Glutamaterge Neurotransmission bei Schizophrenien

Zusammenfassung:

Glutamat ist der wichtigste erregende Neurotransmitter im zentralen Nervensystem. Es gibt Hinweise darauf, dass seine Aktivität bei schizophrenen Patienten vermindert, an anderen Stellen vermehrt ist. In den letzten Jahren wurden mit epidemiologischen, genetischen, histopathologischen und bildgebenden Untersuchungen deutliche Fortschritte in der Aufklärung der Krankheitsursachen erreicht und es wurden zunehmend integrative Modelle zur Pathogenese und Pathophysiologie schizophrener Psychosen entwickelt. Wenngleich auch verschiedene Vulnerabilitätsfaktoren und Stressoren zur Manifestation von schizophrenen Psychosen führen können, bildet die Glutamathypothese mit dem Modell eines kortiko-striato-thalamo-kortikalen Regelkreises weiterhin eine interessante Grundlage und bietet auch künftig zahlreiche Forschungsansätze, insbesondere in der weiteren Aufklärung der Affektion von Glutamatrezeptoren (z. B. NMDA-Rezeptoren), der glutamatergen Transmission sowie deren pharmakologische Beeinflussbarkeit.

Glutamatergic Neurotransmission in Schizophrenics:

Glutamate is the most abundant amino acid in the brain, where it plays an important role as a well-established major excitatory neurotransmitter in the central nervous system. It has been suggested that reduced glutamate neurotransmission may be involved in the pathophysiology of schizophrenia. The glutamate hypothesis of schizophrenia postulates alterations in the glutamatergic system as an important neurobiochemical event in the pathophysiology of this group of psychotic disorders. An altered glutamate release from synaptosomes including a hypofunction of different glutamate receptors (i.e. NMDA receptors) from different brain areas have previously been reported. Furthermore, partial agonists at the glycine co-agonist site of the NMDA receptor might be a new approach in the treatment of schizophrenic symptoms but further studies are necessary to clarify the role and efficacy of these substances in schizophrenia. Changes in the glutamatergic cortico-striatal connections in schizophrenia could precipitate a potential perceptive overstimulation of the neocortex from thalamic input and an inhibiting influence of the striatum on the thalamus would modulate the information input of the cortex, thereby possibly counteracting the disturbed information processing which is relatively characteristic for schizophrenic psychoses.

