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Pharmacology of Glutamate Receptors

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Glutamate and Addiction

Part of the book series: Contemporary Clinical Neuroscience ((CCNE))

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Abstract

Glutamate is the principal excitatory neurotransmitter in the central nervous system, playing an essential role in virtually every brain system and their associated behavioral functions. Modulation of glutamate-mediated neurotransmission is a major way in which the function of the nervous system is modified in response to experience (see Chapter 4). Drug addiction and the related behavioral and pharmacological states of sensitization, tolerance, and physical dependence appear to develop and be maintained in ways that may be functionally equivalent to other neural plasticity phenomena for which changes in the strength of glutamate-mediated synaptic transmission plays a principal role (cf. ref. 1). As such, understanding the physiological roles of glutamatergic neurotransmission and its modulation by drugs of abuse is important in identifying the neurobiological substrates of addiction and relevant molecular targets for therapeutic intervention. Agents that target glutamate receptors are the main pharmacological tools available for investigating the functions of glutamatergic synapses and their roles in behavior. The present chapter is therefore devoted to glutamate-receptor pharmacology and provides the background necessary to appreciate the use of drugs that target glutamate receptors in the specific applications discussed in later Chapters. Here, we focus on the specificity of action of these agents, their particular advantages and disadvantages as tools for neurobiological inquiry, and their efficacies and side-effect profiles, including information from studies of human subjects where available. In addition, we briefly consider agents that modify glutamate neurotransmission through effects on glutamate release, by inhibition of NAALADase, and through effects on the downstream effector nitric oxide.

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References

  1. Vanderschuren, L. J. and Kalivas, P. W. (2000) Alterations in dopaminergic and glutamatergic transmission in the induction and expression of behavioral sensitization: a critical review of preclinical studies. Psychopharmacology 151, 99–120.

    Article  PubMed  CAS  Google Scholar 

  2. Parsons, C. G., Danysz, W., and Quack, G. (1998) Glutamate in CNS disorders as a target for drug development: An update. Drug News Perspect. 11, 523–569.

    Article  PubMed  CAS  Google Scholar 

  3. Witkin, J. M. (1995) Role of N-methyl-D-aspartate receptors in behavior and behavioral effects of drugs, in CNS Neuro-transmitters and Neuromodulators, Volume 1: Glutamate ( Stone, T. W., ed.), CRC P, Boca Raton, FL., pp. 323–350.

    Google Scholar 

  4. Rogawski, M. A. (1996) Epilepsy, in Neurotherapeutics: Emerging Strategies (Pullan, L. and Patel, J., eds.) Humana P,Totowa, NJ, pp. 193–273.

    Google Scholar 

  5. Bräuner-Osborne, H., Egebjerg, J., Nielsen, E. 0., Madsen, U., and Krogsgaard-Larsen, P. (2000). Ligands for glutamate receptors: design and therapeutic prospects. J. Med. Chem. 43, 2609–2645.

    Article  PubMed  CAS  Google Scholar 

  6. MacDonald, J. F., Bartlett, M. C., Mody, I., Pahapill, P., Reynolds, J. N., Salter, M. W., et al. (1991) Actions of ketamine, phencyclidine and MK-801 on NMDA receptor currents in cultured mouse hippocampal neurones. J. Physiol. 432, 483–508.

    PubMed  CAS  Google Scholar 

  7. Dingledine, R., Borges, K., Bowie, D., and Traynelis, S. F. (1999) The glutamate receptor ion channels. Pharmacol. Rev. 51, 7–61.

    PubMed  CAS  Google Scholar 

  8. Rogawski, M. A. (2000) Low affinity channel blocking (uncompetitive) NMDA receptor antagonists as therapeutic agents-toward an understanding of their favorable tolerability. Amino Acids 19, 133–149.

    Article  PubMed  CAS  Google Scholar 

  9. Maurice, T., Vignon, J., Kamenka, J. M., and Chicheportiche, R. D. (1991) Differential interaction of phencyclidine-like drugs with the dopamine uptake complex in vivo. J Neurochem. 56, 553–559.

    Article  PubMed  CAS  Google Scholar 

  10. Rothman, R. B. (1994) PCP site 2: a high affinity MK-801-insensitive phencyclidine binding site. Neurotoxicol. Teratol. 16, 343–353.

    Article  PubMed  CAS  Google Scholar 

  11. ffrench-Mullen, J. M. H. and Rogawski, M. A. (1989) Interaction of phencyclidine with voltage-dependent potassium channels in cultured rat hippocampal neurons: comparison with block of the NMDA receptor-ionophore complex. J. Neurosci. 9, 4051–4061.

    PubMed  CAS  Google Scholar 

  12. Wong, E. H. G., Knight, A. R., and Woodruff, G. N. (1988) [3H]MK-801 labels a site on the N-methyl-n-aspartate receptor complex in rat brain membranes. J. Neurochem. 50, 274–281.

    Google Scholar 

  13. Witkin, J. M., Gasior, M., Heifets, B., and Tortella, F. C. (1999) Anticonvulsant efficacy of N-methyl-n-aspartate antagonists against convulsions induced by cocaine. J. Pharmacol. Exp. Thee. 289, 703–711.

    CAS  Google Scholar 

  14. Ginski, M. and Witkin, J. M. (1994) Sensitive and rapid behavioral differentiation of N-methyl-n-aspartate receptor antagonists. Psychopharmacology 114, 573–582.

    Article  PubMed  CAS  Google Scholar 

  15. Tricldebank, M. D., Singh, L., Oles, R. J., Preston, C., and Iversen, S. D. (1989) The behavioural effects of MK-801: a comparison with antagonists acting non-competitively and competitively at the NMDA receptor. Eur. J Pharmacol. 167, 127–135.

    Article  Google Scholar 

  16. Koek, W. and Colpaert, F. C. (1990) Selective blockade of N-methyl-n-aspartate (NMDA)-induced convulsions by the NMDA antagonists and putative glycine antagonists: relationships with phencyclidine-like behavioral effects. J. Pharmacol. Exp. Thee. 252, 349–357.

    CAS  Google Scholar 

  17. Balster R. L. and Willetts, J. (1988) Receptor mediation of the discriminative stimulus properties of phencyclidine and sigma-opioid agonists, in Psychopharmacology: Transduction Mechanisms of Drug Stimuli, (Colpaert, F. C. and Balster, R. L., eds. ), Springer-Verlag Berlin, pp. 122–135.

    Google Scholar 

  18. Grant, K. A., Colombo, G., Grant, J., and Rogawski, M. A. (1996) Dizocilpine-like discriminative stimulus effects of low-affinity uncompetitive NMDA antagonists. Neuropharmacology 35, 1709–1719.

    Article  PubMed  CAS  Google Scholar 

  19. Geter-Douglass, B. and Witkin, J. M. (1997) Dizocilpine-like discriminative stimulus effects of competitive NMDA receptor antagonists in mice. Psychopharmacology 133, 43–50.

    Article  PubMed  CAS  Google Scholar 

  20. Troupin, A. S., Mendius, J. R., Cheng, F., and Risinger, M. W. (1986) MK-801, in New Anticonvulsant Drugs ( Meldrum, B. and Porter, R. J., eds.), Libey, London, pp. 191–201.

    Google Scholar 

  21. Crystal, J. H., Karper, L. P., Seibyl, J. P., Freeman, G. K., Delaney, R., Bremner, J. D. et al. (1994) Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch. Gen. Psychiatry 51, 199–214.

    Article  Google Scholar 

  22. Olney, J. W., Labruyere, J., Wang, G., Wozniak, D. F., Price, M. T., and Sesma, M. A. (1991) NMDA antagonist neurotoxicity: mechanism and prevention. Science 254, 1515–1518.

