Exzitatorische Neurotransmission bei chronischem Alkoholismus

Zusammenfassung

Glutamat ist der wichtigste erregende Neurotransmitter im zentralen Nervensystem. Unter bestimmten Bedingungen wirken Glutamat und weitere exzitatorische Aminosäuren (z. B. Homocystein) toxisch, indem es über Aktivierung spezifischer Glutamatrezeptoren zu akutem oder auch chronischem Nervenzelluntergang führt. Chronische Exposition gegenüber hohen Dosen an Ethanol bewirkt eine Inhibition der glutamatergen Neurotransmission und konsekutiv eine Hochregulierung des N-Methyl-D-Aspartat(NMDA)-Rezeptorproteins, einen Anstieg an mRNA-funktioneller Rezeptoruntereinheiten und eine verstärkte Rezeptorfunktion. Chronischer Alkoholismus ist mit Störungen im Bereich der exzitatorischen Aminosäuren assoziiert. Unter den Bedingungen des Alkoholentzuges treffen pathologisch erhöhte exzitatorische Aminosäuren (z. B. Homocystein) auf vermehrt exprimierte NMDA-Rezeptoren und bewirken durch Agonismus an den Bindungsstellen der NMDA-Rezeptoren eine überschießende glutamaterge Neurotransmission. Diese Alkoholimus-assoziierten pathophysiologischen Umstände könnten Alkoholentzugsanfälle sowie Mechanismen der Exzitotoxizität induzieren. Weiterhin kann die NMDA-vermittelte Verstärkung exzitatorischer Neurotransmission als wichtiger neuroadaptiver Prozess angesehen werden, der das exzitatorische Syndrom beim Alkoholentzug verursacht. Im Folgenden sollen die wichtigsten Bedeutungen der glutamatergen Neurotransmission für Neurotoxizität und Exzitotoxizität beim chronischen Alkoholismus dargestellt werden.

Abstract

Glutamate is the neurotransmitter at the majority of excitatory synapses in the mammalian CNS. It has been proposed that neurotoxicity linked to chronic alcoholism is mediated primarily by activation of glutamate N-methyl-D-aspartate (NMDA) receptors. Since ethanol stabilizes the membrane potential of NMDA receptors a persistent attenuation of glutamatergic neurotransmission occurs in chronic alcoholism resulting in a compensatory up-regulation of NMDA receptors. Thus, delayed neurotoxicity can be triggered by rebound activation of NMDA receptor-mediated neurotransmission during the withdrawal state. Besides glutamate, homocysteine and excitatory amino acids (EAA) have been shown to act as endogenous agonists at the NMDA receptor and increase excitatory postsynaptic potentials. There is evidence that chronic alcoholism is associated with a derangement in this sulfur amino acid metabolism. These findings indicate the role of hyperhomocysteinemia for withdrawal symptoms, the withdrawal state, and alcoholism-associated brain atrophy. The role of alcoholism-associated hyperhomocysteinemia in respect to NMDA-receptor mediated neurotoxicity and excitotoxicity is discussed.

Literatur

• 1 Tsai G, Gastfriend D R, Coyle J T. The glutamatergic basis of human alcoholism.  Am J Psychiatry. 1995;  152 332-340
• 2 Tsai G E, Ragan P, Chang R, Chen S, Linnoila V M, Coyle J T. Increased glutamatergic neurotransmission and oxidative stress after alcohol withdrawal.  Am J Psychiatry. 1998;  155 726-732
• 3 Chen X, Michaelis M R, Michaelis E K. Effects of chronic ethanol treatment on the expression of calcium transport carriers and NMDA receptor proteins in brain synaptic membranes.  J Neurochem. 1997;  69 1559-1569
• 4 Diamond I, Gordon A S. Cellular and molecular neuroscience of alcoholism.  Physiol Rev. 1997;  77 1-20
• 5 Follesa P, Ticku M K. Chronic ethanol-mediated up-regulation of the N-methyl-D-aspartate receptor polypeptide.  J Biol Chem. 1996;  271 13 297-13 299
