Hostname: page-component-7479d7b7d-q6k6v Total loading time: 0 Render date: 2024-07-11T05:18:08.512Z Has data issue: false hasContentIssue false

Cerebrospinal fluid kynurenic acid in male patients with schizophrenia – correlation with monoamine metabolites

Published online by Cambridge University Press:  24 June 2014

Linda K. Nilsson-Todd*
Affiliation:
Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
Conny Nordin
Affiliation:
Department of Neuroscience and Locomotion, Psychiatry Section, Linköpings Universitet, Linköping, Sweden
Erik G. Jönsson
Affiliation:
Department of Clinical Neuroscience, Psychiatry Section, HUBIN Project, Karolinska Institutet and Hospital, Stockholm, Sweden
Elisabeth Skogh
Affiliation:
Department of Neuroscience and Locomotion, Psychiatry Section, Linköpings Universitet, Linköping, Sweden
Sophie Erhardt
Affiliation:
Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
*
Linda K. Nilsson-Todd, Department of Physiology and Pharmacology, Karolinska Institutet, SE-171 77, Stockholm, Sweden. Tel: +46 8 5248 67 06; Fax: +46 8 31 0622; E-mail: linda.nilsson.1@ki.se

Abstract

Background:

The tryptophan metabolite kynurenic acid (KYNA) is an endogenous glutamate/nicotinic receptor antagonist. Previous studies have shown that the concentration of the compound is increased in cerebrospinal fluid (CSF) of patients with schizophrenia. Furthermore, it has been found that the CSF concentration of KYNA is positively correlated to CSF concentrations of the monoamine metabolites homovanillic acid (HVA) and 5-hydroxy indoleacetic acid (5-HIAA) in healthy control subjects.

Objectives:

To study the correlations between KYNA and the monoamine metabolites HVA, 5-HIAA and 4-hydroxy-3-methoxyphenylglycol (HMPG) in CSF of male patients (n= 53, ranging from 20 to 48 years of age) with verified schizophrenia.

Methods:

CSF was obtained by lumbar puncture, and KYNA analysis was performed with an isocratic reversed-phase high-performance liquid chromatography system connected to a fluorescence detector. HVA, 5-HIAA and HMPG concentrations were measured by mass fragmentography with deuterium-labelled internal standards.

Results:

Positive intercorrelations were found between CSF KYNA, HVA and 5-HIAA, while CSF content of HMPG did not correlate to KYNA or any of the monoamine metabolites in CSF.

Conclusion:

The results of this study suggest that increased KYNA formation is associated with an increased dopamine and serotonin turnover in male patients with schizophrenia.

