Advertisement

Psychopharmacology

, Volume 169, Issue 1, pp 35–41 | Cite as

Flumazenil and tacrine increase the effectiveness of ondansetron on scopolamine-induced impairment of spatial learning in rats

  • M. Diez-Ariza
  • C. Redondo
  • M. García-Alloza
  • B. Lasheras
  • J. Del Río
  • M. J. Ramírez
Original Investigation

Abstract

Rationale

Cholinergic receptor blockade produces memory deficits in animal models. These deficits can be prevented by 5-HT3 receptor antagonists, such as ondansetron, which increases acetylcholine release. We investigated the effects on cognitive performance of combined treatments of ondansetron with either flumazenil, a GABAA receptor benzodiazepine site antagonist, or tacrine, a cholinesterase inhibitor, which are also able to prevent scopolamine-induced cognitive impairment.

Methods

Spatial learning and memory was assessed by studying the effects of single and combined treatments on acquisition and retention of the Morris water maze task in rats.

Results

Scopolamine (0.6 mg/kg) induced significant learning and retention deficits. Both ondansetron (0.1 μg/kg) and tacrine (3 mg/kg) partially prevented the scopolamine-induced learning deficit. A full reversal was only found after the combined treatment of ondansetron with flumazenil (10 mg/kg) and also after tacrine in combination with ondansetron. Likewise, scopolamine-induced retention deficit was fully counteracted by the combined treatment of ondansetron with either flumazenil or tacrine, and only partially by any of the single treatments tested.

Conclusions

The scopolamine-induced impairment of learning and retention in the water maze is fully prevented by ondansetron when given in combination with either flumazenil or tacrine, suggesting that both combined treatments result in a potentiated cholinergic function and may constitute the basis of a new therapy for cognitive disorders.

Keywords

Serotonin GABA Ondansetron Tacrine Flumazenil Morris water maze 

Notes

Acknowledgements

Supported in part by a grant from Gobierno de Navarra (Spain). Monica Garcia-Alloza is a fellow from FIS (Instituto de Salud Carlos III, Spain). We thank Mari-Luz Muro for technical help.

