Neuroscience and Behavioral Physiology

, Volume 45, Issue 3, pp 295–301 | Cite as

Influence of Ionotropic Glutamate Receptor Channel Blockers on the Effects of Sleep Deprivation in Rats

  • S. I. Vataev
  • G. A. Oganesyan
  • N. Ya. Lukomskaya
  • L. G. Magazanik

Experiments on Krushinskii–Molodkina rats, with an inherited predisposition to audiogenic convulsions, and Wistar rats, which are resistant to the convulsion-inducing effects of sound, were performed to study the influence of selective noncompetitive NMDA glutamate receptor blockers (memantine and IEM-1921) and mixed-type antagonists acting on both NMDA and Ca-permeable AMPA-kainate receptors (IEM-1754 and IEM-1925) on the effects of sleep deprivation. These studies showed that the actions of these ionotropic glutamate receptor channel blockers on the effects of sleep deprivation in rats of both strains were similar, despite the differences in their predispositions to audiogenic seizures. During the first three hours after administration of memantine and IEM-1921 on the background of prior sleep deprivation, increases in the total duration of waking were seen, with a significant decrease in the proportion of slow-wave sleep and almost complete blockade of REM (paradoxical) sleep. These effects were probably due to blockade of NMDA receptors in the functional systems of the brain regulating the duration and depth of slow-wave sleep and responsible for triggering and maintaining REM sleep. During the first three hours after administration of the nonselective dicationic glutamate receptor antagonists (IEM-1754 and IEM-1925) on the background of sleep deprivation, their blocking actions on REM sleep were significantly decreased. During the second 3-h period after sleep deprivation in control experiments and after treatment with all glutamate receptors other than memantine, there were significant increases in the total duration of REM sleep, i.e., a rebound phenomenon was seen. The blocking action of memantine on the system triggering and maintaining REM sleep lasted about 6 h, after which the rebound phenomenon was also seen. Overall, memantine produced more marked and longer-lasting changes in the organization of sleep than the other glutamate receptor antagonists studied.


Krushinskii–Molodkina and Wistar rats sleep deprivation organization of sleep ionotropic glutamate receptor blockers memantine IEM-1921 IEM-1925 IEM-1754 