    Article  PubMed  CAS  Google Scholar 

  23. Fix, A. S., Horn, J. W., Wightman, K. A., Johnson, C. A., Long, G. G., Storts, R. W., et al. (1993) Neuronal vacuolization and necrosis induced by the noncompetitive N-methyl-D-aspartate (NMDA) antagonist MK(+)801 (dizocilpine maleate): a light and electron microscopic evaluation of the rat retrosplenial cortex. Exp. Neurol. 123, 204–215.

    Article  PubMed  CAS  Google Scholar 

  24. Palmer, G.0. and Wiszowski, D. (2000) Low affinity use-dependent NMDA receptor antagonists show promise for clinical development. Amino Acids 19, 151–155.

    Article  Google Scholar 

  25. Rogawski, M. A. (1993) Therapeutic potential of excitatory amino acid antagonists:channel blockers and 2,3-benzodiazepines. Trends Pharmacol. Sci. 14, 325–331

    Article  PubMed  CAS  Google Scholar 

  26. Parsons, C. G., Quack G Bresink, I., Baran, L., Przegalinski, E., Kostowski, W., et al, (1995) Comparison of the potency, kinetics and voltage-dependency of a series of uncompetitive NMDA receptor antagonists in vitro with anticonvulsive and motor impairment activity in vivo. Neuropharmacology 34, 1239–1258.

    Google Scholar 

  27. Bubser, M., Zadow, B., Kronthaler, U. O., Felsheim, U., Rückert, G. H., and Schmidt, W. J. (1997) Behavioural pharmacology of the non-competitive NMDA antagonists dextrorphan and ADCI: relations between locomotor stimulation, anti-cataleptic potential and forebrain dopamine metabolism. Naunyn-Schmiedeberg’s Arch. Pharmacol. 355, 767–773.

    Google Scholar 

  28. Grant, K. A., Snell, L. D., Rogawski, M. A., Thurkauf, A., and Tabakoff, B. (1992) Comparison of the effects of the uncompetitive N-methyl-D-aspartate antagonist (±)-5-aminocarbonyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (ADCI) with its structural analogs dizocilpine (MK-801) and carbamazepine on ethanol withdrawal seizures. J. Pharmacol. Exp. Ther. 269, 1017–1022.

    Google Scholar 

  29. Geter-Douglass, B. and Witkin, J. M. (1999) Behavioral effects and anticonvulsant efficacies of low affinity, uncompetitive NMDA antagonists in mice. Psychopharmacology 146, 280–289.

    Article  PubMed  CAS  Google Scholar 

  30. Sanger, D. J., Terry, P., and Katz, J. L. (1992) Memantine has phencyclidine-like but not cocaine-like discriminative stimulus effects in rats. Behay. Pharmacol. 3, 265–268.

    CAS  Google Scholar 

  31. Danysz, W., Parsons, G. G., Kornhuber, J., Schmidt, W. J., and Quack, G. (1997) Aminoadamantanes as NMDA receptor antagonists and antiparkinsonian agents-preclinical studies. Neurosci-Biobehay. Rev. 21, 455–468.

    Article  CAS  Google Scholar 

  32. Ditzler, K. (1991) Efficacy and tolerability of memantine in patients with dementia syndrome Arzneimettelforschung/Drug Res. 41, 773–780.

    CAS  Google Scholar 

  33. Riederer, P., Lange, K. W., Kornhuber, J., and Danielczyk, W. (1991) Pharmacotoxic psychosis after memantine in Parkinson’s disease. Lancet 338, 1022–1023.

    Article  PubMed  CAS  Google Scholar 

  34. Rabey, J. M., Nissipeanu, P., and Korczyn, A. D. (1992) Efficacy of memantine, an NMDA receptor antagonist, in the treatment of Parkinson’s disease../. Neural Transm. 4, 277–282.

    Article  CAS  Google Scholar 

  35. Mueller, A. L., Artman, L. D., Balandrin, M. F., Brady E., Chien Y., Delmar, E. G., et al, (1999) NPS 1506, a novel NMDA receptor antagonist and neuroprotectant. Review of preclinical and clinical studies. Ann. NYAcad. Sci. 890, 450–457.

    Article  CAS  Google Scholar 

  36. Porter, P. H., and Greenamyre, J. T., (1995) Regional variations in the pharmacology of NMDA receptor channel blockers: implications for therapeutic potential. J. Neurochem. 64, 614–623.

    Google Scholar 

  37. Bresink, I., Danysz, W., Parsons, C. G., and Mutschler, E. (1995) Different binding affinities of NMDA receptor channel blockers in various brain regions—indication of NMDA receptor heterogeneity. Neuropharmacology 34, 533–540.

    Google Scholar 

  38. Baumann, M. H., Rothman, R. B., and Ali, S. F. (2000) Comparative neurobiological effects of ibogaine and MK-801 in rats. Drug Alcohol Depend. 59, 143–151.

    Google Scholar 

  39. Rho, J. M., Donevan, S. D., and Rogawski, M. A. (1994) Mechanism of action of the anticonvulsant felbamate: opposing effects on NMDA and GABA, receptors. Ann. Neurol. 35, 229–234.

    Article  PubMed  CAS  Google Scholar 

  40. Popik, P., Layer, R. T., and Skolnick, P. (1995) 100 years of ibogaine:neurochemical and pharmacological actions of a putative anti-addictive drug. Pharmacol. Rev. 47, 235–253.

    Google Scholar 

  41. Mash, D. C., Kovera, C. A., Buck, B.E., Norenberg, M. D., Shapshak, P., Hearn, W. L., et al. (1998) Medication development of ibogaine as a pharmacotherapy for drug dependence. Ann. NYAcad. Sci. 844, 274–292.

    Google Scholar 

  42. Popik., P., Layer, R. T., Fossom, L. H., Benveniste, M., Geter-Dopuglass, B., Witkin, J. M. et al, (1995) NMDA antagonist properties of the putative anti-addictive drug, ibogaine. J. Pharmacol. Exp. Ther. 275, 753–760.

    Google Scholar 

  43. Chen, K., Kokate, T. G., Donevan, S. D., Carroll, F. I., and Rogawski, M. A. (1996) Ibogaine block of the NMDA receptor: in vitro and in vivo studies. Neuropharmacology 35, 423–431.

    Article  PubMed  CAS  Google Scholar 

  44. Newman, A. H.(2000) Novel pharmacotherapies for cocaine abuse 1997–2000. Exp. Opin. Ther. Patents 10, 1095–1122.

    Google Scholar 

  45. Willetts, J., Balster, R. L., and Leander, J. D. (1990) The behavioral pharmacology of NMDA receptor antagonists. Trends Pharmacol. Sci. 11, 423–428.

    Google Scholar 

  46. Kornhuber, J. and Weller, M. (1997) Psychotogenicity and N-methyl-D-aspartate receptor antagonism: implications for neuroprotective pharmacotherapy. Biol. Psychiatry 41, 135–144.

    Article  PubMed  CAS  Google Scholar 

  47. Sveinbjornsdottir, S., Sander, J. W. A. S., Upton, D., Thompson, P. J., Patsalos, P. N., Hirt, D., et al. (1993) The excitatory amino acid antagonist D-CPP-ene (SDZ EAA-494) in patients with epilepsy. Epilepsy Res. 16, 165–174.

    Article  PubMed  CAS  Google Scholar 

  48. Bullock, R. (1995) Strategies for neuroprotection with glutamate antagonists. Extrapolating from evidence taken from the first stroke and head injury studies. Ann. NYAcad. Sci. 765, 272–278.

    Article  CAS  Google Scholar 

  49. Carter, A. (1994) Many agents that antagonize the NMDA receptor—channel complex in vivo also cause disturbances of motor coordination. J. Pharmacol. Exp. Ther. 269, 573–580.

