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Pharmacopsychiatry 2013; 46(S 01): S53-S63
DOI: 10.1055/s-0033-1337920
Original Paper
© Georg Thieme Verlag KG Stuttgart · New York

The Neurochemical Mobile with Non-Linear Interaction Matrix: An Exploratory Computational Model

Z. Qi
1   Department of Biomedical Engineering, Georgia Institute of Technology and Emory University Medical School, Atlanta, GA, USA
2   Integrative BioSystems Institute, Georgia Institute of Technology, Atlanta, GA, USA
3   Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA, USA
,
D. Fieni
1   Department of Biomedical Engineering, Georgia Institute of Technology and Emory University Medical School, Atlanta, GA, USA
,
F. Tretter
4   Isar-Amper-Klinikum gemeinnützige GmbH, Klinikum München-Ost, Haar, Landkreis München, Germany
,
E. O. Voit
1   Department of Biomedical Engineering, Georgia Institute of Technology and Emory University Medical School, Atlanta, GA, USA
2   Integrative BioSystems Institute, Georgia Institute of Technology, Atlanta, GA, USA
› Author Affiliations
Further Information

Publication History

Publication Date:
18 April 2013 (online)

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Abstract

Several years ago, the “neurochemical mobile” was introduced as a visual tool for explaining the different balances between neurotransmitters in the brain and their role in mental disorders. Here we complement this concept with a non-linear computational systems model representing the direct and indirect interactions between neurotransmitters, as they have been described in the “neurochemical interaction matrix.” The model is constructed within the framework of biochemical systems theory, which facilitates the mapping of numerically ill-characterized systems into a mathematical and computational construct that permits a variety of analyses. Simulations show how short- and long-term perturbations in any of the neurotransmitters migrate through the entire system, thereby affecting the balances within the mobile. In cases of short-term alterations, transients are of particular interest, whereas long-term changes shed light on persistently altered, allostatic states, which in mental diseases and sleep disorders could be due to a combination of unfavorable factors, resulting from a specific genetic predisposition, epigenetic effects, disease, or the repeated use of drugs, such as opioids and amphetamines.

Key words

allostasis - biochemical systems ­analysis - brain chemistry - computational systems ­biology - homeostasis - network analysis - neurotransmitter
 