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  1. 1.
    A. Yu. Bespalov and E. E. Zvartau, The Neuropsychology of NMDA Receptor Antagonists, Nevskii Dialekt, St. Petersburg (2000).Google Scholar
  2. 2.
    S. I. Vataev and G. A. Oganesyan, “Effects of sleep deprivation in rats with inherited predisposition to audiogenic seizures,” Zh. Evolyuts. Biokhim. Fiziol., 40, No. 1, 60–66 (2004).Google Scholar
  3. 3.
    S. I. Vataev and G. A. Oganesyan, “Effects of total sleep deprivation in rats with inherited predisposition to audiogenic seizures,” Zh. Evolyuts. Biokhim. Fiziol., 41, No. 1, 82–88 (2005).Google Scholar
  4. 4.
    S. I. Vataev, E. P. Zhabko, N. Ya. Lukomskaya, et al., “Effects of memantine on convulsive reactions and the organization of sleep in Krushinskii–Molodkina rats with inherited predisposition to audiogenic seizures,” Ros. Fiziol. Zh., 95, No. 8, 802–812 (2009).Google Scholar
  5. 5.
    S. I. Vataev, G. A. Oganesyan, V. E. Gmiro, et al., “Effects of ionotropic glucocorticoid receptor channel blockers on the organization of sleep in rats,” Ros. Fiziol. Zh., 98, No. 7, 809–818 (2012).Google Scholar
  6. 6.
    S. V. Kalemenev, O. E. Zubareva, N. Ya. Lukomskaya, and L. G. Magazanik, “The neuroprotective actions of the noncompetitive NMDA receptor blockers IEM-1957 and memantine in a model of focal cerebral ischemia,” Dokl. Akad. Nauk., 443, No. 4, 1–3 (2012).Google Scholar
  7. 7.
    L. G. Magazanik, D. B. Tikhonov, T. B. Tikhonov, and N. Ya. Lukomskaya, “Mechanisms of glutamate receptor channel blockade: significance for structural and physiological investigations,” Ros. Fiziol. Zh., 92, No. 1, 27–38 (2006).Google Scholar
  8. 8.
    G. A. Oganesyan, E. A. Aristakesyan, I. V. Romanova, et al., “The phylo- and ontogenetic establishment of the dopamine regulation of the sleep-waking cycle in invertebrates,” Ros. Fiziol. Zh., 98, No. 10, 1213–1227 (2012).Google Scholar
  9. 9.
    T. N. Oniani, “Paradoxical sleep and the regulation of motivatory processes,” in: The Neurophysiology of Motivation, Memory, and the Sleep-Waking Cycle, T. N. Oniani (ed.), Metsniereba, Tbilisi (1985), pp. 9–58.Google Scholar
  10. 10.
    V. I. Petrov and N. V. Onishchenko, “Current directions in studies and clinical application of glutamatergic agents,” Eksperim. Klin. Farmacol., 65, No. 4, 66–70 (2002).Google Scholar
  11. 11.
    K. V. Bolshakov, D. B. Tikhonov, V. E. Gmiro, and L. G. Magazanik, “Different arrangement of hydrophobic and nucleophilic components of channel binding sites in N-methyl-D-aspartate and AMPA receptors of rat brain is revealed by channel blockade,” Neurosci. Lett., 291, No. 2, 101–104 (2000).CrossRefPubMedGoogle Scholar
  12. 12.
    I. G. Campbell and I. Feinberg, “Noncompetitive NMDA cannel blockade during waking intensely stimulates NREM delta,” J. Pharmacol. Exp. Ther., 276, No. 2, 737–742 (1996).PubMedGoogle Scholar
  13. 13.
    H. S. Chen and S. A. Lipton, “The chemical biology of clinically tolerated NMDA receptor antagonists,” J. Neurochem., 97, No. 6, 1611–1626 (2006).CrossRefPubMedGoogle Scholar
  14. 14.
    O. Clément, E. Sapin, A. Bérod, et al., “Evidence that neurons of the sublaterodorsal nucleus triggering paradoxical (REM) sleep are glutamatergic,” Sleep, 34, No. 4, 419–423 (2011).PubMedCentralPubMedGoogle Scholar
  15. 15.
    C. Creeley, D. F. Wozniak, J. Labruyere, et al., “Low doses of memantine disrupt memory in adult rats,” J. Neurosci., 26, No. 15, 3923–3932 (2006).CrossRefPubMedGoogle Scholar
  16. 16.
    W. C. Dement, “The effect of dream deprivation,” Science, 131, No. 3415, 1705–1707 (1960).CrossRefPubMedGoogle Scholar
  17. 17.
    T. Endo, B. Schwierin, A. A. Borbely, and I. Tobler, “Selective and total sleep deprivation: effect on the sleep EEG in the rat,” Psychiatry Res., 66, No. 2–3, 97–110 (1997).CrossRefPubMedGoogle Scholar
  18. 18.
    I. Feinberg and I. G. Campbell, “Glutamate neurotransmission and sleep,” in: Neurochemistry of Sleep and Wakefulness, J. M. Monty et al. (eds.), Cambridge University Press (2008), pp. 224–243.Google Scholar
  19. 19.
    J. Filakovszky, S. Kantor, P. Halasz, and G. Bagdy, “8-OH-DPAT and MK-801 affect epileptic activity independently of vigilance,” Neurochem. Int., 38, No. 7, 551–556 (2001).CrossRefPubMedGoogle Scholar
  20. 20.
    T. Ishida and C. Kamei, “Characteristic effects of anti-dementia drugs on rat sleep patterns,” J. Pharmacol. Sci., 109, No. 3, 449–455 (2009).CrossRefPubMedGoogle Scholar