    PubMed  CAS  Google Scholar 

  50. Löscher, W. and Hönack, D. (1991a) Anticonvulsant and behavioral effects of two novel competitive N-methyl-o-aspartic acid receptor antagonists, CGP 37849 and CGP 39551, in the kindling model of epilepsy. Comparison with MK-801 and carbamazepine. J. Pharmacol. Exp. Ther. 256, 432–440.

    PubMed  Google Scholar 

  51. Löscher, W. and Hönack, D. (1991b) The novel competitive N-methyl-D-aspartate (NMDA) antagonist CGP 37849 preferentially induces phencylidine-like behavioral effects in kindled rats: attenuation by manipulation of dopamine, alpha-1, and serotoniniA receptors. J. Pharmacol. Exp. Ther. 257, 1146–1153.

    PubMed  Google Scholar 

  52. Smith, S. E. and Chapman, A. G. (1993) Acute and chronic anticonvulsant effects of D(—)CPPene in genetically epilepsy-prone rats. Epilepsy Res. 15, 193–199.

    Article  PubMed  CAS  Google Scholar 

  53. Willetts, J., Clissold, D. B., Hartman, T. L., Brandsgaard, R. R., Hamilton, G. S., and Ferkany, J. W. (1993) Behavioral pharmacology of NPC 17742, a competitive N-methyl-n-aspartate (NMDA) antagonist. J. Pharmacol. Exp. Ther. 265, 1055–1062.

    PubMed  CAS  Google Scholar 

  54. Johnson, J. W. and Ascher, P. (1987) Glycine potentiates the NMDA response in cultured mouse brain neurons. Nature 325, 529–531.

    Article  PubMed  CAS  Google Scholar 

  55. Kleckner, N. W. and Dindeldine, R. (1988) Requirement for glycine in activation of NMDA-receptors expressed in Xeno-pus oocytes. Science 241, 444–449.

    Google Scholar 

  56. Mothet, J-P., Parent, A. T., Wolosker, H., Brady, R. O., Jr., Linden, D. J., Ferris, C. D., et al. (2000) D-Serine is an endogenous ligand for the glycine site of the N-Mehtyl-D-aspartate receptor. Proc. Natl.Acad. Sci. USA 97, 4926–4931.

    Article  PubMed  CAS  Google Scholar 

  57. Viu, E., Zapata, A., Capdevila, J. et al. (2000) Glycine(B) receptor antagonists and partial agonists prevent memory deficits in inhibitory avoidance learning. Neurobiol. Learn. Mem. 74, 146–160.

    Article  PubMed  CAS  Google Scholar 

  58. Balster, R. L., Mansbach, R. S., Shelton, K. L., Nicholson, K. L., Grech, D. M., Wiley, J. L., et al. (1995) Behavioural pharmacology of two novel substituted quinoxalinedione glutamate antagonists. Behay. Pharmacol. 6, 577–590.

    CAS  Google Scholar 

  59. Witkin, J. M., Brave, S., French, D., and Geter-Douglass, B. (1995) Discriminative stimulus effects of R-(+)-3-amino-lhydroxypyrrolid-2-one, [(+)-HA-966], a partial agonist of the strychnine-insensitive modulatory site of the N-methyl-Daspartate receptor. J. Pharmacol. Exp. Thee. 275, 1267–1273.

    CAS  Google Scholar 

  60. Witkin, J. M., Steele T. D., and Sharpe, L. G. (1997) Effects of strychnine-insensitive glycine receptor ligands in rats discriminating either dizocilpine or phencyclidine from saline. J. Pharmacol. Exp. Thee. 280, 46–52.

    CAS  Google Scholar 

  61. Kotlinska, J. and Bialwa, G. (2000) Memantine and ACPC affect conditioned place preference induced by cocaine in rats. Pol. J. Pharmacol. 52, 179–185.

    PubMed  CAS  Google Scholar 

  62. Honer, M., Benke, D., Laube, B., Kuhse, J., Heckendorn, R., Allgeier, H., et al. (1998) Differentiation of glycine antagonist sites of N-methyl-D-aspartate receptor subtypes. J. Biol. Chem. 273, 11,158–11, 163.

    Google Scholar 

  63. Carling, R. W., Leeson, P. D., Moore, K. W., Smith, J. D., Moyes, C. R., Mawer, I. M., et al. (1993) 3-Nitro-3,4-dihydro2(1H)-quinolones. Excitatory amino acid antagonists acting at glycine-site NMDA and (RS)-a-amino-3-hydroxy-5-methyl4-isoxazolepropionic acid receptors. J. Med. Chem. 36, 3397–3408.

    Google Scholar 

  64. Kloog, Y., Haring, R., and Sokolovsky, M. (1988) Kinetic characterization of the phencylidine-N-methyl-D-aspartate receptor interaction: evidence for a steric blockade of the channel. Biochemistry 27, 843–848.

    Article  PubMed  CAS  Google Scholar 

  65. Ascher, P. and Nowak, L. (1987) Electrophysiological studies of NMDA receptors. Trends Neurosci. 10, 284–287.

    Article  CAS  Google Scholar 

  66. Salt, T. E. (1989) Modulation of NMDA receptor-mediated responses by glycine and D-serine in the rat thalamus in vivo. Brain Res. 481, 403–406.

    Article  CAS  Google Scholar 

  67. Thomson, A. M., Walker, V. E., and Flynn, D. M. (1989) Glycine enhances NMDA-receptor medicated synaptic potentials in neocortical slices. Nature 338, 422–424.

    Article  PubMed  CAS  Google Scholar 

  68. Toth, E. and Lajtha, A. (1986) Antagonism of phencyclidine-induced hyperactivity by glycine in mice. Neurochem. Res. 11, 393–400.

    Article  PubMed  CAS  Google Scholar 

  69. Evoniuk, G. E., Hertzman, R. P., and Skolknick, P. (1991) A rapid method for evaluating the behavioral effects of phencyclidine-like dissociative anesthetics in mice. Psychopharmacology 105, 125–128.

    Article  PubMed  CAS  Google Scholar 

  70. Contreras, R. (1990) D-Serine antagonized phencyclidine and MK-80l-induced stereotyped behavior and ataxia. Neuropharmacology 29, 291–293.

    Article  PubMed  CAS  Google Scholar 

  71. Tanii, Y., Nishikawa, T., Hashimoto, A., and Takahaski, K. (1991) Stereoselective inhibition by D- and L-alanine of phencyclidine-induced locomotor stimulation in the rat. Brain Res. 563, 281–284.

    Article  PubMed  CAS  Google Scholar 

  72. Tanii, Y., Nishikawa, T., Hashimoto, A., and Takahaski, K. (1994) Stereoselective antagonism by enantiomers of alanine and serine of phencyclidine-induced hyperactivity, stereotypy and ataxia. J. Pharmacol. Exp. Thee. 269, 1040–1048.

    CAS  Google Scholar 

  73. McBain, C. J., and Mayer, M. L. (1994) N-Methyl-D-aspartic acid receptor structure and function. Physiol. Rev. 74, 723–760.

    Article  PubMed  CAS  Google Scholar 

  74. Avenet, P., Léonardon, J., Besnard, F., Graham, D., Depoortere, H., and Scatton, B. (1997) Anagonist properties of eliprodil and other NMDA receptor antagonists at rat NR1A/NR2A and NR1A/NR2B receptors expressed in Xenopus oocytes. Neurosci. Lett. 223, 133–136.

    Article  CAS  Google Scholar 

  75. Brimecombe, J. C., Boeckman, F. A., and Aizenman, E. (1997) Functional consequences of NR2 subunit composition in single recombinant N-methyl-D-aspartate receptors. Proc. Natl. Acad. Sci. USA 94, 11109–11024.

    Article  Google Scholar 

  76. Fischer, G., Mutel, V., Trube, G., Malherbe, P., Kew, J. N. C., Mohacsi, E., et al. (1997) Ro 25–6981, a highly potent and selective blocker of N-methyl-D-aspartate receptors containing the NR2B subunit. Characterization in vitro. J. Pharmacol. Exp. Then.283, 1285–1292.