  • References

  • 1 Creese I, Burt DR, Snyder SH. Dopamine receptor binding predicts clinical and pharmacological potencies of antischizophrenic drugs. Science 1976; 192: 481-483
    CrossrefPubMedGoogle Scholar
  • 2 Davis KL, Kahn RS, Ko G et al. Dopamine in schizophrenia: a review and reconceptualization. Am J Psychiatry 1991; 148: 1474-1486
    PubMedGoogle Scholar
  • 3 Howes OD, Kapur S. The dopamine hypothesis of schizophrenia: version III – -the final common pathway. Schizophr Bull 2009; 35: 549-562
    Google Scholar
  • 4 Javitt DC, Zukin SR. Recent advances in the phencyclidine model of schizophrenia. Am J Psychiatry 1991; 148: 1301-1308
    PubMedGoogle Scholar
  • 5 Krystal JH, Karper LP, Seibyl JP et al. Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry 1994; 51: 199-214
    CrossrefPubMedGoogle Scholar
  • 6 Parwani A, Weiler MA, Blaxton TA et al. The effects of a subanesthetic dose of ketamine on verbal memory in normal volunteers. Psychopharmacology (Berl) 2005; 183: 265-274
    CrossrefPubMedGoogle Scholar
  • 7 Perry TL, Kish SJ, Buchanan J et al. Gamma-aminobutyric-acid deficiency in brain of schizophrenic patients. Lancet 1979; 1: 237-239
    CrossrefPubMedGoogle Scholar
  • 8 Seeman P, Chau-Wong M, Tedesco J et al. Brain receptors for antipsychotic drugs and dopamine: direct binding assays. Proc Natl Acad Sci USA 1975; 72: 4376-4380
    CrossrefPubMedGoogle Scholar
  • 9 Seeman P, Lee T, Chau-Wong M et al. Antipsychotic drug doses and neuroleptic/dopamine receptors. Nature 1976; 261: 717-719
    Google Scholar
  • 10 Umbricht D, Schmid L, Koller R et al. Ketamine-induced deficits in auditory and visual context-dependent processing in healthy volunteers: implications for models of cognitive deficits in schizophrenia. Arch Gen Psychiatry 2000; 57: 1139-1147
    CrossrefPubMedGoogle Scholar
  • 11 Carlsson A. The current state of the dopamine hypothesis of schizophrenia. Neuropsychopharmacol 1988; 1: 179-186
    CrossrefPubMedGoogle Scholar
  • 12 Carlsson A, Waters N, Holm-Waters S et al. Interactions between monoamines, glutamate, and GABA in schizophrenia: New Evidence. Annu Rev Pharmacol Toxicol 2001; 41: 237-260
    CrossrefPubMedGoogle Scholar
  • 13 Koob G, Le Moal M. Neurobiology of Addiction. New York: Academic Press; 2006
    Google Scholar
  • 14 Winterer G, Weinberger DR. Genes, dopamine and cortical signal-to-noise-ratio in schizophrenia. Trends in Neurosciences 2004; 27: 683-690
    CrossrefPubMedGoogle Scholar
  • 15 Goto Y, Grace AA. The dopamine system and the pathophysiology of schizophrenia: a basic science perspective. Int Rev Neurobiol 2007; 78: 41-68
    PubMedGoogle Scholar
  • 16 Guillin O, Abi-Dargham A, Laruelle M. Neurobiology of dopamine in schizophrenia. Int Rev Neurobiol 2007; 78: 1-39
    PubMedGoogle Scholar
  • 17 Aghajanian GK, Marek GJ. Serotonin model of schizophrenia: emerging role of glutamate mechanisms. Brain Research Reviews 2000 31: 302-312
    PubMedGoogle Scholar
  • 18 Vollenweider FX, Kometer M. The neurobiology of psychedelic drugs: implications for the treatment of mood disorders. Nature Reviews Neuroscience 2010; 11: 642-651
    CrossrefPubMedGoogle Scholar
  • 19 Wassef A, Baker J, Kochan LD. GABA and schizophrenia: a review of basic science and clinical studies. J Clin Psychopharmacol 2003; 23: 601-640
    CrossrefPubMedGoogle Scholar
  • 20 Yamamoto K, Hornykiewicz O. Proposal for a noradrenaline hypothesis of schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2004; 28: 913-922
    CrossrefPubMedGoogle Scholar
  • 21 Berman JA, Talmage DA, Role LW. Cholinergic circuits and signaling in the pathophysiology of schizophrenia. Int Rev Neurobiol 2007; 78: 193-223
    PubMedGoogle Scholar
  • 22 Moghaddam B. Bringing order to the glutamate chaos in schizophrenia. Neuron 2003; 40: 881-884
    CrossrefPubMedGoogle Scholar
  • 23 Trimble MR. Biological Psychiatry. New York: Wiley; 2002
    Google Scholar
  • 24 Tretter F, Albus M. Einfürhung in die Psychiopharmakotherapie. Stuttgart: Thieme; 2004
    Google Scholar
  • 25 Cooper JR, Bloom FE, Roth RH. The Biochemical Basis of Neuropharmacology. New York: Oxford University Press; 2004