Type
Brief Report
Copyright
Copyright © 2007 Blackwell Munksgaard

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Carlsson, A, Lindqvist, M. Effect of chlorpromazine or haloperidol on formation of 3-methoxytyramine and normetanephrine in mouse brain. Acta Pharmacol Toxicol 1963;20:140144. CrossRefGoogle ScholarPubMed
Carlsson, A. The current status of the dopamine hypothesis of schizophrenia. Neuropsychopharmacology 1988;1:179186. CrossRefGoogle ScholarPubMed
Carlsson, A, Waters, N, Holm-Waters, S, Tedroff, J, Nilsson, M, Carlsson, ML. Interactions between monoamines, glutamate, and GABA in schizophrenia: new evidence. Ann Rev Pharmacol Toxicol 2001;41:237260. CrossRefGoogle ScholarPubMed
Javitt, DC, Zukin, SR. Recent advances in the phencyclidine model of schizophrenia. Am J Psychiatry 1991;148:13011308. Google ScholarPubMed
Jentsch, JD, Roth, RH. The neuropsychopharmacology of phencyclidine: from NMDA receptor hypofunction to the dopamine hypothesis of schizophrenia. Neuropsychopharmacology 1999;20:201225. CrossRefGoogle ScholarPubMed
Javitt, DC. Glutamate as a therapeutic target in psychiatric disorders. Mol Psychiatry 2004;9:984997. CrossRefGoogle ScholarPubMed
Persson, T, Roos, BE. Acid metabolites from monoamines in cerebrospinal fluid of chronic schizophrenics. Br J Psychiatry 1969;115:9598. CrossRefGoogle ScholarPubMed
Post, RM, Fink, E, Carpenter, WT Jr, Goodwin, FK. Cerebrospinal fluid amine metabolites in acute schizophrenia. Arch Gen Psychiatry 1975;32:10631069. CrossRefGoogle ScholarPubMed
Berger, PA, Faull, KF, Kilkowski, Jet al. CSF monoamine metabolites in depression and schizophrenia. Am J Psychiatry 1980;137:174180. Google Scholar
Nybäck, H, Berggren, BM, Hindmarsh, T, Sedvall, G, Wiesel, FA. Cerebroventricular size and cerebrospinal fluid monoamine metabolites in schizophrenic patients and healthy volunteers. Psychiatry Res 1983;9:301308. CrossRefGoogle ScholarPubMed
Bjerkenstedt, L, Edman, G, Hagenfeldt, L, Sedvall, G, Wiesel, FA. Plasma amino acids in relation to cerebrospinal fluid monoamine metabolites in schizophrenic patients and healthy controls. Br J Psychiatry 1985;147:276282. CrossRefGoogle ScholarPubMed
Lindström, LH. Low HVA and normal 5HIAA CSF levels in drug-free schizophrenic patients compared to healthy volunteers: correlations to symptomatology and family history. Psychiatry Res 1985;14:265273. CrossRefGoogle ScholarPubMed
Wieselgren, IM, Lindström, LH. CSF levels of HVA and 5-HIAA in drug-free schizophrenic patients and healthy controls: a prospective study focused on their predictive value for outcome in schizophrenia. Psychiatry Res 1998;81:101110. CrossRefGoogle Scholar
Kim, JS, Kornhuber, HH, Schmid-Burgk, W, Holzmuller, B. Low cerebrospinal fluid glutamate in schizophrenic patients and a new hypothesis on schizophrenia. Neurosci Lett 1980;20:379382. CrossRefGoogle Scholar
Gattaz, WF, Gattaz, D, Beckmann, H. Glutamate in schizophrenics and healthy controls. Arch Psychiatr Nervenkr 1982;231:221225. CrossRefGoogle ScholarPubMed
Perry, TL. Normal cerebrospinal fluid and brain glutamate levels in schizophrenia do not support the hypothesis of glutamatergic neuronal dysfunction. Neurosci Lett 1982;28:8185. CrossRefGoogle Scholar
Korpi, ER, Kaufmann, CA, Marnela, KM, Weinberger, DR. Cerebrospinal fluid amino acid concentrations in chronic schizophrenia. Psychiatry Res 1987;20:337345. CrossRefGoogle ScholarPubMed
