Neurochemical Research

, Volume 28, Issue 10, pp 1501–1515

Presynaptic Modulation Controlling Neuronal Excitability and Epileptogenesis: Role of Kainate, Adenosine and Neuropeptide Y Receptors

  • João O. Malva
  • Ana P. Silva
  • Rodrigo A. Cunha


Based on the idea that seizures may arise from an overshoot of excitation over inhibition, all substances that may decrease glutamatergic function while having no effect or even increasing GABAergic neurotransmission are likely to be effective anticonvulsants. We now review the possible role of three such neuromodulators, kainate, adenosine, and neuropeptide Y receptors in controlling hyperexcitability and epileptogenesis. Particular emphasis is given on the robust neuromodulatory role of these three groups of receptors on the release of glutamate in the hippocampus, a main focus of epilepsy. Moreover, we also give special attention to the mechanisms of receptor activation and coupled signaling events that can be explored as attractive targets for the treatment of epilepsy and excitotoxicity. The present paper is a tribute to Arsélio Pato de Carvalho who has been the main driving force for the development of Neuroscience in Portugal, notably with a particular emphasis on the presynaptic mechanisms of modulation of neurotransmitter release.

Kainate receptors adenosine receptors neuropeptide Y receptors glutamate epilepsy hippocampus 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    deLorenzo, R. J., Towne, A. R., Pellock, J. M., and Ko, D. J. 1992. Status epilepticus in children, adults and the elderly. Epilepsia 33(Suppl. 4):S15-S25.PubMedGoogle Scholar
  2. 2.
    Schmidt, D. and Krämer, G. 1994. The new anticonvuisant drugs: Implications for avoidance of adverse effects. Drug Safety 11:422-431.PubMedGoogle Scholar
  3. 3.
    Dalby, N. O. and Mody, I. 2001. The process of epileptogenesis: A pathophysiological approach. Curr. Opin. Neurol. 14:187-192.PubMedGoogle Scholar
  4. 4.
    Mathern, G. W., Babb, T. L., Leite, J. P., Pretorius, K., Yeoman, K. M., and Kuhlman, P. A. 1996. The pathogenic and progressive features of chronic human epilepsy. Epilepsy Res. 26:151-161.PubMedGoogle Scholar
  5. 5.
    Cole, A. J. 2000. Is epilepsy a progressive disease? The neurobiological consequences of epilepsy. Epilepsia 41(Suppl. 2): S13-S22.Google Scholar
  6. 6.
    Racine, R. J. 1972. Modification of seizure activity by electrical stimulation. I. Afterdischarge threshold. Electroencephalogr. Clin. Neurophysiol. 32:269-279.PubMedGoogle Scholar
  7. 7.
    Racine, R. J. 1972. Modification of seizure activity by electrical stimulation. II. Motor seizure. Electroencephalogr. Clin. Neurophysiol. 32:281-294.PubMedGoogle Scholar
  8. 8.
    Cavazos, J. E. and Sutula, T. P. 1990. Progressive neuronal loss induced by kindling: A possible mechanism for mossy fiber synaptic reorganization and hippocampal sclerosis. Brain Res. 527:1-6.PubMedGoogle Scholar
  9. 9.
    Cavazos, J. E., Das, I., and Sutula, T. P. 1994. Neuronal loss induced in limbic pathways by kindling: Evidence for induction of hippocampal sclerosis by repeated brief seizures. J. Neurosci. 14:106-121.Google Scholar
  10. 10.
    Bengzon, J., Kokaia, Z., Elmer, E., Nanobashvili, A., Kokaia, M., and Lindvall, O. 1997. Apoptosis and proliferation of dentate gyrus neurons after single and intermitent limbic seizures. Proc. Natl. Acad. Sci. USA 94:10432-10437.PubMedGoogle Scholar
  11. 11.
    Tasch, E., Cendes, F., Li, L. M., Dubeau, F., Andermann, F., and Arnold, D. L. 1999. Neuroimaging evidence of progressive neuronal loss and dysfunction in temporal lobe epilepsy. Ann. Neurol. 45:568-576.PubMedGoogle Scholar
  12. 12.
    DeGiorgio, C. M., Tomiyasu, U., Gott, P. S., and Treiman, D. M. 1992. Hippocampal pyramidal cell loss in human status epilepticus. Epilepsia 33:23-27.PubMedGoogle Scholar
  13. 13.
    Wieshmann, U. C., Woermann, F. G., Lemieux, L., Free, S. L., Bartlett, P. A., Smith, S. J., Duncan, J. S., Stevens, J. M., and Shorvon, S. D. 1997. Development of hippocampal atrophy: A serial magnetic resonance imaging study in a patient who developed epilepsy after generalized status epilepticus. Epilepsia 38:1238-1241.PubMedGoogle Scholar
  14. 14.
    Willow, M., Gonoi, T., and Catterall, W. A. 1985. Voltage clamp analysis of the inhibitory actions of diphenylhydantoin and carbamazepine on voltage-sensitive sodium channels in neuroblastoma cells. Mol. Pharmacol. 27:549-558.PubMedGoogle Scholar
  15. 15.
    Bonifácio, M. J., Sheridan, R. D., Parada, A., Cunha, R. A., Patmore, L., and Soaresda-Silva, P. 2001. Interaction of the novel anticonvulsant, BIA 2-093, with voltage-gated sodium channels: Comparison with carbamazepine. Epilepsia 42:600-608.PubMedGoogle Scholar
  16. 16.
    Reynolds, E. H. 1995. Do anticonvulsants alter the natural time course of epilepsy? Treatment should be started as early as possible. Br. Med. J. 301:176-180.Google Scholar
  17. 17.
    Coutinho-Netto, J. C., Abdul-Ghani, A. S., Collins, J. F., and Bradford, H. F. 1981. Is glutamate a trigger factor in epileptic hyperactivity? Epilepsia 22:289-296.PubMedGoogle Scholar
  18. 18.
    Chapman, A. G. 1998. Glutamate receptors in epilepsy. Prog. Brain Res. 116:371-383.PubMedGoogle Scholar
  19. 19.
    Löscher, W. 1998. Pharmacology of glutamate receptor antagonists in the kindling model of epilepsy. Prog. Neurobiol. 54:721-741.PubMedGoogle Scholar
  20. 20.
    Cain, D. P. 1989. Long-term potentiation and kindling: How similar are the mechanisms? Trends Neurosci. 12:6-10.PubMedGoogle Scholar
  21. 21.
    Lipton, P. 1999. Ischemic cell death in brain neurons. Physiol. Rev. 79:1431-1568.PubMedGoogle Scholar
  22. 22.
    Michaelis, E. K. 1998. Molecular biology of glutamate receptors in the central nervous system and their role in excitotoxicity, oxidative stress and aging. Prog. Neurobiol. 54:369-415.PubMedGoogle Scholar
  23. 23.
    Lees, G. J. 2000. Pharmacology of AMPA/kainate receptor ligands and their therapeutic potential in neurological and psychiatric disorders. Drugs 59:33-78.PubMedGoogle Scholar
  24. 24.
    MacDermott, A. B., Role, L. W., and Siegelbaum, S. A. 1999. Presynaptic ionotropic receptors and the control of transmitter release. Ann. Rev. Neurosci. 22:443-485.PubMedGoogle Scholar
  25. 25.
    Schoepp, D. D. 2001. Unveiling the functions of presynaptic metabotropic glutamate receptors in the central nervous system. J. Pharmacol. Exp. Ther. 299:12-20.PubMedGoogle Scholar
  26. 26.
    Ben-Ari, Y. 1985. Limbic seizure and brain damage produced by kainic acid: Mechanisms and relevance to human temporal lobe epilepsy. Neuroscience 14:375-403.PubMedGoogle Scholar
  27. 27.
    Coyle, J. T. 1983. Neurotoxic action of kainic acid. J. Neurochem. 41:1-11.PubMedGoogle Scholar
  28. 28.
    Represa, A., Tremblay, E., and Ben-Ari, Y. 1987. Kainate binding sites in the hippocampal mossy fibers: Localization and plasticity. Neuroscience 20:739-748.PubMedGoogle Scholar
  29. 29.
    Gaiarsa, J.-L., Zagrean, L., and Ben-Ari, Y. 1994. Neonatal irradiation prevents the formation of hippocampal mossy fibers and the epileptic action of kainate on rat CA3 pyramidal neurons. J. Neurophysiol. 71:204-215.PubMedGoogle Scholar
  30. 30.
    Ben-Ari, Y. and Cossart, R. 2000. Kainate: A double agent that generates seizures—Two decades of progress. Trends Neurosci. 23:580-587.PubMedGoogle Scholar
  31. 31.
    Chittajallu, R., Braithwaite, S. P., Clarke, V. R. J., and Henley, J. M. 1999. Kainate receptor: Subunits, synaptic localization and function. Trends Pharmacol. Sci. 20:26-35.PubMedGoogle Scholar
  32. 32.