• 6 Hu X J, Ticku M K. Chronic ethanol treatment upregulates the NMDA receptor function and binding in mammalian cortical neurons.  Mol Brain Res. 1995;  30 347-356
• 7 Hu X J, Follesa P, Ticku M K. Chronic ethanol treatment produces a selective upregulation of the NMDA receptor subunit gene expression in mammalian cultured cortical neurons.  Mol Brain Res. 1996;  36 211-218
• 8 Lovinger D M. Alcohols and neurotransmitter gated ion channels: past, present and future.  Naunyn-Schmiedeberg's Arch Pharmacol. 1997;  356 267-282
• 9 Snell L D, Nunley K R, Lickteig R L, Browning M D, Tabakoff B, Hoffmann P L. Regional and subunit specific changes in NMDA receptor mRNA and immunoreactivity in mouse brain following chronic ethanol ingestion.  Mol Brain Res. 1996;  40 71-78
• 10 Tabakoff B, Hoffmann P L. Alcohol addiction: an enigma among us.  Neuron. 1996;  16 909-912
• 11 Tabakoff B, Ellevuo K, Hoffmann P L. Alcohol. In: Schuster CR, Kuhar MJ (Hrsg.). Pharmacological aspects of drug dependence, handbook of experimental pharmacology. Berlin: Springer 1996: 374-460
• 12 Beal M F. Mechanisms of excitotoxicity in neurologic diseases.  FASEB J. 1992;  6 3338-3344
• 13 Chapman A G. Glutamate and epilepsy.  J Nutr Suppl. 2000;  130 1043-1045
• 14 Kruman I I, Culmsee C, Chan S L, Kruman Y, Guo Z, Penix L R. Homocysteine elicits a DNA damage response in neurons that promotes apoptosis and hypersensitivity to excitotoxicity.  J Neurosci. 2000;  20 6920-6926
• 15 Lipton S A, Rosenberg P A. Mechanisms of disease: Excitatory amino acids as a final common pathway for neurologic disorders.  N Eng J Med. 1994;  330 613-622
• 16 Meldrum B S. Glutamate as a neurotransmitter in the brain: Review of physiology and pathology.  J Nutr Suppl. 2000;  130 1007-1015
• 17 Meldrum B, Garthwaite J. Excitatory amino acid neurotoxicity and neurodegenerative disease.  TIPS. 1990;  11 379-387
• 18 Outinen P A, Sood S K, Liaw P CY, Sarge K D, Maeda N, Hirsh J, Ribau J, Podor T J, Weitz J I, Austin R C. Characterization of the stress-inducing effects of homocysteine.  Biochem J. 1998;  332 213-221
• 19 Parsons C G, Danysz W, Quack G. Glutamate in CNS disorders as a target for drug development: an update.  Drug News Perspect. 1998;  11 523-569
• 20 Parsons R B, Waring R H, Ramsden D B, Williams A C. In vitro effect of the cysteine metabolites homocysteic acid, homocysteine and cysteic acid upon human neuronal cell lines.  Neurotoxicology. 1998;  19 599-604
• 21 Kornhuber J, Bleich S. Memantin. In: Riederer P, Laux G, Pöldinger W (eds). Neuro-Psychopharmaka, Bd. 5, 2. Auflage. Wien: Springer Verlag 1999: 687-704
• 22 Ripley T L, Little H J. Effects of chronic ethanol withdrawal hyperexcitability of chronic treatment with a competitive N-methyl-D-aspartate receptor antagonist.  J Pharmacol Exp Ther. 1995;  272 112-118
• 23 Grant K A, Valverius P, Hudspith M, Tabakoff B. Ethanol withdrawal seizures and the NMDA receptor complex.  Eur J Pharmacol. 1990a;  176 289-296
• 24 Liljequist S. The competitive NMDA receptor antagonist, CGP-39 551, inhibits ethanol withdrawal seizures.  Eur J Pharmacol. 1991;  192 197-198
• 25 Morrisett R A, Rezvani A H, Overstreet D, Janowsky D S, Wilson W A, Swartzwelder H S. MK-801 potently inhibits alcohol withdrawal seizures in rats.  Eur J Pharmacol. 1990;  176 103-106
• 26 Rosetti Z L, Carboni S. Ethanol withdrawal is associated with increased extracellular glutamate in the rat striatum.  Eur J Pharmacol. 1995;  283 177-183
• 27 Danysz W, Janowska E, Glazewsky S, Kostowsky W. The involvement of NMDA receptors in acute and chronic effects of ethanol.  Alcohol Clin Exp Res. 1992;  16 499-504