    CAS  Google Scholar 

  77. Tamiz, A. P., Whittemore, E. R., Zhou, Z.-L., Huang, J.-C, Drewe, J. A., Chen, J.-C., et al. (1998) Structure-activity relationships for a series of bis(phenylalkyl) amines: potent subtype-selective inhibitors of N-methyl-D-aspartate receptors. J. Med. Chem. 41, 3499–3506.

    Article  PubMed  CAS  Google Scholar 

  78. Mott, D., Doherty, J., Zhang, S., Washburn, M., Fendley, M., Lyuboslaysky, P., et al. (1998) Enhancement of proton inhibition: a novel mechanism for NMDA receptor inhibition by phenylethenolamines. Nature Neurosci. 1, 659–667.

    Article  PubMed  CAS  Google Scholar 

  79. Scatton B., Avenet, P., Benavides, J., Carter, C., Duverger, D., Oblin, A., et al. (1994) Neuroprotective potential of the polyamine site-directed NMDA receptor antagonists-ifenprodil and eliprodil, in Direct and Allosteric Control of Glutamate Receptors ( Palfreyman, M. G., Reynolds, I. J., and Skolnick, P., eds.), CRC, Boca Raton Fl, pp. 139–154.

    Google Scholar 

  80. Duval, D., Roome, N., Gauffeny, C., Nowicki, J. P., and Scatton, B. (1992) SL 82.0715, an NMDA antagonist acting at the polyamine site, does not induce neurotoxic effects on rat cortical neurons. Neurosci. Lett. 137, 193–197.

    Article  PubMed  CAS  Google Scholar 

  81. Deren-Wesolek, A. and Maj, J. (1993) Central effects of SL 82.0715, an antagonist of polyamine site of the NMDA receptor complex. Pol. J. Pharmacol. 45, 467–480.

    PubMed  CAS  Google Scholar 

  82. Harty, T. P. and Rogawski, M. A. (1997) Channel block of NMDA receptors by the anticonvulsant ADCI: studies with cloned NR1a/NR2A and NR1a/NR2B subunits. Soc. Neurosci. Abst. 23, 2165.

    Google Scholar 

  83. Harty, T. P. and Rogawski, M. A. (2000) Felbamate block of recombinant N-methyl-D-aspartate receptors: selectivity for the NR2B subunit. Epilepsy Res. 29, 47–55.

    Article  Google Scholar 

  84. Donevan, S. D. and McCabe, R. T. (2000) Conantokin G is an NR2B-selective competitive antagonist of N-methyl-D-aspartate receptors. Mol. Pharmacol. 58, 614–623.

    PubMed  CAS  Google Scholar 

  85. Gallagher, M. J., Huang, H., and Lynch, D. R. (1998) Modulation of the N-methyl-D-aspartate receptor by haloperidol: NR2B-specific interactions. J. Neurochem. 70, 2120–2128.

    Article  PubMed  CAS  Google Scholar 

  86. Yamakura, T., Sakimura, K., Mishina, M., and Shimoji, K. (1998) Sensitivity of the N-methyl-D-aspartate receptor channel to butyrophenones is dependent on the r2 subunit. Neuropharmacology 37, 709–717.

    Article  PubMed  CAS  Google Scholar 

  87. Mori, H. and Mishina, M. (1995) Structure and function of the NMDA receptor channel. Neuropharmacology 34, 1219–1237.

    Article  PubMed  CAS  Google Scholar 

  88. Li, H. and Rogawski, M. A. (1998) GluRS kainate receptor mediated synaptic transmission in rat basolateral amygdala in vitro. Neuropharmacology 37, 1279–1286.

    Article  CAS  Google Scholar 

  89. Lerma, J. (1998) Kainate receptors: an interplay between excitatory and inhibitory synapses. FEBS Lett. 430, 100–104.

    Article  PubMed  CAS  Google Scholar 

  90. Rodriguez-Moreno, A., Lopez-Garcia, J. C., and Lerma, J. (2000) Two populations of kainate receptors with separate signaling mechanisms in hippocampal interneurons. Proc. Natl. Acad. Sci. 97, 1293–1298.

    Article  PubMed  CAS  Google Scholar 

  91. Bleakman, D. and Lodge, D. (1998) Neuropharmacology of AMPA and kainate receptors. Neuropharmacology 37, 1187–1204.

    Article  PubMed  CAS  Google Scholar 

  92. Rogawski, M. A. and Donevan, S. D. (1999) AMPA receptors in epilepsy and as targets for antiepileptic drugs, in Jasper’s Basic Mechanisms of the Epilepsies: 3rd ed. Advances in Neurologic Vol. 79 (Delgado-Escueta, A. V. Wilson, W. A., Olsen, R. W., and Porter, R. J., eds.), Lippincott Williams and Wilkins, Philadelphia, pp 947–963.

    Google Scholar 

  93. Lees, G. J. (2000) Pharmacology of AMPA/kainate receptor ligands and their therapeutic potential in neurological and psychiatric disorders. Drugs 59, 33–78.

    Article  PubMed  CAS  Google Scholar 

  94. Honoré, T. (1991) Inhibitors of kainate and AMPA ionophore receptors, in: Excitatory Amino Acid Antagonists ( Meldrum, B. S., ed.), Blackwell, Oxford, pp. 180–194.

    Google Scholar 

  95. Watjen, F., Nielsen, E. O., Drejer, J., and Jensen, L. H. (1993) Isatin oximes-a novel series of bioavailable non-NMDA antagonists. Bioorg. Med. Chem. Lett. 3, 105–106.

    Article  CAS  Google Scholar 

  96. Nijholt, I., Blank T., Grafelmann, B., Cepok, S., Kugler, H., and Spiess, J. (1999) NS-257, a novel competitive AMPA receptor antagonist, interacts with kainate and NMDA receptors. Brain Res. 821, 374–382.

    Article  PubMed  CAS  Google Scholar 

  97. Witkin, J. M. (1993) Blockade of the locomotor stimulant effects of cocaine and methamphetamine by glutamate antagonists. Life Sci. 53, PL405–PL410.

    Google Scholar 

  98. Li, Y., Hu, X. T., Berney, T. G., Vartanian, A. J., Stine, C. D., Wolf, M. E., et al. (1999) Both glutamate receptor antagonists and prefrontal cortex lesions prevent induction of cocaine sensitization and associated neuroadaptations. Synapse 34, 169–180.

    Article  PubMed  CAS  Google Scholar 

  99. Comish, J. L. and Kalivas, P. W. (2000) Glutamate neurotransmission in the nucleus accumbens mediates relapse in cocaine addiction. J. Neurosci. 20, 1–5.

    Google Scholar 

  100. Ingwersen, S. H., Öhrström, J. K., Petersen, P. Drustrup, J., Bruno, L., and Nordholm, L. (1994) Human pharmacokinetics of the neuroprotective agent NBQX. Am. J. Then 1, 296–303.

    Google Scholar 

  101. Ohmori, J., Sakamoto, S., Kubota, H., Shimizu-Sasamata, M., Okada, M., Kawasaki, S., et al. (1994) 6-(IH-Imidazol-1-yl)7-nitro-2,3(1H,4H)-quinoxalinedione hydrochloride (YM90K) and related compounds:structure—activity relationships for the AMPA-type non-NMDA receptor. J. Med. Chem. 37, 467–475.

    Google Scholar 

  102. Umemura, K., Kondo, K., Ikeda, Y, Teraya, Y., Yoshida, H., Homma. M., et al. (1997) Pharmacokinetics and safety of the novel amino-3-hydroxy-5-methylisoxazole-4-propionate receptor antagonist YM90K in healthy men. J. Clin. Pharmacol. 37, 719–727.