    Lerma, J., Paternain, A. V., Rodríguez-Moreno, A., López-García, J. C. 2001. Molecular physiology of kainate receptors. Physiol. Rev. 81:971-998.PubMedGoogle Scholar
  33. 33.
    Rosenmund, C., Stern-Bach, Y., and Stevens, C. F. 1998. The tetrameric structure of a glutamate receptor channel. Science 280:1596-1599.PubMedGoogle Scholar
  34. 34.
    Malva, J. O., Carvalho, A. P., and Carvalho, C. M. 1998. Kainate receptors in hippocampal CA3 subregion: Evidences for a role in regulating neurotransmitter release. Neurochem. Int. 32:1-6.PubMedGoogle Scholar
  35. 35.
    Herb, A., Burnashev, N., Werner, P., Sakmann, B., Wisden, W., and Seeburg, P. H. 1992. The KA-2 subunit of excitatory amino acid receptors shows widespread expression in brain and forms ion channels with distantly related subunits. Neuron 8:775-785.PubMedGoogle Scholar
  36. 36.
    Patneau, D. K., Wright, P. W., Winters, C., Mayer, M. L., and Gallo, V. 1994. Glial cells of the oligodendrocyte lineage express both kainate-and AMPA-preferring subtypes of glutamate receptor. Neuron 12:357-371.PubMedGoogle Scholar
  37. 37.
    Huettner, J. E. 1990. Glutamate receptor channels in rat DRG neurons: Activation by kainate and quisqualate and blockade of desensitization by Con A. Neuron 5:255-266.PubMedGoogle Scholar
  38. 38.
    Bleakman, D. and Lodge, D. 1998. Neuropharmacology of AMPA and kainate receptors. Neuropharmacol. 37:1187-1204.Google Scholar
  39. 39.
    Bleakman, D. 1999. Kainate receptor pharmacology and physiology. Cell. Mol. Life Sci. 56:558-566.PubMedGoogle Scholar
  40. 40.
    Castillo, P. E., Malenka, R. C., and Nicoll, R. A. 1997. Kainate receptors mediate a slow postsynaptic current in hippocampal CA3 neurons. Nature 388:182-186.PubMedGoogle Scholar
  41. 41.
    Vignes, M. and Collingridge, G. L. 1997. The synaptic activation of kainate receptors. Nature 388:179-182.PubMedGoogle Scholar
  42. 42.
    Chittajallu, R., Vignes, M., Dev, K. K., Barnes, J. M., Collingridge, G. L., and Henley, J. M. 1996. Regulation of glutamate release by presynaptic kainate receptors in the hippocampus. Nature 379:78-81.PubMedGoogle Scholar
  43. 43.
    Cunha, R. A. and Ribeiro, J. A. 2001. ATP as a presynaptic modulator. Life Sci. 68:119-137.Google Scholar
  44. 44.
    Mulle, C., Sailer, A., Pérez-Otaño, I., Bureau, I., Maron, C., Gage, F. H., Mann, J. R., Bettler, B., and Heinemann, S. F. 1998. Altered synaptic physiology and reduced susceptibility to kainate-induced seizures in GluR6-deficient mice. Nature 392:601-605.PubMedGoogle Scholar
  45. 45.
    Hollmann, M. and Heinemann, S. 1994. Cloned glutamate receptors. Annu. Rev. Neurosci. 17:31-108.PubMedGoogle Scholar
  46. 46.
    Malva, J. O., Ambrósio, A. F., Cunha, R. A., Ribeiro, J. A., Carvalho, A. P., and Carvalho, C. M. 1995. A functionally active presynaptic high-affinity kainate receptor in the rat hippocampal CA3 subregion. Neurosci. Lett. 185:83-86.PubMedGoogle Scholar
  47. 47.
    Malva, J. O., Carvalho, A. P., and Carvalho, C. M. 1996. Domoic acid induces the release of glutamate in the rat CA3 sub-region. Neuroreport 7:1330-1334.PubMedGoogle Scholar
  48. 48.
    Cunha, R. A., Constantino, M. D., and Ribeiro, J. A. 1997 Inhibition of H3-gamma-aminobutyric acid release by kainate receptor activation in rat hippocampal synaptosomes. Eur. J. Pharmacol. 323:167-172.PubMedGoogle Scholar
  49. 49.
    Lerma, J., Partenain, A. V., Naranjo, J. R., and Mellström, B. 1993. Functional kainate-selective glutamate receptors in cultured hippocampal neurons. Proc. Natl. Acad. Sci. USA 90:11688-11692.PubMedGoogle Scholar
  50. 50.
    Clarke, V. R. J., Ballyk, B. A., Hoo, K. H., Mandelzys, A., Pellizzari, A., Bath, C. P., Thomas, J., Sharpe, E. F., Davies, C. H., Ornstein, P. L., Schoepp, D. D., Kamboj, R. K., Collingridge, G. L., Lodge, D., and Bleakman, D. 1997. A hippocampal GluR5 kainate receptor regulating inhibitory synaptic transmission. Nature 389:599-603.PubMedGoogle Scholar
  51. 51.
    Rodríguez-Moreno, A., Herreras, O., and Lerma, J. 1997. Kainate receptors presynaptically downregulate GABAergic inhibition in the rat hippocampus. Neuron 19:893-901.PubMedGoogle Scholar
  52. 52.
    Monaghan, D. T. and Cotman, C. W. 1982. The distribution of [3H]kainic acid binding sites in rat CNS as determined by autoradiography. Brain Res. 252:91-100.PubMedGoogle Scholar
  53. 53.
    Petralia, R. S., Wang, Y. X., and Wenthold, R. J. 1994. Histological and ultrastructural localization of the kainate receptors, KA2 and GluR6/7, in the rat nervous system using selective antipeptide antibodies. J. Comp. Neurol. 349:85-110.PubMedGoogle Scholar
  54. 54.
    Bettler, B. and Mulle, C. 1995. Neurotransmitter receptors II: AMPA and kainate receptors. Neuropharmacol. 34:123-139.Google Scholar
  55. 55.
    Kamiya H., Ozawa, S., and Manabe, T. 2002. Kainate receptor-dependent short-term plasticity of presynaptic Ca2+ influx at the hippocampal mossy fiber synapses. J. Neurosci. 22:9237-9243.PubMedGoogle Scholar
  56. 56.
    Lauri, S. E., Bortolotto, Z. A., Bleakman, D., Ornstein, P. L., Lodge, D., Isaac, J. T. R., and Collingridge, G. L. 2001. A critical role of a facilitatory presynaptic kainate receptor in mossy fiber LTP. Neuron 32:697-709.PubMedGoogle Scholar
  57. 57.
    Lauri, S. E., Delany, C., Clarke, V. R. J., Bortolotto, Z. A., Ornstein, P. L., Isaac, J. T. R., and Collingridge, G. L. 2001. Synaptic activation of a presynaptic kainate receptor facilitates AMPA receptor-mediated synaptic transmission at hippocampal mossy fiber synapses. Neuropharmacol. 41:907-915.Google Scholar
  58. 58.
    Schmitz, D., Mellor, J., Frerking, M., and Nicoll, R. A. 2001. Presynaptic kainate receptors at hippocampal mossy fiber synapses. Proc. Natl. Acad. Sci. USA 98:11003-11008.PubMedGoogle Scholar
  59. 59.
    Schmitz, D., Mellor, J., and Nicoll, R. A. 2001. Presynaptic kainate receptor mediation of frequency facilitation at hippocampal mossy fiber synapses. Science 291:1972-1976.PubMedGoogle Scholar
  60. 60.
    Teitelbaum, J. S., Zatorre, R. J., Carpenter, S., Gendron, D., Evans, A. C., Gjedde, A., and Cashman, N. R. 1990. Neurologic sequelae of domoic acid intoxication due to the ingestion of contaminated mussels. N. Engl. J. Med. 322:1781-1787.PubMedGoogle Scholar
  61. 61.
    Contractor, A., Swanson, G. T., Sailer, A., O'Gorman, S., and Heinemann, S. F. 2000. Identification of the kainate receptor subunits underlying modulation of excitatory synaptic transmission in the CA3 region of the hippocampus. J. Neurosci. 20:8269-8278.PubMedGoogle Scholar
  62. 62.
    Vignes, M., Clarke, V. R. J., Parry, M. J., Bleakman, D., Lodge, D., Ornstein, P. L., and Collingridge, G. L. 1998. The GluR5 subtype of kainate receptor regulates excitatory synaptic transmission in areas CA1 and CA3 of the rat hippocampus. Neuropharmacol. 37:1269-1277.Google Scholar
  63. 63.