References

  1. Anger WK (1991) Animal test system to study behavioral dysfuctions of neurodegenerative disorders. Neurotoxicology 12:403–414PubMedGoogle Scholar
  2. Arendt T, Lehmann K, Seeger G, Gartner U (1999) Synergistic effects of tetrahydroaminoacridine and lithium on cholinergic function after excitotoxic basal forebrain lesions in rat. Pharmacopsychiat 32:242–247CrossRefGoogle Scholar
  3. Arnsten AF, Lin CH, Van Dyck CH, Stanhope KT (1997) The effects of 5-HT3 receptor antagonists on cognitive performance in aged monkeys. Neurobiol Aging 18:21–28CrossRefPubMedGoogle Scholar
  4. Astur RS, Ortiz ML, Sutherland RJ (1998) A characterization of performance by men and women in a virtual Morris water task: a large and reliable sex difference. Brain Res 93:185–190CrossRefPubMedGoogle Scholar
  5. Barnes JM, Barnes NM, Costall B, Naylor MJ, Tyers MB (1989) 5-HT3 receptor mediate inhibition on acetylcholine release in cortical tissue. Nature 338:762–763Google Scholar
  6. Barnes NM, Costall B, Naylor RJ, Williams TJ, Wischik CM (1990) Normal densities of 5-HT3 receptor recognition sites in Alzheimer's disease. Neuroreport 1:253–254PubMedGoogle 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. Binetti G, Cappa SF, Magni E, Padovani A, Bianchetti A, Trabucchi M (1996) Disorders of visual and spatial perception in the early stage of Alzheimer's disease. Ann NY Acad Sci 777:221–225PubMedGoogle Scholar
  9. Bloom FE, Morales M (1998) The central 5-HT3 receptor in CNS disorders. Neurochem Res 23:653–659PubMedGoogle Scholar
  10. Broocks A, Little JT, Martin A, Minichello MD (1998) The influence of ondansetron and m-chlorophenylpiperazine on scopolamine-induced cognitive, behavioral and physiological responses in young healthy controls. Biol Psychiatry 43:408–416PubMedGoogle Scholar
  11. Buffett-Jerrott SE, Stewart SH (2002) Cognitive and sedative effects of benzodiazepine use. Curr Pharm Des 8:45–58PubMedGoogle Scholar
  12. Buhot MC (1997) Serotonin receptors in cognitive behaviors. Curr Opin Neurobiol 7:243–254PubMedGoogle Scholar
  13. Buhot MC, Martin S, Segu L (2000) Role of serotonin in memory impairment. Ann Med 32:210–221PubMedGoogle Scholar
  14. Butler A, Hill JM, Ireland SJ, Jordan CC, Tyers MB (1988) Pharmacological properties of GR 38032F, a novel antagonist at 5-HT3 receptors. Br J Pharmacol 94:397–412PubMedGoogle Scholar
  15. Carey GJ, Costall B, Domeney AM, Gerrard PA, Jones DNC, Naylor RJ, Tyers MB (1992) Ondansetron and arecoline prevent scopolamine-induced cognitive deficits in the marmoset. Pharmacol Biochem Behav 42:75–83CrossRefPubMedGoogle Scholar
  16. Carli M, Luschi R, Samanin R (1997) Dose-related impairment of spatial learning by intrahippocampal scopolamine: antagonism by ondansetron, a 5-HT3 receptor antagonist. Behav Brain Res 82:185–194CrossRefPubMedGoogle Scholar
  17. Cassel JC, Jeltsch H (1995) Serotonergic modulation of cholinergic function in the central nervous system: cognitive implications. Neuroscience 69:1–41Google Scholar
  18. Corradetti R, Ballerini L, Pugliese A, Pepeu G (1992) Serotonin blocks the long-term potentiation induced by primed burst stimulation in the CA1 region of rat hippocampal slices. Neuroscience 46:511–518.PubMedGoogle Scholar
  19. Costall B, Naylor RJ (1997) Neuropharmacology of 5-HT3 receptors ligands. In: Baumgarten HG, Göthert M (eds) Serotoninergic neurons and 5-HT receptors in the CNS. Springer, Berlin Heidelberg New York, pp 409–438Google Scholar
  20. Costall B, Domeney AM, Kelly ME, Naylor RJ (1992) Influence of 5-HT on cognitive performance. Adv Biosci 85:147–164Google Scholar
  21. Dawson RM, Poretski M (1991) The interaction of tacrine with benzodiazepine and GABA binding sites of guinea pig brain. Neurosci Lett 129:251–3CrossRefPubMedGoogle Scholar
  22. De Belleroche J, Gardiner IM (1988) Inhibitory effect of 1,2,3,4-tetrahydro-9-aminoacridine on the despolarization-induced release of GABA from cerebral cortex. Br J Pharmacol 94:1017–1019PubMedGoogle Scholar
