Advertisement

New Pharmacological Treatment Strategies for Relapse Prevention

  • Rainer SpanagelEmail author
  • Valentina Vengeliene
Chapter
Part of the Current Topics in Behavioral Neurosciences book series (CTBN, volume 13)

Abstract

Here we discuss treatment strategies that are based on pharmacological interventions to reduce craving and relapse in alcohol-dependent patients. We will first provide a historical overview about relapse prevention strategies. We will then review the development of disulfiram, naltrexone, acamprosate, and nalmefene and discuss their neurobiological modes of action. Then the concept of convergent genomic analysis will be introduced for the discovery of new molecular treatment targets. Finally, we will provide convincing evidence for the use of N-methyl-D-aspartate (NMDA) receptor channel blockers as substitution drugs. Important conclusions of this review are: (i) learning from other addictive substances is very helpful—e.g., substitution therapies as applied to opiate addiction for decades could also be translated to alcoholics, (ii) the glutamate theory of alcohol addiction provides a convincing framework for the use of NMDA receptor antagonists as substitution drugs for alcohol-dependent patients, (iii) a combination of behavioral and pharmacological therapies may be the optimal approach for future treatment strategies—one promising example concerns the pharmacological disruption of reconsolidation processes of alcohol cue memories, (iv) given that many neurotransmitter systems are affected by chronic alcohol consumption, numerous druggable targets have been identified; consequently, a “cocktail” of different compounds will further improve the treatment situation, (v) in silico psychopharmacology, such as drug repurposing will yield new medications, and finally, (vi) the whole organism has to be taken into consideration to provide the best therapy for our patients. In summary, there is no other field in psychiatric research that has, in recent years, yielded so many novel, druggable targets and innovative treatment strategies than for alcohol addiction. However, it will still be several years before the majority of the “treatment-seeking population” will benefit from those developments.

Keywords

Antabuse Campral Revia Vivitrol Nalmefene Acetaldehyde dehydrogenase Hyper-glutamatergic state Kappa opioid receptors Genome-wide analysis Alcohol deprivation effect 

Abbreviations

ADE

Alcohol deprivation effect

CRH

Corticotropin-releasing hormone

D3R

Dopamine D3 receptor

FDA

Food and Drug Administration

fMRI

Functional magnetic resonance imaging

GHB

γ-Hydroxybutyric acid

GWAS

Genome-wide association study

GlyT

Glycine transporter

HPA

Hypothalamic–pituitary–adrenal

KOR

κ-Opioid receptor

MR

Magnetic resonance

MOR

μ-Opioid receptor

NMDA

N-metlyl-D-aspartat

Per

Period

RCT

Randomized controlled trial

RR

Relative risk

SNP

Single nucleotide polymorphisms

Ent1

Type 1 equilibrative nucleoside transporter

Notes

Acknowledgments

This work was supported by the Bundesministerium für Bildung und Forschung (NGFN Plus; FKZ: 01GS08152, FKZ: 01GS08155 see under www.ngfn-alkohol.de and Spanagel et al. 2010; FKZ: 01GS08151) and the Deutsche Forschungsgemeinschaft (DFG): SFB636/Project B1 and D7, Reinhart-Koselleck Award SP 383/5-1, and The Deep Brain Stimulation project SP383/6-1.

References

  1. Addolorato G, Leggio L, Ferrulli A, Cardone S, Vonghia L, Mirijello A, Abenavoli L, D’Angelo C, Caputo F, Zambon A, Haber PS, Gasbarrini G (2007) Effectiveness and safety of baclofen for maintenance of alcohol abstinence in alcohol-dependent patients with liver cirrhosis: randomised, double-blind controlled study. Lancet 370:1915–1922PubMedGoogle Scholar
  2. Adermark L, Clarke RB, Olsson T, Hansson E, Söderpalm B, Ericson M (2011) Implications for glycine receptors and astrocytes in ethanol-induced elevation of dopamine levels in the nucleus accumbens. Addict Biol 16:43–54PubMedGoogle Scholar
  3. Andronis C, Sharma A, Virvilis V, Deftereos S, Persidis A (2011) Literature mining, ontologies and information visualization for drug repurposing. Brief Bioinform 12:357–368PubMedGoogle Scholar
  4. Anton RF et al (2006) Combined pharmacotherapies and behavioral interventions for alcohol dependence: the COMBINE study: a randomized controlled trial. JAMA 295:2003–2017PubMedGoogle Scholar
  5. Bachteler D, Spanagel R (2005) Glutamatergic compounds: a perspective. In Drugs for Relapse Prevention of Alcoholism, eds. R Spanagel, K Mann, Birkhäuser Basel: 205–217Google Scholar
  6. Barr CS (2010) Commentary on Nelson et al. (2010). Addict Biol 15:12–14PubMedGoogle Scholar
  7. Bazov I, Kononenko O, Watanabe H, Kuntić V, Sarkisyan D, Taqi MM, Hussain MZ, Nyberg F, Yakovleva T, Bakalkin G (2011) The endogenous opioid system in human alcoholics: molecular adaptations in brain areas involved in cognitive control of addiction. Addict Biol [Epub ahead of print]Google Scholar
  8. Bienkowski P, Koros E, Kostowski W, Danysz W (1999) Effects of N-methyl-D-aspartate receptor antagonists on reinforced and nonreinforced responding for ethanol in rats. Alcohol 18:131–137PubMedGoogle Scholar
  9. Bienkowski P, Krzascik P, Koros E, Kostowski W, Scinska A, Danysz W (2001) Effects of a novel uncompetitive NMDA receptor antagonist, MRZ 2/579 on ethanol self-administration and ethanol withdrawal seizures in the rat. Eur J Pharmacol 413:81–89PubMedGoogle Scholar
  10. Blednov YA, Walker D, Martinez M, Harris RA (2006) Reduced alcohol consumption in mice lacking preprodynorphin. Alcohol 40:73–86PubMedCentralPubMedGoogle Scholar
  11. Blomeyer D, Treutlein J, Esser G, Schmidt MH, Schumann G, Laucht M (2008) Interaction between CRHR1 gene and stressful life events predicts adolescent heavy alcohol use. Biol Psychiatry 63:146–151PubMedGoogle Scholar
  12. Brager AJ, Prosser RA, Glass JD (2011a) Circadian and acamprosate modulation of elevated ethanol drinking in mPer2 clock gene mutant mice. Chronobiol Int 28:664–672PubMedCentralPubMedGoogle Scholar
  13. Brager A, Prosser RA, Glass JD (2011b) Acamprosate-responsive brain sites for suppression of ethanol intake and preference. Am J Physiol Regul Integr Comp Physiol 301:R1032–R1043PubMedGoogle Scholar
  14. Chamorro AJ, Marcos M, Mirón JA, Pastor I, González-Sarmiento R, FJ Laso (2011) Association of μ-opioid Receptor (OPRM1) gene polymorphism with response to naltrexone in alcohol dependence: a systematic review and meta-analysis. Addict Biol [Epub ahead of print]Google Scholar
  15. Chatterton JE, Awobuluyi M, Premkumar LS, Takahashi H, Talantova M, Shin Y, Cui J, Tu S, Sevarino KA, Nakanishi N, Tong G, Lipton SA, Zhang D (2002) Excitatory glycine receptors containing the NR3 family of NMDA receptor subunits. Nature 415:793–798PubMedGoogle Scholar
  16. Chefer V, Meis J, Wang G, Kuzmin A, Bakalkin G, Shippenberg T (2011) Repeated exposure to moderate doses of ethanol augments hippocampal glutamate neurotransmission by increasing release. Addict Biol 16:229–237PubMedCentralPubMedGoogle Scholar
  17. Ciccocioppo R et al (2004) Attenuation of ethanol self-administration and of conditioned reinstatement of alcohol-seeking behaviour by the antiopioid peptide nociceptin/orphanin FQ in alcohol-preferring rats. Psychopharmacology (Berl) 172:170–178Google Scholar
  18. Cole JC, Littleton JM, Little HJ (2000) Acamprosate, but not naltrexone, inhibits conditioned abstinence behaviour associated with repeated ethanol administration and exposure to a plus-maze. Psychopharmacology (Berl) 147:403–411Google Scholar
  19. Colombo G, Addolorato G, Agabio R, Carai MA, Pibiri F, Serra S, Vacca G, Gessa GL (2004) Role of GABA(B) receptor in alcohol dependence: reducing effect of baclofen on alcohol intake and alcohol motivational properties in rats and amelioration of alcohol withdrawal syndrome and alcohol craving in human alcoholics. Neurotox Res 6:403–414PubMedGoogle Scholar
  20. D’Addario C, Caputi FF, Rimondini R, Gandolfi O, Del Borrello E, Candeletti S, Romualdi P (2011) Different alcohol exposures induce selective alterations on the expression of dynorphin and nociceptin systems related genes in rat brain. Addict Biol [Epub ahead of print]Google Scholar
  21. Dahchour A, De Witte P (2003) Effects of acamprosate on excitatory amino acids during multiple ethanol withdrawal periods. Alcohol Clin Exp Res 27:465–470PubMedGoogle Scholar
  22. De Witte P, Pinto E, Ansseau M, Verbanck P (2003) Alcohol and withdrawal: from animal research to clinical issues. Neurosci Biobehav Rev 27:189–197PubMedGoogle Scholar
  23. Diana M (2011) The dopamine hypothesis of drug addiction and its potential therapeutic value. Front Psychiatry 2:64PubMedCentralPubMedGoogle Scholar
  24. Dole VP, Nyswander ME (1967) Rehabilitation of heroin addicts after blockade with methadone. N Y State J Med 66:2011–2017Google Scholar
  25. Domart MC, Benyamina A, Lemoine A, Bourgain C, Blecha L, Debuire B, Reynaud M, Saffroy R (2011) Association between a polymorphism in the promoter of a glutamate receptor subunit gene (GRIN2A) and alcoholism. Addict Biol [Epub ahead of print]Google Scholar
  26. Edwards S, Kenna GA, Swift RM, Leggio L (2011) Current and promising pharmacotherapies, and novel research target areas in the treatment of alcohol dependence: a review. Curr Pharm Des 17:1323–1332PubMedGoogle Scholar
  27. Ehlers CL, Walter NA, Dick DM, Buck KJ, Crabbe JC (2010) A comparison of selected quantitative trait loci associated with alcohol use phenotypes in humans and mouse models. Addict Biol 15:185–199PubMedCentralPubMedGoogle Scholar
  28. Fasano S, Brambilla R (2011) Ras-Erk signaling in behavior: old questions and new perspectives. Front Behav Neurosci 5:79PubMedCentralPubMedGoogle Scholar
  29. Feeney GF et al (2006) Combined acamprosate and naltrexone, with cognitive behavioural therapy is superior to either medication alone for alcohol abstinence: a single centres’ experience with pharmacotherapy. Alcohol Alcohol 41:321–327PubMedGoogle Scholar
  30. Femenía T, Manzanares J (2012) Increased ethanol intake in prodynorphin knockout mice is associated to changes in opioid receptor function and dopamine transmission. Addict Biol 17:322–337PubMedGoogle Scholar
  31. Flory JD, Pytte CL, Hurd Y, Ferrell RE, Manuck SB (2011) Alcohol dependence, disinhibited behavior and variation in the prodynorphin gene. Biol Psychol 88:51–56PubMedCentralPubMedGoogle Scholar
  32. Frank J, Cichon S, Treutlein J, Ridinger M, Mattheisen M, Hoffmann P, Herms S, Wodarz N, Soyka M, Zill P, Maier W, Mössner R, Gaebel W, Dahmen N, Scherbaum N, Schmäl C, Steffens M, Lucae S, Ising M, Müller-Myhsok B, Nöthen MM, Mann K, Kiefer F, Rietschel M (2012) Genome-wide significant association between alcohol dependence and a variant in the ADH gene cluster. Addict Biol 17:171–180PubMedCentralPubMedGoogle Scholar
  33. Garbutt JC, West SL, Carey TS, Lohr KN, Crews FT (1999) Pharmacological treatment of alcohol dependence: a review of the evidence. JAMA 281:1318–1325PubMedGoogle Scholar
  34. Gass JT, Olive MF (2008) Glutamatergic substrates of drug addiction and alcoholism. Biochem Pharmacol 75: 218–265Google Scholar
  35. Gass JT, Sinclair CM, Cleva RM, Widholm JJ (2011) Olive MF (2011) Alcohol-seeking behavior is associated with increased glutamate transmission in basolateral amygdala and nucleus accumbens as measured by glutamate-oxidase-coated biosensors. Addict Biol 16:215–228PubMedCentralPubMedGoogle Scholar
  36. Gastfriend DR (2011) Intramuscular extended-release naltrexone: current evidence. Ann N Y Acad Sci 1216:144–166PubMedGoogle Scholar
  37. Gebicke-Haerter P (2005) Expression profiling methods used in drug abuse research. Addict Biol 10:37–46PubMedGoogle Scholar
  38. George DT, Gilman J, Hersh J, Thorsell A, Herion D, Geyer C, Peng X, Kielbasa W, Rawlings R, Brandt JE, Gehlert DR, Tauscher JT, Hunt SP, Hommer D, Heilig M (2008) Neurokinin 1 receptor antagonism as a possible therapy for alcoholism. Science 319:1536–1539PubMedGoogle Scholar
  39. Goldman D, Oroszi G, Ducci F (2005) The genetics of addictions: uncovering the genes. Nat Rev Genet 6:521–532PubMedGoogle Scholar
  40. Goldstein M, Anagnoste B, Lauber E, McKeregham MR (1964) Inhibition of dopamine-beta-hydroxylase by disulfiram. Life Sci 3:763–767PubMedGoogle Scholar
  41. Hald J, Jacobsen E (1948) A drug sensitizing the organism to ethyl alcohol. Lancet 2:1001–1004PubMedGoogle Scholar
  42. Hansson AC, Cippitelli A, Sommer WH, Fedeli A, Björk K, Soverchia L, Terasmaa A, Massi M, Heilig M, Ciccocioppo R (2006) Variation at the rat Crhr1 locus and sensitivity to relapse into alcohol seeking induced by environmental stress. Proc Natl Acad Sci U S A 103:15236–15241PubMedCentralPubMedGoogle Scholar
  43. Heidbreder CA, Gardner EL, Xi ZX, Thanos PK, Mugnaini M, Hagan JJ, Ashby CR Jr (2005) The role of central dopamine D3 receptors in drug addiction: a review of pharmacological evidence. Brain Res Brain Res Rev 49:77–105PubMedCentralPubMedGoogle Scholar
  44. Heilig M (2011) Our focus on the pharmacogenetics of CRF(1) antagonists is simply because they are in clinical development. Nat Rev Neurosci 13:70Google Scholar
  45. Heilig M, Koob GF (2007) A key role for corticotropin-releasing factor in alcohol dependence. Trends Neurosci 30:399–406PubMedCentralPubMedGoogle Scholar
  46. Heilig M, Thorsell A, Sommer WH, Hansson AC, Ramchandani VA, George DT, Hommer D, Barr CS (2010a) Translating the neuroscience of alcoholism into clinical treatments: from blocking the buzz to curing the blues. Neurosci Biobehav Rev 35:334–344PubMedCentralPubMedGoogle Scholar
  47. Heilig M, Egli M, Crabbe JC, Becker HC (2010b) