Fortschr Neurol Psychiatr 2003; 71: 45-50
DOI: 10.1055/s-2003-40505
Originalarbeit
© Georg Thieme Verlag Stuttgart · New York

Bedeutung glutamaterger Mechanismen für die Alkoholabhängigkeit - Ergebnisse genetischer, molekularbiologischer und neuropharmakologischer Studien

Glutamatergic Mechanisms in Alcohol Dependence - Genetic, Molecular-Biological and Neuropharmacological Findings M.  Soyka1 , U.  Preuss1
  • 1Psychiatrische Klinik der Universität München
Further Information

Publication History

Publication Date:
08 July 2003 (online)

Zusammenfassung

Zahlreiche präklinische und klinische Befunde deuten darauf hin, dass das Glutamatsystem und im Besonderen NMDA-Rezeptoren nicht nur für zahlreiche neuropsychiatrische Folgeschäden des Alkoholismus, sondern auch für zentrale Suchtmechanismen wie zum Beispiel Craving oder das Suchtgedächtnis insgesamt von Relevanz sind. Dafür sprechen nicht nur genetische und molekularbiologische, sondern auch neuere neuropharmakologische Untersuchungen. NMDA-Modulatoren und -Antagonisten haben sich in der pharmakogestützten Rückfallprophylaxe der Alkoholabhängigkeit als wirksame Substanzen erwiesen und zum Teil schon Einzug in die Klinik gehalten. Von einem besseren Verständnis der glutamatergen Mechanismen bei der Alkoholabhängigkeit profitiert nicht nur die Grundlagen- sondern auch die Therapieforschung.

Abstract

A number of preclinical and clinical findings suggest that the glutamate system, especially NMDA-receptors has a major function in neuropsychiatric disorders related to chronic alcoholism. Other findings suggest, that glutamatergic mechanisms may also play a role for the addictive process itself including craving and addiction memory. A number of genetic and molecular-biological findings and more recent neuropharmacological studies point in this direction. NMDA-modulators and antagonists have been found to be possible or even clinically effective so called anti-craving-drugs. A better understanding of the glutamatergic mechanisms in alcohol dependence may therefore also be of relevance for the development of new anti-craving-drugs and therapy-research.