Faustman, WO, Bardgett, M, Faull, KF, Pfefferbaum, A, Csernansky, JG. Cerebrospinal fluid glutamate inversely correlates with positive symptom severity in unmedicated male schizophrenic/schizoaffective patients. Biol Psychiatry 1999;45:6875. CrossRefGoogle ScholarPubMed
Ganong, AH, Cotman, CW. Kynurenic acid and quinolinic acid act at N-methyl-D-aspartate receptors in the rat hippocampus. J Pharmacol Exp Ther 1986;236:293299. Google ScholarPubMed
Birch, PJ, Grossman, CJ, Hayes, AG. Kynurenic acid antagonises responses to NMDA via an action at the strychnine-insensitive glycine receptor. Eur J Pharmacol 1988;154:8587. CrossRefGoogle ScholarPubMed
Kessler, M, Terramani, T, Lynch, G, Baudry, M. A glycine site associated with N-methyl-D-aspartic acid receptors: characterization and identification of a new class of antagonists. J Neurochem 1989;52:13191328. CrossRefGoogle ScholarPubMed
Parsons, CG, Danysz, W, Quack, Get al. Novel systemically active antagonists of the glycine site of the N-methyl-D-aspartate receptor: electrophysiological, biochemical and behavioral characterization. J Pharmacol Exp Ther 1997;283:12641275. Google ScholarPubMed
Hilmas, C, Pereira, EF, Alkondon, M, Rassoulpour, A, Schwarcz, R, Albuquerque, EX. The brain metabolite kynurenic acid inhibits alpha7 nicotinic receptor activity and increases non-alpha7 nicotinic receptor expression: physiopathological implications. J Neurosci 2001;21:74637473. Google ScholarPubMed
Erhardt, S, Blennow, K, Nordin, C, Skogh, E, Lindström, LH, Engberg, G. Kynurenic acid levels are elevated in the cerebrospinal fluid of patients with schizophrenia. Neurosci Lett 2001;13:9698. CrossRefGoogle Scholar
Nilsson, LK, Linderholm, KR, Engberg, Get al. Elevated levels of kynurenic acid in the cerebrospinal fluid of male patients with schizophrenia. Schizophr Res 2005;80:315322. CrossRefGoogle ScholarPubMed
Schwarcz, R, Rassoulpour, A, Wu, H-Q, Medoff, D, Tamminga, CA, Roberts, RC. Increased cortical kynurenate content in schizophrenia. Biol Psychiatry 2001;50:521530. CrossRefGoogle Scholar
Spitzer, RL, Endicott, J, Robins, E. Research diagnostic criteria; rationale and reliability. Arch Gen Psychiatry 1978;35:773782. CrossRefGoogle ScholarPubMed
Härnryd, C, Bjerkenstedt, L, Björk, Ket al. Clinical evaluation of sulpiride in schizophrenic patients – a double-blind comparison with chlorpromazine. Acta Psychiatr Scand 1984;311:730. CrossRefGoogle ScholarPubMed
Oxenstierna, G, Bergstrand, G, Bjerkenstedt, L, Sedvall, G, Wik, G. Evidence of disturbed CSF circulation and brain atrophy in cases of schizophrenic psychosis. Br J Psychiatry 1984;144:654661. CrossRefGoogle ScholarPubMed
Oxenstierna, G, Bergstrand, G, Edman, G, Flyckt, L, Nybäck, H, Sedvall, G. Increased frequency of abberant CSF circulation in schizophrenic patients compared to healthy volunteers. Eur Psychiatry 1996;11:1620. CrossRefGoogle Scholar
Jönsson, EG. Genetic aspects on schizophrenia and cerebrospinal fluid monoamine metabolites. Focus on association studies with candidate genes. Ph.D. Thesis, Department of Clinical Neuroscience, Psychiatry Section, Karolinska Institutet, Stockholm, 1997. Google Scholar
Sedvall, G, Fyro, B, Gullberg, B, Nybäck, H, Wiesel, FA, Wode-Helgodt, B. Relationships in healthy volunteers between concentrations of monoamine metabolites in cerebrospinal fluid and family history of psychiatric morbidity. Br J Psychiatry 1980;136:366374. CrossRefGoogle ScholarPubMed
