, Volume 193, Issue 1, pp 63–73 | Cite as

Improvement of episodic contextual memory by S 18986 in middle-aged mice: comparison with donepezil

  • D. Béracochéa
  • J. N. Philippin
  • S. Meunier
  • P. Morain
  • K. Bernard
Original Investigation



This study compared the effects of S 18986, a positive allosteric modulator of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors, to those of donepezil a cholinesterase inhibitor on memory impairments induced by ageing in a contextual serial discrimination (CSD) task in middle-aged mice.

Materials and methods

The CSD task involved the learning of two consecutive discriminations in a four-hole board, each performed on two different floors. This model has been developed to study simultaneously different forms of memory in mice (i.e., episodic-like vs semantic-like forms of memory). We showed that placebo-middle-aged mice (14–15 months old) and placebo-aged subjects (19–20 months old) exhibited a severe memory deficit for the first but not the second discrimination, which was due to an increase in interference, as compared with placebo-treated young mice (5 months old). Middle-aged mice were given (9 days) per os administration of either donepezil, S 18986, or placebo.

Results and discussion

Both 0.3 mg/kg donepezil and 0.1 mg/kg S 18986 reversed the deficit of middle-aged mice through a significant increase in contextually correct responses and in parallel a tendency to reduce interfering responses.


Overall, S 18986 emerges as having a beneficial impact on contextual memory processes in middle-aged mice.


Ageing Mice Contextual memory Episodic memory Semantic memory S 18986 Donepezil AMPA receptors 


