A systems medicine research approach for studying alcohol addiction

According to the World Health Organization, about 2 billion people drink alcohol. Excessive alcohol consumption can result in alcohol addiction, which is one of the most prevalent neuropsychiatric diseases afflicting our society today. Prevention and intervention of alcohol binging in adolescents and treatment of alcoholism are major unmet challenges affecting our health‐care system and society alike. Our newly formed German SysMedAlcoholism consortium is using a new systems medicine approach and intends (1) to define individual neurobehavioral risk profiles in adolescents that are predictive of alcohol use disorders later in life and (2) to identify new pharmacological targets and molecules for the treatment of alcoholism. To achieve these goals, we will use omics‐information from epigenomics, genetics transcriptomics, neurodynamics, global neurochemical connectomes and neuroimaging (IMAGEN; Schumann et al. ) to feed mathematical prediction modules provided by two Bernstein Centers for Computational Neurosciences (Berlin and Heidelberg/Mannheim), the results of which will subsequently be functionally validated in independent clinical samples and appropriate animal models. This approach will lead to new early intervention strategies and identify innovative molecules for relapse prevention that will be tested in experimental human studies. This research program will ultimately help in consolidating addiction research clusters in Germany that can effectively conduct large clinical trials, implement early intervention strategies and impact political and healthcare decision makers.

[1]  G. Uhl,et al.  NrCAM‐regulating neural systems and addiction‐related behaviors , 2014, Addiction biology.

[2]  K. Mann,et al.  A randomised, double-blind, placebo-controlled, efficacy study of nalmefene, as-needed use, in patients with alcohol dependence , 2013, European Neuropsychopharmacology.

[3]  D. Hommer,et al.  A genetic determinant of the striatal dopamine response to alcohol in men , 2010, Molecular Psychiatry.

[4]  R. Spanagel,et al.  Rescue of Infralimbic mGluR2 Deficit Restores Control Over Drug-Seeking Behavior in Alcohol Dependence , 2013, The Journal of Neuroscience.

[5]  Roland Eils,et al.  An integrated genome research network for studying the genetics of alcohol addiction , 2010, Addiction biology.

[6]  An-Yuan Guo,et al.  ERGR: An ethanol-related gene resource , 2008, Nucleic Acids Res..

[7]  G. Bakalkin,et al.  The endogenous opioid system in human alcoholics: molecular adaptations in brain areas involved in cognitive control of addiction , 2013, Addiction biology.

[8]  Vernell S. Williamson,et al.  Using genetic information from candidate gene and genome‐wide association studies in risk prediction for alcohol dependence , 2014, Addiction biology.

[9]  R. Rimondini,et al.  Different alcohol exposures induce selective alterations on the expression of dynorphin and nociceptin systems related genes in rat brain , 2013, Addiction biology.

[10]  D. Rujescu,et al.  Systematic analysis of glutamatergic neurotransmission genes in alcohol dependence and adolescent risky drinking behavior. , 2008, Archives of general psychiatry.

[11]  Ashley R. Smith,et al.  The effect of intravenous alcohol on the neural correlates of risky decision making in healthy social drinkers , 2012, Addiction biology.

[12]  B. Everitt,et al.  Hierarchical recruitment of phasic dopamine signaling in the striatum during the progression of cocaine use , 2012, Proceedings of the National Academy of Sciences.

[13]  M. Rietschel,et al.  Determinants of Early Alcohol Use In Healthy Adolescents: The Differential Contribution of Neuroimaging and Psychological Factors , 2012, Neuropsychopharmacology.

[14]  M. Rietschel,et al.  Adolescent impulsivity phenotypes characterized by distinct brain networks , 2012, Nature Neuroscience.

[15]  G. Koob,et al.  Systemic κ‐opioid receptor antagonism by nor‐binaltorphimine reduces dependence‐induced excessive alcohol self‐administration in rats , 2011, Addiction biology.

[16]  A. Grace The tonic/phasic model of dopamine system regulation and its implications for understanding alcohol and psychostimulant craving. , 2000, Addiction.

[17]  L. Cook,et al.  The integrated genome , 1976 .

[18]  Jon W. Huss,et al.  BioGPS: an extensible and customizable portal for querying and organizing gene annotation resources , 2009, Genome Biology.

[19]  H. Edenberg The Genetics of Alcohol Metabolism: Role of Alcohol Dehydrogenase and Aldehyde Dehydrogenase Variants , 2007, Alcohol research & health : the journal of the National Institute on Alcohol Abuse and Alcoholism.