    Bortolotto, Z. A., Clarke, V. R. J., Delany, C. M., Parry, M, C,, Smolders. I., Vignes, M., Ho, K. H., Miu, P., Brinton, B. T., Fantaske, R., Ogden, A., Gates, M., Ornstein, P. L., Lodge, D., Bleakman, D., and Collingridge, G. J. 1999. Kainate receptors are involved in synaptic plasticity. Nature 402:297-301.PubMedGoogle Scholar
  64. 64.
    Bahn, S., Volk, B., and Wisden, W. 1994. Kainate receptor gene expression in the developing rat brain. J. Neurosci. 14:5525-5547.PubMedGoogle Scholar
  65. 65.
    Phillips, G. R., Huang, J. K., Wang, Y., Tanaka, H., Shapiro, L., Zhang, W., Shan, W.-S., Arndt, K., Frank, M., Gordon, R. E., Gawinowicz, M. A., Zhao, Y., and Colman, D. R. 2001. The presynaptic particle web: Ultrastructure, composition, dissolution, and reconstitution. Neuron 32:1-20.PubMedGoogle Scholar
  66. 66.
    Pinheiro, P. S., Rodrigues, R. J., Silva, A. P., Cunha, R. A., Oliveira, C. R., and Malva, J. O. 2003. Solubilization and immunological identification of presynaptic alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors in the rat hippocampus. Neurosci. Lett. 336:97-100.PubMedGoogle Scholar
  67. 67.
    Kamiya, H. and Ozawa, S. 1998. Kainate receptor-mediated inhibition of presynaptic Ca2+ influx and EPSP in area CA1 of the rat hippocampus. J. Physiol. 509:833-845.PubMedGoogle Scholar
  68. 68.
    Kamiya H. and Ozawa, S. 2000. Kainate receptor-mediated presynaptic inhibition at the mouse hippocampal mossy fibre synapse. J. Physiol. 523:653-665.PubMedGoogle Scholar
  69. 69.
    Frerking, M., Schmitz, D., Zhou, Q., Johansen, J., and Nicoll, R. A. 2001. Kainate receptors depress excitatory synaptic transmission at CA3-CA1 synapses in the hippocampus via a direct presynaptic action. J. Neurosci. 21:2958-2966.PubMedGoogle Scholar
  70. 70.
    Burnashev, N., Villaroel, A., and Sackmann, B. 1996. Dimensions and ion selectivity of recombinant AMPA and kainate receptor channels and their dependence on Q/R site residues. J. Physiol. 496:165-173.PubMedGoogle Scholar
  71. 71.
    Rodrígues-Moreno, A. and Lerma, J. 1998. Kainate receptor modulation of GABA release involves a metabotropic function. Neuron 20:1211-1218.PubMedGoogle Scholar
  72. 72.
    Cunha, R. A., Malva, J. O., and Ribeiro, J. A. 1999. Kainate receptors coupled to Gi/Go proteins in the rat hippocampus. Mol. Pharmacol. 56:429-433.PubMedGoogle Scholar
  73. 73.
    Cunha, R. A., Malva, J. O. and Ribeiro, J. A. 2000. Presynaptic inhibition by kainate receptors of [3H]GABA release is pertussistoxin-sensitive in the rat hippocampus. FEBS Lett. 469:159-162.PubMedGoogle Scholar
  74. 74.
    Rodríguez-Moreno, A., López-Garcia, J. C., and Lerma, J. 2000. Two populations of kainate receptors with separate signaling mechanisms in hippocampal interneurons. Proc. Natl. Acad. Sci. USA 97:1293-1298.PubMedGoogle Scholar
  75. 75.
    Semyanov, A. and Kullmann, D. M. 2001. Kainate receptor-dependent axonal depolarization and action potential initiation in interneurons. Nat. Neurosci. 4:718-723.PubMedGoogle Scholar
  76. 76.
    Cossart, R., Esclapez, M., Hirsch, J. C., Bernard, C., and Ben-Ari, Y. 1998. GluR5 kainate receptor activation in interneurons increases tonic inhibition of pyramidal cells. Nat. Neurosci. 1:470-478.PubMedGoogle Scholar
  77. 77.
    Frerking, M., Malenka, R. C., and Nicoll, R. A. 1998. Synaptic activation of kainate receptors on hippocampal interneurons. Nat. Neurosci. 1:479-486.PubMedGoogle Scholar
  78. 78.
    Bureau, I., Bischoff, S., Heinemann, S. F., and Mulle, C. 1999. Kainate receptor-mediated response in the CA1 field of wild-type and GluR6-deficient mice. J. Neurosci. 19:653-663.PubMedGoogle Scholar
  79. 79.
    Mulle, C., Sailer, A., Swanson, G. T., Brana, C., O'Gorman, S., Bettler, B., and Heinemann, S. F. 2000. Subunit composition of kainate receptors in hippocampal interneurons. Neuron 28:475-484.PubMedGoogle Scholar
  80. 80.
    Paternain, A. V., Herrera, M. T., Nieto, M. A., and Lerma, J. 2000. GluR5 and GluR6 kainate receptor subunits coexist in hippocampal neurons and coassemble to form functional receptors. J. Neurosci. 20:196-205.PubMedGoogle Scholar
  81. 81.
    Frerking, M., Petersen, C. C., and Nicoll, R. A. 1999. Mechanisms underlying kainate receptor-mediated disinhibition in the hippocampus. Proc. Natl. Acad. Sci. USA 96:12917-12922.PubMedGoogle Scholar
  82. 82.
    Cossart, R., Tyzio, R., Dinocourt, C., Esclapez, M., Hirsch, J. C., Ben-Ari, Y., and Bernard, C. 2001. Presynaptic kainate receptors that enhance the release of GABA on CA1 hippocampal interneurons. Neuron 29:497-508.PubMedGoogle Scholar
  83. 83.
    Jiang, L., Xu, J., Nedergaard, M., and Kang, J. 2001. A kainate receptor increases the efficacy of GABAergic synapses. Neuron 30:503-513.PubMedGoogle Scholar
  84. 84.
    Kullmann, D. M. and Semyanov, A. 2002. Glutamatergic modulation of GABAergic signaling among hippocampal interneurons: Novel mechanisms regulating hippocampal excitability. Epilepsia 43:174-178.PubMedGoogle Scholar
  85. 85.
    Cunha, R. A. 2001. Adenosine as a neuromodulator and as a homeostatic regulator in the nervous system: Different roles, different sources and different receptors. Neurochem. Int. 38:107-125.PubMedGoogle Scholar
  86. 86.
    Dunwiddie, T. V. and Masino, S. A. 2001. The role and regulation of adenosine in the central nervous system. Ann. Rev. Neurosci. 24:31-55.PubMedGoogle Scholar
  87. 87.
    Dunwiddie, T. V. 1985. The physiological role of adenosine in the central nervous system. Int. Rev. Neurobiol. 27:63-139.PubMedGoogle Scholar
  88. 88.
    Greene, R. W. and Haas H. L. 1991. The electrophysiology of adenosine in the mammalian central nervous system. Prog. Neurobiol. 36:329-341.PubMedGoogle Scholar
  89. 89.
    Phillis, J. W. and Wu P. H. 1981. The role of adenosine and its nucleotides in central synaptic transmission. Prog. Neurobiol. 16:187-239.PubMedGoogle Scholar
  90. 90.
    Dunwiddie, T. V. 1980. Endogenously released adenosine regulates excitability in the in vitro hippocampus. Epilepsia 21:541-548.PubMedGoogle Scholar
  91. 91.
    Mitchell, J. B., Lupica, C. R., and Dunwiddie, T. V. 1993. Activity-dependent release of endogenous adenosine modulates synaptic responses in the rat hippocampus. J. Neurosci. 13:3439-3447.PubMedGoogle Scholar
  92. 92.
    Cunha, R. A. 2001. Regulation of the ecto-nucleotidase pathway in rat hippocampal nerve terminals. Neurochem. Res. 26:979-991.PubMedGoogle Scholar
  93. 93.
    Zimmermann, H. and Braun, N. 1999. Ecto-nucleotidases: Molecular structures, catalytic properties, and functional roles in the nervous system. Prog. Brain Res. 120:371-385.PubMedGoogle Scholar
  94. 94.
    Latini, S. and Pedata, F. 2001. Adenosine in the central nervous system: Release mechanisms and extracellular concentrations. J. Neurochem. 79:463-484.PubMedGoogle Scholar
  95. 95.
    Lambert, N. A. and Tyler, T. J. 1991. Adenosine depresses excitatory but not fast inhibitory synaptic transmission in area CA1 of the rat hippocampus. Neurosci. Lett. 122:50-52.PubMedGoogle Scholar
  96. 96.
    Yoon, K. W. and Rothman, S. M. 1991. Adenosine inhibits excitatory but not inhibitory synaptic transmission in the hippocampus. J. Neurosci. 11:1375-1380.PubMedGoogle Scholar
  97. 97.
    Proctor, W. R. and Dunwiddie, T. V. 1987. Pre-and postsynaptic actions of adenosine in the in vitro hippocampus. Brain Res. 426:187-190.PubMedGoogle Scholar
  98. 98.