Literatur

  • 1 Soyka M. Optimierte Arzneimitteltherapie: Alkoholabhängigkeit. Berlin, Heidelberg: Springer 1999
  • 2 Soyka M. Ratgeber Alkohol. Bremen: Unimed-Verlag 2000
  • 3 Soyka M. Relapse Prevention in Alcoholism: Recent Advances and Future Possibilities.  CNS Drugs. 1997;  7 313-327
  • 4 Sass H, Soyka M, Mann K, Zieglgansberger W. Relapse prevention by acamprosate: results from a placebo controlled study on alcohol dependence.  Arch Gen Psychiatry. 1996;  53 673-680
  • 5 Soyka M, Bondy B, Eisenburg B, Schmutz C G. NMDA receptor challenge with dextromethorphan - subjective response, neuroendocrinological findings and possible clinical implications.  J Neural Transm. 2000;  107 701-714
  • 6 Soyka M, Chick J. Treatment of alcohol dependence with acamprosate - an European perspective.  Am J Addict. 2003 (im Druck); 
  • 7 Tsai G, Gastfriend D R, Coyle J T. The glutamatergic basis of human alcoholism.  Am J Psychiatry. 1995;  152 332-340
  • 8 Tsai G, Coyle J T. The role of glutamatergic neurotransmission in the pathophysiology of alcoholism.  Annu Rev Med. 1998;  49 173-184
  • 9 Dodd P R, Beckmann A M, Davidson M S, Wilce P A. Glutamate-mediated transmission, alcohol, and alcoholism.  Neurochem Int. 2000;  37 509-533
  • 10 Pulvirenti L, Diana M. Drug dependence as a disorder of neural plasticity: focus on dopamine and glutamate.  Rev Neurosci. 2001;  12 141-158
  • 11 Spanagel R, Zieglgansberger W. Anti-craving compounds for ethanol: new pharmacological tools to study addictive processes.  Trends Pharmacol Sci. 1997;  18 54-59
  • 12 Trevisan L, Fitzgerald L W, Brose N, Gasic G P, Heinemann S F, Duman R S, Nestler E J. Chronic ingestion of ethanol up-regulates NMDAR1 receptor subunit immunoreactivity in rat hippocampus.  J Neurochem. 1994;  62 1635-1638
  • 13 Danysz W, Jankowska E, Glazewski S, Kostowski W. The involvement of NMDA receptors in acute and chronic effects of ethanol.  Alchol Clin Exp Res. 1992;  16 499-504
  • 14 Trevisan L A, Charney D S. Dose-related ethanol-like effects of the NMDA antagonist, ketamine, in recently detoxified alcoholics.  Arch Gen Psychiatry. 1998;  55 354-360
  • 15 Baretto P S, Lemos T, Morato G S. NMDA-receptor antagonists block the development of rapid tolerance to ethanol in mice.  Addiction Biology. 1998;  3 55-64
  • 16 Kalivas P W. Interactions between dopamine and excitatory amino acids in behavioral sensitization to psychostimulants.  Drug Alcohol Depend. 1995;  37 95-100
  • 17 Hollmann M, Heinemann S. Cloned glutamate receptors.  Annu Rev Neurosci. 1994;  17 31-108
  • 18 Mori H, Mishina M. Structure and function of the NMDA receptor channel.  Neuropharmacology. 1995;  34 1219-1237
  • 19 Wenzel A, Fritschy J M, Mohler H, Benke D. NMDA receptor heterogeneity during postnatal development of the rat brain: differential expression of the NR2A, NR2B, and NR2C subunit proteins.  J Neurochem. 1997;  68 469-478
  • 20 Pin J P, Duvoisin R. The metabotropic glutamate receptors: structure and functions.  Neuropharmacology. 1995;  34 1-26
  • 21 Chiamulera C, Epping-Jordan M P, Zocchi A, Marcon C, Cottiny C, Tacconis S, Corsi M, Orzi F, Conquet F. Reinforcing and locomotor stimulant effects of cocaine are absent in mGluR5 null mutant mice.  Nat Neurosci. 2001;  4 873-874
  • 22 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.  Brain Res Mol Brain Res. 1996;  36 211-218
  • 23 Follesa P, Ticku M K. Chronic ethanol-mediated up-regulation of the N-methyl-D-aspartate receptor polypeptide subunits in mouse cortical neurons in culture.  J Biol Chem. 1996;  271 13297-13299
  • 24 Kumari M, Ticku M K. Ethanol and regulation of the NMDA receptor subunits in fetal cortical neurons.  J Neurochem. 1998;  70 1467-1473
  • 25 Winkler A, Mahal B, Kiianmaa K, Zieglgansberger W, Spanagel R. Effects of chronic alcohol consumption on the expression of different NR1 splice variants in the brain of AA and ANA lines of rats.  Brain Res Mol Brain Res. 1999;  72 166-175
  • 26 Snell L D, Nunley K R, Lickteig R L, Browning M D, Tabakoff B, Hoffman P L. Regional and subunit specific changes in NMDA receptor mRNA and immunoreactivity in mouse brain following chronic ethanol ingestion.  Molec Brain Res. 1996;  40 71-78
  • 27 Chandler L J, Sutton G, Norwood D, Sumners C, Crews F T. Chronic ethanol increases N-methyl-D-aspartate-stimulated nitric oxide formation but not receptor density in cultured cortical neurons.  Mol Pharmacol. 1997;  51 733-740
  • 28 Chen X, Michaelis M L, Michaelis E K. Effects of chronic ethanol treatment on the expression of calcium transport carriers and NMDA/glutamate receptor proteins in brain synaptic membranes.  J Neurochem. 1997;  69 1559-1569