Bertilsson, L, ÅSberg, M. Amine metabolites in the cerebrospinal fluid as a measure of central neurotransmitter function: methodological aspects. Adv Biochem Psychopharmacol 1984;39:2734. Google ScholarPubMed
Heyes, MP, Quearry, BJ. Quantification of kynurenic acid in cerebrospinal fluid: effects of systemic and central L-kynurenine administration. J Chromatogr 1990;530:108115. CrossRefGoogle ScholarPubMed
Swahn, C-G, Sandgärde, B, Wiesel, F-A, Sedvall, G. Simultaneous determination of the three major monoamine metabolites in brain tissue and body fluids by a mass fragmentographic method. Psychopharmacology 1976;48:147152. CrossRefGoogle Scholar
Nilsson, LK, Nordin, C, Jönsson, EG, Engberg, G, Erhardt, S. Cerebrospinal fluid kynurenic acid in male and female healthy controls – correlation with monoamine metabolites and influence of confounding factors. J Psychiatr Res 2007;41:144151. CrossRefGoogle Scholar
ÅGren, H, Mefford, IN, Rudorfer, MV, Linnoila, M, Potter, WZ. Interacting neurotransmitter systems. A non-experimental approach to the 5HIAA-HVA correlation in human CSF. J. Psychiatr Res 1986;20:175193. Google Scholar
Jibson, M, Faull, KF, Csernansky, JG. Intercorrelations among monoamine metabolite concentrations in human lumbar CSF are not due to a shared acid transport system. Biol Psychiatry 1990;28:595602. CrossRefGoogle Scholar
Dray, A, Gonye, TJ, Oakley, NR, Tanner, T. Evidence for the existence of a raphe projection to the substantia nigra in rat. Brain Res 1976;113:4557. CrossRefGoogle ScholarPubMed
Park, MR, Gonzales-Vegas, JA, Kitai, ST. Serotonergic excitation from dorsal raphe stimulation recorded intracellularly from rat caudate-putamen. Brain Res 1982;243:4958. CrossRefGoogle ScholarPubMed
Fuenmayor, LD, Bermudez, M. Effect of the cerebral tryptaminergic system on the turnover of dopamine in the striatum of the rat. J Neurochem 1985;44:670674. CrossRefGoogle ScholarPubMed
Wolfson, LI, Escriva, A. Clearance of 3-methoxy-4-hydroxyphenylglycol from the cerebrospinal fluid. Neurology 1976;26:781784. CrossRefGoogle ScholarPubMed
Scheinin, M. Monoamine metabolites in human cerebrospinal fluid: indicators of neuronal activity? Med Biol 1985;63:117. Google ScholarPubMed
Fukui, S, Schwarcz, R, Rapoport, SI, Takada, Y, Smith, QR. Blood-brain barrier transport of kynurenines: implications for brain synthesis and metabolism. J Neurochem 1991;56:20072017. CrossRefGoogle ScholarPubMed
Erhardt, S, ÖBerg, H, Mathé, JM, Engberg, G. Pharmacological elevation of endogenous kynurenic acid levels activates nigral dopamine neurons. Naunyn Schmiedeberǵs Arch Pharmacol 2001;20:353362. Google ScholarPubMed
Erhardt, S, Engberg, G. Increased phasic activity of dopaminergic neurons in the rat ventral tegmental area following pharmacologically elevated levels of endogenous kynurenic acid. Acta Physiol Scand 2002;175:4553. CrossRefGoogle ScholarPubMed
Schwieler, L, Erhardt, S, Nilsson, L, Linderholm, K, Engberg, G. Effects of COX-1 and COX-2 inhibitors on the firing of rat midbrain dopaminergic neurons – possible involvement of endogenous kynurenic acid. Synapse 2006;59:290298. CrossRefGoogle ScholarPubMed
Reith, J, Benkelfat, C, Sherwin, Aet al. Elevated dopa decarboxylase activity in living brain of patients with psychosis. Proc Natl Acad Sci U S A 1994;91:1165111654. CrossRefGoogle ScholarPubMed
Laruelle, M, Abi-Dargham, A, Van Dyck, CHet al. Single photon emission computerized tomography imaging of amphetamine-induced dopamine release in drug-free schizophrenic subjects. Proc Natl Acad Sci U S A 1996;93:92359240. CrossRefGoogle ScholarPubMed