Literatur

• 1 Altamura C A, Mauri M C, Ferrara A, Moro A R, D'Andrea G, Zamberlan F. Plasma and platelet excitatory amino acids in psychiatric disorders.  Am J Psychiatry. 1993;  150 1731-1733
• 2 Aparicio-Legarza M I, Davis B, Hutson P H, Reynolds G P. Increased density of glutamate/N-methyl-D-aspartate receptors in putamen from schizophrenic patients.  Neurosci Lett. 1998;  241 143-146
• 3 Bandelow B, Bleich S, Kropp S. Handbuch Psychopharmaka. Göttingen, Bern, Toronto, Seattle: Hogrefe-Verlag 2000
• 4 Baron M, Gruen R, Rainer J D. A family study of schizophrenic and normal control probands: implications for the spectrum concept of schizophrenia.  Am J Psychiatry. 1985;  142 447-455
• 5 Bissette G, Nemeroff C B. Neurotensin and the mesocorticolimbic dopamine system. In: Kalivas PW, Nemeroff CB (eds). The mesocorticolimbic system.   In: Kalivas PW, Nemeroff CB (eds). The mesocorticolimbic system.  Ann NY Acad Sci. 1988;  537 397-404
• 6 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
• 7 Bleich S, Degner D, Kornhuber J. Repeated ethanol withdrawal delays development of focal seizures in hippocampal kindling.  Alcohol Clin Exp Res. 2000b;  24 244-245
• 8 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
• 9 Carlsson A. The current status of the dopamine hypothesis of schizophrenia.  Neuropsychopharmacology. 1988;  1 179-186
• 10 Carlsson A, Lindquist M. Effect of chlorpromazine and haloperidol on the formation of 3-methoxytyramine and normetanophrine in mouse brain.  Acta Pharmacol. 1963;  20 140-144
• 11 Carlsson A, Waters N, Hansson L O. Neurotransmitter aberrations in schizophrenia: new findings. In: Fog R, Gerlach J, Hemmingsen R (eds). Schizophrenia. An integrated view Copenhagen: Munksgaard 1995: 332-340
• 12 Cascella N G, Macciardi F, Cavallini C, Smeraldi E. d-cycloserine adjuvant therapy to conventional neuroleptic treatment in schizophrenia: an open-label study.  J Neural Transm Gen Sect. 1994;  95 105-111
• 13 Costa J, Khaled E, Sramek J, Bunney Jr W, Potkin S G. An open trial of glycine as an adjunct to neuroleptics in chronic treatment-refractory schizophrenics.  J Clin Psychopharmacol. 1990;  10 71-72
• 14 Crow T J. A re-evaluation of the viral hypothesis: Is psychosis the result of retroviral integration at a side close to the cerebral dominance gene?.  Br J Psychiatry. 1984;  145 243-253
• 15 Deckert J, Gleiter C H. Adenosinergic psychopharmaceuticals: just an extra cup of coffee?.  J Psychopharmacol. 1990;  4 183-187
• 16 Eastwood S L, Burnet P W, Harrison P J. GluR2 glutamate receptor subunit flip and flop isoforms are decreased in the hippocampal formation in schizophrenia: a reverse transcriptase-polymerase chain reaction (RT-PCR) study.  Brain Res Mol Brain Res. 1997;  44 92-98
• 17 Farde L, Wiesel F A, Stone-Elander S, Halldin C, Nordstrom A L, Hall H, Sedvall G. D2 dopamine receptors in neuroleptic-naive schizophrenic patients. A positron emission tomography study with [11C]raclopride.  Arch Gen Psychiatry. 1990;  47 213-219
• 18 Feldberg . Possible association of schizophrenia with a disturbance in prostaglandin metabolism. A physiological hypothesis.  Psychol Med. 1976;  6 359-369
• 19 Gao X M, Sakai K, Roberts R C, Conley R R, Dean B, Tamminga C A. Ionotropic glutamate receptors and expression of N-methyl-D-aspartate receptor subunits in subregions of human hippocampus: effects of schizophrenia.  Am J Psychiatry. 2000;  157 1141-1149
• 20 Garbutt J C, van Kammen D P. The interaction between GABA and dopamine: implications for schizophrenia.  Schizophr Bull. 1983;  9 336-353
• 21 Gottesman J J, Shields H. Schizophrenia, the epigenetic puzzle. Cambridge: Cambridge University Press 1982
• 22 Gross G, Huber G. Sensorische Störungen bei Schizophrenien.  Arch Psychiatr Nervenkr. 1972;  216 119-130
• 23 Heston L L. Psychiatric disorders in faster home reared children of schizophrenic mothers.  Br J Psychiatry. 1966;  112 819-827
• 24 Horrobin D F. Schizophrenia as a prostaglandin deficiency disease.  Lancet. 1977;  I 936-937
• 25 Hudson C J, Young L T, Li P P, Warsh J J. CNS signal transduction in the pathophysiology and pharmacotherapy of affective disorders and schizophrenia.  Synapse. 1993;  13 278-293
• 26 Javitt D C, Zukin S R. Recent advances in the phencyclidine model of schizophrenia.  Am J Psychiatry. 1991;  148 1301-1308
• 27 Javitt D C, Zylberman I, Zukin S R, Heresco-Levy U, Lindenmayer J P. Amelioration of negative symptoms in schizophrenia by glycine.  Am J Psychiatry. 1994;  151 1234-1236
• 28 Javitt D C, Balla A, Sershen H, Lajtha A. A.E. Bennett Research Award. Reversal of phencyclidine-induced effects by glycine and glycine transport inhibitors.  Biol Psychiatry. 1999;  45 668-679
• 29 Karson C N, Casanova M F, Kleinman J E, Griffin W ST. Choline acetyltransferase in schizophrenia.  Am J Psychiatry. 1993;  150 454-459
• 30 Kim J S, Kornhuber H H, Schmid-Burgk W, Holzmüller B. Low cerebrospinal fluid glutamate in schizophrenic patients and a new hypothesis on schizophrenia.  Neurosci Lett. 1980;  20 379-382
