter H, Buechler J, Wunderlich AP, Schwab M, Kovar KA, Hermle L, Gron G (2001) Enantio-selective cognitive and brain activation effects of N-ethyl-3,4-methylenedioxyamphetamine in humans. Neuropharmacology 41:263–271CrossRefPubMedGoogle Scholar
  55. Tiseo PJ, Rogers SL, Friedhoff LT (1998) Pharmacokinetic and pharmacodynamic profile of donepezil HCl following evening administration. Br J Clin Pharmacol 46:13–18CrossRefPubMedGoogle Scholar
  56. Treisman A, Sato S (1990) Conjunction search revisited. J Exp Psychol Hum Percept Perform 16:459–478CrossRefPubMedGoogle Scholar
  57. Wechsler D (1987) Wechsler memory scale-revised manual. Psychological Corporation, San Antonio, TX, USAGoogle Scholar
  58. Wilkinson DG (1999) The pharmacology of donepezil: a new treatment of Alzheimer's disease. Expert Opin Pharmacother 1:121–135CrossRefPubMedGoogle Scholar
  59. Winkler J, Suhr ST, Gage FH, Thal LJ, Fisher LJ (1995) Essential role of neocortical acetylcholine in spatial memory. Nature 375:484–487CrossRefPubMedGoogle Scholar
  60. Woodruff-Pak DS, Vogel RW III, Wenk GL (2001) Galantamine: effect on nicotinic receptor binding, acetylcholinesterase inhibition, and learning. Proc Natl Acad Sci U S A 98:2089–2094CrossRefPubMedGoogle Scholar
  61. Yesavage JA, Mumenthaler MS, Taylor JL, Friedman L, O'Hara R, Sheikh J, Tinklenberg J, Whitehouse PJ (2002) Donepezil and flight simulator performance: effects on retention of complex skills. Neurology 59:123–125PubMedCrossRefGoogle Scholar
  62. Zihl J, Gron G, Brunnauer A (1998) Cognitive deficits in schizophrenia and affective disorders: evidence for a final common pathway disorder. Acta Psychiatr Scand 97:351–357PubMedCrossRefGoogle Scholar
  63. Zimmermann P, Fimm A (1994) Testbatterie zur Aufmerksamkeitsprüfung TAP(V. 1 02). Würselen, PsytestGoogle Scholar

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Georg Grön
    • 1
    • 4
  • Matthias Kirstein
    • 1
  • Axel Thielscher
    • 1
  • Matthias W. Riepe
    • 2
  • Manfred Spitzer
    • 1
    • 3
  1. 1.Department of PsychiatryUniversity of UlmUlmGermany
  2. 2.Department of Psychiatry Mental Health and Old Age PsychiatryCharité Medical UniversityBerlinGermany
  3. 3.Transfer Center for Neuroscience and Learning (ZNL)University of UlmUlmGermany
  4. 4.Department of Psychiatry, Neuropsychological SectionUniversity of UlmUlmGermany

Personalised recommendations