  • 29 Hardy P A, Chen W, Wilce P A. Chronic ethanol exposure and withdrawal influence NMDA receptor subunit and splice variant mRNA expression in the rat cerebral cortex.  Brain Res. 1999;  819 33-39
  • 30 Kalluri H S, Mehta A K, Ticku M K. Up-regulation of NMDA receptor subunits in rat brain following chronic ethanol treatment.  Brain Res Mol Brain Res. 1998;  58 221-224
  • 31 Darstein M B, Landwehrmeyer G B, Feuerstein T J. Changes in NMDA receptor subunit gene expression in the rat brain following withdrawal from forced long-term ethanol intake.  Naunyn Schmiedebergs Arch Pharmacol. 2000;  361 206-213
  • 32 Snell L D, Tabakoff B, Hoffman P L. Radioligand binding to the N-methyl-D-aspartate receptor/ionophore complex: alterations by ethanol in vitro and by chronic in vivo ethanol ingestion.  Brain Res. 1993;  602 91-98
  • 33 Bruckner M K, Rossner S, Arendt T. Differential changes in the expression of AMPA receptors genes in rat brain after chronic exposure to ethanol: an in situ hybridization study.  J Hirnforsch. 1997;  38 369-376
  • 34 Ulrichsen J, Bech B, Ebert B, Diemer N H, Allerup P, Hemmingsen R. Glutamate and benzodiazepine receptor autoradiography in rat brain after repetition of alcohol dependence.  Psychopharmacology (Berl). 1996;  126 31-41
  • 35 Davidson M S, Wilce P A, Shanley B C. Ethanol and synaptosomal calcium homeostasis.  Biochem Pharmacol. 1990;  39 1283-1288
  • 36 Davidson M, Wilce P A, Shanley B C. Chronic ethanol administration sensitizes hippocampal neurons to neurotoxicity of N-methyl-D-aspartic acid.  Alcohol Alcohol Suppl. 1993;  2 365-369
  • 37 Davidson M, Shanley B, Wilce P. Increased NMDA-induced excitability during ethanol withdrawal: a behavioural and histological study.  Brain Res. 1995;  674 91-96
  • 38 Krystal J H, Petrakis I L, Webb E, Cooney N L, Karper L P, Namanworth S, Stetson P, Trevisan L A, Charney D S. Dose-related ethanol-like effects of the NMDA antagonist, ketamine, in recently detoxified alcoholics.  Arch Gen Psychiatry. 1998;  55 354-360
  • 39 Dodd P R, Thomas G J, Harper C G, Kril J J. Amino acid neurotransmitter receptor changes in cerebral cortex in alcoholism: effect of cirrhosis of the liver.  J Neurochem. 1992;  59 1506-1515
  • 40 Freund G, Anderson K J. Glutamate receptors in the cingulate cortex, hippocampus, and cerebellar vermis of alcoholics.  Alcohol Clin Exp Res. 1999;  23 1-6
  • 41 Michaelis E K, Freed W J, Galton N, Foye J, Michaelis M L, Phillips I, Kleinman J E. Glutamate receptor changes in brain synaptic membranes from human alcoholics.  Neurochem Res. 1990;  15 1055-1063
  • 42 Michaelis E K, Michaelis M L, Freed W J, Foye J. Glutamate receptor changes in brain synaptic membranes during chronic alcohol intake.  Alcohol Alcohol Suppl. 1993;  2 377-381
  • 43 Cummins J T, Sack M, Hungen K von. The effect of chronic ethanol on glutamate binding in human and rat brain.  Life Sci. 1990;  47 877-882
  • 44 Breese C R, Freedman R, Leonard S S. Glutamate receptor subtype expression in human postmortem brain tissue from schizophrenics and alcohol abusers.  Brain Res. 1995;  674 82-90
  • 45 Sander T, Ostapowicz A, Samochowiec J, Smolka M, Winterer G, Schmidt L G. Genetic variation of the glutamate transporter EAAT2 gene and vulnerability to alcohol dependence.  Psychiatr Genet. 2000a;  10 103-107
  • 46 Preuss U W, Koller G, Bahlmann M, Zill P, Soyka M, Bondy B. No association between metabotropic glutamate receptors 7 and 8 (mGlur 7 and mGlur 8) gene polymorphisms and withdrawal seizures and delirium tremens in alcohol-dependent individuals.  Alcohol Alcohol. 2002;  37 174-178
  • 47 Rujescu D, Soyka M, Dahmen N, Preuss U, Hartmann A, Giegling I, Koller G, Bondy B, Möller H J, Schumann G, Szegedi A. The GRIN1 locus may modify the susceptibility to seizures during alcohol withdrawal.  2003 (eingereicht); 
  • 48 Wernicke C, Samochowiec J, Schmidt L G, Winterer G, Smolka M, Kucharska-Mazur J, Horodnicki J, Gallinat J, Rommelspacher H. Polymorphisms in the N-Methyl-D-Aspartat Receptor 1 and 2B subunits are associated with alcoholism-related traits.  Biolog Psychiatry. 2003 (in press); 
  • 49 Rice S R, Niu N, Berman D B, Heston L L, Sobell J L. Identification of single nucleotide polymorphisms (SNPs) and other sequence changes and estimation of nucleotide diversity in coding and flanking regions of the NMDAR1 receptor gene in schizophrenic patients.  Mol Psychiatry. 2001;  6 274-284