    Article  PubMed  CAS  Google Scholar 

  103. Ohmori,J., Shimizu-Sasamata, M., Okada, M., and Sakamoto S. (1997) 8(1H-Imidazol-1-yl)-7-nitro-4(5H)-imidazo[l,2alpha]quinoxalinone and related compounds; synthesis and structure activity relationships for the AMPA-type non-NMDA receptor. J. Med Chem. 40, 2053–2063

    Google Scholar 

  104. Ohmori, J., Shimizu-Sasamata, M., Okada, M., and Sakamoto S. (1996) Novel AMPA receptor antagonists: synthesis and structure-activity relationships of 1-hydroxy-7-(1H-imidazol-1-yl)-6-nitro-2,3(1H,4H)-quinoxalinedione and related compounds. J. Med. Chem. 39, 3971–3979.

    Article  PubMed  CAS  Google Scholar 

  105. Kohara, A., Okada, M., Tsutsumi, R., Ohno, K., Takahashi, M., Shimizu-Sasamata, M., et al. (1998) In-vitro characterization of YM872, a selective, potent and highly water-soluble alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate receptor antagonist. J. Pharm. Pharmacol. 50, 795–801.

    Article  PubMed  CAS  Google Scholar 

  106. Takahashi, M., Ni, J. W., Kawasaki-Yatsugi, S., Toya, T., Yatsugi, S. I., Shimizu-Sasamata, M., et al. (1998) YM872, a novel selective alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor antagonist, reduces brain damage after permanent focal cerebral ischemia in cats. J. Pharmacol. Exp. Thee 284, 467–473.

    Google Scholar 

  107. Kawasaki-Yatsugi, S., Ichiki, C., Yatsugi, S., Takahashi, M., Shimizu-Sasamata, M., Yamaguchi, T., et al. (2000) Neuroprotective effects of an AMPA receptor antagonist YM872 in a rat transient middle cerebral artery occlusion model. Neuropharmacology 39, 211–217.

    Article  PubMed  CAS  Google Scholar 

  108. Nishiyama, T., Gyermek, L., Lee, C., Kawasaki-Yatsugi, S., and Yamaguchi, T. (1999) The systemically administered competitive AMPA receptor antagonist, YM872, has analgesic effects on thermal or formalin-induced pain in rats. Adnaesth. Analg. 89, 1534–1537.

    Google Scholar 

  109. Schoepp, D. D., Lodge D., Bleakman, D., Leander, J. D., Tizzano, J. P., Wright, R. A., et al. (1995) In vitro and in vivo antagonism of AMPA receptor activation by (3S4aR6R,8aR)-6-[2-(I(2)H-tetrazole-5-yl)ethyl]-decahydroisoquinoline-3carboxylic acid. Neuropharmacology 34, 1159–1168.

    Google Scholar 

  110. Bleakman, R., Schoepp, D. D., Ballyk, B., Bufton, H., Sharpe, E. F., Thomas, K., et al. (1996) Pharmacological discrimination of G1uR5 and G1uR6 kainate receptor subtypes by (3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl]decahydroisdoquinoline-3 carboxylic-acid. Mol. Pharmacol. 49, 581–585.

    Google Scholar 

  111. Rogawski, M. A., Kurzman, P., Yamaguchi, S., and Li, H. (2000) Role of AMPA and G1uR5 kainate receptors in the development and expression of amygdala kindling in the mouse. Neuropharmacology, 40, 28–35.

    Article  Google Scholar 

  112. Carlezon, W. A., Jr., Rasmussen, K., and Nestler, E. J. (1999) AMPA antagonist LY293558 blocks the development, without blocking the expression, of behavioral sensitization to morphine. Synapse 31, 256–262.

    Article  PubMed  CAS  Google Scholar 

  113. Kest, B., McLemore, G., Kao, B., and Inturrisi, C. E. (1997) The competitive alpha-amino-3-hydroxy-5-methylisoxazole-4propionate receptor antagonist LY293558 attenuates and reverses analgesic tolerance to morphine but not to delta or kappa opioids. J. Pharmacol. Exp. Ther. 283, 1249–1255.

    PubMed  CAS  Google Scholar 

  114. Rasmussen, K., Kendrick, W. T., Kogan J. H., and Aghajanian, G. K. (1996) A selective AMPA antagonist, LY293558, suppresses morphine withdrawal-induced activation of locus coeruleus neurons and behavioral signs of morphine withdrawal. Neuropsychopharmacology 15, 497–505.

    Article  PubMed  CAS  Google Scholar 

  115. Sang, C. N., Hostetter, M. P., Gracely, R. H., Chappell, A. S., Schoepp, D. D., Lee, G., et al. (1998) AMPA/kainate antagonist LY293558 reduces capsaicin-evoked hyperalgesia but not pain in normal skin in humans. Anesthesiology 89, 1060–1067.

    Google Scholar 

  116. Mutel, V., Trube, G., Klingelschmidt, A., Messer, J., Bleuel, Z., Humbel U., et al. (1998) Binding characteristics of a potent AMPA receptor antagonist [3H]Ro 48–8587 in rat brain. J. Neurochem. 71, 418–426.

    Article  PubMed  CAS  Google Scholar 

  117. Löscher, W., Lehmann, H., Behl, B., Seemann, D., Teschendorf, H. J., Hofmann, H. P., et al. (1999) A new pyrrolyl-quinoxalinedione series of non-NMDA glutamate receptor antagonists: pharmacological characterization and comparison with NBQX and valproate in the kindling model of epilepsy. Eur. J. Neurosci. 11, 250–262.

    Article  PubMed  Google Scholar 

  118. Turski, L., Huth, A., Sheardown, M., McDonald, F., Neuhaus, R., Schneider, H. H., et al. (1998) ZK200775: a phosphonate quinoxalinedione AMPA antagonist for neuroprotection in stroke and trauma. Proc. Natl. Acad. Sci. USA 95, 10,960–10,965.

    Google Scholar 

  119. Löscher, W., Rundfeldt, C., and Hönack, D. (1993) Low doses of NMDA receptor antagonists synergistically increase the anticonvulsant effect of the AMPA receptor antagonist NBQX in the kindling model of epilepsy. Eur. J. Neurosci. 5, 1545–1550.

    Article  PubMed  Google Scholar 

  120. Löscher, W. (1998) New visions in the pharmacology of anticonvulsion. Eur. J. Pharmacol. 342, 1–13.

    Article  PubMed  Google Scholar 

  121. Potschka, H., Löscher, W., Wlaz, P., Behl, B., Hofmann, H. P., Treiber, H. J., et al (1998) LU73068, a new non-NMDA and glycine/NMDA receptor antagonist: pharmacological characterization and comparison with NBQX and L-701,324 in the kindling model of epilepsy. Be J. Pharmacol. 125, 1258–1266.

    Article  CAS  Google Scholar 

  122. Tarnawa, I., Farkas, S., Berzsenyi, P., Pataki, A., and Andrasi, F. (1989) Electrophysiological studies with a 2,3-benzodiazepine muscle relaxant: GYKI 52466. Eur. J. Pharmacol. 167, 193–199.

    Article  PubMed  CAS  Google Scholar 

  123. Bleakman, D., Ballyk, B. A., Schoepp, D. D., Palmer, A. J., Bath, C. P., Sharpe, E. F., et al. (1996) Activity of 2,3-benzodiazepines at native rat and recombinant human glutamate receptors in vitro: stereospecificity and selectivity profiles. Neuropharmacology 35, 1689–1702.

    Article  PubMed  CAS  Google Scholar 

  124. Donevan, S. D., Yamaguchi, S., and Rogawski, M. A. (1994) Non-N-methyl-D-aspartate receptor antagonism by 3-N-substituted 2,3-benzodiazepines: relationship to anticonvulsant activity. J. Pharmacol. Exp. Thee. 271, 25–29.