Breier, A, Su, TP, Saunders, Ret al. Schizophrenia is associated with elevated amphetamine-induced synaptic dopamine concentrations: evidence from a novel positron emission tomography method. Proc Natl Acad Sci U S A 1997;94:25692574. CrossRefGoogle ScholarPubMed
Abi-Dargham, A, Gil, R, Krystal, Jet al. Increased striatal dopamine transmission in schizophrenia: confirmation in a second cohort. Am J Psychiatry 1998;155:761767. Google Scholar
Lindström, LH, Gefvert, O, Hagberg, Get al. Increased dopamine synthesis rate in medial prefrontal cortex and striatum in schizophrenia indicated by L-(beta-11C) DOPA and PET. Biol Psychiatry 1999;46:681688. CrossRefGoogle ScholarPubMed
Abi-Dargham, A, Rodenhiser, J, Printz, Det al. Increased baseline occupancy of D2 receptors by dopamine in schizophrenia. Proc Natl Acad Sci U S A 2000;97:81048109. CrossRefGoogle Scholar
Abi-Dargham, A, Laruelle, M. Mechanisms of action of second generation antipsychotic drugs in schizophrenia: insights from brain imaging studies. Eur Psychiatry 2005;20:1527. CrossRefGoogle ScholarPubMed
Wode-Helgodt, B, Fyro, B, Gullberg, B, Sedvall, G. Effect of chlorpromazine treatment on monoamine metabolite levels in cerebrospinal fluid of psychotic patients. Acta Psychiatr Scand 1977;56:129142. CrossRefGoogle ScholarPubMed
Härnryd, C, Bjerkenstedt, L, Gullberg, B, Oxenstierna, G, Sedvall, G, Wiesel, FA. Time course for effects of sulpiride and chlorpromazine on monoamine metabolite and prolactin levels in cerebrospinal fluid from schizophrenic patients. Acta Psychiatr Scand Suppl 1984;311:7592. CrossRefGoogle ScholarPubMed
Kahn, RS, Davidson, M, Knott, P, Stern, RG, Apter, S, Davis, KL. Effect of neuroleptic medication on cerebrospinal fluid monoamine metabolite concentrations in schizophrenia. Serotonin-dopamine interactions as a target for treatment. Arch Gen Psychiatry 1993;50:599605. CrossRefGoogle Scholar
Ceresoli-Borroni, G, Rassoulpour, A, Wu, HQ, Guidetti, P, Schwarcz, R. Chronic neuroleptic treatment reduces endogenous kynurenic acid levels in rat brain. J Neural Transm 2006;113:13551365. CrossRefGoogle ScholarPubMed
Miller, CL, Llenos, IC, Dulay, JR, Barillo, MM, Yolken, RH, Weis, S. Expression of the kynurenine pathway enzyme tryptophan 2,3-dioxygenase is increased in the frontal cortex of individuals with schizophrenia. Neurobiol Disease 2004;15:618629. CrossRefGoogle ScholarPubMed
Roberts, GW, Colter, N, Lofthouse, R, Bogerts, B, Zech, M, Crow, TJ. Gliosis in schizophrenia: a survey. Biol Psychiatry 1986;21:10431050. CrossRefGoogle ScholarPubMed
Roberts, GW, Colter, N, Lofthouse, R, Johnstone, EC, Crow, TJ. Is there gliosis in schizophrenia? Investigation of the temporal lobe. Biol Psychiatry 1987;22:14591468. CrossRefGoogle ScholarPubMed
Arnold, SE, Franz, BR, Trojanowski, JQ, Moberg, PJ, Gur, RE. Glial fibrillary acidic protein-immunoreactive astrocytosis in elderly patients with schizophrenia and dementia. Acta Neuropathol (Berl) 1996;91:269277. CrossRefGoogle ScholarPubMed
Arnold, SE, Trojanowski, JQ, Gur, RE, Blackwell, P, Han, LY, Choi, C. Absence of neurodegeneration and neural injury in the cerebral cortex in a sample of elderly patients with schizophrenia. Arch Gen Psychiatry 1998;55:225232. CrossRefGoogle Scholar
Falkai, P, Honer, WG, David, S, Bogerts, B, Majtenyi, C, Bayer, TA. No evidence for astrogliosis in brains of schizophrenic patients. A post-mortem study. Neuropathol Appl Neurobiol 1999;25:4853. CrossRefGoogle ScholarPubMed
