Systems Biology and Addiction

Abstract

The onset of addiction is marked with drug induced positive experiences that keep being repeated. During that time, adaptation occurs and addiction is stabilized. Interruption of those processes induces polysymptomatic withdrawal syndromes. Abstinence is accompanied by risks of relapse. These features of addiction suggest adaptive brain dynamics with common pathways in complex neuronal networks. Addiction research has used animal models, where some of those phenomena could be reproduced, to find correlates of addictive behavior. The major thrust of those approaches has been on the involvement of genes and proteins. Recently, an enormous amount of data has been obtained by high throughput technologies in these fields. Therefore, (Computational) “Systems Biology” had to be implemented as a new approach in molecular biology and biochemistry. Conceptually, Systems Biology can be understood as a field of theoretical biology that tries to identify patterns in complex data sets and that reconstructs the cell and cellular networks as complex dynamic, self-organizing systems. This approach is embedded in systems science as an interdisciplinary effort to understand complex dynamical systems and belongs to the field of theoretical neuroscience (Computational Neuroscience). Systems biology, in a similar way as computational neuroscience is based on applied mathematics, computer-based computation and experimental simulation. In terms of addiction research, building up “computational molecular systems biology of the (addicted) neuron” could provide a better molecular biological understanding of addiction on the cellular and network level. Some key issues are addressed in this article.

References

• 1 Abarca C, Albrecht U, Spanagel R. Cocaine sensitization and reward are under the influence of circadian genes and rhythm.  Proc Natl Acad Sci USA. 2002;  99 ((13)) 9026-9030
• 2 Abbott L, Regehr WG. Synaptic computation.  Nature. 2004;  31 ((7010)) 796-803
• 3 Ahmed SH, Koob G. Transition to drug addiction: a negative reinforcement model based on an allostatic decrease in reward function.  Psychopharmacology. 2005;  180 473-490
• 4 Alberghina L, Colangelo AM. The modular systems biology approach to investigate the control of apoptosis in Alzheimer's disease neurodegeneration.  BMC Neurosci. 2006;  7 ((Suppl 1)) S2 , doi:10.1186/1471-2202-7-S1-S2
• 5 Alon U. Systems Biology – Design principles of biological circuits. New York: Chapman & Hall 2007
• 6 An der Heiden U, Schwegler H, Tretter F. Patterns of Alcoholism – A Mathematical Model. Mathematical Models and Methods.  Appl Sci. 1998;  8 521-541
• 7 Basar E, Güntekin B. A review of brain oscillations in cognitive disorders and the role of neurotransmitters.  Brain Res. 2008;  15 ((1235)) 172-193
• 8 Bechara A. Decision making, impulse control and loss of willpower to resist drugs: a neurocognitive perspective.  Nat Neurosci. 2005;  8 ((11)) 1458-1463
• 9 Beck AT, Wright FD, Newman CF. et al . Cognitive Therapy of Substance Abuse. New York: Guilford Press 2001
• 10 Bender W, Albus M, Möller HJ. et al . Towards systemic theories in biological psychiatry.  Pharmacopsychiatry. 2006;  39 ((Suppl.1)) S4-S9
• 11 Bhave SV, Hornbaker C, Phang TL. et al . The PhenoGen informatics website: tools for analyses of complex traits.  BMC Genet. 2007;  8 59