    Thompson, S. M., Hass, H. L., and Gahwiller, B. H. 1992. Comparison of the actions of adenosine at pre-and postsynaptic receptors in the rat hippocampus in vitro. J. Physiol. 451:347-363.PubMedGoogle Scholar
  99. 99.
    Ambrósio, A. F., Malva, J. O., Carvalho, A. P., and Carvalho, A. M. 1997. Inhibition of N-, P/Q-and other types of Ca2+channels in rat hippocampal nerve terminals by adenosine A1 receptor. Eur. J. Pharmacol. 340:301-310.PubMedGoogle Scholar
  100. 100.
    Yawo, H. and Chuhma, N. 1993. Preferential inhibition of ω-conotoxin-sensitive presynaptic Ca2+ channels by adenosine autoreceptors. Nature 365:256-258.PubMedGoogle Scholar
  101. 101.
    Wu, L. G. and Saggau, P. 1994. Adenosine inhibits evoked synaptic transmission primarily by reducing presynaptic calcium influx in area CA1 of hippocampus. Neuron 12:1139-1148.PubMedGoogle Scholar
  102. 102.
    Scholz, K. P. and Miller, R. J. 1996. Presynaptic inhibition at excitatory hippocampal synapses: Development and role of presynaptic Ca2+ channels. J. Neurophysiol. 76:39-46.PubMedGoogle Scholar
  103. 103.
    Scholz, K. P. and Miller, R. J. 1992. Inhibition of quantal transmitter release in the absence of calcium influx by a G protein-linked adenosine receptor at hippocampal synapses. Neuron 8:1139-1150.PubMedGoogle Scholar
  104. 104.
    Capogna, M., Gähwiler, B. H., and Thompson, S. M. 1996. Presynaptic inhibition of calcium-dependent and calcium-dependent and calcium-independent release elicited with ionomycin, gadolinium, and α-latrotoxin in the hippocampus. J. Neurophysiol. 75:2017-2028.PubMedGoogle Scholar
  105. 105.
    Dittman, J. S. and Regehr, W. G. 1996. Contributions of calcium-dependent and calcium-independent mechanisms to presynaptic inhibition at a cerebellar synapse. J. Neurosci. 16:1623-1633.PubMedGoogle Scholar
  106. 106.
    Silinsky, E. M., Hirsh, J. K., Searl, T. J., Redman, R. S., and Watanabe, M. 1999. Quantal ATP release from motor nerve endings and its role in neurally mediated depression. Prog. Brain Res. 120:145-158.PubMedGoogle Scholar
  107. 107.
    Tetzlaff, W., Schubert, G. W., and Kreutzberg, G. W. 1987. Synaptic and extrasynaptic localization of adenosine binding sites in the rat hippocampus. Neuroscience 21:869-875.PubMedGoogle Scholar
  108. 108.
    de Mendonça, A., Sebastião, A. M., and Ribeiro, J. A., 1995. Inhibition of NMDA receptor-mediated currents in isolated rat hippocampal neurons by adenosine A1 receptor activation. Neuroreport 6:1097-1100.PubMedGoogle Scholar
  109. 109.
    Klishin, A., Tsintsadze, T., Lozovaya, N., and Krishtal, O. 1995. Latent N-methyl-D-aspartate receptors in the recurrent excitatory pathway between hippocampal CA1 pyramidal neurons: Ca2+-dependent activation by blocking A1 adenosine receptors. Proc. Natl. Acad. Sci. USA 92:12431-12435.PubMedGoogle Scholar
  110. 110.
    Mogul, D. J., Adams, M. E., and Fox, A. P. 1993. Differential activation of adenosine receptors decreases N-type but potentiates P-type Ca2+ currents in hippocampal CA3 neurons. Neuron 10:327-334.PubMedGoogle Scholar
  111. 111.
    McCool, B. A. and Farroni, J. S. 2001. A1 adenosine receptors inhibit multiple voltage-gated Ca2+ channel subtypes in acutely isolated rat basolateral amygdala neurons. Br. J. Pharmacol. 132:879-888.PubMedGoogle Scholar
  112. 112.
    de Mendonça, A. and Ribeiro, J. A. 2001. Adenosine and synaptic plasticity. Drug Dev. Res. 52:283-290.Google Scholar
  113. 113.
    de Mendonca, A., Sebastião, A. M., and Ribeiro, J. A. 2000. Adenosine: Does it have a neuroprotective role after all? Brain Res. Rev. 33:258-274.PubMedGoogle Scholar
  114. 114.
    Sebastião, A. M., de Mendonça, A., Moreira, T., and Ribeiro, J. A. 2001. Activation of synaptic NMDA receptors by action potential-dependent release of transmitter during hypoxia impairs recovery of synaptic transmission on reoxygenation. J. Neurosci. 21:8564-8571.PubMedGoogle Scholar
  115. 115.
    Gerber, U. and Gahwiler, B. H. 1994. GABAB and adenosine receptors mediate enhancement of the K+ current, IAHP, by reducing adenylyl cyclase activity in rat CA3 hippocampal neurons. J. Neurophysiol. 72:2360-2367.PubMedGoogle Scholar
  116. 116.
    Luscher, C., Jan, L. Y., Stoffel, M., Malenka, R. C., and Nicoll, R. A. 1997. G protein-coupled inwardly rectifying K+ channels (GIRKs) mediate postsynaptic but not presynaptic transmitter actions in hippocampal neurons. Neuron 19:687-695.PubMedGoogle Scholar
  117. 117.
    Wetherington, J. P. and Lambert, N. A. 2002. Differential desensitisation of responses mediated by presynaptic and postsynaptic A1 adenosine receptors. J. Neurosci. 22:1248-1255.PubMedGoogle Scholar
  118. 118.
    Barraco, R. A., Swanson, T. H., Phillis, J. W., and Berman, R. F. 1984. Anticonvulsant effects of adenosine analogues on amygdaloid-kindled seizures in rats. Neurosci. Lett. 46:317-322.PubMedGoogle Scholar
  119. 119.
    Dragunow, M. and Goddard, G. V. 1984. Adenosine modulation of amygdala kindling. Exp. Neurol. 84:654-665.PubMedGoogle Scholar
  120. 120.
    Dragunow, M., Goddard, G. V. and Laverty, R. 1985. Is adenosine an endogenous anticonvulsant? Epilepsia 26:480-487.PubMedGoogle Scholar
  121. 121.
    Dunwiddie, T. V. and Worth, T. 1982. Sedative and anticonvulsant effects of adenosine analogs in mouse and rat. J. Pharmacol. Exp. Ther. 220:70-76.PubMedGoogle Scholar
  122. 122.
    Eldridge, F. L., Paydarfar, D., Scott, S. C., and Dowell, R. T. 1989. Role of endogenous adenosine in recurrent generalized seizures. Exp. Neurol. 103:179-185.PubMedGoogle Scholar
  123. 123.
    Franklin, P. H., Zhang, G., Tripp, E. D., and Murray, T. F. 1989. Adenosine A1 receptor activation mediates suppresion of (-)-bicuculline methiodide-induced seizures in rat prepiriform cortex. J. Pharmacol. Exp. Ther. 251:1229-1236.PubMedGoogle Scholar
  124. 124.
    Khan, G. M., Smolders, I., Ebinger, G., and Michotte, Y. 2001 2-Chloro-N 6-cyclopentyladenosine-elicited attenuation of evoked glutamate release is not sufficient to give complete protection against pilocarpine-induced seizures in rats. Neuropharmacology 40:657-667.PubMedGoogle Scholar
  125. 125.
    Maitre, M., Chesielski, L., Lehmann, A., Kempf, E., and Mandel, P. 1974. Protective effect of adenosine and nicotinamide against audiogenic seizures. Biochem. Pharmacol. 23:2807-2816.PubMedGoogle Scholar
  126. 126.
    Petersen, E. N. 1991. Selective protection by adenosine agonists of DMCM-induced seizures. Eur. J. Pharmacol. 195:256-261.Google Scholar
  127. 127.
    Rosen, L. B. and Berman, R. F. 1987. Differential effects of adenosine analogs on amygdala, hippocampus and caudate nucleus kindled seizures. Epilepsia 28:658-666.PubMedGoogle Scholar
  128. 128.
    Simonato, M., Varani, K., Muzzolini, A., Bianchi, C., Beani, L. and Borea, P. A. 1994. Adenosine A1 receptors in the rat brain in the kindling model of epilepsy. Eur. J. Pharmacol. 265:121-124.PubMedGoogle Scholar
  129. 129.
