, Volume 126, Issue 4, pp 323–330 | Cite as

The neurosteroid pregnenolone sulfate reduces learning deficits induced by scopolamine and has promnestic effects in mice performing an appetitive learning task

  • H. Meziane
  • C. Mathis
  • A. Ungerer
  • S. M. Paul
Original Investigation


The effects of the neurosteroid pregnenolone sulfate (PS) on learning as well as on scopolamine-induced learning deficits were studied in Swiss mice using an appetitively reinforced Go-No Go visual discrimination task. Subcutaneous (SC) administration of scopolamine (0.3–3 mg/kg) after the first session of training dose-dependently impairs learning during the following sessions in this task. Moreover, intracerebroventricular (ICV) administration of PS (0.01–10 nmol) dose-dependently blocks learning deficits induced by scopolamine (3 mg/kg), with the most potent effects at the dose of 0.5 nmol PS. In addition to antagonizing the amnestic effects of scopolamine, PS (0.5 nmol ICV) has a memory-enhancing effect, when administered alone after the first training session. Scopolamine (3 mg/kg SC) also produced substantial deficits on retrieval performance in the Go-No Go visual discrimination task, and caused motor disturbances, when administered 15 min before testing. PS (0.5 nmol ICV) also reduced scopolamine-induced deficits on retrieval but had no effect on scopolamine-induced motor impairments in the traction reflex test. Such a rapid effect of PS on memory processes may be mediated via NMDA and/or GABAA receptors.