• 28 Davidson M, Shanley B, Wilce P A. Increased NMDA-induced excitability during ethanol withdrawal: a behavioural and histological study.  Brain Res. 1995;  674 91-96
• 29 Sanna E, Serra M, Cossu A, Colombo G, Follesa P, Cuccheddu T, Concas A, Biggio G. Chronic ethanol intoxication induces differential effects on GABA A and NMDA receptor function in the rat brain.  Alcohol Clin Exp Res. 1993;  17 115-123
• 30 Carboni S, Isola R, Gessa G L, Rosetti Z L. Ethanol prevents the glutamate release induced by N-methyl-D-aspartate in the rat striatum.  Neurosci Lett. 1993;  152 133-136
• 31 Moghaddam B, Bolinao M. Biphasic effects of ethanol on extracellular accumulation of glutamate in the hippocampus and the nucleus accumbens.  Neurosci Lett. 1994;  178 99-102
• 32 Bustos G A, Abarca J, Forray M I, Gysling K, Bradberry C W, Roth R H. Regulation of excitatory amino acid release by N-methyl-D-aspartate receptors in rat striatum: in vivo microdialysis studies.  Brain Res. 1992;  585 105-115
• 33 Morari M, O'Connor W T, Ungerstedt U, Bianchi C, Fuxe K. Functional neuroanatomy of the nigrostriatal pathways as studied with dual probe microdialysis in the awake rat. 2. Evidence for striatal N-methyl-D-aspartate receptor regulation of striatonigral GABAergic transmission and motor function.  Neuroscience. 1996;  72 89-97
• 34 Rosetti Z L, Carboni S, Melis F, Vaccari A, Gessa G L. NMDA receptor activation mediated glutamate and aspartate release from rat striatum: prevention by MK-801.  Neurochem Int. 1990;  6 63
• 35 Young A M, Bradford H F. N-methyl-D-aspartate releases excitatory amino acids in the corpus striatum in vivo.  J Neurochem. 1991;  56 1677-1683
• 36 Gonzales R, Bungay P M, Kiianmaa K, Sansom H H, Rosetti Z L. In vivo links between neurochemistry and behavioral effects of ethanol.  Alcohol Clin Exp Res. 1996;  20 203A-205A
• 37 Dumuis A, Sebben M, Haynes L, Pin J P, Bockaert J. NMDA receptors activate the arachidonic-acid cascade system in striatal neurons.  Nature. 1988;  336 68-70
• 38 Pellegrini-Giampetro D E, Clerici G, Alesiani M, Carla V, Moroni F. Excitatory amino acid release from rat hippocampus slices as a consequence of free radical formation.  J Neurochem. 1988;  51 1960-1963
• 39 Williams C H. Arachidonic acid induces a long-term activity-dependent enhancement of synaptic transmission in the hippocampus.  Nature. 1989;  341 739-742
• 40 Volterra A, Trotti D, Gambino G, Racagni G. Convergent inhibition of glutamate uptake by arachidonic acid and oxygen free radicals: molecular mechanisms and relevance to neurodegenerative pathologies. In: Racagni G, Brunello N, Langer SL (Hrsg). Recent Advances in the treatment of neurodegenerative disorders and cognitive dysfunction. Volume 7. Basel: Karger 1994: 129-137
• 41 Schuman E R, Madison D V. Nitric oxide and synaptic function.  Ann Rev Neurosci. 1994;  17 153-183
• 42 Bogdanov M B, Wurtman R J. Possible involvement of nitric oxide in NMDA-induced glutamate release in the rat striatum: an in vivo microdialysis study.  Neurosci Lett. 1997;  221 197-201
• 43 Nei K, Matsuyama S, Shuntoh H, Tanaka C. NMDA receptor activation induces glutamate release through nitric oxide synthesis in guinea pig dentate gyrus.  Brain Res. 1996;  728 105-110
• 44 Siegel S, Brose N, Janssen W G, Gasic G P, Jahn R, Heinemann S F. Regional cellular and ultrastructural distribution of N-methyl-D-aspartate receptor subunit in monkey hippocampus.  Proc Natl Acad Sci USA. 1994;  91 564-568