    Turski, W. A., Cavalheiro, E. A., Ikonomidou, C., Moraes-Mello, L. E. A., Bortolotto, Z. A., and Turski, L. 1985. Effects of aminophylline and 2-chloroadenosine on seizures produced by pilocarpine in rats: Morphological and electroencephalographic correlates. Brain Res. 361:309-323.PubMedGoogle Scholar
  130. 130.
    von Lubitz, D. K., Paul, I. A., Carter, M., and Jacobson, K. A. 1993. Effects of N 6-cyclopentyl adenosine and 8-cyclopentyl-1,3-dipropylxanthine on N-methyl-D-asparte-induced seizures in mice. Eur. J. Pharmacol. 249:265-270.PubMedGoogle Scholar
  131. 131.
    Young, D. and Dragunow, M. 1994. Status epilepticus may be caused by loss of adenosine anticonvulsant mechanisms. Neuroscience 58:245-261.PubMedGoogle Scholar
  132. 132.
    Dunwiddie, T. V. 1999. Adenosine and suppression of seizures. Pages 1001-1010, in Delgado-Escueta, A. V., Wilson, W. A., Olsen, R. W., and Porter, R. J. (eds.), Jasper's Basic Mechanisms of the Epilepsies, 3rd ed., Advances in Neurology, Vol. 79, Lippincott Williams & Wilkins, Philadelphia.Google Scholar
  133. 133.
    Dragunow, M. 1988. Purinergic mechanisms in epilepsy. Prog. Neurobiol. 31:85-108.PubMedGoogle Scholar
  134. 134.
    Ault, B. and Wang, C. M. 1986. Adenosine inhibits epileptiform activity arising in hippocampal area CA3. Br. J. Pharmacol. 87:695-703.PubMedGoogle Scholar
  135. 135.
    Lee, K. S., Schubert, P., and Heinemann, U. 1984. The anticonvulsant action of adenosine: A postsynaptic dendritic action by a possible endogenous anticonvulsant. Brain Res. 321:160-164.PubMedGoogle Scholar
  136. 136.
    Tancredi, V., D'Antuono, M., Nehlig, A., and Avoli, M. 1998. Modulation of epileptiform activity by adenosine A1 receptor-mediated mechanisms in the juvenile rat hippocampus. J. Pharmacol. Exp. Ther. 286:1412-1419.PubMedGoogle Scholar
  137. 137.
    Dragunow, M. 1986. Adenosine: The brain's natural anticonvulsant. Trends Pharmacol. Sci. 7:128-130.Google Scholar
  138. 138.
    Chu, N. S. 1981. Caffeine-and aminophylline-induced seizures. Epilepsia 22:85-94.PubMedGoogle Scholar
  139. 139.
    Dragunow, M. and Robertson, H. A. 1987. 8-Cyclopentyl-1,3-dimethylxanthine prolongs epileptic seizures in rats. Brain Res. 417:377-379.PubMedGoogle Scholar
  140. 140.
    Francis, A. and Fochtmann, L. 1994. Caffeine augmentation of electroconvulsive seizures. Psycopharmacology 115:320-324.Google Scholar
  141. 141.
    Kostopoulos, G., Drapeau, C., Avoli, M., Olivier, A., and Villemeure, J. G. 1989. Endogenous adenosine can reduce epileptiform activity in the human epileptogenic cortex maintained in vitro. Neurosci. Lett. 106:119-124.PubMedGoogle Scholar
  142. 142.
    Mori, H., Mizutani, T., Yoshimura, M., Yamanouchi, H., and Shimada, H. 1992. Unilateral brain damage after prolonged hemiconvulsions in the elderly associated with theophylline administration. J. Neurol. Neurosurg. Psychiatry 55:466-469.PubMedGoogle Scholar
  143. 143.
    Peters, S. G., Wochos, D. N., and Peterson, G. C. 1984. Status epilepticus as a complication of concurrent electroconvulsive and theophylline therapy. Mayo Clin. Proc. 59:568-570.PubMedGoogle Scholar
  144. 144.
    Whitcomb, K., Lupica, C. R., Rosen, J. B., and Berman, R. F. 1990. Adenosine involvement in postictal events in amygdala-kindled rats. Epilepsy Res. 6:171-179.PubMedGoogle Scholar
  145. 145.
    Alzheimer, C., Sutor, B., and ten Bruggencate, G. 1993. Disinhibition of hippocampal CA3 neurons induced by suppression of an adenosine A1 receptor-mediated inhibitory tonus: Pre-and postsynaptic components. Neuroscience 57:565-575.PubMedGoogle Scholar
  146. 146.
    Ault, B., Olney, M. A., Joyner, J. L., Boyer, C. E., Notrica, M. A., Soroko, F. E., and Wang, C. M. 1987. Pro-convulsant actions of theophylline and caffeine in the hippocampus: Implications for the management of temporal lobe epilepsy. Brain Res. 426:93-102.PubMedGoogle Scholar
  147. 147.
    Chesi, A. J. R. and Stone, T. W. 1997. Alkylxanthine adenosine antagonists and epileptiform activity in rat hippocampal slices in vitro. Exp. Brain Res. 113:303-310.PubMedGoogle Scholar
  148. 148.
    Berman, R. F., Fredholm, B. B., Aden, U., and O'Connor, W. T. 2000. Evidence for increased dorsal hippocampal adenosine release and metabolism during pharmacologically induced seizures in rats. Brain Res. 872:44-53.PubMedGoogle Scholar
  149. 149.
    During, M. J., and Spencer, D. D. 1992. Adenosine: A potential mediator of seizure arrest and postictal refractoriness. Ann. Neurol. 32:618-624.PubMedGoogle Scholar
  150. 150.
    Lewin, E. and Bleck, V. 1981. Electroshock seizures in mice: Effect on brain adenosine and its metabolites. Epilepsia 22:577-581.PubMedGoogle Scholar
  151. 151.
    Park, T. S., van Wylen, D. G. L., Rubio, R., and Berne, R. M. 1987. Interstitial fluid adenosine and sagital sinus blood flow during bicuculline-seizures in newborn piglets. J. Cereb. Blood Flow Metabol. 7:633-639.Google Scholar
  152. 152.
    Schrader, J., Wahl, M., Kuschinsky, W., and Kreutzberg, G. N. 1980. Increase of adenosine content in cerebral cortex of the cat during bicuculline-induced seizure. Pflügers Arch. 387:245-251.Google Scholar
  153. 153.
    Winn, H. R., Welsh, J. E., Bryner, C., Rubio, R., and Berne, R. N. 1979. Brain adenosine production during the initial 60 seconds of bicuculline seizures in rats. Acta Physiol. Scand. 72:536-537.Google Scholar
  154. 154.
    Winn, H. R., Welsh, J. E., Rubio, R., and Berne, R. N. 1980. Changes in brain adenosine during bicuculline-induced seizures in rats: Effects of hypoxia and altered systemic blood pressure. Circ. Res. 47:868-877.Google Scholar
  155. 155.
    Kulkarni, C., David, J., and Joseph, T. 1994. Involvement of adenosine in postictal events in rats given electroshock. Indian J. Physiol. Pharmacol. 38:39-43.PubMedGoogle Scholar
  156. 156.
    Fredholm, B. B. 1997. Adenosine and neuroprotection. Int. Rev. Neurobiol. 40:259-280.PubMedGoogle Scholar
  157. 157.
    Brodie, M. S., Lee, K. S., Fredholm, B. B., Stahle L., and Dunwiddie, T. V. 1987. Central versus peripheral mediation of responses to adenosine receptor agonists: Evidence against a central mode of action. Brain Res. 415:323-330.PubMedGoogle Scholar
  158. 158.
    Katims, J. J., Annau, Z., and Snyder, S. H. 1983. Interactions in the behavioral effects of methylxanthines and adenosine derivatives. J. Pharmacol. Exp. Ther. 227:167-17PubMedGoogle Scholar
  159. 159.
    Malhotra, J. and Gupta, Y. K. 1997. Effect of adenosine receptor modulation on pentylenetetrazole-induced seizures in rats. Br. J. Pharmacol. 120:282-288.PubMedGoogle Scholar
  160. 160.
    Huber, A., Padrum, V., Déglon, N., Aebischer, P., Mölher, H., and Boison, D. 2001. Grafts of adenosine-releasing cells suppress seizures in kindling epilepsy. Proc. Natl. Acad. Sci. USA 98:7611-7616.PubMedGoogle Scholar
  161. 161.
    Ashton, D., de Prins, E., Willems, R., van Belle, H., and Wauquier, A. 1988. Anticonvulsant action of the nucleoside transport inhibitor, soluflazine, on synaptic and non-synaptic epileptogenesis in the guinea-pig hippocampus. Epilepsy Res. 2:65-71.PubMedGoogle Scholar
  162. 162.
    Zhang, G., Franklin, P. H., and Murray, T. F. 1993. Manipulation of endogenous adenosine in the rat prepiriform cortex modulates seizure susceptibility. J. Pharmacol. Exp. Ther. 264:1415-1424.PubMedGoogle Scholar
  163. 163.
