Abstract
Cessation of chronic administration of orally administered large amounts of ethanol for 7 days resulted in a markedly increased frequency of audiogenic seizures in Sprague-Dawley rats. Oral administration of the novel glycine receptor antagonist, L-701,324, produced a dose-dependent (2.5 and 5.0 mg/kg; − 30 min) inhibition of ethanol withdrawal signs when measured about 12 h after withdrawal of the ethanol treatment. Similarly, using the same experimental paradigm, oral administration of the specific polyamine receptor antagonist, eliprodil, caused a dose-related (2.0 and 5.0 mg/kg; − 30 min) inhibition of ethanol withdrawal-induced audiogenic seizure activity. The inhibition of ethanol withdrawal seizures produced by L-701,324 and eliprodil, respectively, was obtained at doses which by themselves did not change the locomotor activity in naive Sprague-Dawley rats. The findings that L-701,324 and eliprodil are potent inhibitors of seizure activity induced by cessation of chronic ethanol administration and the fact that they, in contrast to currently available NMDA receptor antagonists, do not produce psychotomimetic and/or sedative effects, suggest that these drugs may represent a new class of therapeutically useful pharmacological agents for the treatment of ethanol withdrawal seizures. Furthermore, since there is evidence that eliprodil produces its pharmacological actions through a specific inhibition of NMDAR1 and/or NMDAR2B subunits, these data may indicate that certain NMDA receptor subunits may be of particular importance for the mediation of seizure activity following the discontinuation of chronic ethanol exposure.
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References
Adams ML, Sewing BN, Chen J, Meyer ER, Cicero TJ (1995) Nitric oxide-related agents alter alcohol withdrawal in male rats. Alcohol Clin Exp Res 19: 195–199.
Carter C, Benavides B, Dana C, Shoemaker H, Perrault G, Sanger D, Scatton B (1991) Non-competitive NMDA receptor antagonists acting on the polyamine site. In: Meldrum BS (ed) Excitatory amino acids. Blackwell, Oxford, pp 130–163.
Chandler LJ, Newsom H, Summers C, Crews F (1993) Chronic ethanol exposure potentiates NMDA excitotoxicity in cerebral cortical neurons. J Neurochem 60: 1578–1581
Chapman AG, Dürmüller N, Harrison BL, Baron BM, Parvez N, Meldrum BS (1995) Anticonvulsant activity kindled and sound-induced seizures. Eur J Pharmacol 274: 83–88.
Danysz W, Dyr W, Jankowska E, Glazewski W (1992) The involvement of NMDA receptors in acute and chronic effects of ethanol. Alcohol Clin Exp Res 16: 499–504.
Davidson MD, Wilce P, Shanley BC (1993) Increased sensitivity of the hippocampus in ethanol-dependent rats to toxic effect ofN-methyl-d-aspartic acid in vivo. Brain Res 606: 5–9
Dildy JE, Leslie SW (1989) Ethanol inhibits NMDA-induced increases in free intracellular Ca2+ in dissociated brain cells. Brain Res 499: 383–387
Ericson E, Samuelsson J, Ahlenius S (1991) Photocell measurements of rat, motor activity. A contribution to sensitivity and variation in behavioral observations J Pharmacol Methods 25: 111–122
Follesa P, Ticku MK (1995) Chronic ethanol treatment differentially regulates NMDA receptor subunit mRNA expression in rat brain. Mol Brain Res 29: 99–106.