    CAS  Google Scholar 

  125. Donevan, S. D. and Rogawski, M. A. (1993) GYKI 52466, a 2,3-benzodiazepine, is a highly selective, noncompetitive antagonist of AMPA/kainate receptor responses. Neuron 10, 51–59.

    Article  PubMed  CAS  Google Scholar 

  126. Zorumski, C. F., Yamada, K A., Price, M. T., and Olney, J. W. (1993) A benzodiazepine recognition site associated with the non-NMDA glutamate receptor. Neuron 10: 61–67.

    Article  PubMed  CAS  Google Scholar 

  127. Tarnawa, I. and Vizi, E. S. (1998) 2,3-Benzodiazepine AMPA antagonists. Restor. Neurol. Neurosurg. 13, 41–57.

    Google Scholar 

  128. Yamaguchi, S., Donevan, S. D., and Rogawski, M. A. (1993) Anticonvulsant activity of AMPA/kainate antagonists: comparison of GYKI 52466 and NBQX in maximal electroshock and chemoconvulsant models, Epilepsy Res. 15, 179–184.

    Article  PubMed  CAS  Google Scholar 

  129. Lodge, D., Bond, A., O’Neill, M. J., Hicks, C. A., and Jones, M. G. (1996) Stereoselective effects of 2,3-benzodiazepines in vivo: electrophysiology and neuroprotection studies. Neuropharmacology 35, 1681–1688.

    Google Scholar 

  130. Abraham, G., Solyom, S., Csuzdi, E., Berzsenyi, P., Ling, I., Tarnawa, I., et al. (2000) New non competitive AMPA antagonists. Bioorg. Med. Chem. 8, 2127–2143.

    Article  PubMed  CAS  Google Scholar 

  131. Pelletier, J. C., Hesson, D. P., Jones, K. A., and Costa, A. M. (1996) Substituted 1,2-dihydrophthalazines: potent, selective, and noncompetitive inhibitors of the AMPA receptor. J. Med. Chem. 39, 343–346

    Article  PubMed  CAS  Google Scholar 

  132. Pei, X.-F., Sturgess, M. A., Valenzuela, C. F., and Maccecchini, M.-L. (1999) Allosteric modulators of the AMPA receptor:novel 6-substituted dihydrophthalazines. Bioorg. Med. Chem. Lett. 9, 539–542.

    Article  PubMed  CAS  Google Scholar 

  133. Grasso, S., De Sarro, G., De Sarro, A., Micale, N., Zappalà, M., Puja, G., et al (2000) Synthesis and anticonvulsant activity of novel and potent 6,7-methylenedioxyphthalazin-1(2H)-ones. J. Med. Chem. 43, 2851–2859.

    Article  PubMed  CAS  Google Scholar 

  134. Chenard, B. L., Menniti, F. S., Pagnozzi, M. J., Shenk, K. d., Ewing, F. E., and Welch, W. M. (2000) Methaqualone derivatives are potent noncompetitive AMPA receptor antagonists. Bioorg. Med. Chem. Lett. 10, 1203–1205.

    Article  PubMed  CAS  Google Scholar 

  135. Yamada, K. A. (1998) Modulating excitatory synaptic neurotransmission: potential treatment for neurological disease? Neurobiol. Dis. 5, 67–80.

    Article  PubMed  CAS  Google Scholar 

  136. Zivkovic, I., Thompson, D. M., Bertolino, M., Uzunov, D., DiBella, M., Costa, E., et al. (1957) 7-Chloro-3-methyl-3–4dihydro-2H-1,2,4 benzothiadiazine S,S-dioxide (IDRA 21): a benzothiadiazine derivative that enhances cognition by attenuating DL-alpha-amino-2,3-dihydro-5-methyl-3-oxo-4-isoxazolepropanoic acid (AMPA) receptor desensitization. J. Pharmacol. Exp. Ther. 272, 300–309.

    Google Scholar 

  137. Thompson, D. M., Guidotti, A., DiBella, M., and Costa, E. (1995) 7-Chloro-3-methyl-3,4-dihydro-2H-1–2,4-benzothiadiazine S,S-dioxide (IDRA 21), a congener of aniracetam, potently abates pharmacologically induced cognitive impairments in patas monkeys. Proc. Natl. Acad. Sci. USA 92, 7667–7671.

    Google Scholar 

  138. Hampson, R. E., Rogers, G., Lynch, G., and Deadwyler, S. A. (1998) Facilitative effects of the ampakine CX516 on short-term memory in rats: enhancement of delayed-nonmatch-to-sample performance. J. Neurosci. 18, 2740–2747.

    PubMed  CAS  Google Scholar 

  139. Hampson, R. E., Rogers, G., Lynch, G., and Deadwyler, S. A. (1998b) Facilitative effects of the ampakine CX516 on short-term memory in rats: correlations with hippocampal neuronal activity. J. Neurosci. 18, 2748–2763.

    PubMed  CAS  Google Scholar 

  140. Ingvar, M., Ambros-Ingerson, J., Davis, M., Granger, R., Kessler, M., Rogers, G. A., et al. (1997) Enhancement by an ampakine of memory encoding in humans. Exp. Neurol. 146, 553–559.

    Google Scholar 

  141. Lynch, G., Granger, R., Ambros-Ingerson, J., Davis, C. M., Kessler, M., and Schehr, R. (1997) Evidence that a positive modulator of AMPA-type glutamate receptors improves delayed recall in aged humans. Exp. Neurol. 145, 89–92.

    Article  PubMed  CAS  Google Scholar 

  142. Meador-Woodruff, J. H. and Healy, D. J. (2000) Glutamate receptor expression in schizophrenic brain. Brain Res. Brain. Res. Rev. 31, 288–294.

    Article  PubMed  CAS  Google Scholar 

  143. Johnson, S. A., Luu, N. T., Herbst, T. A., Knapp, R., Lutz, D., Arai, A., et al. (1999) Synergistic interactions between ampakines and antipsychotic drugs. J. Pharmacol. Exp. Ther. 289, 392–397.

    PubMed  CAS  Google Scholar 

  144. Bowie, D. and Smart, T. G. (1993) Thiocyanate ions selectively antagonize AMPA-evoked responses in Xenopus laevis oocytes injected with chick brain mRNA. Neurosci. Lett. 121, 68–72.

    Article  Google Scholar 

  145. Donevan, S. D. and Rogawski, M. A. (1998) Allosteric regulation of AMPA receptors SCN- and cyclothiazide at a common modulatory site distinct from that of 2,3-benzodiazepines. Neuroscience 87, 615–629.

    Article  PubMed  CAS  Google Scholar 

  146. Chittajallu, R., Braithwaite, S. P., Clarke, V. R., and Henley, J. M. (1999) Kainate receptors: subunits, synaptic localization and function. Trends Pharmacol. Sci. 20, 26–35.

    Article  PubMed  CAS  Google Scholar 

  147. Frerking, M. and Nicoll, R. A. (2000) Synaptic kainate receptors. Curr. Opin. Neurobiol. 10, 342–351.

    Article  PubMed  CAS  Google Scholar 

  148. Johansen, T. H., Drejer, J., Watjen, F., and Nielsen, E. O. (1993) A novel non-NMDA receptor antagonist shows selective displacement of low-affinity [3H]kainate binding. Eur. J. Pharmacol. 246, 195–204.

    Article  PubMed  CAS  Google Scholar 

  149. Verdoom, T. A., Johansen, T. H., Drejer, J., and Nielsen, E. O. (1994) Selective block of recombinant glur6 receptors by NS-102, a novel non-NMDA, receptor antagonist. Eta - . J. Pharmacol. 269, 43–49.

    Google Scholar 

  150. Patemain, A. V., Morales, M., and Lerma, J. (1995) Selective antagonism of AMPA receptors unmasks kainate receptor-mediated responses in hippocampal neurons. Neuron 14, 185–189.