  • 50 Williams N M, Bowen T, Spurlock G, Norton N, Williams H J, Hoogendoorn B, Owen M J, O'Donovan M C. Determination of the genomic structure and mutation screening in schizophrenic individuals for five subunits of the N-methyl-D-aspartate glutamate receptor.  Mol Psychiatry. 2002;  7 508-514
  • 51 Ohtsuki T, Sakurai K, Dou H, Toru M, Yamakawa-Kobayashi K, Arinami T. Mutation analysis of the NMDAR2B (GRIN2B) gene in schizophrenia.  Mol Psychiatry. 2001a;  6 211-216
  • 52 Hung C C, Chen H Y, Chen C H. Systematic mutation analysis of the human glutamate receptor, ionotropic, N-methyl-D-aspartate 1 gene(GRIN1) in schizophrenic patients.  Psychiatr Genet. 2002;  12 225-230
  • 53 Sakurai K, Toru M, Yamakawa-Kobayashi K, Arinami T. Mutation analysis of the N-methyl-D-aspartate receptor NR1 subunit gene (GRIN1) in schizophrenia.  Neurosci Lett. 2002;  296 168-170
  • 54 Tani A, Kikuta R, Itoh K, Joo A, Shibata H, Ninomiya H, Tashiro N, Fukumaki Y. Polymorphism analysis of the upstream region of the human N-methyl-D-aspartate receptor subunit NR1 gene (GRIN1): implications for schizophrenia.  Schizophr Res. 2002;  58 83-86
  • 55 Nishiguchi N, Shirakawa O, Ono H, Hashimoto T, Maeda K. Novel polymorphism in the gene region encoding the carboxyl-terminal intracellular domain of the NMDA receptor 2B subunit: analysis of association with schizophrenia.  Am J Psychiatry. 2000;  157 1329-1331
  • 56 Schumann G, Rujescu D, Szegedi A, Singer P, Wiemann S, Wellek S, Giegling I, Klawe C, Anghelescu I, Heinz A, Spanagel R, Mann K, Henn F A, Dahmen N. No association of ethanol dependence with an NMDA receptor 2B gene variant.  Mol Psychiatry. 2002;  8 11-12
  • 57 Hong C J, Yu Y W, Lin C H, Cheng C Y, Tsai S J. Association analysis for NMDA receptor subunit 2B (GRIN2B) genetic variants and psychopathology and clozapine response in schizophrenia.  Psychiatr Genet. 2001;  11 219-222
  • 58 Veenstra-VanderWeele J, Kim S J, Gonen D, Hanna G L, Leventhal B L, Cook E H. Genomic organization of the SLC1A1/EAAC1 gene and mutation screening in early-onset obsessive-compulsive disorder.  Mol Psychiatry. 2001;  6 160-167
  • 59 Sander T, Berlin W, Ostapowicz A, Samochowiec J, Gscheidel N, Hoehe M R. Variation of the genes encoding the human glutamate EAAT2, serotonin and dopamine transporters and Susceptibility to idiopathic generalized epilepsy.  Epilepsy Res. 2000b;  41 75-81
  • 60 Catalano M, Lorenzi C, Bocchio L, Racagni G. No occurrence of the glutamate transporter EAAT2 A206G polymorphism in schizophrenic subjects.  Mol Psychiatry. 2002;  7 671-672
  • 61 Joo A, Shibata H, Ninomiya H, Kawasaki H, Tashiro N, Fukumaki Y. Structure and polymorphisms of the human metabotropic glutamate receptor type 2 gene (GRM2): analysis of association with schizophrenia.  Mol Psychiatry. 2001;  6 186-192
  • 62 Ohtsuki T, Toru M, Arinami T. Mutation screening of the metabotropic glutamate receptor mGluR4 (GRM4) gene in patients with schizophrenia.  Psychiatr Genet. 2001b;  11 79-83
  • 63 Bolonna A A, Kerwin R W, Munro J, Arranz M J, Makoff A J. Polymorphisms in the genes for mGluR types 7 and 8: association studies with schizophrenia.  Schizophr Res. 2001;  47 99-103
  • 64 Bray N J, Williams N M, Bowen T, Cardno A G, Gray M, Jones L A, Murphy K C, Sanders R D, Spurlock G, Odonovan M C, Owen M J. No evidence for association between a non-synonymous polymorphism in the gene encoding human metabotropic glutamate receptor 7 and schizophrenia.  Psychiatr Genet. 2000 Jun;  10 (2) 83-86
  • 65 Goodwin H, Curran N, Chioza B, Blower J, Nashef L, Asherson P, Makoff A J. No association found between polymorphisms in genes encoding mGluR7 and mGluR8 and idiopathic generalised epilepsy in a case control study.  Epilepsy Res 2000. 2000 Mar;  39 (1) 27-31
  • 66 Begni S, Popoli M, Moraschi S, Bignotti S, Tura G B, Gennarelli M. Association between the ionotropic glutamate receptor kainate 3 (GRIK3) ser310ala polymorphism and schizophrenia.  Mol Psychiatry. 2002;  7 416-418
  • 67 Schumann G, Rujescu D, Kissling C, Soyka M, Dahmen M, Preuss U W, Wieman S, Müller A, Wellek S, Lascorz J, Bondy B, Giegling I, Anghelescu I, Cowen M S, Poustka A, Spanagel R, Mann K, Henn F A, Szegedi A. Analysis of genetic variations of Protein Tyrosine Kinase fyn and their association with alcohol dependence in two independent cohorts.  Biolog Psychiatry. 2003 (revidierte Fassung eingereicht); 

Prof. Dr. Michael Soyka

Psychiatrische Klinik der Universität München

Nußbaumstr. 7

80336 München

Email: Michael.Soyka@psy.med.uni-muenchen.de

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