• 31 Kornhuber J, Bleich S. Memantin. In: Riederer P, Laux G, Pöldinger W (eds). Neuro-Psychopharmaka, Bd. 5, 2. Aufl Wien: Springer Verlag 1999: 687-704
• 32 Kornhuber H H, Kornhuber J, Kim J S, Kornhuber M E. Zur biochemischen Theorie der Schizophrenie.  Nervenarzt. 1984;  55 602-606
• 33 Kornhuber J, Weller M. Aktueller Stand der biochemischen Hypothesen zur Pathogenese der Schizophrenien.  Nervenarzt. 1994;  65 741-754
• 34 Kornhuber M E, Kornhuber J, Zettlmeissl H, Kornhuber H H. Phencyclidin und das glutamaterge System. In: Keupp W (ed). Biologische Psychiatrie, Forschungsergebnisse Berlin, Heidelberg, New York, Tokyo: Springer Verlag 1986: 176-180
• 35 Kornhuber J, Weller M. Psychotogenicity and NMDA receptor antagonism: implications for neuroprotective pharmacotherapy.  Biol Psychiatry. 1997;  41 135-144
• 36 Kornhuber J, Riederer P, Reynolds G P, Beckmann H, Jellinger K, Gabriel E. ³H-Spiperone binding sites in post-mortem brains from schizophrenic patients: relationship to neuroleptic drug treatment, abnormal movements, and positive symptoms.  J Neural Transm. 1989a ;  75 1-10
• 37 Kornhuber J, Mack-Burkhardt F, Riederer P, Hebenstreit G F, Reynolds G P, Andrews H B, Beckmann H. [³H]MK-801 binding sites in postmortem brain regions of schizophrenic patients.  J Neural Transm. 1989b ;  77 231-236
• 38 Kornhuber J, Thome J, Riederer P. Modellvorstellungen zur Ätiopathogenese der Schizophrenien. In: Riederer P, Laux G, Pöldinger W (eds). Neuro-Psychopharmaka, Bd. 4, 2. Aufl Wien: Springer Verlag 1998
• 39 Korpi E R, Kaufmann C A, Marnela K M, Weinberger D R. Cerebrospinal fluid amino acid concentrations in chronic schizophrenia.  Psychiatry Res. 1987;  20 337-345
• 40 Lieberman J A, Koreen A R. Neurochemistry and neuroendocrinology of schizophrenia: a selective review.  Schizophr Bull. 1993;  19 371-429
• 41 Lipton S A, Rosenberg P A. Excitatory amino acids as a final common pathway for neurological disorders.  N Eng J Med. 1994;  330 613-622
• 42 Meltzer H Y. Clinical studies on the mechanism of action of clozapine: the dopamine-serotonin hypothesis of schizophrenia.  Psychopharmacology. 1989;  99 S18-S27
• 43 Nair N PV, Lal S, Bloom D M. Cholecystokinin and schizophrenia. In: van Ree JM, Matthysse S (eds). Progress in brain research Vol. 65 Amsterdam: Elsevier 1994: 237-258
• 44 Olney J W, Labruyere J, Price M T. Pathological changes induced in cerebrocortical neurons by phencyclidine and related drugs.  Science. 1989;  244 1360-1362
• 45 Owen F, Cross A J, Crow T J, Longden A, Poulter M, Riley G J. Increased dopamine-receptor sensitivity in schizophrenia.  Lancet. 1978;  2 (8083) 223-226
• 46 Pearlson G D. Psychiatric and medical syndromes with phencyclidine (PCP) abuse.  Johns Hopkins Med J. 1981;  148 25-33
• 47 Reynolds G P. Beyond the dopamine hypothesis. The neurochemical pathology of schizophrenia.  Br J Psychiatry. 1989;  155 305-316
• 48 Roberts D A, Balderson D, Pickering-Brown S M, Deakin J F, Owen F. The relative abundance of dopamine D4 receptor mRNA in post mortem brains of schizophrenics and controls.  Schizophr Res. 1996;  20 171-174
• 49 Seeman P, Guan H C, Van Tol H H. Dopamine D4 receptors elevated in schizophrenia.  Nature. 1993;  365 (6445) 441-445
• 50 Serval V, Galli T, Cheramy A, Glowinski J, Lavielle S. In vitro and in vivo inhibition of N-acetyl-L-aspartyl-L-glutamate catabolism by N-acylated L-glutamate analogs.  J Pharmacol Exp Ther. 1992;  260 1093-1100
• 51 Simeon J, Fink M, Itil T M, Ponce D. d-Cycloserine therapy of psychosis by symptom provocation.  Compr Psychiatry. 1970;  11 80-88
• 52 Svensson A, Carlsson M L, Carlsson A. Interaction between glutamatergic and dopaminergic tone in the nucleus accumbens of mice: evidence for a dual glutamatergic function with respect to psychomotor control.  J Neural Transm. 1992;  88 235-240
• 53 Tandon R, Greden J F. Cholinergic hyperactivity and negative schizophrenic symptoms. A model of cholinergic/dopaminergic interactions in schizophrenia.  Arch Gen Psychiatry. 1989;  46 745-753
• 54 Terenius L, Wahlström A, Lindström L, Widerlov E. Increased CSF levels of endorphins in chronic psychoses.  Neurosci Lett. 1976;  3 157-162
• 55 Trist D G. Excitatory amino acid agonists and antagonists: pharmacology and therapeutic applications.  Pharm Acta Helv. 2000;  74 221-229
• 56 Tsai G, Passani L A, Slusher B S, Carter R, Baer L, Kleinman J E, Coyle J T. Abnormal excitatory neurotransmitter metabolism in schizophrenic brains.  Arch Gen Psychiatry. 1995;  52 829-836
• 57 Walker J M, Bowen W D, Walker F O, Matsumoto R R, de Costa B, Rice K C. Sigma receptors: biology and function.  Pharmacol Rev. 1990;  42 355-402
• 58 Waziri R. Glycine therapy of schizophrenia.  Biol Psychiatry. 1988;  23 210-211
• 59 Wiegant V M, Ronken E, Kovács G, de Wied D. Endorphins and schizophrenia.  Prog Brain Res. 1992;  93 433-453