Key words

Retrieval NMDA receptor GABAA receptor Memory Amnesia Go-No Go visual discrimination Mice 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Bartus RT, Johnson HR (1976) Short-term memory in the Rhesus monkey: disruption from the anticholinergic scopolamine. Pharmacol Biochem Behav 5:39–46CrossRefPubMedGoogle Scholar
  2. Bartus RT, Dean RL, Beer B, Lippa AS (1982) The cholinergic hypothesis of geriatric memory dysfunction. Science 217:408–417Google Scholar
  3. Beatty WW, Butters N, Janowsky DS (1986) Patterns of memory failures after scopolamine treatment: implications for cholinergic hypothesis of dementia. Behav Neural Biol 45:196–211Google Scholar
  4. Bowlby MR (1993) Pregnenolone sulfate potentiation ofN-methyl-d-aspartate receptor channels in hippocampal neurons. Mol Pharmacol 43:813–819PubMedGoogle Scholar
  5. Cheney DL, Uzunov D, Guidotti A (1995) Pregnenolone antagonizes dizocilpine amnesia: role for allopregnanolone. Neuroreport 6:1697–1700PubMedGoogle Scholar
  6. Collerton D (1986) Cholinergic function and intellectual decline in Alzheimer's disease. Neuroscience 19:1–28CrossRefPubMedGoogle Scholar
  7. Corpéchot C, Synguelakis M, Talha S, Axelson M, Sjövall J, Vihko R, Baulieu E-E, Robel P (1983) Pregnenolone and its sulfate ester in the rat brain. Brain Res 270:119–125CrossRefPubMedGoogle Scholar
  8. Coyle JT, Price DL, Delong MR (1983) Alzheimer's disease: a disorder of cortical cholinergic innervation. Science 219:1184–1190PubMedGoogle Scholar
  9. Curran HV, Schifano F, Lader M (1991) Models of memory dysfunction? A comparison of the effects of scopolamine and lorazepam on memory, psychomotor performance and mood. Psychopharmacology 103:83–90PubMedGoogle Scholar
  10. Dawson GR, Bentley G, Draper F, Rycroft W, Iversen SD, Pagella PG (1991) The behavioral effects of heptyl physostigmine, a new cholinesterase inhibitor, in tests of long-term and working memory in rodents. Pharmacol Biochem Behav 39:865–871Google Scholar
  11. Dawson GR, Heyes CM, Iversen SD (1992) Pharmacological mechanisms and animal models of cognition. Behav Pharmacol 3:285–297PubMedGoogle Scholar
  12. Deutsch JA, Rocklin KW (1967) Amnesia induced by scopolamine and its temporal variations. Nature 216:89–90Google Scholar
  13. Drachmann D (1977) Memory and cognitive function in man: does the cholinergic system have a specific role. Neurology 27:783–790PubMedGoogle Scholar
  14. Flood JF, Roberts E (1988) Dehydroepiandrosterone sulfate improves memory in aging mice. Brain Res 448:178–181CrossRefPubMedGoogle Scholar
  15. Flood JF, Smith GE, Roberts E (1988) Dehydroepiandrosterone and its sulfate enhance memory retention in mice. Brain Res 447:269–278CrossRefPubMedGoogle Scholar
  16. Flood JF, Morley JE, Roberts E (1992) Memory-enhancing effects in mice of pregnenolone and steroids metabolically derived from it. Proc Natl Acad Sci USA 89:1567–1571PubMedGoogle Scholar
  17. Hu ZY, Bourreau E, Jung-Testas I, Robel P, Baulieu E-E (1987) Neurosteroids: oligodendrocytes mitochondria convert cholesterol to prenenolone. Proc Natl Acad Sci USA 84:8215–8219PubMedGoogle Scholar
  18. Irwin RP, Maragakis NJ, Rogawski MA, Purdy RH, Farb DH, Paul SM (1992) Pregnenolone sulfate augments NMDA receptor increases in intracellular Ca2+ in cultured rat hippocampal neurons. Neurosci Lett 141:30–34CrossRefPubMedGoogle Scholar
  19. Itoh S, Takashima A, Katsuura G (1988) Preventive effect of cholecystokinin octapeptide on scopolamine-induced memory impairment in the rat. Drug Dev Res 12:63–70CrossRefGoogle Scholar
  20. Jaffard R, Durkin T, Toumane A, Marighetto A, Lebrun C (1989) Experimental dissociation of memory systems in mice: behavioral and neurochemical aspects. Arch Gerontol Geriatr Suppl 1:55–70PubMedGoogle Scholar
  21. Kawano J, Kotani T, Ohtaki S, Minamino N, Matsuo H, Oinuma T, Aikawa E (1989) Characterization of rat and human steroid sulfatases. Biochem Biophys Acta 997:199–205PubMedGoogle Scholar
  22. Kopelman MD, Corn TH (1988) Cholinergic “blockade” as a model for cholinergic depletion. A comparison of the memory deficits with those of Alzheimer type dementia and the alcoholic Korsakoff syndrome. Brain 111:1079–1110PubMedGoogle Scholar
  23. Lamberty Y, Gower J (1991) Cholinergic modulation of spatial learning in mice in a Morris-type water maze. Arch Int Pharmacodyn Ther 309:5–19PubMedGoogle Scholar
  24. Magnani M, Pozzi O, Biagetti R, Banfi S, Dorigotti L (1992) Oxiracetam antagonizes the disruptive effects of scopolamine on memory in the radial maze. Psychopharmacology 106:175–178PubMedGoogle Scholar
