, Volume 196, Issue 4, pp 555–564

Improvement of contextual memory by S 24795 in aged mice: comparison with memantine

  • Daniel Beracochea
  • Aurelie Boucard
  • Caryn Trocme-Thibierge
  • Philippe Morain
Original Investigation



In comparison with 5-month-old mice, 18- to 19-month-old mice exhibited a severe and specific memory impairment in a contextual serial discrimination (CSD) task involving the learning and remembering of two successive spatial discriminations carried out on two distinct floors. This impairment was specific, as spatial memory, simultaneously tested on a simple discrimination (SD) task, was not affected in these aged mice. This deficit was completely reversed by 9-day per os administration of S 24795, a partial agonist of α7 nicotinic receptors, at either 0.3 or 1.0 mg/kg. Memantine, an NMDA receptor antagonist, also had a memory-enhancing effect at a dose of 3.0 mg/kg, but not at 0.3 mg/kg.


The memory-enhancing effect of S 24795 was due to a strong enhancement of contextual memory as indicated by a decrease in interference rate, whereas memantine enhanced spatial/semantic memory. S 24795 was more effective than memantine and also appears to be more specific to flexible forms of memory, one of the first cognitive domains (i.e. episodic memory) affected in Alzheimer’s disease.


Ageing Mice Contextual memory Episodic memory S 24795 Memantine Nicotinic receptors 