Schwarcz, R, Guidetti, P, Roberts, RC. Quinolinic acid and kynurenic acid: glia-derived modulators of excitotoxic brain injury. In: Aschner, M, Kimelberg, HK, eds. The role of glia in neurostoxicity. Boca Raton: CRC, 1996; pp 245262. Google Scholar
Kiss, C, Ceresoli-Borroni, G, Guidetti, P, Zielke, CL, Zielke, HR, Schwarcz, R. Kynurenate production by cultured human astrocytes. J Neural Transm 2003;110:114. Google ScholarPubMed
Lara, DR, Gama, CS, Belmonte-De-Abreu, Pet al. Increased serum S100B protein in schizophrenia: a study in medication-free patients. J Psychiatr Res 2001;35:1114. CrossRefGoogle ScholarPubMed
Rothermundt, M, Missler, U, Arolt, Vet al. Increased S100B blood levels in unmedicated and treated schizophrenic patients are correlated with negative symptomatology. Mol Psychiatry 2001;6:445449. CrossRefGoogle ScholarPubMed
Schroeter, ML, Abdul-Khaliq, H, Fruhauf, Set al. Serum S100B is increased during early treatment with antipsychotics and in deficit schizophrenia. Schizophr Res 2003;62:231236. CrossRefGoogle ScholarPubMed
Rothermundt, M, Ponath, G, Glaser, T, Hetzel, G, Arolt, V. S100B serum levels and long-term improvement of negative symptoms in patients with schizophrenia. Neuropsychopharmacology 2004;29:10041011. CrossRefGoogle ScholarPubMed
Rothermundt, M, Falkai, P, Ponath, Get al. Glial cell dysfunction in schizophrenia indicated by increased S100B in the CSF. Mol Psychiatry 2004;9:897899. CrossRefGoogle ScholarPubMed
Schmitt, A, Bertsch, T, Henning, Uet al. Increased serum S100B in elderly, chronic schizophrenic patients: negative correlation with deficit symptoms. Schizophr Res 2005;80:305313. CrossRefGoogle ScholarPubMed
Poeggeler, B, Rassoulpour, A, Guidetti, P, Wu, HQ, Schwarcz, R. Dopaminergic control of kynurenate levels and N-methyl-D-aspartate toxicity in the developing rat striatum. Dev Neurosci 1998;20:146153. CrossRefGoogle ScholarPubMed
Rassoulpour, A, Wu, HQ, Poeggeler, B, Schwarcz, R. Systemic d-amphetamine administration causes a reduction of kynurenic acid levels in rat brain. Brain Res 1998;802:111118. CrossRefGoogle ScholarPubMed
Wu, HQ, Rassoulpour, A, Schwarcz, R. Effect of systemic L-DOPA administration on extracellular kynurenate levels in the rat striatum. J Neural Transm 2002;109:239249. CrossRefGoogle ScholarPubMed
Rassoulpour, A, Wu, HQ, Ferre, S, Schwarcz, R. Nanomolar concentrations of kynurenic acid reduce extracellular dopamine levels in the striatum. J Neurochem 2005;93:762765. CrossRefGoogle ScholarPubMed
Porrino, LJ, Lucignani, G, Dow-Edwards, D, Sokoloff, L. Correlation of dose-dependent effects of acute amphetamine administration on behavior and local cerebral metabolism in rats. Brain Res 1984;307:311320. CrossRefGoogle ScholarPubMed
Trugman, JM, James, CL. D1 dopamine agonist and antagonist effects on regional cerebral glucose utilization in rats with intact dopaminergic innervation. Brain Res 1993;607:270274. CrossRefGoogle ScholarPubMed
Zanassi, P, Paolillo, M, Montecucco, A, Avvedimento, EV, Schinelli, S. Pharmacological and molecular evidence for dopamine D(1) receptor expression by striatal astrocytes in culture. J Neurosci Res 1999;58:544552. 3.0.CO;2-9>CrossRefGoogle ScholarPubMed
Khan, ZU, Koulen, P, Rubinstein, M, Grandy, DK, Goldman-Rakic, PS. An astroglia-linked dopamine D2-receptor action in prefrontal cortex. Proc Natl Acad Sci U S A 2001;98:19641969. CrossRefGoogle ScholarPubMed