    Wiesner, J. B., Ugarkar, B. G., Castellino, A. J., Barankiewicz, J., Dumas, D. P., Gruber, H. E., Foster, A. C., and Erion, M. D. 1999. Adenosine kinase inhibitors as a novel approach to anticonvulsant therapy. J. Pharmacol. Exp. Ther. 289:1669-1677.PubMedGoogle Scholar
  164. 164.
    Szot, P., Sanders, R. C., and Murray, T. F. 1987. Theophylline-induced upregulation of A1-adenosine receptors associated with reduced sensitivity to anticonvulsants. Neuropharmacology 26:1173-1180.PubMedGoogle Scholar
  165. 165.
    Janusz, C. A. and Berman, R. F. 1993. The adenosine binding enhancer, PD 81,723, inhibits epileptiform bursting in the hippocampal brain slice. Brain Res. 619:131-136.PubMedGoogle Scholar
  166. 166.
    Ekonomou, A., Angelatou, F., Vergnes, M., and Kostopoulos, G. 1998. Lower density of A1 adenosine receptors in nucleus reticularis thalami in rats with genetic absence epilepsy. Neuroreport 9:2135-2140.PubMedGoogle Scholar
  167. 167.
    Ekonomou, A., Sperk, G., Kostopoulos, G., and Angelatou, F. 2000. Reduction of A1 adenosine receptors in rat hippocampus after kainic acid-induced limbic seizures. Neurosci. Lett. 284:49-52.PubMedGoogle Scholar
  168. 168.
    Glass, M., Faull, R. L. M., Bullock, J. Y., Jansen, K., Mee, E. W., Walker, E. B., Synek, B. J. L., and Dragunow, M. 1996. Loss of A1 adenosine receptors in human temporal lobe epilepsy. Brain Res. 710:56-68.PubMedGoogle Scholar
  169. 169.
    Ochiisshi, T., Takita, M., Ikemoto, M., Nakata, H., and Suzuki, S. S. (1999) Immunohistochemical analysis on the role of adenosine A1 receptors in epilepsy. Neuroreport 10:3535-3541.PubMedGoogle Scholar
  170. 170.
    Angelatou, F., Pagonopoulou, O., and Kostopoulos, G. 1990. Alterations of A1 adenosine receptors in different mouse brain areas afer pentylentetrazol-induced seizures, but not in the epileptic mutant mouse 'tottering.' Brain Res. 534:251-256.PubMedGoogle Scholar
  171. 171.
    Daval, J. L. and Werck, M. C. 1991. Autoradiographic changes in brain adenosine A1 receptors and their coupling to G proteins following seizures in the developing rat. Dev. Brain Res. 59:237-247.Google Scholar
  172. 172.
    Vanore, G., Giraldez, L., Rodriguez de Lores Arnaiz, G., and Girardi, E. 2001. Seizure activity produces differential changes in adenosine A1 receptors within rat hippocampus. Neurochem. Res. 26:225-230.PubMedGoogle Scholar
  173. 173.
    Cunha, R. A., Coelho, J. E., Costenla, A. R., Lopes, L. V., Parada, A., Soares-da-Silva, P., and de Mendonça, A. 2002. Modification of the extracellular metabolism and inhibitory effect of adenosine in the hippocampus of kindled rats. Proc. 3rd Forum Eur. Neurosci.Google Scholar
  174. 174.
    Wieraszko, A. and Seyfried, T. N. 1989. Increased amount of extracellular ATP in stimulated hippocampal slices of seizure prone mice. Neurosci. Lett. 106:287-293.PubMedGoogle Scholar
  175. 175.
    Vianna, E. P., Ferreira, A. T., Naffah-Mazzacoratti, M. G., Sanabria, E. R., Funke, M., Cavalheiro, E. A., and Fernandes, M. J. 2002. Evidence that ATP participates in the pathophysiology of pilocarpine-induced temporal lobe epilepsy: Fluorimetric, immunohistochemical, and Western blot studies. Epilepsia 43(Suppl. 5): 227-229.PubMedGoogle Scholar
  176. 176.
    Bonan, C. D., Amaral, O. B., Rockenbach, I. C., Walz, R., Battastini, A. M., Izquierdo, I., and Sarkis, J. J. 2000. Altered ATP hydrolysis induced by pentylenetetrazol kindling in rat brain synaptosomes. Neurochem. Res. 25:775-779.PubMedGoogle Scholar
  177. 177.
    Bonan, C. D., Walz, R., Pereira, G. S., Worm, P. V., Battastini, A. M., Cavalheiro, E. A., Izquierdo, I., and Sarkis, J. J. 2000. Changes in synaptosomal ectonucleotidase activities in two rat models of temporal lobe epilepsy. Epilepsy Res. 39:229-238.PubMedGoogle Scholar
  178. 178.
    Nagy, A. K., Houser, C. R., and Delgado-Escueta, A. V. 1990. Synaptosomal ATPase activities in temporal cortex and hippocampal formation of humans with focal epilepsy. Brain Res. 529:192-201.PubMedGoogle Scholar
  179. 179.
    Schoen, S. W., Ebert, U., and Loscher, W. 1999. 5′-NucleotiPharmacology of adenosine dase activity in mossy fibers in the dentate gyrus of normal and epileptic rats. Neuroscience 93:519-526.PubMedGoogle Scholar
  180. 180.
    Pagonopoulou, O. and Angelatou, F. 1998. Time development and regional distribution of [3H]nitrobenzylthioinosine adenosine uptake binding in the mouse brain after acute pentylenetetrazol-induced seizures. J. Neurosci. Res. 53:433-442.PubMedGoogle Scholar
  181. 181.
    Cunha, R. A., Correia-de-Sá, P., Sebastião, A. M., and Ribeiro, J. A. 1996. Preferential activation of excitatory adenosine receptors at rat hippocampal and neuromuscular synapses by adenosine formed from released adenine nucleotides. Br. J. Pharmacol. 119:253-260.PubMedGoogle Scholar
  182. 182.
    Fredholm, B. B., Cunha, R. A., and Svenningsson, P. 2002. Pharmacology of adenosine A2A receptors and therapeutic applications. Curr. Top. Med. Chem. 3:1349-1364.Google Scholar
  183. 183.
    Adami, M., Bertorelli, R., Ferri, N., Foddi, M. C., and Ongini, E. 1995. Effects of repeated administration of selective adenosine A1 and A2A receptor agonists on pentylenetetrazole-induced convulsions in the rat. Eur. J. Pharmacol. 294:383-389.PubMedGoogle Scholar
  184. 184.
    De Sarro, G., De Sarro, A., Paola, E. D., and Bertorelli, R. 1999. Effects of adenosine receptor agonists and antagonists on audiogenic seizure-sensible DBA/2 mice. Eur. J. Pharmacol. 371:137-145.PubMedGoogle Scholar
  185. 185.
    Huber, A., Güttinger, M., Möhler, H., and Boison, D. 2002. Seizure suppression by adenosine A2A receptor activation in a rat model of audiogenic brainstem epilepsy. Neurosci. Lett. 329:289-292.PubMedGoogle Scholar
  186. 186.
    Klitgaard, H., Knutsen, L. J. S., and Thomsen, C. 1993. Contrasting effects of adenosine A1 and A2 receptor ligands in different chemoconvulsive rodent models. Eur. J. Pharmacol. 242:221-228.PubMedGoogle Scholar
  187. 187.
    Morgan, P. F. and Durcan, M. J. 1990. Caffeine-induced seizures: Apparent proconvulsant action of N-ethylcarboxamidoadenosine (NECA). Life Sci. 47:1-8.PubMedGoogle Scholar
  188. 188.
    Zgodzinski, W., Rubaj, A., Kleinrok, Z., and Sieklucka-Dziuba, M. 2001. Effect of adenosine A1 and A2 receptor stimulation on hypoxia-induced convulsions in adult mice. Pol. J. Pharmacol. 53:83-92.PubMedGoogle Scholar
  189. 189.
    Zhang, G., Franklin, P. H., and Murray, T. F. 1994. Activation of adenosine A1 receptor underlies anticonvulsant effect of CGS21680. Eur. J. Pharmacol. 255:239-243.PubMedGoogle Scholar
  190. 190.
    El Yacoubi, M., Ledent, C., Parmentier, M., Daoust, M., Costentin, J., Vaugeois, J. M. 2001. Absence of the adenosine A2A receptor or its chronic blockade decrease ethanol withdrawal-induced seizures in mice. Neuropharmacology 40:424-432.PubMedGoogle Scholar
  191. 191.
    Vaugeois, J. M., Benmaamar, R., Depaulis, A., Ledent, C., Parmentier, M., Costentin, J., and El Yacoubi, M. 2002. Adenosine A2A receptor deficient mice are more resistant to seizures. Proc. 3rd Forum Eur. Neurosci.Google Scholar
  192. 192.