  21. 21.
    T. Ishida, Y. Obara, and C. Kamei, “Studies on wakefulness-promoting effect of memantine in rats,” Behav. Brain Res., 206, No. 2, 274–278 (2010).CrossRefPubMedGoogle Scholar
  22. 22.
    B. E. Jones, “From waking to sleeping: neuronal and chemical substrates,” Trends Pharmacol. Sci., 26, No. 11, 578–586 (2005).CrossRefPubMedGoogle Scholar
  23. 23.
    J. Y. Jung, M. Roh, K. K. Ko, et al., “Effects of single treatment of anti-dementia drugs on sleep-wake patterns in rats,” Korean J. Physiol. Pharmacol., 16, No. 4, 231–236 (2012).CrossRefPubMedCentralPubMedGoogle Scholar
  24. 24.
    S. E. Kotermanski and J. W. Johnson, “Mg2+ imparts NMDA receptor subtype selectivity to the Alzheimer’s drug memantine,” J. Neurosci., 29, No. 9, 2774–2779 (2009).CrossRefPubMedCentralPubMedGoogle Scholar
  25. 25.
    V. Larsson, D. Aarsland, C. Ballard, et al., “The effect of memantine on sleep behaviour in dementia with Lewy bodies and Parkinson’s disease dementia,” Int. J. Geriatr. Psychiatr., 25, No. 10, 1030–1038 (2010).CrossRefGoogle Scholar
  26. 26.
    F. Lante, J.-C. Toledo-Salas, T. Ondrejcak, et al., “Removal of synaptic Ca2+-permeable AMPA receptors during sleep,” J. Neurosci., 21, No. 11, 3953–3961 (2011).CrossRefGoogle Scholar
  27. 27.
    S. A. Lipton, “The molecular basis of memantine action in Alzheimer’s disease and other neurologic disorders: low-affinity, uncompetitive antagonism,” Curr. Alzheimer Res., 2, No. 2, 155–165 (2005).CrossRefPubMedGoogle Scholar
  28. 28.
    P. H. Luppi, O. Clement, E. Spain, et al., “Brainstem mechanisms of paradoxical (REM) sleep generation,” Pflügers Arch., 463, No. 1, 43–52 (2012).CrossRefPubMedGoogle Scholar
  29. 29.
    P. H. Luppi, D. Gervasoni, L. Verret, et al., “Paradoxical (REM) sleep genesis: The switch from an aminergic-cholinergic to GABAergic-glutamatergic hypothesis,” J. Physiol. (Paris), 100, No. 5–6, 271–283 (2006).CrossRefGoogle Scholar
  30. 30.
    J. M. Monti and D. Monti, “The involvement of dopamine in the modulation of sleep and waking,” Rev. Sleep Med. Rev., 11, No. 2, 113–133 (2007).CrossRefGoogle Scholar
  31. 31.
    A. Novati, H. J. Hulshof, J. Granic, and P. Meerlo, “Chronic partial sleep deprivation reduces brain sensitivity to glutamate N-methyl-d-aspartate receptor-mediated neurotoxicity,” J. Sleep Res., 21, No. 1, 3–9 (2012).CrossRefPubMedGoogle Scholar
  32. 32.
    C. G. Parsons, W. Danysz, and G. Quack, “Memantine is a clinically well tolerated N-methyl-D-aspartate (NMDA) receptor antagonist – a review of preclinical data,” Neuropharmacol., 38, No. 6, 735–767 (1999).CrossRefGoogle Scholar
  33. 33.
    C. G. Parsons, G. Quack, I. Bresink, et al., “Comparison of the potency, kinetics, and voltage-dependent of a series of uncompetitive NMDA receptor antagonists in vitro with anticonvulsive and motor impairment activity in vitro,” Neuropharmacol., 34, No. 10, 1239–1258 (1995).CrossRefGoogle Scholar
  34. 34.
    G. Paxinos and C. Watson, The Rat Brain in Stereotaxic Coordinates, Academic Press, San Diego, Compact 3rd Edition CD-ROM (1997).Google Scholar
  35. 35.
    R. Spanagel, B. Eilbacher, and R. Wilke, “Memantine-induced dopamine release in the prefrontal cortex and striatum of the rat – a pharmacokinetic microdialysis study,” Eur. J. Pharmacol., 262, No. 1–2, 21–26 (1994).CrossRefPubMedGoogle Scholar
  36. 36.
    W. S. Stone, D. L. Walker, and P. E. Gold, “Sleep deficits in rats after NMDA receptor blockade,” Physiol. Behav., 52, No. 3, 609–612 (1992).CrossRefPubMedGoogle Scholar
  37. 37.
    F. C. Tortella and R. G. Hill, “EEG seizure activity and behavioral neurotoxcity produced by (+)-MK-801, but not the glycine site antagonist L-687,414, in the rat,” Neuropharmacology, 35, No. 4, 441–448 (1996).CrossRefPubMedGoogle Scholar
  38. 38.
    C. J. Watson, R. Lydic, and H. A. Baghdoyan, “Sleep duration varies as a function of glutamate and GABA in rat pontine reticular formation,” J. Neurochem., 118, No. 4, 571–580 (2011).CrossRefPubMedCentralPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • S. I. Vataev
    • 1
  • G. A. Oganesyan
    • 1
  • N. Ya. Lukomskaya
    • 1
  • L. G. Magazanik
    • 1
    • 2
  1. 1.Sechenov Institute of Evolutionary Physiology and BiochemistryRussian Academy of SciencesSt. PetersburgRussia
  2. 2.Faculty of MedicineSt. Petersburg State UniversitySt. PetersburgRussia

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