[20]  S. Batalov,et al.  A gene atlas of the mouse and human protein-encoding transcriptomes. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[21]  H. Scholz,et al.  Invertebrate models of alcoholism. , 2013, Current topics in behavioral neurosciences.

[22]  M. Heilig,et al.  Medications development to treat alcohol dependence: a vision for the next decade , 2012, Addiction biology.

[23]  J. Manzanares,et al.  Increased ethanol intake in prodynorphin knockout mice is associated to changes in opioid receptor function and dopamine transmission , 2012, Addiction biology.

[24]  R. Spanagel,et al.  Neuropharmacology of alcohol addiction , 2008, British journal of pharmacology.

[25]  Mary Goldman,et al.  The UCSC Genome Browser database: extensions and updates 2013 , 2012, Nucleic Acids Res..

[26]  H. Walter,et al.  Neural activation during processing of aversive faces predicts treatment outcome in alcoholism , 2014, Addiction biology.

[27]  D. Ciraulo,et al.  Topiramate for treating alcohol dependence: a randomized controlled trial. , 2007, JAMA.

[28]  R. Spanagel,et al.  The alcohol deprivation effect model for studying relapse behavior: a comparison between rats and mice. , 2014, Alcohol.

[29]  C. Lüscher,et al.  Cocaine-evoked synaptic plasticity: persistence in the VTA triggers adaptations in the NAc , 2009, Nature Neuroscience.

[30]  M. Tewari,et al.  The Limits of Reductionism in Medicine: Could Systems Biology Offer an Alternative? , 2006, PLoS medicine.

[31]  Anne Beck,et al.  Effect of brain structure, brain function, and brain connectivity on relapse in alcohol-dependent patients. , 2012, Archives of general psychiatry.

[32]  R. Spanagel,et al.  The role of the NMDA receptor in alcohol relapse: a pharmacological mapping study using the alcohol deprivation effect , 2005, Neuropharmacology.

[33]  K. Befort,et al.  Reward processing by the opioid system in the brain. , 2009, Physiological reviews.

[34]  Helen Young,et al.  Society for the study of addiction. , 1999, Addiction biology.

[35]  Karl Mann,et al.  Validating incentive salience with functional magnetic resonance imaging: association between mesolimbic cue reactivity and attentional bias in alcohol‐dependent patients , 2012, Addiction Biology.

[36]  The genetics of the opioid system and specific drug addictions , 2012, Human Genetics.

[37]  M. Frye,et al.  Replication of Genome Wide Association Studies of Alcohol Dependence: Support for Association with Variation in ADH1C , 2013, PloS one.

[38]  R. Harris,et al.  Reduced alcohol consumption in mice lacking preprodynorphin. , 2006, Alcohol.

[39]  Ethanol-induced alterations of amino acids measured by in vivo microdialysis in rats: a meta-analysis , 2013, In Silico Pharmacology.

[40]  N. Volkow,et al.  Dysfunction of the prefrontal cortex in addiction: neuroimaging findings and clinical implications , 2011, Nature Reviews Neuroscience.

[41]  D. Couper,et al.  An evaluation of mu-opioid receptor (OPRM1) as a predictor of naltrexone response in the treatment of alcohol dependence: results from the Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence (COMBINE) study. , 2008, Archives of general psychiatry.

[42]  Andreas Meyer-Lindenberg,et al.  The future of fMRI and genetics research , 2012, NeuroImage.

[43]  E. Nestler,et al.  HUMAN STUDY: FOSB proteins in the orbitofrontal and dorsolateral prefrontal cortices of human alcoholics , 2009, Addiction biology.

[44]  R. Spanagel,et al.  New pharmacological treatment strategies for relapse prevention. , 2013, Current topics in behavioral neurosciences.

[45]  R. Spanagel,et al.  The mGluR2/3 Agonist LY379268 Induced Anti-Reinstatement Effects in Rats Exhibiting Addiction-like Behavior , 2013, Neuropsychopharmacology.

[46]  Joanna M Biernacka,et al.  Genetic variability in the NMDA‐dependent AMPA trafficking cascade is associated with alcohol dependence , 2012, Addiction biology.

[47]  J. Crabbe,et al.  REVIEW: Acute withdrawal, protracted abstinence and negative affect in alcoholism: are they linked? , 2010, Addiction biology.

[48]  R. Spanagel,et al.  Acamprosate and alcohol: I. Effects on alcohol intake following alcohol deprivation in the rat. , 1996, European journal of pharmacology.

[49]  D. Oslin,et al.  A Functional Polymorphism of the μ-Opioid Receptor Gene is Associated with Naltrexone Response in Alcohol-Dependent Patients , 2003, Neuropsychopharmacology.

[50]  K. Mann,et al.  Extending the Treatment Options in Alcohol Dependence: A Randomized Controlled Study of As-Needed Nalmefene , 2013, Biological Psychiatry.

[51]  Ronald F. Mucha,et al.  Motivational properties of kappa and mu opioid receptor agonists studied with place and taste preference conditioning , 2004, Psychopharmacology.

[52]  S. Cichon,et al.  Epigenetic alteration of the dopamine transporter gene in alcohol‐dependent patients is associated with age , 2014, Addiction biology.

[53]  V. Chefer,et al.  Dynorphin and the pathophysiology of drug addiction. , 2007, Pharmacology & therapeutics.

[54]  G. Koob Theoretical frameworks and mechanistic aspects of alcohol addiction: alcohol addiction as a reward deficit disorder. , 2013, Current topics in behavioral neurosciences.

[55]  R. Spanagel Alcoholism: a systems approach from molecular physiology to addictive behavior. , 2009, Physiological reviews.

[56]  T. Shippenberg,et al.  Neuroanatomical sites mediating the motivational effects of opioids as mapped by the conditioned place preference paradigm in rats. , 1993, The Journal of pharmacology and experimental therapeutics.

[57]  R. Spanagel,et al.  Opposing tonically active endogenous opioid systems modulate the mesolimbic dopaminergic pathway. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[58]  R. Spanagel,et al.  Inhibition of the Casein-Kinase-1-Epsilon/Delta Prevents Relapse-Like Alcohol Drinking , 2012, Neuropsychopharmacology.

[59]  New measurement criteria for studying alcohol drinking and relapse in rodents , 2013, In Silico Pharmacology.

[60]  T. Robbins,et al.  Neural systems of reinforcement for drug addiction: from actions to habits to compulsion , 2005, Nature Neuroscience.

[61]  H. Kranzler,et al.  Pilot study of iPS-derived neural cells to examine biologic effects of alcohol on human neurons in vitro. , 2012, Alcoholism, clinical and experimental research.

[62]  H. Kalant What neurobiology cannot tell us about addiction. , 2010, Addiction.

[63]  R. Spanagel,et al.  Global ethanol-induced enhancements of monoaminergic neurotransmission: a meta-analysis study. , 2013, Alcoholism, clinical and experimental research.

[64]  R. Spanagel,et al.  Novel uncompetitive N-methyl-D-aspartate (NMDA)-receptor antagonist MRZ 2/579 suppresses ethanol intake in long-term ethanol-experienced rats and generalizes to ethanol cue in drug discrimination procedure. , 2000, The Journal of pharmacology and experimental therapeutics.

[65]  Xiang Yang Zhang,et al.  Genome‐wide DNA methylation analysis in alcohol dependence , 2013, Addiction biology.

[66]  P. Hipskind,et al.  Upregulation of Voluntary Alcohol Intake, Behavioral Sensitivity to Stress, and Amygdala Crhr1 Expression Following a History of Dependence , 2008, Biological Psychiatry.

[67]  D. Goldman,et al.  Pharmacogenetic approaches to the treatment of alcohol addiction , 2011, Nature Reviews Neuroscience.

[68]  T. Robbins,et al.  From the ventral to the dorsal striatum: Devolving views of their roles in drug addiction , 2013, Neuroscience & Biobehavioral Reviews.

[69]  R. Spanagel,et al.  Neurocircuitry for modeling drug effects , 2012, Addiction biology.

[70]  Samira N. Kashefi,et al.  Selection of novel reference genes for use in the human central nervous system: a BrainNet Europe Study , 2012, Acta Neuropathologica.

[71]  B. Everitt,et al.  Intrastriatal Shifts Mediate the Transition from Drug-Seeking Actions to Habits , 2012, Biological Psychiatry.

[72]  M. Rietschel,et al.  Multiple polymorphisms in genes of the adrenergic stress system confer vulnerability to alcohol abuse , 2012, Addiction biology.

[73]  M. Heilig,et al.  Translational approaches to medication development. , 2013, Current topics in behavioral neurosciences.

[74]  G. Koob,et al.  A key role for corticotropin-releasing factor in alcohol dependence , 2007, Trends in Neurosciences.

[75]  Susumu Higuchi,et al.  Genetics of alcohol dependence , 2011, Psychiatry and clinical neurosciences.

[76]  B. Walker,et al.  κ-opioid receptors are implicated in the increased potency of intra-accumbens nalmefene in ethanol-dependent rats , 2011, Neuropharmacology.

[77]  G. Bakalkin,et al.  Prodynorphin CpG‐SNPs associated with alcohol dependence: elevated methylation in the brain of human alcoholics , 2011, Addiction biology.

[78]  Manuel Mattheisen,et al.  Genome‐wide significant association between alcohol dependence and a variant in the ADH gene cluster , 2012, Addiction biology.

[79]  Computational pharmacokinetics at a crossroads , 2013, In Silico Pharmacology.

[80]  B. Everitt,et al.  Cocaine Seeking Habits Depend upon Dopamine-Dependent Serial Connectivity Linking the Ventral with the Dorsal Striatum , 2008, Neuron.

[81]  P. Piazza,et al.  Prefrontal synaptic markers of cocaine addiction-like behavior in rats , 2013, Molecular Psychiatry.

[82]  L. Bierut,et al.  A meta-analysis of two genome-wide association studies to identify novel loci for maximum number of alcoholic drinks , 2013, Human Genetics.

[83]  N. Rathod Society for the Study of Addiction , 1977 .

[84]  R. Moyzis,et al.  Genetic variations in the dopaminergic system and alcohol use: a system‐level analysis , 2011, Addiction biology.

[85]  R. Sprengel,et al.  Involvement of the AMPA Receptor GluR-C Subunit in Alcohol-Seeking Behavior and Relapse , 2006, The Journal of Neuroscience.

[86]  M. Krebs,et al.  CNR1 gene polymorphisms in addictive disorders: a systematic review and a meta‐analysis , 2011, Addiction biology.

[87]  Bankole A Johnson,et al.  Topiramate in the new generation of drugs: efficacy in the treatment of alcoholic patients. , 2010, Current pharmaceutical design.

[88]  A. Heinz,et al.  Results of a double‐blind, placebo‐controlled pharmacotherapy trial in alcoholism conducted in Germany and comparison with the US COMBINE study , 2013, Addiction biology.

[89]  H. Emrich,et al.  Psychotomimesis mediated by kappa opiate receptors , 1986, Science.

[90]  Joachim Haß,et al.  An Approximation to the Adaptive Exponential Integrate-and-Fire Neuron Model Allows Fast and Predictive Fitting to Physiological Data , 2012, Front. Comput. Neurosci..

[91]  M. Ashburner,et al.  Gene Ontology: tool for the unification of biology , 2000, Nature Genetics.

[92]  Kuei Yuan Tseng,et al.  Formation of accumbens GluR2-lacking AMPA receptors mediates incubation of cocaine craving , 2008, Nature.

[93]  S. Cichon,et al.  Involvement of the atrial natriuretic peptide transcription factor GATA4 in alcohol dependence, relapse risk and treatment response to acamprosate , 2011, The Pharmacogenomics Journal.

[94]  Tianye Jia,et al.  Analytical strategies for large imaging genetic datasets: experiences from the IMAGEN study , 2013, Annals of the New York Academy of Sciences.

[95]  A. Heinz,et al.  Pharmacogenetics of alcohol, nicotine and drug addiction treatments , 2011, Addiction biology.

[96]  Joseph P. Schacht,et al.  Functional neuroimaging studies of alcohol cue reactivity: a quantitative meta‐analysis and systematic review , 2013, Addiction biology.

[97]  F. Tretter,et al.  REVIEW: The systems view in addiction research , 2008, Addiction biology.

[98]  S. Armeli,et al.  Variation in OPRM1 moderates the effect of desire to drink on subsequent drinking and its attenuation by naltrexone treatment , 2013, Addiction biology.

[99]  S. Cichon,et al.  Genome-wide association study of alcohol dependence. , 2009, Archives of general psychiatry.

[100]  Oliver Stählin Characterisation of transcriptome changes caused by alcohol addiction , 2013 .

[101]  A. Grace,et al.  The tonic/phasic model of dopamine system regulation and its implications for understanding alcohol and psychostimulant craving. , 2000, Addiction.

[102]  E. Claus,et al.  Dopaminergic genes modulate response inhibition in alcohol abusing adults , 2012, Addiction biology.

[103]  T. Banaschewski,et al.  Impact of pubertal stage at first drink on adult drinking behavior. , 2013, Alcoholism, clinical and experimental research.

[104]  Y. Shaham,et al.  Neurobiology of the incubation of drug craving , 2011, Trends in Neurosciences.

[105]  R. González-Sarmiento,et al.  Association of µ‐opioid receptor (OPRM1) gene polymorphism with response to naltrexone in alcohol dependence: a systematic review and meta‐analysis , 2012, Addiction biology.

[106]  E. Kandel,et al.  Neuroscience thinks big (and collaboratively) , 2013, Nature Reviews Neuroscience.

[107]  R. Spanagel,et al.  The use of a novel drinkometer system for assessing pharmacological treatment effects on ethanol consumption in rats. , 2013, Alcoholism, clinical and experimental research.

[108]  Hamid R Noori,et al.  In silico pharmacology: drug design and discovery’s gate to the future , 2012, In Silico Pharmacology.

[109]  U. Zimmermann,et al.  Modeling alcohol self-administration in the human laboratory. , 2011, Current topics in behavioral neurosciences.

[110]  R. Spanagel,et al.  Publication trends in addiction research , 2011, Addiction biology.

[111]  K. Mann Addiction research centres and the nurturing of creativity
department of addictive behaviour and addiction medicine, central institute of Mental Health, Mannheim, University of Heidelberg. , 2010, Addiction.

[112]  R. Miller,et al.  An Australian Brain Bank: a critical investment with a high return! , 2008, Cell and Tissue Banking.

[113]  G. Koob,et al.  The role of the dynorphin–κ opioid system in the reinforcing effects of drugs of abuse , 2010, Psychopharmacology.

[114]  F. Simonin,et al.  Decreased oral self-administration of alcohol in kappa-opioid receptor knock-out mice. , 2005, Alcoholism, clinical and experimental research.

[115]  J. Morrison,et al.  The addicted synapse: mechanisms of synaptic and structural plasticity in nucleus accumbens , 2010, Trends in Neurosciences.

[116]  David Goldman,et al.  The genetics of addictions: uncovering the genes , 2005, Nature Reviews Genetics.

[117]  R. Spanagel,et al.  REVIEW: Behavioural assessment of drug reinforcement and addictive features in rodents: an overview , 2006, Addiction biology.

[118]  Laura J. Bierut,et al.  A genome-wide association study of alcohol dependence , 2010, Proceedings of the National Academy of Sciences.

[119]  B. Lutz,et al.  The endocannabinoid system: emotion, learning and addiction , 2008, Addiction biology.

[120]  Gustavo Deco,et al.  Computational significance of transient dynamics in cortical networks , 2007, The European journal of neuroscience.

[121]  P. Elliott,et al.  RASGRF2 regulates alcohol-induced reinforcement by influencing mesolimbic dopamine neuron activity and dopamine release , 2012, Proceedings of the National Academy of Sciences.

[122]  P. Kalivas Addiction as a pathology in prefrontal cortical regulation of corticostriatal habit circuitry , 2008, Neurotoxicity Research.

[123]  G. Koob,et al.  Corticotropin-Releasing Factor within the Central Nucleus of the Amygdala Mediates Enhanced Ethanol Self-Administration in Withdrawn, Ethanol-Dependent Rats , 2006, The Journal of Neuroscience.

[124]  R. Spanagel,et al.  Glycine Transporter-1 Blockade Leads to Persistently Reduced Relapse-like Alcohol Drinking in Rats , 2010, Biological Psychiatry.

[125]  D. Oslin,et al.  A functional polymorphism of the mu-opioid receptor gene is associated with naltrexone response in alcohol-dependent patients. , 2003, Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology.

[126]  M. Heilig,et al.  The kappa opioid receptor antagonist JDTic attenuates alcohol seeking and withdrawal anxiety , 2012, Addiction biology.

[127]  U. Heberlein,et al.  The hangover gene defines a stress pathway required for ethanol tolerance development , 2005, Nature.

[128]  Karl Mann,et al.  Effects of Cue-Exposure Treatment on Neural Cue Reactivity in Alcohol Dependence: A Randomized Trial , 2011, Biological Psychiatry.

[129]  Soyoung Q. Park,et al.  Prefrontal Cortex Fails to Learn from Reward Prediction Errors in Alcohol Dependence , 2010, The Journal of Neuroscience.

[130]  X. Zhuang,et al.  Faculty Opinions recommendation of A selective role for dopamine in stimulus-reward learning. , 2010 .

[131]  J. Deussing,et al.  Brain-Specific Inactivation of the Crhr1 Gene Inhibits Post-Dependent and Stress-Induced Alcohol Intake, but Does Not Affect Relapse-Like Drinking , 2012, Neuropsychopharmacology.

[132]  P. O’Reilly,et al.  Genome-wide association and genetic functional studies identify autism susceptibility candidate 2 gene (AUTS2) in the regulation of alcohol consumption , 2011, Proceedings of the National Academy of Sciences.