• 45 Liu H, Wang H, Sheng M, Jan L Y, Basbaum A I. Evidence for presynaptic N-methyl-D-aspartate receptors in the spinal cord dorsal horn.  Proc Natl Acad Sci USA. 1994;  91 8383-8387
• 46 Collins G G, Anson J, Surtees L. Presynaptic kainate and N-methyl-D-aspartate receptors regulate excitatory amino acid release in the olfactory cortex.  Brain Res. 1983;  265 157-159
• 47 Berretta N, Jones R S. Tonic facilitation of glutamate release by presynaptic N-methyl-D-aspartate autoreceptors in the entorhinal cortex.  Neurosci. 1996;  75 339-344
• 48 Garcia-Munoz M, Young S J, Groves P M. Terminal excitability of the corticostriatal pathway. II. Regulation by glutamate receptor stimulation.  Brain Res. 1991;  551 207-215
• 49 Mayer M L, Westbrook G L. The physiology of excitatory amino acids in the vertebrate nervous system.  Prog Neurobiol. 1987;  28 198-276
• 50 Amores-Sanchez M I, Medina M A. Methods for the determination of plasma total homocysteine: a review.  Clin Chem Lab Med. 2000;  38 199-204
• 51 Graeme J H, Eikelboom J W. Homocysteine and vascular disease.  Lancet. 1999;  354 407-413
• 52 Andreotti F, Burzotta F, Manzoli A, Robinson K. Homocysteine and risk of cardiovascular disease.  J Thromb Thrombolysis. 2000;  9 13-21
• 53 Seitz H K, Maier H, Stickel F, Simanowski U A. Alkohol und Krebs. In: Seitz HK, Lieber CS, Simanowski UA (Hrsg): Alkoholbedingte Organschäden. Leipzig, Heidelberg: JA Barth-Verlag 1995
• 54 Bleich S, Degner D, Javaheripour K, Kurth C, Kornhuber J. Homocysteine and alcoholism.  J Neural Transm Suppl. 2000;  60 187-196
• 55 Bleich S, Spilker K, Kurth C, Degner D, Quintela-Schneider M, Javaheripour K, Rüther E, Kornhuber J, Wiltfang J. Oxidative stress and an altered methionine metabolism in alcoholism.  Neurosci Lett. 2000a;  293 171-174
• 56 Bleich S, Degner D, Wiltfang J, Maler J M, Niedmann P, Cohrs S, Mangholz A, Porzig J, Sprung R, Rüther E, Kornhuber J. Elevated homocysteine levels in alcohol withdrawal.  Alcohol Alcohol. 2000c ;  35 351-354
• 57 Bleich S, Bleich K, Kropp S, Degner D, Bittermann H J, Sperling W, Rüther E, Kornhuber J. Moderate alcohol consumption in social drinkers raises plasma homocysteine levels: a contradiction to the „French paradox”?.  Alcohol Alcohol. 2001;  36 189-192
• 58 Cravo M L, Camilo M E. Hyperhomocysteinemia in chronic alcoholism: relations to folic acid and vitamins B₆ and B₁₂ status.  Nutrition. 2000;  16 296-302
• 59 Cravo M L, Gloria L M, Selhub J, Nadeau M R, Camilo M E, Resende M P, Cardoso J N, Leitao C N, Mira F C. Hyperhomocysteinemia in chronic alcoholism: correlation with folate, vitamin B₁₂, and vitamin B₆ status.  Am J Clin Nutr. 1996;  63 220-224
• 60 Hultberg B, Berglund M, Andersson A, Frank A. Elevated plasma homocysteine in alcoholics.  Alcohol Clin Exp Res. 1993;  17 687-689
• 61 Eikelboom J W, Lonn E, Genest Jr J, Hankey G, Yusuf S. Homocyst(e)ine and cardiovascular disease: A critical review of the epidemiologic evidence.  Ann Intern Med. 1999;  131 363-375
• 62 Nygard O, Refsum H, Ueland P M, Vollset S E. Major lifestyle determinants of plasma total homocysteine distribution: the Hordaland Homocysteine Study.  Am J Clin Nutr. 1998;  67 263-270
• 63 Gibson J B, Carson N AJ, Neill D W. Pathological findings in homocystinuria.  J Clin Pathol. 1964;  17 427-437
• 64 McCully K S. Vascular pathology of homocysteinemia: implications for the pathogenesis of arteriosclerosis.  Am J Pathol. 1969;  56 111-128
• 65 Watkins D, Rosenblatt D S. Functional methionine synthase deficiency (cblE and cblG): clinical and biochemical heterogeneity.  Am J Med Genet. 1989;  34 427-434