    Google Scholar
  • 26 Krystal JH. N-methyl-D-aspartate glutamate receptor antagonists and the promise of rapid-acting antidepressants. Arch, Gen Psychiatry 2010; 67: 1110-1111
    CrossrefPubMedGoogle Scholar
  • 27 Luscher B, Shen QNS. The GABAergic deficit hypothesis of major depressive disorder. Mol Psychiatry 2010; 16: 383-406
    PubMedGoogle Scholar
  • 28 Schatzberg AF, Rothschild AJ, Langlais P et al. A corticosteroid/dopamine hypothesis for psychotic depression and related states. J Psychiatr Res 1985; 19: 57-64
    CrossrefPubMedGoogle Scholar
  • 29 Schildkraut JJ. The catecholamine hypothesis of affective disorders: a review of supporting evidence. Amer J Psychiat 1965; 122: 609-622
    PubMedGoogle Scholar
  • 30 Coppen A. The biochemistry of affective disorders. Br J Psychiatry 1967; 113: 1237-1264
    CrossrefPubMedGoogle Scholar
  • 31 Janowsky DS, Overstreet DH. The role of acetylcholine mechanisms in mood disorders. New York: Raven Press; 1995
    Google Scholar
  • 32 Blier P, El Mansari M. The importance of serotonin and noradrenaline in anxiety. Int J Psychiatry Clin Pract 2007; 11: 16-23
    PubMedGoogle Scholar
  • 33 Degroot A, Treit D. Dorsal and ventral hippocampal cholinergic systems modulate anxiety in the plus-maze and shock-probe tests. Brain Res 2002; 949: 60-70
    CrossrefPubMedGoogle Scholar
  • 34 Heinz A, Siessmeier T, Wrase J et al. Correlation between dopamine D2 receptors in the ventral striatum and central processing of alcohol cues and craving. Am J Psychiatry 2004; 101: 1783-1789
    PubMedGoogle Scholar
  • 35 Tretter F. Suchtmedizin. Suchtkrankeiten in Klinik und Praxis. Stuttgart: Schattauer; 2008
    Google Scholar
  • 36 Benes FM. Neural circuitry models of schizophrenia: is it dopamine, GABA, glutamate or something else?. Biol Psychiatry 2009; 65: 1003-1005
    CrossrefPubMedGoogle Scholar
  • 37 Tretter F, an der Heiden U, Rujescu D et al. Computational modeling of schizophrenic symptoms – basic issues. Pharmacopsychiatry 2012; 45: S2-S11
    Article in Thieme ConnectPubMedGoogle Scholar
  • 38 an der Heiden U. Schizophrenia as a dynamical disease. Pharmacopsychiatry 2006; 39: S36-S42
    Article in Thieme ConnectPubMedGoogle Scholar
  • 39 Bélair J, Glass L, an der Heiden U et al. (eds.). Dynamical disease – mathematical analysis of human illness. Woodbury, USA: American Institute of Physics; 1995
    Google Scholar
  • 40 Tretter F, Gebicke-Haerter PJ, an der Heiden U et al. Affective disorders as complex dynamic diseases – a perspective from systems biology. Pharmacopsychiatry 2011; 44: S2-S8
    Article in Thieme ConnectPubMedGoogle Scholar
  • 41 Tretter F, Gebicke-Haerter PJ, Mendoza ER et al. (eds.). Systems Biology in Psychiatric Research: From High-Throughput Data to Mathematical Modelling. Weinheim: Wiley-VCH; 2010
    CrossrefGoogle Scholar
  • 42 Voit EO. A First Course in Systems Biology. New York, NY: Garland Science; 2012
    Google Scholar
  • 43 Barabasi AL, Gulbahce N, Loscalzo J. Network medicine: a network-based approach to human disease. Nat Rev Genet 2011; 12: 56-68
    CrossrefPubMedGoogle Scholar
  • 44 Wang K, Lee I, Carlson G et al. Systems biology and the discovery of diagnostic biomarkers. Dis Markers 2010; 28: 199-207
    CrossrefPubMedGoogle Scholar
  • 45 Voit EO. A systems-theoretical framework for health and disease: inflammation and preconditioning from an abstract modeling point of view. Mathematical biosciences 2009; 217: 11-18
    CrossrefPubMedGoogle Scholar
  • 46 Fritze J. Biologische Psychiatrie. Stuttgart: Fischer; 1989
    Google Scholar
  • 47 Bender W, Albus M, Mőller H-J et al. Towards systemic theoriesin biological psychiatry. Pharnmacopsychiatry 2006; 39: S4-S9
    PubMedGoogle Scholar
  • 48 Iversen LL, Iversen SD, Bloom F et al. Introduiction to Neuropsychopharmacology. New York: Oxford Unvi. Press; 2009
    CrossrefGoogle Scholar
  • 49 Savageau MA. Biochemical systems analysis. I. Some mathematical properties of the rate law for the component enzymatic reactions. J Theor Biol 1969; 25: 365-369
    CrossrefPubMedGoogle Scholar