    Behan, W. M. H. and Stone, T. W. 2002. Enhanced neuronal damage by co-administration of quinolinic acid and free radicals, and protection by adenosine A2A receptor antagonists. Br. J. Pharmacol. 135:1435-1442.PubMedGoogle Scholar
  193. 193.
    Chen, J. F., Huang, Z., Ma, J., Zhu, J., Moratalla, R., Standaert, D., Moskowitz, M. A., Fink, J. S., and Schwarzschild, M. A. 1999. A2A adenosine receptor deficiency attenuates brain injury induced by transient focal ischemia in mice. J. Neurosci. 19:9192-9200.PubMedGoogle Scholar
  194. 194.
    Chen, J. F., Xu, K., Petzer, J. P., Staal, R., Xu, Y. H., Beilstein, M., Sonsalla, P. K., Castagnoli, K., Castagnoli, N. Jr., and Schwarzschild, M. A. 2001. Neuroprotection by caffeine and A2A adenosine receptor inactivation in a model of Parkinson's disease. J. Neurosci. 21:RC143.PubMedGoogle Scholar
  195. 195.
    Dall'Igna, O. P., Porciúncula, L. O., Souza, D. O., Cunha, R. A., and Lara, D. R. 2003. Neuroprotection by caffeine and adenosine A2A receptor blockade of β-amyloid neurotoxicity. Br. J. Pharmacol. in press.Google Scholar
  196. 196.
    Ikeda, K., Kurokawa, M., Aoyama, S., and Kuwana, Y. 2002. Neuroprotection by adenosine A2A receptor blockade in experimental models of Parkinson's disease. J. Neurochem. 80:262-270.PubMedGoogle Scholar
  197. 197.
    Monopoli, A., Lozza, G., Forlani, A., Mattavelli, A., and Ongini, E. 1998. Blockade of adenosine A2A receptors by SCH 58261 results in neuroprotective effects in cerebral ischaemia in rats. Neuroreport 9:3955-3959.PubMedGoogle Scholar
  198. 198.
    Popoli, P., Pintor, A., Domenici, M. R., Frank, C., Tebano, M. T., Pezzola, A., Scarchilli, L., Quarta, D., Reggio, R., Malchiodi-Albedi, F., Falchi, M., and Massotti, M. 2002. Blockade of striatal adenosine A2A receptor reduces, through a presynaptic mechanism, quinolinic acid-induced excitotoxicity: Possible relevance to neuroprotective interventions in neurodegenerative diseases of the striatum. J. Neurosci. 22:1967-1975.PubMedGoogle Scholar
  199. 199.
    Reggio, R., Pezzola, A., and Popoli, P. 1999. The intrastriatal injection of an adenosine A2 receptor antagonist prevents frontal cortex EEG abnomalities in a rat model of Huntington's disease. Brain Res. 831:315-318.PubMedGoogle Scholar
  200. 200.
    Cunha, R. A., Johansson, B., van der Ploeg, I., Sebastião, A. M., Riberio, J. A., and Fredholm, B. B. 1994. Evidence for functionally important adenosine A2a receptors in the rat hippocampus. Brain Res. 649:208-216.PubMedGoogle Scholar
  201. 201.
    Kobayashi, S. and Millhorn, D. E. 1999. Stimulation of expression for the adenosine A2A receptor gene by hypoxia in PC12 cells; A potential role in cell protection. J. Biol. Chem. 274:20358-20365.PubMedGoogle Scholar
  202. 202.
    Rebola, N., Soares-da-Silva, P., Oliveira, C. R., and Cunha, R. A. 2002. Increased density of adenosine A2A receptors in the cerebral cortex of kindled rats. Proc. 23th Meet. Portuguese Pharmacol. Soc. C64.Google Scholar
  203. 203.
    Diógenes, M. J., Sebastião, A. M., and Ribeiro, J. A. 2002. Brain derived neurotrophic factor facilitates synaptic transmission in rat hippocampus through A2A adenosine receptor activation. Proc. 23th Meet. Portuguese Pharmacol. Soc. C66.Google Scholar
  204. 204.
    Lee, F. S. and Chao, M. V. 2001. Activation of Trk neurotrophin receptors in the absence of neurotrophins. Proc. Natl. Acad. Sci. USA 98:3555-3560.PubMedGoogle Scholar
  205. 205.
    Ernfors, P., Bengzon, J., Kokais, Z., Persson, H., and Lindvall, O. 1991. Increased levels of messenger RNAs for neurotrophic factors in the brain during kindling epileptogenesis. Neuron 7:165-176.PubMedGoogle Scholar
  206. 206.
    Kokaia, M., Ernfors, P., Kokaia, Z., Elmer, E., Jaenisch, R., and Lindvall, O. 1995. Suppressed epileptogenesis in BDNF mutant mice. Exp. Neurol. 133:215-224.PubMedGoogle Scholar
  207. 207.
    Binder, D. K., Routbort, M. J., Ryan, T. E., Yancopoulos, G. D., and McNamara, J. O. 1999. Selective inhibition of kindling development by intraventricular administration of TrkB receptor body. J. Neurol. Sci. 19:1424-1436.Google Scholar
  208. 208.
    Halldner, L., Lozza, G., Lindström, K., and Fredholm, B. B. 2000. Lack of tolerance to motor stimulant effects of a selective adenosine A2A receptor antagonist. Eur. J. Pharmacol. 406:345-354.PubMedGoogle Scholar
  209. 209.
    Pinna, A., Fenu, S., and Morelli, M. 2001. Motor stimulant effects of the adenosine A2A receptor antagonist SCH 58261 do not develop tolerance after repeated treatments in 6-hydroxydopamine-lesioned rats. Synapse 39:233-238.Google Scholar
  210. 210.
    Popoli, P., Reggio, R., and Pezzola, A. 2000. Effects of SCH 58261, an adenosine A2A receptor antagonist, on quinpirole-induced turning in 6-hydroxydopamine-lesioned rats: Lack of tolerance after chronic caffeine intake. Neuropsychopharmacology 22:522-529.PubMedGoogle Scholar
  211. 211.
    Lopes, L. V., Cunha, R. A., and Ribeiro, J. A. 1999. Increase in the number, G protein coupling, and efficiency of facilitatory adenosine A2A receptors in the limbic cortex, but not striatum, of aged rats. J. Neurochem. 73:1733-1738.PubMedGoogle Scholar
  212. 212.
    Rebola, N., Sebastião, A. M., de Mendonça, A., Oliveira, C. R., Ribeiro, J. A., and Cunha, R. A. 2003. Enhanced adenosine A2A receptor facilitation of synaptic transmission in the hippocampus of aged rats. J. Neurophysiol. in press.Google Scholar
  213. 213.
    Kimmel, J. R., Hayden, L. J., and Pollock, H. G. 1975. Isolation and characterization of a new pancreatic polypeptide hormone. J. Biol. Chem. 250:9369-9374.PubMedGoogle Scholar
  214. 214.
    Larhammar, D., Blomqvist, A. G., and Söderberg, C. 1993. Evolution of neuropeptide Y and its related peptides. Comp. Biochem. Physiol. 106C:743-752.Google Scholar
  215. 215.
    Larhammar, D., Söderberg, C., and Blomqvist, A. G. 1993. Evolution of neuropeptide Y family of peptides. Pages 1-41, in Colmers, W. F. and Wahlestedt, C. (eds.), The Biology of Neuropeptide Y and Related Peptides, Humana Press, Totowa, New Jersey.Google Scholar
  216. 216.
    Allen, J. M. and Baldi, D. 1993. Structure and expression of the neuropeptide Y gene. Pages 43-64, in Colmers, W. F. and Wahlestedt, C. (eds.). The Biology of Neuropeptide Y and Related Peptides, Humana Press, Totowa, New Jersey.Google Scholar
  217. 217.
    Sundler, F., Böttcher, G., Ekblad, E., and Håkanson, R. 1993. PP, PYY and NPY: Occurrence and distribution in the periphery. Pages 157-196, in Colmers, W. F. and Wahlestedt, C. (eds.), The Biology of Neuropeptide Y and Related Peptides, Humana Press, Totowa, New Jersey.Google Scholar
  218. 218.
    Lundberg, J. M. 1996. Pharmacology and cotransmission in the autonomic nervous system: Integrative aspects on amines, neuropeptides, adenosine triphosphate, amino acids and nitric oxide. Pharmacol. Rev. 48:113-178.PubMedGoogle Scholar
  219. 219.
    Michel, M. C., Beck-Sickinger, A., Cox, H., Doods, H. N., Herzog, H., Larhammar, D., Quirion, R., Schwartz, T., and Westfall, T. 1998. XVI. International union of pharmacology recommendations for the nomenclature of neuropeptide Y, peptide YY, and pancreatic polypeptide receptors. Pharmacol. Revi. 50:143-150.Google Scholar
  220. 220.