• 12 Burmeister M, McInnis MG, Zöllner S. Psychiatric genetics – Progress amid controversy.  Nat Rev Genet. 2008;  9 ((7)) 527-540
• 13 Cappell H, Greeley H. Alcohol and tension reduction: an update on research and theory. In: Blane HT, Leonard KE, eds. Psychological theories of drinking and alcoholism. New York: Guilford Press 1987: 15-54
• 14 Cardelli L. Abstract machines of systems biology. Transactions on Computational Systems Biology. III, LNBI. Berlin: Springer 2005 3737: 145-168
• 15 Crespo JA, Sturm K, Saria A. et al . Activation of muscarinic and nicotinic acetylcholine receptors in the nucleus accumbens score is necessary for the acquisition of drug reinforcement.  J Neurosci. 2006;  26 ((22)) 6004-6010
• 16 Davis KM, Wu JY. Role of glutamatergic and GABAergic systems in alcoholism.  J Biomed Sci. 2001;  8 ((1)) 7-19
• 17 De Witte Ph. Imbalance between exictatory and inhibitory amino acids causes craving for ethanol: frooma naimal studies to human being studies. In: Miller P, Kavanagh D. Translation of addictions science into practice. Amsterdam: Elsevier 2007: 57-79
• 18 Dollard J, Doob LW, Miller NE. et al . Frustration and Aggression. New Haven: Yale University Press 1939
• 19 Durstewitz D. A few important points about dopamine's role in neural network dynamics.  Pharmacopsychiatry. 2006;  39 ((Suppl.1)) S1-S88
• 20 Edelman GM, Tononi G. A Universe of Consciousness: How Matter Becomes Imagination. New York: Basic Books 2000
• 21 Everitt BJ, Robbins TW. Neural systems of reinforcement for drug addiction: from actions to habits to compulsion.  Nat Neurosci. 2005;  8 ((11)) 1481-1489
• 22 Fischer HP. Mathematical modelling of complex biological systems.  Alcohol Res Health. 2008;  31 ((1)) 49-59
• 23 Fernandez E, Schlappe R, Girault JA. et al . DARPP-32 is a robust integrator of dopamine and glutamate signals.  PloS Comput Biol. 2006;  2 ((12)) e176
• 24 Fritze J, Lanczyk M. Einführung in die biologische Psychiatrie. München: Urban & Fischer 1989
• 25 Gebicke-Haerter P. Systems biology in molecular psychiatry.  Pharmacopsychiatry. 2008;  41 ((Suppl 1)) S19-S27
• 26 Goldstein RZ, Volkow ND. Drug Addiction and its underlying neurobiological basis:Neuroimaging evidence for the involvement of the frontal cortex.  Am J Psychiatry. 2002;  159 1642-1652
• 27 Grant SG. Toward a molecular catalogue of synapses.  Brain Res Rev. 2007;  55 ((2)) 445-449
• 28 Guo Co M, Zakhri S. Commentary – systems biology and its relevance to alcohol research.  Alcohol Research Health. 2008;  31 ((1)) 5-10
• 29 Grüsser SM, Thalemann R. Computerspielsüchtig? Rat und Hilfe. Bern: Verlag Hans Huber 2006
• 30 Gutkin BS, Dehaene S, Changeux J-P. A neruocomputational hypothesis fro nicotine addiction.  Proc Natl Acad Sci USA. 2006;  103 ((4)) 1106-1111
• 31 Harrigan GG, Maguire G, Boros L. Metabolomics in alcohol research and drug development.  Alcohol Res Health. 2008;  31 ((1)) 26-35
• 32 Hobson JA. Sleep and dreaming.  J Neurosci. 1990;  10 371-382
• 33 Holst Ev, Mittelstaedt H. Das Reafferenzprinzip.  Naturwissenschaften. 1950;  37 464-476
• 34 Hyman SE, Malenka RC, Nestler EJ. Neural mechanisms of addiction: the role of reward-related learning and memory.  Annu Rev Neurosci. 2006;  29 565-598