    Article  Google Scholar 

  151. O’Neill, M. J., Bogaert, L., Hicks, C. A., Bond, A., Ward, M. A., Ebinger. G., et al. (2000) LY377770, a novel iGlu5 Kainate receptor antagonist with neuroprotective effects in global and focal cerebral ischaemia. Neuropharmacology 39, 1575–1588.

    Article  PubMed  Google Scholar 

  152. O’Neill, M. J., Bond, A., Ornstein, P. L., Ward, M. A., Hicks, C. A., Hoo, K., et al. (1998) Decahydroisoquinolines:novel competitive AMPA/Kainate antagonists with neuroprotective effects in global cerebral ischaemia. Neuropharmacology 37, 1211–1222.

    Article  PubMed  Google Scholar 

  153. Vignes, M. and Collingridge, G. L. (1997) The synaptic activation of kainate receptors. Nature 388, 179–182.

    Article  PubMed  CAS  Google Scholar 

  154. Clarke, V. R. J., Ballyk, B. A., Hoo, K. H., Mandelzys, A., Pellizzari, A., Bath, C. P., et al (1997) A hippocampal G1uR5 kainate receptor regulating inhibitory synaptic transmission. Nature 389, 599–603.

    Article  PubMed  CAS  Google Scholar 

  155. Pemberton, K. E., Belcher, S. M., Ripellino, J. A., and Howe, J. R. (1998) High-affinity kainate-type ion channels in rat cerebellar granule cells. J. Physiol. 510, 401–420.

    Article  PubMed  CAS  Google Scholar 

  156. Li, P., Wilding, T., Kim, S. J., Calejesan, A. A., Huettner, J. E., and Zhuo, M. (1999) Kainate receptor-mediated sensory synaptic transmission in mammalian spinal cord. Nature 397, 161–164.

    Article  PubMed  CAS  Google Scholar 

  157. Simmons R. M. A., Li, D. L., Hoo, K. H., Deverill, M., Omstein, P. L., and Iyengar, S. (1998) Kainate GIuR5 receptor subtype mediates the nociceptive response to formalin in the rat. Neuropharmacology 37, 25–36.

    Article  PubMed  CAS  Google Scholar 

  158. Sailer, A., Swanson, G. T., Perez-Otano, I, O’Leary, L., Malkmus, S. A., Dyck, R. H., et al. (1999) Generation and analysis of G1uR5(Q636R) kainate receptor mutant mice. J. Neurosci. 19, 8757–8764.

    PubMed  CAS  Google Scholar 

  159. Li, H. and Rogawski, M. A. (1999) Kainate receptor mediated heterosynaptic facilitation in the amygdala, Soc. Neurosci. Abst. 25, 974.

    Google Scholar 

  160. Cartmell, J. and Schoepp, D. D. (2000) Regulation of neurotransmitter release by metabotropic glutamate receptors. J. Neurochem. 75, 889–907.

    Article  PubMed  CAS  Google Scholar 

  161. Conn, P. J. and Pin, J.-P. (1997) Pharmacology and functions of metabotropic glutamate receptors. Annu Rev. Pharmacol. Toxicol. 37, 205–237.

    Article  PubMed  CAS  Google Scholar 

  162. Anwyl, R. (1999) Metabotropic glutamate receptors: electrophysiological properties and role in placticity. Brain Res. Rev. 29, 83–120.

    Article  PubMed  CAS  Google Scholar 

  163. Bordi, F. and Ugolini, A. (1999) Group I metabotropic glutamate receptors: implications for brain diseases. Prog. Neurobiol. 59, 55–79.

    Article  PubMed  CAS  Google Scholar 

  164. Schoepp, D. D., Jane, D. E., and Monn, J. A. (1999) Pharmacological agents acting at subtypes of metabotropic glutamate receptors, Neuropharmacology 38, 1431–1476.

    Article  PubMed  CAS  Google Scholar 

  165. Monn, J. A. and Schoepp, D. D. (2000) Metabotropic glutamate receptor modulators: recent advances and therapeutic potential. Annu. Rep. Med. Chem. 35, 1–10.

    Article  CAS  Google Scholar 

  166. Varney, M. A. and Suto, C. M. (2000) Discovery of subtype-selective metabotropic glutamate receptor ligands using functional HTS assays. Drug Discov. Today 1 (HTS Suppl.), 20–26.

    Article  CAS  Google Scholar 

  167. Gasparini, F., Inderbitzin, W., Francotte, E., Lecis, G., Richert, P., Dragic, Z., et al. (2000) (+)-4-Phosphonophenylglycine (PPG) a new group III selective metabotropic glutamate receptor agonist. Bioorg. Med. Chem. Lett. 10, 1241–1244.

    Google Scholar 

  168. Moghaddam, B. and Adams, B. W. (1998) Reversal of phencyclidine effects by a group II metabotropic glutamate receptor agonist in rats. Science 281, 1349–1352.

    Article  PubMed  CAS  Google Scholar 

  169. Cartmell, J., Monn, J. A., and Schoepp, D. D. (1999) The metabotropic glutamate 2/3 receptor agonists LY354740 and LY379268 selectively attenuate phencyclidine versus d-amphetamine motor behaviors in rats. Z Pharmacol. Exp. Thee. 291, 161–170.

    CAS  Google Scholar 

  170. Helton, D. R., Tizzano, J. P., Monn, J. A., Schoepp, D. D., and Kaltman, M. J. (1997) LY354740: a potent, orally active, highly selective metabotropic glutamate receptor agonist which ameliorates symptoms of nicotine withdrawal. Neuropharmacology 36, 1511–1516.

    Article  PubMed  CAS  Google Scholar 

  171. Vandergriff, B. C. and Rasmussen, K. (1999) The selective mGlu2/3 receptor agonist LY354740 attenuates morphine-withdrawal-induced activation of locus coerulus neurons and behavioral signs of morphine withdrawal. Neurophannacology 38, 217–222.

    Article  CAS  Google Scholar 

  172. Popik, P., Kozela, E., and Pilc, A. (2000) Selective agonist of group II glutamate metabotropic receptors, LY354740, inhibits tolerance to analgesic effects of morphine in mice. Be J Pharmacol. 130, 1425–1431.

    Article  CAS  Google Scholar 

  173. Chapman, A. G., Nanan, K., Williams, M., and Meldrum, B. S. (2000) Anticonvulsant activity of two metabotropic glutamate Group I antagonists selective for mGlu5 receptor: 2-methyl-6-(phenylethynyl)-pyridine (MPEP), and (E)-6-methyl-2styryl-pyridine (SIB 1893). Neuropharmacology 39, 1567–1574.

    Article  PubMed  CAS  Google Scholar 

  174. Neugebauer, V., Zinebi, F., Russell, R., Gallagher, J. P., and Shinnick-Gallagher, P. (2000) Cocaine and kindling alter the sensitivity of group II and III metabotropic glutamate receptors in the central amygdala. J Neurophysiol. 84, 759–770.

    PubMed  CAS  Google Scholar 

  175. Stefani, A., Spadoni, F., and Benardi, G. (1997) Differential inhibition by riluzole, lamotrigine and phenytoin of sodium and calcium currents in cortical neurones:implicaitons for neuroprotective strategies. Exp. Neurol. 147, 115–122.

    Article  PubMed  CAS  Google Scholar 

  176. Zhu, W. and Rogawski, M. A. (1999) Zonisamide depresses excitatory synaptic transmission by a presynaptic action. Epilepsia 40 (Suppl. 7), 244.

    Google Scholar 

  177. Cunningham, M. O. and Jones, R. S. G. (2000) The anticonvulsant, lamotrigine decreases spontaneous glutamate release but increases spontaneous GABA release in the rat entorhinal cortex in vitro. Neuropharmacology 39, 2139–2146.