  1. Bartus RT, Dean RL, Beer B, Lippa AS (1982) The cholinergic hypothesis of geriatric memory dysfunction. Science 217(4558):408–414PubMedCrossRefGoogle Scholar
  2. 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
  3. 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
  4. Bontempi B, Whelan KT, Risbrough VB, Lloyd GK, Menzaghi F (2003) Cognitive enhancing properties and tolerability of cholinergic agents in mice: a comparative study of nicotine, Donepezil and SIB-1553A, a subtype-selective ligand for nicotinic acethylcholine receptors. Neuropsychopharmacology 28:1235–1246PubMedCrossRefGoogle Scholar
  5. 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
  6. Celerier C, Pierard C, Beracochea D (2004b) Effects of βCCM on retrieval memory processes. Behav Pharmacol 15:123–131PubMedCrossRefGoogle Scholar
  7. Chauveau F, Pierard C, Drouet I, Beracochea D (2005) First evidence of the involvement of hippocampal corticosterone membranar receptors on the effects of an acute stress on memory retrieval in mice. Abstract of the French Neurosciences Society (G16), Lille, FranceGoogle Scholar
  8. Davis HP, Small SA, Stern Y, Mayeux R, Feldstein SN, Keller FR (2003) Acquisition, recall, and forgetting of verbal information in long-term memory by young, middle-aged, and elderly individuals. Cortex 39:1063–1091PubMedCrossRefGoogle Scholar
  9. 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
  10. Eichenbaum H (2000) A cortical-hippocampal system for declarative memory. Nat Rev Neurosci 2:844–847Google Scholar
  11. Francia N, Cirulli F, Chiarotti F, Antonelli A, Aloe L, Alleva E (2006) Spatial memory deficits in middle-aged mice correlate with lower exploratory activity and a subordinate status: role of hippocampal neurotrophins. Eur J Neurosci 23(3):711–728PubMedCrossRefGoogle Scholar
  12. Francis PT (2005) The interplay of neurotransmitters in Alzheimer’s disease. CNS Spectr 11(Suppl 18):6–9Google Scholar
  13. Gill KM, Mizumori SJ (2006) Context-dependent modulation by D(1) receptors: differential effects in hippocampus and striatum. Behav Neurosci 120:377–392PubMedCrossRefGoogle Scholar
  14. Hobin JA, Maren S (2006) Ventral hippocampal muscimol disrupts context-specific fear memory retrieval after extinction in rats. Hippocampus 16:174–182PubMedCrossRefGoogle Scholar
  15. Lebrun C, Pilliere E, Lestage P (2000) Effects of S 18986-1, a novel cognitive enhancer, on memory performances in an object recognition task in rats. Eur J Pharmacol 401:205–212PubMedCrossRefGoogle Scholar
  16. Lepagnol J, Lebrun C, Pilliere E, Thomas JY, Desos P, Cordi A, Lestage P (1997) Neuroexcitatory and cognition enhancing effect of S 18986, a positive allosteric modulator of glutamate AMPA receptor. 27th Annual Meeting of the Neuroscience Society, New Orleans, October 1997. Am Soc Neurosci 23(2):1841Google Scholar
  17. Lockhart B, Iop F, Closier M, Lestage P (2000) (S)-2,3-dihydro-(3,4) cyclopentano-1,2,4-benzothiadiazine-1,1-dioxide: (S18986-1) a positive modulator of AMPA receptors enhances (S)-AMPA-mediated (3H) noradrenaline release from rat hippocampal and frontal cortex slices. Eur J Pharmacol 401:145–153PubMedCrossRefGoogle Scholar
  18. Malin EL, McGaugh JL (2006) Differential involvement of the hippocampus, anterior cingulate cortex, and basolateral amygdala in memory for context and footshock. Proc Natl Acad Sci USA 103:1959–1963PubMedCrossRefGoogle Scholar
  19. Rex CS, Kramar EA, Colgin LL, Lin B, Gall CM, Lynch G (2005) Long-term potentiation is impaired in middle-aged rats: regional specificity and reversal by adenosine receptor antagonists. J Neurosci 25(25):5956–5966PubMedCrossRefGoogle Scholar
  20. Rosi S, Giovannini MG, Lestage PJ, Munoz C, Corte LD, Pepeu G (2004) S 18986, a positive modulator of AMPA receptors with cognition-enhancing properties, increases Ach release in the hippocampus of young and aged rat. Neurosci Lett 361:120–123PubMedCrossRefGoogle Scholar
  21. Shimamura AP (1994) Neuropsychological perspectives on memory and cognitive decline in normal human ageing. Semin Neurosci 6:387–394CrossRefGoogle Scholar
  22. Smith AD, Park DC, Earles JL, Shaw RJ, Whiting WL (1998) Age differences in context integration. Psychol Ageing 13:21–28CrossRefGoogle Scholar
  23. Spencer WD, Raz N (1995) Differential effects of ageing on memory for content and context: a meta-analysis. Psychol Ageing 10:527–539CrossRefGoogle Scholar
  24. Teipel SJ, Drzezga A, Bartenstein P, Moller HJ, Schwaiger M, Hampel H (2006) Effects of Donepezil on cortical metabolic response to activation during (18)FDG-PET in Alzheimer’s disease: a double-blind cross-over trial. Psychopharmacology 187:86–94PubMedCrossRefGoogle Scholar
  25. Ward MT, Oler JA, Markus EJ (1999a) Hippocampal dysfunction during ageing I: deficits in memory consolidation. Neurobiol Ageing 20(4):363–372CrossRefGoogle Scholar
  26. Ward MT, Stoelzel CR, Markus EJ (1999b) Hippocampal dysfunction during ageing II: deficits the radial-arm maze. Neurobiol Ageing 20(4):373–380CrossRefGoogle Scholar
  27. Westphalen RI, Scott HL, Dodd PR (2003) Synaptic vesicle transport and synaptic membrane transporter sites in excitatory amino acid nerve terminals in Alzheimer’s disease. J Neural Transm 110(9):1013–1027PubMedCrossRefGoogle Scholar
  28. Wilkinson DG, Francis PT, Schwam E, Payne-Parrish J (2004) Cholinesterase inhibitors used in the treatment of Alzheimer’s disease: the relationship between pharmacological effects and clinical efficacy. Drugs Ageing 21:453–478CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • D. Béracochéa
    • 1
  • J. N. Philippin
    • 1
  • S. Meunier
    • 2
  • P. Morain
    • 2
  • K. Bernard
    • 2
  1. 1.Centre de Neurosciences Intégratives et Cognitives(CNIC), UMR CNRS 5228, Bat Biologie AnimaleUniv. Bordeaux 1 et 2Talence-cedexFrance
  2. 2.Institut de Recherches Internationales Servier (IRIS)Courbevoie cedexFrance

Personalised recommendations