  23. Díez-Ariza M, Ramírez MJ, Lasheras B, Del Río J (1998) Differential interactions between 5-HT3 receptors and GABAergic neurons inhibiting acetylcholine release in rat entorhinal cortex slices. Brain Res 801:228–232CrossRefPubMedGoogle Scholar
  24. Díez-Ariza M, García-Alloza M, Lasheras B, Del Río J, Ramírez MJ (2002) GABAA receptor antagonists enhance cortical acetylcholine release induced by 5-HT3 receptor blockade in freely moving rats. Brain Res 956:81–85CrossRefPubMedGoogle Scholar
  25. Dixon CM, Colthup PV, Serabjit-Singh CJ, Kerr BM, Boehlert CC, Park GR, Tarbit MH (1995) Multiple forms of cytochrome P450 are involved in the metabolism of ondansetron in human. Drug Metab Dispos 23:1225–1230PubMedGoogle Scholar
  26. Dringenberg HC, Laporte PP, Diavolitsis P (2000) Increased effectiveness of tacrine by deprenyl co-treatment in rats: EEG and behavioral evidence. NeuroReport 11:3513–3516Google Scholar
  27. Duka T, Goerke D, Dorow R, Holler L, Fichte K (1988) Human studies on the benzodiazepine receptor antagonist beta-carboline ZK 93 426:antagonism of lormetazepam's psychotropic effects. Psychopharmacology 95:463–471PubMedGoogle Scholar
  28. Duka T, Ott H, Rohloff A, Voet B (1996) The effects of a benzodiazepine receptor antagonist beta-carboline ZK-93426 on scopolamine-induced impairment on attention, memory and psychomotor skills. Psychopharmacology 123:361–373Google Scholar
  29. Fontana DJ, Daniels SE, Henderson C, Eglen RM, Wong EHF (1995) Ondansetron improves cognitive performance in the Morris water maze spatial navigation task. Psychopharmacology 120:409–417PubMedGoogle Scholar
  30. Freeman SE, Dawson RM (1991) Tacrine: a pharmacological review. Prog Neurobiol 36:257–277CrossRefPubMedGoogle Scholar
  31. Gage FH, Dunnett SB, Bjorklund A (1984) Spatial learning and motor deficits in aged rats. Neurobiol Aging 5:43–48CrossRefPubMedGoogle Scholar
  32. Gallagher M, Colombo PJ (1995) Aging: the cholinergic hypothesis of cognitive decline. Curr Opin Neurobiol 5:161–168CrossRefPubMedGoogle Scholar
  33. Giorgetti M, Bacciottini L, Giovannini MG, Colivicchi MA, Goldfarb J (2000) Local GABAergic modulation of acetylcholine release from the cortex of freely moving rats. Eur J Neurosci 12:1941–1948CrossRefPubMedGoogle Scholar
  34. Greenshaw AJ (1993) Behavioural pharmacology of 5-HT3 receptor antagonists: a critical update on therapeutic potential. TIPS 14:265–270CrossRefPubMedGoogle Scholar
  35. Henderson VW, Mack W, Willians BW (1989) Spatial disorientation in Alzheimer's disease. Arch Neurol 46:391–394PubMedGoogle Scholar
  36. Hindmarch I (1998) Cognition and anxiety: the cognitive effects of anti-anxiety medication. Acta Pschiatr Scand 393:89–94Google Scholar
  37. Hodges H, Sowinski P, Sinden JD, Netto CA, Fletcher A (1995) The selective 5-HT3 receptor antagonists, WAY 100289, enhances spatial memory in rats with ibotenate lesions of the forebrain cholinergic projection system. Psychopharmacology 117:318–322PubMedGoogle Scholar
  38. Hodges H, Sowinski P, Turner JJ, Fletcher A (1996) A comparision of the effects of the 5-HT3 receptor antagonists WAY-100579 and ondansetron on spatial learning in the water maze in rats with excitotoxic lesions of the forebrain cholinergic projection system. Psychopharmacology 125:146–161PubMedGoogle Scholar
  39. Klotz U (1988) Drug interactions and clinical pharmacokinetics of flumazenil. Eur J Anaesthesiol [Suppl] 2:103–108Google Scholar
  40. Knopman D (2001) Pharmacotherapy for Alzheimer's disease. Curr Neurol Neurosci Rep 1:428–434PubMedGoogle Scholar
  41. Lal H, Forster MJ (1990) Flumazenil improves active avoidance performance in aging NZB/BINJ and C57BL/6Nnia mice. Pharmacol Biochem Behav 35:747–750CrossRefPubMedGoogle Scholar
  42. Lal H, Kumar BA, Forster MJ (1988) Enhancement of learning and memory in mice by benzodiazepine antagonists. FASEB J 2:2707–2711PubMedGoogle Scholar