Gilman AG, Wall TW, Nies AS, Taylor P (1990) Goodman and Gilman’s The pharmacological basis of therapeutics. Pergamon Press, New York
Göthert M, Fink K (1989) Inhibition ofN-methyl-d-aspartate (NMDA)- and 1-glutamate-induced noradrenaline and acetylcholine release in the rat brain by ethanol. Naunyn-Schmiedeberg’s Arch Pharmacol 340: 516–521
Grant KA (1994) Emerging neurochemical concepts in the actions of ethanol at ligand-gated ion channels. Behav Pharmacol 5: 383–404
Grant KA, Valverius P, Tabakoff B (1990) Ethanol withdrawal seizures and the NMDA receptor complex. Eur J Pharmacol 176: 289–296
Grant KA, Snell LD, Rogawski MA, Thurkauf A, Tabakoff B (1992) Comparison of the effects of the uncompetitive N-methyl-D-aspartate antagonist (±)-5-aminocarbonyl-10,11-dihydro-5H-dibenzo[a,b]cyclohepton-5,10-imine (ADCI) with its structural analogs dizocilpine (MK-801) and carbamazepine on ethanol withdrawal seizures. J Pharmacol Exp Ther 260: 1017–1022
Gulya K, Grant KA, Valverius P, Hoffman PL Tabakoff B (1991) Brain regional specificity and time-course of changes in the NMDA receptor-ionophore complex during ethanol with-drawal. Brain Res 547: 129–134
Hoffman PL (1995a) The effects of alcohol on excitatory amino acid receptor function. In: Kranzler H (ed) Handbook of experimental pharmacology, vol. 114, the pharmacology of alcohol abuse. Springer. Heidelberg, pp 75–102
Hoffman PL (1995b) Glutamate receptors in alcohol withdrawal-induced neurotoxicity. Metab Brain Dis 10: 73–79.
Hoffman PL, Rabe CS, Moses F, Tabakoff B (1989)N-Methyl-d-aspartate receptors and ethanol: inhibition of calcium flux and cyclic GMP production. J Neurochem 52: 1937–1940
Hu H-J, Ticku MK (1995) Chronic ethanol treatment upregulates the NMDA receptor function and binding in mammalian cortical neurons. Mol Brain Res 30: 347–356
Iorio KR, Reinlib L, Tabakoff B, Hoffman PL (1992) Chronic exposure of cerebellar granule cells to ethanol results in increasedN-methyl-d-aspartate receptors function. Mol Pharmacol 41: 1141–1148
Javitt De, Zukin SR (1991) Recent advances in the phencyclidine model of schizophrenia. Am J Psychiatry 148: 1301–1308
Johnson JW, Ascher P (1987) Glycine potentiates the NMDA response in cultured mouse brain neurons. Nature 325: 529–531
Kehne JH, Baron BM, Harrison BL, McCloskey TC, Palfreyman MG, Poirot M, Salituro FG, Siegel BW, Slone AL, Van Giersbergen PLM, White HS (1995) MDL 100,458 and MDL 102,288: two potent and selective glycine receptor antagonists with different functional profiles. Eur J Pharmacol 284: 109–118.
Kemp JA, Leeson PD (1993) The glycine site of the NMDA receptor —five years on. Trends Pharmacol Sci 14: 20–25
Koek W, Colpaert FC (1990) Selective blockade ofN-methyl-d-aspartate (NMDA)-induced convulsions by NMDA antagonists and putative glycine antagonists: relationship with phencyclidine-like behavioral effects. J Pharmacol Exp Ther 252: 349–357
Koltchine V, Anantharam V, Wilson A, Bayley H, Treistman SN (1993) Homomeric assemblies of NMDAR1 splice variants are sensitive to ethanol. Neurosci Lett 152: 13–16
Kotlinska J, Langwinski R (1986) Audiogenic seizures during ethanol withdrawal can be blocked by a delta opioid agonist. Drug Alcohol Depend 18: 361–367
Kulkarni SK, Mehta AK, Ticku MK (1990) Comparison of anticonvulsant effect of ethanol against NMDA-, Kainic acid- and picrotoxin-induced convulsions in rats. Life Sci 46: 481–487