  25. Maione S, Berrino L, Vitagliano S, Leyva J, Rossi F (1992) Pregnenolone sulfate increases the convulsant potency ofN-methyl-d-aspartate in mice. Eur J Pharmacol 219:477–479CrossRefPubMedGoogle Scholar
  26. Majewska MD, Schwartz RD (1987) Pregnenolone sulfate: an endogenous antagonist of the γ-aminobutyric acid receptor complex in the brain? Brain Res 404:355–360CrossRefPubMedGoogle Scholar
  27. Mathis C, Paul SM, Crawley JN (1994) The neurosteroid pregnenolone sulfate blocks NMDA antagonist-induced deficits in a passive avoidance memory task. Psychopharmacology 116:201–206CrossRefPubMedGoogle Scholar
  28. Mathur C, Prasad VVK, Raju VS, Welch M, Liberman S (1993) Steroids and their conjugates in the mammalian brain. Proc Natl Acad Sci USA 90:85–88PubMedGoogle Scholar
  29. Mayo W, Dellu F, Robel P, Cherkaoui J, Le Moal M, Baulieu E-E, Simon H (1993) Infusion of neurosteroids into the nucleus basalis magnocellularis affects cognitive processes in the rat. Brain Res 607:324–328CrossRefPubMedGoogle Scholar
  30. Melchior CL, Ritzmann RF (1996) Neurosteroids block the memory-impairing effects of ethanol in mice. Pharmacol Biochem Behav 53:51–56CrossRefPubMedGoogle Scholar
  31. Meziane H, Devigne C, Tramu G, Soumireu-Mourat B (1993) Effects of anti-CCK-8 antiserum on acquisition and retrieval by mice in an appetitive task. Peptides 14:67–73CrossRefPubMedGoogle Scholar
  32. Mienville J-M, Vicini S (1989) Pregnenolone sulfate antagonizes GABA-A receptor-mediated currents via a reduction of channel opening frequency. Brain Res 489:190–194CrossRefPubMedGoogle Scholar
  33. Okaichi H Oshima Y, Jarrard LE (1989) Scopolamine impairs both working and reference memory in rats: a replication and extension. Pharmacol Biochem Behav 34:599–602Google Scholar
  34. Orentreich N, Brind JL, Rizer RL, Vogelman JH (1984) Age changes and sex differences in serum dehydroepiandrosterone sulfate concentrations throughout adulthood. J Clin Endocrinol Metab 59:551–555PubMedGoogle Scholar
  35. Paul SM, Purdy R (1992) Neuroactive steroids. FASEB J 6:2311–2322PubMedGoogle Scholar
  36. Pepeu G, Giovannelli L (1994) The central cholinergic system during aging. Prog Brain Res 100:67–71PubMedGoogle Scholar
  37. Reinikainen KJ, Soininen H, Riekkinen PJ (1990) Neurotransmitter changes in Alzheimer's disease: implications to diagnostics and therapy. J Neurosci Res 27:576–586CrossRefPubMedGoogle Scholar
  38. Roberts E (1995) Pregnenolone: From Selye to Alzheimer and a model of the pregnenolone sulfate binding site on the GABA-A receptor. Biochem Pharmacol 49[1]:1–16CrossRefPubMedGoogle Scholar
  39. Romeo E, Cheney DL, Zivkovic I, Costa E, Guidotti A (1994) Mitochondrial diazepam-binding inhibitor receptor complex agonists antagonize dizocilpine amnesia: putative role for allopregnanolone. J Pharmacol Exp Ther 270:89–96PubMedGoogle Scholar
  40. Rosat R, Da-Silva RC, Zanatta MS, Medina JH, Izquierdo I (1992) Memory consolidation of a habitution task: role ofN-methyl-d-aspartate cholinergic muscarinic and GABA-A receptors in different brain regions. Braz J Med Biol Res 25:267–273PubMedGoogle Scholar
  41. Rush D, Streit K (1992) Memory consolidation with peripherally acting cholinergic drugs. Psychopharmacology 106:375–382CrossRefPubMedGoogle Scholar
  42. Sirviö J, Ekonsalo T, Riekkinen Jr P, Lahtinen H, Riekkinen Sr P (1992)d-Cycloserine a modulator of theN-methyl-d-aspartate receptor, improves spatial learning in rats treated with muscarinic antagonist. Neurosci Lett 146:215–218CrossRefPubMedGoogle Scholar
  43. Spencer DG, Lal H (1983) Effects of anticholinergic drugs on learning and memory. Drug Dev Res 3:489–502CrossRefGoogle Scholar
  44. Stone WS, Walser B, Gold SD, Gold PE (1991) Scopolamine-and morphine-induced impairments of spontaneous alternation performance in mice: reversal with glucose and with cholinergic and adrenergic agonists. Behav Neurosci 105:264–271Google Scholar
  45. Wu F-S, Gibbs TT, Farb DH (1991) Pregnenolone sulfate: a positive allosteric modulator at theN-methyl-D-aspartate receptor. Mol Pharmacol 40:333–336PubMedGoogle Scholar

Copyright information

© Springer-Verlag 1996

Authors and Affiliations

  • H. Meziane
    • 1
  • C. Mathis
    • 1
  • A. Ungerer
    • 1
  • S. M. Paul
    • 2
  1. 1.Laboratoire de Psychophysiologie, ULP, URA-CNRS 1295StrasbourgFrance
  2. 2.Lilly Research LaboratoriesA Division of Eli Lilly and Company, Lilly Corporate CenterIndianapolisUSA

Personalised recommendations