• 66 Schwarz S, Zhou G-Z. N-methyl-D-aspartate receptors and CNS symptoms of homocystinuria.  Lancet. 1991;  337 (8751) 1226-1227
• 67 Lipton S A, Kim W K, Choi Y B, Kumar S, Demilia D M, Rayudu P V, Arnelle D R, Stamler J S. Neurotoxicity associated with dual actions of homocysteine at the N-methyl-D-aspartate receptor.  Proc Natl Acad Sci USA. 1997;  94 5923-5928
• 68 Boss V, Nutt K M, Conn P J. L-cysteinesulfinic as an endogenous agonist of a novel metabotropic receptor coupled to stimulation of phospholipase D activity.  Mol Pharmacol. 1994;  5 1177-1182
• 69 Folbergrova J, Haugvicova R, Mares P. Behavioral and metabolic changes in immature rats during seizures induced by homocysteic acid: the protective effect of NMDA and Non-NMDA receptor antagonists.  Exp Neurol. 2000;  161 336-345
• 70 Knöpfel T, Zeise M L, Cuenod M, Zieglgänsberger W. L-homocysteic acid but not glutamate is an endogenous N-methyl-D-aspartic acid receptor preferring agonist in rat neocortical neurons in vitro.  Neurosci Lett. 1987;  81 188-192
• 71 Olney J W, Price M T, Salles K S, Labruyere J, Ryerson R, Mahan K, Friedrich G, Samson L. L-homocysteic acid: an endogenous excitotoxic ligand of the NMDA receptor.  Brain Res Bull. 1987;  19 597-602
• 72 Butcher S P, Cameron D, Kendall L, Griffiths R. Homocysteine-induced alterations in extracellular amino acids in rat hippocampus.  Neurochem Int. 1992;  20 75-80
• 73 Cuenod M, Do K Q, Grandes P, Morino P, Streit P. Localization and release of homocysteic acid, an excitatory sulfur-containing amino acid.  J Histochem Cytochem. 1990;  38 713-1715
• 74 Kubova H, Folbergrova J, Mares P. Seizures induced by homocysteine in rats during ontogenesis.  Epilepsia. 1995;  36 750-756
• 75 Mares P, Folbergrova J, Langmeier M, Haugvicova R, Kubova H. Convulsant action of D,L-homocysteic acid and its stereoisomers in immature rats.  Epilepsia. 1997;  38 767-776
• 76 Bleich S, Degner D, Bandelow B, Ahsen N von, Rüther E, Kornhuber J. Homocysteine is a predictor of alcohol withdrawal seizures.  NeuroReport. 2000;  11 2749-2752
• 77 Kurth C, Wegerer V, Degner D, Sperling W, Kornhuber J, Paulus W, Bleich S. Risk assessment of alcohol withdrawal seizures with a Kohonen Feature Map.  NeuroReport. 2001;  12 45-49
• 78 Bleich S, Degner D, Kropp S, Rüther E, Kornhuber J. Red wine, spirits, beer and serum homocysteine.  Lancet. 2000;  356 (9228) 512
• 79 Barak A J, Beckenhauer H C, Tuma D J. Betaine, ethanol, and liver disease: A review.  Alcohol. 1996;  13 395-398
• 80 Kenyon S H, Nicolaou A, Gibbons W A. The effect of ethanol and its metabolites upon methionine synthase activity in vitro.  Alcohol. 1998;  15 305-309
• 81 Finkelstein J D. Methionine metabolism in mammals: The biochemical basis for homocystinuria.  Metabolism. 1974;  23 387-398
• 82 Bleich S, Bandelow B, Javaheripour K, Müller A, Degner D, Wilhelm J, Havemann-Reinecke U, Sperling W, Rüther E, Kornhuber J. Hyperhomocysteinemia as a new risk factor for brain shrinkage in patients with alcoholism.  Neurosci Lett. 2003;  335 179-182
• 83 Gibson J B, Carson N AJ, Neill D W. Pathological findings in homocystinuria.  J Clin Pathol. 1964;  17 27-437
• 84 Clarke R, Smith D, Jobst K A, Refsum H, Sutton L, Ueland P M. Folate, vitamin B₁₂, and serum total homocysteine levels in confirmed Alzheimer disease.  Arch Neurol. 1998;  55 1449-1455
• 85 Sachdev P S, Valenzuela M, Wang X L, Looi J C, Brodaty H. Relationship between plasma homocysteine levels and brain atrophy in healthy elderly individuals.  Neurology. 2002;  58 1539-1541