  1. Alkondon M, Pereira EF, Albuquerque EX (1998) Alpha-bungarotoxin- and methyllycaconitine-sensitive nicotinic receptors mediate fast synaptic transmission in interneurons of rat hippocampal slices. Brain Res 810:257–263PubMedCrossRefGoogle Scholar
  2. Alkondon M, Pereira EF, Albuquerque EX (2003) NMDA and AMPA receptors contribute to the nicotinic cholinergic excitation of CA1 interneurons in the rat hippocampus. J Neurophysiol 90:1613–1625PubMedCrossRefGoogle Scholar
  3. Barik J, Wonnacott S (2006) Indirect modulation by α7 nicotinic acetylcholine receptors of noradrenaline release in rat hippocampal slices: interaction with glutamate and GABA systems and effect of nicotine withdrawal. Mol Pharmacol 69:618–628PubMedCrossRefGoogle Scholar
  4. 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 8:565–571PubMedCrossRefGoogle Scholar
  5. Bastin C, Van Der Linden M, Michel AP, Friedman WJ (2004) The effects of ageing on location-based and distance-based processes in memory for time. Acta Psychol 116:145–171CrossRefGoogle Scholar
  6. Beracochea D, Celerier A, Pierard C (2004) βCCM but not physostigmine enhancement of memory retrieval depends on emotional processes in mice. Psychopharmacology 176:66–73PubMedCrossRefGoogle Scholar
  7. Beracochea 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 193:63–73PubMedCrossRefGoogle Scholar
  8. Broide RS, Leslie FM (1999) The alpha7 nicotinic acetylcholine receptor in neuronal plasticity. Mol Neurobiol 20:1–16PubMedCrossRefGoogle Scholar
  9. Buccafusco JJ, Jackson WJ, Terry AV Jr, Marsh KC, Decker MW (1995) Improvement in performances of a delayed matching-to-sample task by monkeys following ABT-418: a novel cholinergic channel activator for memory enhancement. Psychopharmacology 120:256–266PubMedCrossRefGoogle Scholar
  10. Celerier A, Pierard C, Sarrieau A, Béracochéa D (2004a) Spatial and contextual discrimination: a new behavioral tool to assess the effects of acute stress on retrieval of flexible or stable information in mice. Learn Mem 11:196–204PubMedCrossRefGoogle Scholar
  11. Celerier C, Piérard C, Béracochéa D (2004b) Effects of βCCM on retrieval memory processes. Behav Pharmacol 15:123–131PubMedCrossRefGoogle Scholar
  12. Clayton NS, Bussey T, Dickinson A (2003) Can animals recall the past and plan for future? Nat Rev 4:685–691CrossRefGoogle Scholar
  13. Creeley C, Wozniak DF, Labruyere J, Taylor GT, Olney JW (2006) Low doses of memantine disrupt memory in adult rats. J Neurosci 26:3923–3932PubMedCrossRefGoogle Scholar
  14. Danysz W, Parsons CG (2003) The NMDA receptor antagonist memantine as a symptomatological and neuroprotective treatment for Alzheimer’s disease: preclinical evidence. Int J Geriatr Psychiatry 18:523–532CrossRefGoogle Scholar
  15. David V, Chauveau F, Pierard C, Beracochea D (2006) Different involvement of the hippocampus and amygdala in the retrieval pattern of serial contextual information after an acute stress in mice. In: FENS Forum Abstracts, vol. 3, Vienna, 8–12 July 2006Google Scholar
  16. Dere E, Kart-Teke E, Huston JP, De Souza Silva (2006) The case for episodic memory in animals. Neurosci Biobehav Rev 30:1206–1224PubMedCrossRefGoogle Scholar
  17. Doyere V, Gisquet-Verrier P, de Marsanich B, Ammassari-Teule M (2000) Age-related modifications of contextual information processing in rats: role of emotional reactivity, arousal and testing procedure. Behav Brain Res 114:153–165PubMedCrossRefGoogle Scholar
  18. Earles JL, Smith AD, Park DC (1996) Adult age differences in the effects of environmental context on memory performance. Exp Aging Res 3:267–280CrossRefGoogle Scholar
  19. Eichembaum H (2000) A cortical-hippocampal system for declarative memory. Nat Rev Neurosci 2:844–847Google Scholar
  20. Frazier CJ, Buhler AV, Weiner JL, Dunwiddie TV (1998) Synaptic potentials mediated via α-bungarotoxin-sensitive nicotinic acetylcholine receptors in rat hippocampal interneurons. J Neurosci 18:8228–8235PubMedGoogle Scholar
  21. Grady CL, Craik FIM (2000) Changes in memory processing with age. Curr Opin Neurobiol 10:224–231PubMedCrossRefGoogle Scholar
  22. Hasselhorn M, Hager W, Cienciala D (1989) Recall and reproduction of words: age-dependent activation of context information in recalling episodic-memory contents. Z Gerontol 22:298–307PubMedGoogle Scholar
  23. Holladay MW, Dart MJ, Linch JK (1997) Neuronal nicotinic acetylcholine receptors as targets for drug discovery. J Med Chem 40:4169–4193PubMedCrossRefGoogle Scholar
  24. Jones S, Sudweeks S, Yakel JL (1999) Nicotinic receptors in the brain: correlating physiology with function. Trends Neurosci 22:555–561PubMedCrossRefGoogle Scholar