    Larhammar, D. 1996. Structural diversity of receptors for neuropeptide Y, peptide YY and pancreatic polypeptide. Regul. Pept. 65:165-174.PubMedGoogle Scholar
  221. 221.
    Schwarzer, C., Sperk, G., Rizzi, M., Gariboldi, M., and Vezzani, A. 1996. Neuropeptides-immunoractivity and their mRNA expression in kindling: Functional implications for limbic epileptogenesis. Brain Res. Rev. 22:27-50.PubMedGoogle Scholar
  222. 222.
    Vezzani, A., Sperk, G., and Colmers, W. F. 1999. Neuropeptide Y: Emerging evidence for a functional role in seizure modulation. Trends Neurosci. 22:25-30.PubMedGoogle Scholar
  223. 223.
    Gruber, G., Greber, S., Rupp, E., and Sperk, G. 1994. Differential NPY mRNA expression in granule cells and interneurons of the rat dentate gyrus after kainic acid injection. Hippocampus 4:474-482.PubMedGoogle Scholar
  224. 224.
    Takahashi, Y., Tsunashima, K., Sadamatsu, M., Schwarzer, C., Amano, S., Ihara, N., Sasa, M., Kato, N., and Sperk, G. 2000. Altered hippocampal expression of neuropeptide Y, somastotatin, and glutamate decarboxylase in Ihara's epileptic rats and spontaneously epileptic rats. Neurosci. Lett. 287:105-108.PubMedGoogle Scholar
  225. 225.
    Klapstein, G. J. and Colmers, W. F. 1997. Neuropeptide Y suppresses epileptiform activity in rat hippocampus in vitro. J. Neurophysiol. 78:1651-1661.PubMedGoogle Scholar
  226. 226.
    Patrylo, P. R., Van Den Pol, A. N., Spencer, D. D., and Williamson, A. 1999. NPY inhibits glutamatergic excitation in the epileptic human dentate gyrus. J. Neurophysiol. 82:478-483.PubMedGoogle Scholar
  227. 227.
    Van den Pol, A. N., Obrietan, K., Chen, G., and Belousov, A. B. 1996. Neuropeptide Y-mediated long-term depression of excitatory activity in suprachiasmatic nucleus neurons. J. Neurosci. 16:5883-5895.PubMedGoogle Scholar
  228. 228.
    Baraban, S. C., Hollopeter, G., Erickson, J. C., Schwartzkroin, P. A., and Palmiter, R. D. 1997. Knock-out mice reveal a critical antiepileptic role for neuropeptide Y. J. Neurosci. 17:8927-8936.PubMedGoogle Scholar
  229. 229.
    Vezzani, A., Michalkiewicz, M., Michalkiewicz, T., Moneta, D., Ravizza, T., Richichi, C. et al. 2002. Seizure susceptibility and epileptogenesis are decreased in transgenic rats overexpressing neuropeptide Y. Neuroscience 110:237-243.PubMedGoogle Scholar
  230. 230.
    Colmers, W. F., Klapstein, G. J., Fournier, A., St-Pierre, S., and Treherne, K. A. 1991. Presynaptic inhibition by neuropeptide Y in rat hippocampal slice in vitro is mediated by a Y2 receptor. Br. J. Pharmacol. 102:41-44.PubMedGoogle Scholar
  231. 231.
    Woldbye, D. P. D., Larsen, P. J., Mikkelsen, J. D., Klemp, K., Madsen, T. M., and Bolwig, T. G. 1997. Powerful inhibition of kainic acid seizures by neuropeptide Y via Y5-like receptors. Nat. Med. 3:761-764.PubMedGoogle Scholar
  232. 232.
    Kopp, J., Nanobashvili, A., Kokaia, Z., Lindvall, O., and Hökfelt, T. 1999. Differential regulation of mRNAs for neuropeptide Y and its receptor subtypes in widespread areas of the rat limbic system during kindling epileptogenesis. Mol. Brain Res. 72:17-29.PubMedGoogle Scholar
  233. 233.
    Röder, C., Schwarzer, C., Vezzani, A., Gobbi, M., Minnini, T., and Sperk, G. 1996. Autoradiographic analysis of neuropeptide Y receptor binding sites in the rat hippocampus after kainic acid-induced limbic seizures. Neuroscience 70:47-55.PubMedGoogle Scholar
  234. 234.
    Bleakman, D., Harrison, N. L., Colmers, W. F., and Miller, R. J. 1992. Investigations into neuropeptide Y-mediated presynaptic inhibition in cultured hippocampal neurones of the rat. Br. J. Pharmacol. 107:334-340.PubMedGoogle Scholar
  235. 235.
    McQuiston, A. R. and Colmers, W. F. 1996. Neuropeptide Y2 receptors inhibit the frequency of spontaneous but not miniature EPSCs in CA3 pyramidal cells of rat hippocampus. J. Neurophysiol. 76:3159-3168.PubMedGoogle Scholar
  236. 236.
    Vezzani, A., Rizzi, M., Conti, M., and Samanin, R. 2000. Modulatory role of neuropeptide in seizures induced in rats by stimulation of glutamate receptors. Am. Soc. Nutri. Sci. 7402:1046S-1048S.Google Scholar
  237. 237.
    McQuiston, A. R., Petrozzino, J. J., Connor, J. A., and Colmers, W. F. 1996. Neuropeptide Y1 receptors inhibit N-type calcium currents and reduce transient calcium increases in rat dentate granule cells. J. Neurosci. 16:1422-1429.PubMedGoogle Scholar
  238. 238.
    Gariboldi, M., Conti, M., Cavaleri, D., Samanin, R., and Vezzani, A. 1998. Anticonvulsant properties of BIBP3226, a non-peptide selective antagonist at neuropeptide Y Y1 receptors. Eur. J. Neurosci. 10:757-759.PubMedGoogle Scholar
  239. 239.
    Brooks, P. A., Kelly, J. S., Allen, J. M., Smith, D. A. S., and Stone, T. W. 1987. Direct excitatory effects of neuropeptide Y (NPY) in rat hippocampal neurons in vitro. Brain Res. 408:295-298.PubMedGoogle Scholar
  240. 240.
    Weiser, T., Wieland, H. A., and Doods, H. N. 2000. Effects of the neuropeptide Y Y2 receptor antagonist BIIE0246 on presynaptic inhibition by neuropeptide Y in rat hippocampal slices. Eur. J. Pharmacol. 404:133-136.PubMedGoogle Scholar
  241. 241.
    Silva, A. P., Carvalho, A. P., Carvalho, C. M., and Malva, J. O. 2001. Modulation of intracellular calcium changes and glutamate release by neuropeptide Y1 and Y2 receptors in the rat hippocampus: Differential effects in CA1, CA3 and dentate gyrus. J. Neurochem. 79:286-296.PubMedGoogle Scholar
  242. 242.
    Greber, S., Schwarzer, C., and Sperk, G. 1994. Neuropeptide Y inhibits potassium-stimulated glutamate release through Y2 receptors in rat hippocampal slices in vitro. Br. J. Pharmacol. 113:737-740.PubMedGoogle Scholar
  243. 243.
    Silva, A. P., Carvalho, A. P., Carvalho, C. M., and Malva, J. O. 2003. Functional interaction between neuropeptide Y receptors and modulation of calcium channels in the rat hippocampus. Neuropharmacology (in press).Google Scholar
  244. 244.
    Marsh, D. J., Baraban, S. C., Hollopeter, G., and Palmiter, R. D. 1999. Role of the Y5 neuropeptide Y receptor in limbic seizures. Proc. Natl. Acad. Sci. USA 96:13518-13523.PubMedGoogle Scholar
  245. 245.
    Guo, H., Castro, P. A., Palmiter, R. D., and Baraban, S. C. 2002. Y5 receptors mediate neuropeptide Y actions at excitatory synapses in area CA3 of the mouse hippocampus. J. Neurophysiol. 87:558-566.PubMedGoogle Scholar
  246. 246.
    Dinger, M. C., Bader, J. E., Kobor, A. D., Kretzschmar, A. K., and Beck-Sickinger, A. G. 2003. Homodimerization of neuropeptide Y receptors investigated by fluorescence resonance energy transfer in living cells. J. Biol. Chem. (in press).Google Scholar
  247. 247.
    Silva, A. P., Pinheiro, P. S., Carvalho, A. P., Carvalho, C. M., Jakobsen, B., Zimmer, J. and Malva, J. O. 2003. Activation of neuropeptide Y receptors is neuroprotective against excitoxicity in organotypic hippocampal slice cultures. FASEB J. (in press).Google Scholar

Copyright information

© Plenum Publishing Corporation 2003

Authors and Affiliations

  • João O. Malva
    • 1
  • Ana P. Silva
    • 1
  • Rodrigo A. Cunha
    • 1
  1. 1.Center for Neuroscience of Coimbra, Institute of Biochemistry, Faculty of MedicineUniversity of CoimbraCoimbraPortugal

Personalised recommendations