  • 50 Savageau MA. Biochemical systems analysis: a study of function and design in molecular biology. Reading, Mass.: Addison-Wesley Pub. Co. Advanced Book Program; 1976
    Google Scholar
  • 51 Torres NV, Voit EO. Pathway Analysis and Optimization in Metabolic Engineering. Cambridge, U.K.: Cambridge University Press; 2002
    CrossrefGoogle Scholar
  • 52 Voit EO. (ed.) Canonical Nonlinear Modeling. S-System Approach to Understanding Complexity. Van Nostrand Reinhold; NY: 1991
  • 53 Voit EO. Computational Analysis of Biochemical Systems. A Practical Guide for Biochemists and Molecular Biologists. Cambridge, UK: Cambridge University Press; 2000
    Google Scholar
  • 54 Voit EO. Biuochemical Systems Theory: A Review. International Scholarly Research Network (ISRN) – Biomathematics 2013; DOI: 897658.
    PubMedGoogle Scholar
  • 55 Noble D. The aims of systems biology: between molecules and organisms. Pharmacopsychiatry 2011; 44 (Suppl. 01) S9-S14
    Article in Thieme ConnectPubMedGoogle Scholar
  • 56 Voit EO, Qi Z, Kikuchi S. Mesoscopic models of neurotransmission as intermediates between disease simulators and tools for discovering design principles. Pharmacopsychiatry 2012; 45 (Suppl. 01) S22-S30
    Article in Thieme ConnectPubMedGoogle Scholar
  • 57 Breen G, McGuffin P, Simmons A. Towards “systems psychiatry”. Rev Bras Psiquiatr 2008; 30: 97-98
    PubMedGoogle Scholar
  • 58 Craver C. Explaining the Brain. New York: Oxford University Press; 2007
    CrossrefGoogle Scholar
  • 59 Qi Z, Miller GW, Voit EO. Computational systems analysis of dopamine metabolism. PLoS One 2008; 3: e2444
    CrossrefPubMedGoogle Scholar
  • 60 Qi Z, Miller GW, Voit EO. A mathematical model of presynaptic dopamine homeostasis: implications for schizophrenia. Pharmacopsychiatry 2008; 41 (Suppl. 01) S89-S98
    Article in Thieme ConnectPubMedGoogle Scholar
  • 61 Herz AV, Gollisch T, Machens CK et al. Modelling single-neuron dynamics and computations: a balance of detail and abstraction. Science 2006; 314: 0-85
    PubMedGoogle Scholar
  • 62 Danbolt N. Glutamate as a neurotransmitter – An overview. Center for Molecular Biology and Neuroscience 2012;
    PubMedGoogle Scholar
  • 63 Divino Filho JC, Hazel SJ, Furst P et al. Glutamate concentration in plasma, erythrocyte and muscle in relation to plasma levels of insulin-like growth factor (IGF)-I, IGF binding protein-1 and insulin in patients on haemodialysis. J Endocrinol 1998; 156: 519-527
    CrossrefPubMedGoogle Scholar
  • 64 Goldstein DS, Eisenhofer G, Kopin IJ. Sources and significance of plasma levels of catechols and their metabolites in humans. J Pharmacol Exp Therap 2003; 305: 800-811
    CrossrefPubMedGoogle Scholar
  • 65 (US) NLoM . Serum Serotonin Level: MedlinePlus Medical Encyclopedia. 2012;
    PubMedGoogle Scholar
  • 66 Minuk GY, Winder A, Burgess ED et al. Serum gamma-aminobutyric acid (GABA) levels in patients with hepatic encephalopathy. Hepato-gastroenterology 1985; 32: 171-174
    PubMedGoogle Scholar
  • 67 Pickut W. What are abnormal dopamine levels?. Livestrong.com 2011
    PubMedGoogle Scholar
  • 68 Plaitakis A, Shashidharan P. Amyotrophic lateral sclerosis, glutamate, and oxidative stress. In: Bloom FF. Kupfer DJ. eds. The Fourth Generation. 1995: pp 1531-1543
    Google Scholar
  • 69 Schulz P, Lloyd KG, Voltz C et al. The plasma concentration of GABA shows no evidence of a circadian-rhythm and is stable over weeks in normal males. Biol Rhythm Res 1994; 25: 291-300
    CrossrefPubMedGoogle Scholar
  • 70 Taylor MJ. The Normal Levels of Norepinephrine in the Body. In: Media D. ed. EHow. 2010
    Google Scholar
  • 71 Ferreira A. Power Law Analysis and Simulation. Version 1.2 ed2000
    PubMedGoogle Scholar
  • 72 Patkar AA, Gopalakrishnan R, Naik PC et al. Changes in plasma noradrenaline and serotonin levels and craving during alcohol withdrawal. Alcohol and alcoholism 2003; 38: 224-231
    CrossrefPubMedGoogle Scholar
  • 73 Linnoila M, Mefford I, Nutt D et al. NIH conference. Alcohol withdrawal and noradrenergic function. Ann intern med 1987; 107: 875-889
    CrossrefPubMedGoogle Scholar