    Article  PubMed  CAS  Google Scholar 

  178. Cunningham, M. O., Dhillon, A., Wood, S. J., and Jones, R. S. G. (2000) Reciprocal modulation of glutamate and GABA release may underlie the anticonvulsant effect of phenytoin. Neuroscinece 95, 343–351.

    Article  CAS  Google Scholar 

  179. Waldmeier, P. C., Baumann, P. A., Wicki, P., Feldtrauer, J.-J., Stierlin, C., and Schmutz, M. (1995) Similar potency of carbamazepine, oxcarbazepine, and lamotrigine in inhibiting the release of glutamate and other neurotransmitters. Neurology 45, 1907–1913.

    Google Scholar 

  180. Snyder, S. H. (1992) Nitric Oxide, first in a new class of neurotransmitters. Science 257, 494–496.

    Article  PubMed  CAS  Google Scholar 

  181. Semba, J., Wantanabe, H., Suhara, T., and Akanuma, N. (2000) Neonatal treatment with L-Name (NG-nitro-L-arginine methylester) attenuates stereotyped behavior induced by acute methamphetamine but not development of behavioral sensitization to methamphetamine. Prog. Neuro-Pyschopharmacol. Biol. Psychiatry 24, 1017–1023.

    Google Scholar 

  182. Haracz, J. L., MacDonall, J. S., and Sircar, R. (1997) Effects of nitric oxide synthase inhibitors on cocaine sensitization. Brain Res. 746, 183–189.

    Article  PubMed  CAS  Google Scholar 

  183. Pulvirenti, L., Balducci, C., and Koob, G. F. (1996) Inhibition of nitric oxide synthesis reduces intravenous cocaine self-administration in the rat. Neuropharmacology 35, 1811–1814.

    Article  PubMed  CAS  Google Scholar 

  184. Itzhak, Y. (1995) Cocaine kindling in mice. Responses to N-methyl-D,L-aspartate (NMDLA) and L-arginine. Mol. Neurobiol. 11, 217–222.

    Article  PubMed  CAS  Google Scholar 

  185. Johansson, C., Deveney, A. M., Reif, D., and Jackson, D. M. (1999) The neuronal selective nitric oxide inhibitor AR-R 17477, blocks some effects of phencyclidine, while having no observable behavioural effects when given alone. Pharmacol. Toxicol. 84, 226–233.

    Article  PubMed  CAS  Google Scholar 

  186. Wiley, J. L., Harvey, S. A., and Balster, R. L. (1999) Nitric oxide synthase inhibitors do not substitute in rats trained to discriminate phencyclidine from saline. Eur. J. Pharmacol. 367, 7–11.

    Article  PubMed  CAS  Google Scholar 

  187. Neale, J. H., Bzdega, T., and Wroblewska, B. (2000) N-Acetylaspartylglutamate: the most abundant peptide neurotransmitter in the mammalian central nervous system. J. Neurochem. 75, 443–452.

    Article  PubMed  CAS  Google Scholar 

  188. Wroblewska, B., Wroblewski, J. T., Pshenichkin, S., Surin, A., Sullivan, S. E., and Neale, J. H. (1997) NAAG selectively activates mGluR3 receptors in transfected cells. J. Neurochem. 69, 174–181.

    Article  PubMed  CAS  Google Scholar 

  189. Jackson, P. F., Cole, D. C., Slusher, B. S., Stetz, S. L., Ross, L. E., Donazanti, B. A., et al. (1996) Design, synthesis, and biological activity of a potent inhibitor of the neuropeptidase N-acetylated a-linked acidic dipeptidase. J. Med. Chem. 39, 619–622.

    Article  PubMed  CAS  Google Scholar 

  190. Slusher, B. S, Vornov, J. J., Thomas, A. G., Hurn, P. D., Harukuni, I., Bhardwaj, A., et al. (1999) Selective inhibition of NAALADase, which converts NAAG to glutamate, reduces ischemic brain injury. Nature Med. 5, 1396–1402.

    Google Scholar 

  191. Shippenberg, T. S., Rea, W., and Slusher, B. S. (2000) Modulation of behavioral sensitization to cocaine by NAALADase inhibition. Synapse, 38, 161–166.

    Article  PubMed  CAS  Google Scholar 

  192. Witkin, J. M., Gasior, M., Zapata, A., Slusher, B. S., and Shippenberg, T. S. (2000) Inhibition of NAALAdase: a novel strategy for preventing sensitization to convulsant stimuli. FASEB J. 14, A1414.

    Google Scholar 

  193. Nestler, E. J., Berhow, M. T., and Brodkin, E. S. (1996) Molecular mechanisms of drug addiction: adaptations in signal transduction pathways. Mol. Psychiatry 1, 190–199.

    PubMed  CAS  Google Scholar 

  194. Skolnick, P. (1999) Antidepressants for the new millennium. Eur. J. Pharmacol. 375, 31–40.

    Article  PubMed  CAS  Google Scholar 

  195. Brandolin, C., Sanna, A., De Bernardi, M. A., Follesa, P., Brooker, G., and Mocchetti, I. (1998) Brain-derived neurotrophic factor and basic fibroblast growth factor downregulate NMDA receptor function in cerebellar granule cells. J. Neurosei. 18, 7953–7961.

    Google Scholar 

  196. Regier, D. A., Farmer, M. E., Rae, D. S., Locke, B. Z., Keith, S. K., Judd, L. L., et al. (1990) Comorbidity of mental disorders with alcohol and other drug abuse. J. Am. Med. Assoc. 264, 2511–2518.

    Article  CAS  Google Scholar 

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Authors
  1. Jeffrey M. Witkin PhD
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  2. Rafal Kaminski MD, PhD
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  3. Michael A. Rogawski MD, PhD
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Editor information

Editors and Affiliations

  1. Clinical Medical Branch, Division of Treatment Research and Development, National Institute on Drug Abuse (NIDA), National Institutes of Health (NIH), Bethesda, MD, USA

    Barbara H. Herman PhD

  2. Pharmacology, Integrative & Cellular Neurobiology Research Branch (PICNRB), Division of Neuroscience & Behavioral Research (DNBR), National Institute on Drug Abuse (NIDA), National Institutes of Health (NIH), Bethesda, MD, USA

    Jerry Frankenheim PhD

  3. Treatment Research Branch, Division of Clinical and Prevention Research, National Institute on Drug Abuse (NIAAA), National Institutes of Health (NIH), Bethesda, MD, USA

    Raye Z. Litten PhD

  4. Division of Neuropharmacological Drug Products Center for Drug Evaluation and Research, Office of Drug Evaluation I, Food and Drug Administration, Rockville, MD, USA

    Philip H. Sheridan MD

  5. Laboratory of Molecular and Cellular Neurobiology, Division of Intramural Clinical and Biological Research, National Institute on Drug Abuse (NIAAA) National Institutes of Health (NIH), Bethesda, MD, USA

    Forrest F. Weight MD

  6. Division of Treatment Research and Development, National Institute on Drug Abuse (NIDA), National Institutes of Health (NIH), Bethesda, MD, USA

    Steven R. Zukin MD

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© 2002 Springer Science+Business Media New York

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Witkin, J.M., Kaminski, R., Rogawski, M.A. (2002). Pharmacology of Glutamate Receptors. In: Herman, B.H., Frankenheim, J., Litten, R.Z., Sheridan, P.H., Weight, F.F., Zukin, S.R. (eds) Glutamate and Addiction. Contemporary Clinical Neuroscience. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-59259-306-4_2

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  • DOI: https://doi.org/10.1007/978-1-59259-306-4_2

  • Publisher Name: Humana Press, Totowa, NJ

  • Print ISBN: 978-1-61737-234-6

  • Online ISBN: 978-1-59259-306-4

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