  25. Kanno T, Yaguchi T, Yamamoto S, Nagata T, Yamamoto H, Fujikawa H, Nishizaki T (2005) Bidirectional regulations for glutamate and GABA release in the hippocampus by α7 and non-α7 ACh receptors. Biochem Biophys Res Commun 338:742–747PubMedCrossRefGoogle Scholar
  26. Kem WR (2000) The brain alpha7 nicotinic receptor may be an important therapeutic target for the treatment of Alzheimer’s disease: studies with DMXBA (GTS-21). Behav Brain Res 113:169–181PubMedCrossRefGoogle Scholar
  27. Kessels RP, Hobbel D, Postma A (2007) Aging, context memory and binding: a comparison of “what, where and when” in young and older adults. Int J Neurosci 117:795–810PubMedCrossRefGoogle Scholar
  28. Levin ED, Simon BB (1998) Nicotinic acetylcholine receptors involvement in cognitive function in animals. Psychopharmacology 138:217–230PubMedCrossRefGoogle Scholar
  29. Levin ED, Bradley A, Addy N, Sigurani N (2002) Hippocampal alpha 7 and alpha 4 beta 2 nicotinic receptors and working memory. Neuroscience 109:757–765PubMedCrossRefGoogle Scholar
  30. Levin ED, McClernon FJ, Rezvani AH (2006) Nicotinic effects on cognitive function: behavioral characterization, pharmacological specification and anatomic localization. Psychopharmacology 184:523–539PubMedCrossRefGoogle Scholar
  31. Lopez-Hernandez G, Placzek AN, Thinschmidt JS, Lestage P, Trocme-Thibierge C, Morain P, Papke RL (2007) Partial agonist and neuromodulatory activity of S 24795 for α7 nACh responses of hippocampal interneurons. Neuropharmacology 53(1):134–144PubMedCrossRefGoogle Scholar
  32. Minkeviciene R, Banerjee P, Tanila H (2004) Memantine improves spatial learning in a transgenic mouse model of Alzheimer’s disease. J Pharmacol Exp Ther 311:677–682PubMedCrossRefGoogle Scholar
  33. Nagele RG, D’Andrea MR, Anderson WJ, Wang H-Y (2002) Intracellular accumulation of beta-amyloid(1-42) in neurons is facilitated by the alpha 7 nicotinic acetylcholine receptor in Alzheimer’s disease. Neuroscience 110:199–211PubMedCrossRefGoogle Scholar
  34. Newhouse P, Potter A, Corwin J (1996) Effects of nicotinic cholinergic agents on cognitive functioning in Alzheimer’s and Parkinson’s disease. Drug Dev Res 38:278–289CrossRefGoogle Scholar
  35. Radcliffe KA, Dani JA (1998) Nicotinic stimulation produces multiple forms of increased glutamatergic synaptic transmission. J Neurosci 18:7075–7083PubMedGoogle Scholar
  36. Rogawski MA, Wenk GL (2003) The neuropharmacological basis for the use of memantine in the treatment of Alzheimer’s disease. CNS Drug Reviews 9(3):275–308CrossRefGoogle Scholar
  37. Shimamura AP (1994) Neuropsychological perspectives on memory and cognitive decline in normal human ageing. Semin Neurosci 6:387–394CrossRefGoogle Scholar
  38. Smith AD, Park DC, Earles JL, Shaw RJ, Whiting WL (1998) Age differences in context integration. Psychol Aging 13:21–28PubMedCrossRefGoogle Scholar
  39. Spencer WD, Raz N (1995) Differential effects of ageing on memory for content and context: a meta-analysis. Psychol Aging 10:527–539PubMedCrossRefGoogle Scholar
  40. Thomas AK, Bulevich JB (2006) Effective cue utilization reduces memory errors in older adults. Psychol Aging 21:379–389PubMedCrossRefGoogle Scholar
  41. Van Dam D, Abramowski D, Staufenbiel M, De Deyn PP (2005) Symptomatic effects of donepezil, rivastigmine, galantamine and memantine on cognitive deficits in the APP23 model. Psychopharmacology 180:177–190PubMedCrossRefGoogle Scholar
  42. Wang HY, Lee DH, D’Andrea MR, Peterson PA, Shank RP, Reitz AB (2000) β-Amyloid1-42 binds to α7 nicotinic acetylcholine receptor with high affinity. Implications for Alzheimer’s disease pathology. J Biol Chem 275:5626–5632PubMedCrossRefGoogle Scholar
  43. Zajaczowski W, Frankiewicz T, Parsons CG, Danysz W (1997) Uncompetitive NMDA receptor antagonists attenuate NMDA-induced impairment of passive avoidance learning and LTP. Neuropharmacology 36:961–976CrossRefGoogle Scholar
  44. Zoladz PR, Campbell AM, Collin RP, Schaefer D, Danysz W, Diamond DM (2006) Enhancement of long-term spatial memory in adult rats by the noncompetitive NMDA receptor antagonists, memantine and neramexane. Pharmacol Biochem Behav 85:298–306PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Daniel Beracochea
    • 1
  • Aurelie Boucard
    • 1
  • Caryn Trocme-Thibierge
    • 2
  • Philippe Morain
    • 2
  1. 1.Centre de Neurosciences Intégratives et Cognitives (CNIC), CNRS UMR 5228Universités de Bordeaux 1 et 2Talence-CédexFrance
  2. 2.Institut de Recherches Internationales ServierCourbevoie CedexFrance

Personalised recommendations