• 35 Jellinek LM. The disease concept of alcoholism. New Brunswick, NJ: Hillhouse 1960
• 36 Kitano H. Systems Biology: a brief overview.  Science. 2002a;  295 1662-1664
• 37 Kitano H. Computational Systems Biology.  Nature. 2002b;  420 206-210
• 38 Kitano H. ed Foundations of Systems Biology. Cambridge, MA: MIT Press 2001
• 39 Klipp E, Herwig R, Kowald A. et al . Systems Biology in Practice. Weinheim: Wiley-VCH 2005
• 40 Koob G, Le Moal M. Drug Addiction, Dysregulation of Reward, Allostasis.  Neuropsychopharmacology. 2001;  24 97-129
• 41 Koob G, Le Moal M. Neurobiology of addiction. New York: Academic Press 2006
• 42 Li C-J, Mao X, Wei L. Genes and (common) pathways underlying drug ediction.  PLoS Comput Biol. 4 ((1)) e2 , Doi:10. 1371/Journal. pcbi. 0040002
• 43 Lindskog M. Modelling of DARPP-32 regulation to understand intracellular signaling in psychiatric disease.  Pharmacopsychiatry. 2008;  41 ((Suppl 1)) S99-S104
• 44 Lindskog M, Kim MS, Wikstrom MA. et al . Transient Calcium and Dopamine Increase PKA Activity and DARPP-32 Phosphorylation.  PLoS Comput Biol. 2006;  2 ((9)) e119
• 45 Lotka AJ. Elements of physical biology. Baltimore: Williams & Wilkins 1925
• 46 Marlatt GA, Gordon JR. ed. Relapse Prevention: Maintenance strategies in the treatment of addictive behaviors. New York: Guilford Press 1985
• 47 Marlatt GA, Witkiewitz K. Addictive Behaviors: New Readings on Etiology, Prevention, and Treatment.  Washington: American Psychological Association (APA). 2008; 
• 48 Montague PR, Hyman SE, Cohen JD. Computational roles for dopamine in behavioral control.  Nature. 2004;  431 760-767
• 49 Murray JD. An introduction to Mathematical Biology. An Introductory Course. New York: Springer 2004
• 50 Nestler E. Historical review: molecular and cellular mechanisms of opiate and cocaine addiction.  Trends Pharmacol Sci. 2004;  25 ((4)) 210-219
• 51 Nestler EJ. Is there a common molecular pathway for addiction?.  Nat Neurosci. 2005;  8 1445-1449
• 52 Neve KA, Semans JK, Trantham-Davidson H. Dopamine receptor signalling.  J Recept Signal Transduct Res. 2004;  24 ((3)) 165-205
• 53 NIH . Systems Biology. 2007;  http://www.nigms.nih.gov/initiatives/sysbio/
• 54 Noble D. Music of life. New York: Oxford University Press 2008
• 55 Palsson BO. Systems Biology. Cambridge, UK: Cambridge University Press 2006
• 56 Pasinetti GM, Hiller-Sturmhöfel S. System biology in the study of neurological disorders: Focus on Alzheimer's diesease.  Alcohol Res Health. 2008;  31 ((1)) 60-65
• 57 Peper A. A theory of drug tolerance and dependence I: a conceptual analysis.  J Theor Biol.. 2004;  229 477-490
• 58 Peper A. A theory of drug tolerance and dependence II: the mathematical model.  J Theor Biol.. 2004;  229 491-500
• 59 Pocklington AJ, Cumiskey M, Armstrong JD. et al . The proteomes of neurotransmitter receptor complexes form modular networks with distributed functionality underlying plasticity and behaviour.  Mol Syst Biol. 2006;  2 0023
• 60 Qi Z, Miller GW, Voit EO. Mathematical model of presenaptic dopamine homeostasis: Implications for schizophrenia.  Pharmacopsychiatry. 2008;  41 ((Suppl 1)) S89-S98
• 61 Rapaka RS, Sadee W. ed. Drug addiction.From basic research to therapy. New York: Springer 2008
• 62 Rangaswamy M, Porjesz B. Uncovering genes for cognitive (dys)function and predisposition for alcoholism spectrum disorders: a review of human brain oscillations as effective endophenotypes.  Brain Res. 2008;  15 ((1235)) 153-171