  43. Lermontova N, Lukoyanov N, Serkova T, Lukoyanova E, Bachurin S (1998) Effects of tacrine on deficits in active avoidance performance induced by AF64A in rats. Mol Chem Neuropathol 33:51–61PubMedGoogle Scholar
  44. Li CY, Wang H, Xue H, Carlier PR, Hui KM, Pang YP, Li ZW, Han YF (1999) Bis (7)-tacrine, a novel dimeric AchE inhibitor, is a potent GABAA receptor antagonist. NeuroReport 10:795–800PubMedGoogle Scholar
  45. Little JT, Broocks A, Martin A, Hill JL, Tune LE, Mack C, Cantillon M, Molchan S, Murphy DL, Sunderland T (1995) Serotonergic modulation of anticholinergic effects on cognition and behavior in elderly humans. Psychopharmacology 120:280–288PubMedGoogle Scholar
  46. Marczynski TJ, Artwohl J, Marczynski B (1994) Chronic administration of flumazenil increases life span and protects rats form age-related loss of cognitive functions: a benzodiazepine/GABAergic hypothesis of brain aging. Neurobiol Aging 15:69–84CrossRefPubMedGoogle Scholar
  47. Maurice T, BP Lockhart (1996) Amnesia induced in mice by centrally administered beta-amyloid peptides involves cholinergic dysfunction. Brain Res 706:181–193CrossRefPubMedGoogle Scholar
  48. Meneses A (1998) Physiological, pathophysiological and therapeutic roles of 5-HT systems in learning and memory. Rev Neurosci 9:275–289Google Scholar
  49. Morales M, Bloom FE (1997) The 5-HT3 receptor is present in different subpopulations of GABAergic neurons in the rat telencephalon. J Neurosci 17:3157–3316PubMedGoogle Scholar
  50. Morris R (1984) Developments of a water maze procedure for studing spatial learning in the rat. J Neurosci Meth 11:47–60PubMedGoogle Scholar
  51. Prather PL, Forster MJ, Lal H (1992) Learning and memory-enhancing effects of Ro 15–4513: a comparision with flumazenil. Neuropharmacology 31:299–306CrossRefPubMedGoogle Scholar
  52. Ramírez MJ, Cenarruzabeitia E, Lasheras B, Del Río J (1996) Involvement of GABA systems in acetylcholine release induced by 5-HT3 receptor blockade in slices from rat entorhinal cortex. Brain Res 712:274–280CrossRefPubMedGoogle Scholar
  53. Riekkinen P, Jakala P, Sirvio J, Riekkinen P (1991) The effects of increased serotonergic and decreased cholinergic activities on spatial navigation performance in rats. Pharmacol Biochem Behav 39:25–29PubMedGoogle Scholar
  54. Riekkinen M, Riekkinen P, Sirvio J, Riekkinen P (1992) Effects of combined methysergide and mecamylamine/scopolamine treatment on spatial navigation. Brain Res 585:322–326CrossRefPubMedGoogle Scholar
  55. Riekkinen P Jr, Ikonen S, Riekkinen M (1998) Tetrahydroaminoacridine, a cholinesterase inhibitor, and D-cycloserine, a partial NMDA receptor-associated glycine site agonist, enhances acquisition of spatial navigation. Neuroreport 9:1633–1637PubMedGoogle Scholar
  56. Ropert N, Guy N (1991) Serotonin facilitates GABAergic transmission in the CA1 region of rat hippocampus in vitro. J Physiol 441:121–136PubMedGoogle Scholar
  57. Smolnik R, Pietrowsky R, Fehm HL, Born J (1998) Enhanced selective attention after low-dose administration of the benzodiazepine antagonist flumazenil. J Clin Psychopharmacol 18:241–247CrossRefPubMedGoogle Scholar
  58. Stemmelin J, Cassel JC, Will B, Kelche C (1999) Sensitivity to cholinergic drug treatment of aged rats with variable degrees of spatial memory impairment. Behav Brain Res 98:53–66CrossRefPubMedGoogle Scholar
  59. Wang T, Tang XC (1998) Reversal of scopolamine-induced deficits in radial maze performance by (-)-huperzine A: a comparison with E2020 and tacrine. Eur J Pharmacol 349:137–142CrossRefPubMedGoogle Scholar
  60. Zhang JY, Zeise ML, Wang RY (1994) Serotonin3 receptor agonists attenuate glutamate-induced firing in rat hippocampal CA1 piramidal cells. Neuropharmacol 33:483–491CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2003

Authors and Affiliations

  • M. Diez-Ariza
    • 1
  • C. Redondo
    • 1
  • M. García-Alloza
    • 1
  • B. Lasheras
    • 1
  • J. Del Río
    • 1
  • M. J. Ramírez
    • 1
  1. 1.Department of Pharmacology, School of MedicineUniversity of NavarraPamplonaSpain

Personalised recommendations