Kuner T, Schoepfer R, Korpi ER (1993) Ethanol inhibits glutamate-induced currents in heteromeric NMDA receptor subtypes. Neuro Report 5: 297–300
Lesson PD, Iversen LL (1994) The glycine site on the NMDA receptor: structure-activity relationships and therapeutic potential. J Med Chem 37: 4053–4067
Liljequist S (1991a) The competitive NMDA receptor antagonist, CGP 39551, inhibits ethanol withdrawal seizures. Eur J Pharmacol 192: 197–198
Liljequist S (1991b) Genetic differences in the effects of competitive and non-competitive NMDA receptor antagonists on locomotor activity in mice. Psychopharmacology 104: 17–21
Lovinger DM, White FF (1989) Ethanol inhibits NMDA-activated ion current in hippocampal neurons. Science 234: 1721–1724
Majchrowicz E (1975) Induction of physical dependence upon ethanol and the associated behavioral changes in rats. Psychopharmacologia 43: 245–254
Masood K, Wu C, Brauncis U, Weight FF (1994) Differential ethanol sensitivity of recombinantN-methyl-d-aspartate receptor units. Mol Pharmacol 45: 324–329
Michaelis EK, Mulvaney MJ, Freed WJ (1978) Effects of acute and chronic ethanol intake on synaptosomal glutamate binding activity. Biochem Pharmacol 27: 1685–1691
Michaelis EK, Freed WJ, Galton N, Foye J, Michaclis ML, Phillips I, Kleinman JE (1990) Glutamate receptor changes in brain synaptic membranes from human alcoholics. Neurochem Res 15: 1055–1063
Mirshahi T, Woodward JJ (1995) Ethanol sensitivity of heteromeric NMDA receptors: effects of subunit assembly, glycine and NMDAR1 Mg2+-insensitive mutants. Neuropharmacology 34: 347–355
Mori H, Mishina M (1995) Structure and function of the NMDA receptor channel. Neuropharmacology 10: 1219–1237
Morrisett RA (1994) Potentiation of N-methyl-d-aspartate receptor-dependent after discharges in rat dentate gyrus following in vitro ethanol withdrawal. Neurosci Lett 167 175–178
Morrisett RA, Rezvani AH, Overstreet D, Janowsky DS, Wilson WA, Swartzwelder HS (1990) MK-801 potently inhibits alcohol withdrawal seizures in rats. Eur J Pharmacol 176: 103–105
Nagata T, Tanno N, Kodo T, Ae N, Yamaguchi H, Nishimura T. Antoku F, Tatsuno T, Kato T, Tanaka Y, Nakamura M (1994) 5,6-Dihydro-1H-pyrido[1,2,3-de] quinoxaline-2,3-diones as potent antagonists for the glycine binding site of the NMDA receptor. J Med Chem 37: 3956–3968
Nevo I, Hamon M (1995) Neurotransmitter and neuromodulatory mechanisms involved in alcohol abuse and alcoholism. Neurochem Int 26: 305–336
Palfreyman MG, Baron BM (1991) Non-competitive NMDA antagonists, acting on the glycine, site. In: Meldrum BS (ed) Excitatory amino acid antagonists. Blackwell, Oxford
Ripley TL, Little HJ (1995) Ethanol withdrawal hyperexcitability in vitro is selectively decreased by a competitive NMDA receptor antagonist. Brain Res 699: 1–11
Rock DM, Macdonald RL (1995) Polyamine regulation ofN-methyl-d-aspartate receptor channels. Annu Rev Pharmacol Toxicol 35: 463–482
Rowley M, Leeson PD, Stevenson GI, Moseley AM, Stansfield I, Sanderson I, Robinson L, Baker R, Kemp JA, Marshall GR, Foster AC, Grimwood S, Tricklebank MD, Saywell KL (1993) 3-Acyl-4-hydroxyquinolin-2(1H)-ones. Systematically active anti-convulsants acting by antagonism at the glycine site of theN-methyl-d-aspartate receptor complex. J Med Chem 36: 3386–3396
Sanna E, Serra M, Cossu A, Colombo G, Follesa P, Cuccheddu T, Concas A, Biggio G (1993) Chronic ethanol intoxication induces differential effects on GABAA and NMDA receptor function in the rat brain. Alcohol Clin Exp Res 17: 115–123
Scatton B (1994) Excitatory amino acid receptor antagonists: a novel treatment for ischemic cerebrovascualar diseases. Life Sci 55: 2115–2124
Scatton B, Avenet P, Benavides J, Carter C, Duverger D, Oblin A, Perrault G, Sanger DJ, Shoemaker H (1994) Neuroprotective potential of the polyamine site-directed NMDA receptor antagonists —ifenprodil and eliprodil. In: Palfreyman MG, Reynolds IJ, Skolnick P (eds) Direct and allosteric control of glutamate receptors. CRC Press. Boca Raton, pp 139–154
Simson PE, Criswell HE, Johnson KB, Hicks RE, Breese GR (1991) Ethanol inhibits NMDA-evoked electrophysiological activity in vivo. J Pharmacol Exp Ther 257: 225–231
Snell LD, Tabakoff B, Hoffman PL (1993) Radioligand binding to theN-methyl-d-aspartate receptor/ionophore complex: alterations by ethanol in vitro and by chronic in vivo ethanol ingestion. Brain Res 602: 91–98
Takadera T, Suzuki R, Mohri T (1990) Protection by ethanol of cortical neurons fromN-methyl-d-aspartate-induced neurotoxicity is associated with blocking calcium influx. Brain Res 537: 109–114
Thomson AM (1989) Glycine modulation of the NMDA receptor/channel complex. Trends Neurosci 12: 349–353
Tremwel MF, Anderson KJ, Hunter BE (1994) Stability of[3H]MK-801 binding sites following chronic ethanol consumption. Alcohol Clin Exp Res 18: 1004–1008
Trevisan L, Fitzgerald LW, Brose N, Gasie GP, Heinemann SF, Duman RS, Nestler EJ (1994) Chronic ingestion of ethanol up-regulates NMDAR1 receptor subunit immunoreactivity in rat hippocampus. J Neurochem 62: 1635–1638
Tricklebank MD, Singh L, Oles RJ, Preston C, Iversen SD (1989) The behavioral effects of MK-801: a comparison with antagonists acting non-competitively and competitively at the NMDA receptor. Eur J Pharmacol 167: 127–135
Vallés S, Felipo V, Montoliu C, Guerri C (1995) Alcohol exposure during brain development reduces3H-MK-801 binding and enhances metabotropic-glutamate receptor-stimulated phosphoinositide hydrolysis in rat hippocampus. Life Sci 56: 1373–1383
Victor M, Adams RD (1953) The effect of alcohol on the nervous system. Res Publ Assoc Nerv Ment Dis 32: 526–573
Warner DS, Martin H, Ludwig P, McAllister A, Keana JFW, Weber E (1995) In vivo models of cerebral, ischemia: effects of parenterally administered NMDA receptor glycine site antagonists. J Cereb Blood Flow Metab 15: 188–196
Weber E (1995) Studies on the side-effect profile of the glycine-site NMDA antagonist ACEA 1021 in rats and healthy human vol-unteers. Symposium on pre- and post-synaptic modulation of the glutamate receptors: molecular pharmacology and therapeutic implications, San Diego, November 11, 1995
Whittington MA, Lambert JDC, Little HJ (1995) Increased NMDA-receptor and calcium channel activity during ethanol withdrawal hyperexcitability. Alcohol Alcohol 30: 105–114
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Kotlinska, J., Liljequist, S. Oral administration of glycine and polyamine receptor antagonists blocks ethanol withdrawal seizures. Psychopharmacology 127, 238–244 (1996). https://doi.org/10.1007/BF02805999
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DOI: https://doi.org/10.1007/BF02805999