• 63 Redish AD, Johnson A. A computational model of craving and obsession.  Ann NY Acad Sci.. 2007;  1104 324-339
• 64 Rommelspacher H, Raeder C, Brüning G. et al . Adaptive changes of dopamine-D2 receptors in rat brain follwoing ethanol withdrawal: a quantiaitve autoradiographic investigation.  Alcohol. 1992;  9 355-362
• 65 Saint-Exupéry A. The little prince. Paris: Gallimard 1943
• 66 Schultz W. Predictive reward signal of dopamine mechanisms.  J Neurophys. 1998;  80 1-27
• 67 Schultz W. Multiple Reward Signals in the Brain.  Nat Rev Neurosci. 2000;  1 199-207
• 68 Sel’kov EE. Self-oscillations in glycolysis.  Eur J. Biochem. 1968;  4 79
• 69 Solomon RL, Corbit JD. An opponent-process theory of motivation. I. Temporal dynamics of affect.  Psychol Rev. 1974;  81 119-145
• 70 Spanagel R, Heilig M. Addiction and ist brain science.  Addiction. 2005;  100 1813-1822
• 71 Spanagel R, Rosenwasser AM, Schumann G. et al . Alcohol consumption and the body's biological clock.  Alcohol Clin Exp Res.. 2005;  29 ((8)) 1550-1557
• 72 Stahl SM. Stahl's Essential Psychopharmacology. New York: Cambridge University Press 2008
• 73 Stelling Sauer UJ, Doyle F. et al .Complexity and robustness of cellular systems. In: Szallasi Z, Stelling J, Periwal V, ed. System modeling in cellular biology. Cambridge, MA: MIT Press 2006: 19-39
• 74 Svenningsson P, Nairn AC, Greengard P. DARPP-32 mediates the actions of multiple drugs of abuse.  AAPS J. 2005;  7 ((2)) e353-360
• 75 Svenningsson P, Nishi A, Fisone G. et al . DARPP-32: an integrator of neurotransmission.  Annu Rev Pharmacol Toxicol. 2004;  44 269-296
• 76 Tretter F. Ökologie der Sucht. Göttingen: Hogrefe 1998
• 77 Tretter F. Systemtheorie im klinischen Kontext. Lengerich:Pabst Science Publishers 2005
• 78 Tretter F, Albus M. Systems biology and psychiatry – modeling molecular and cellular networks of mental disorders.  Pharmacopsychiatry.. 2008;  41 ((Suppl 1)) S2-S18
• 79 Tretter F, Müller W, Carlsson A. , Eds. Systems Science, Computational Science and Neurobiology of Schizophrenia.  Pharmacopsychiatry. 2006;  39 ((Suppl 1))
• 80 Tretter F, Müller WE. ,  eds. Computational neuropsychiatry of working memory disorders in schizophrenia: the network connectivity in prefrontal cortex – data and models.  Pharmacopsychiatry. 2007;  40 ((Suppl 1))
• 81 Tretter F, Gallinat J, Müller W. ,  eds. Systems Biology and psychiatry Pharmacopsychiatry.  . 2008;  41 ((Suppl. 1))
• 82 Vitaterna MH, Takahashi JS, Turek FW. Overview of circadian rhythms.  Alcohol Res Health. 2001;  25 ((2)) 85-93
• 83 Volkow ND, Fowler JS. Addiction, a disease of compulsion and drive: Involvement of the orbitofrontal cortex.  Cereb Cortex. 2000;  10 318-325
• 84 Volkow ND, Fowler JS, Wang GJ. The addicted human brain: insights from imaging studies.  J Clin Invest. 2003;  111 ((10)) 1444-1451
• 85 West R. Theory of addiction. Oxford, UK: Addiction Press, Blackwell 2006
• 86 Wikipedia . Bateman-Funktion.de.wikipedia.org/wiki/Bateman-Funktion.  2009; 
• 87 Wise RA. Brain reward circuitry: insights from unsensed incentives.  Neuron. 2002;  36 229-240
• 88 Yuferov V, Bart G, Kreek MJ. Clock reset for alcoholism.  Nat Med. 2005;  11 ((1)) 23-24

Correspondence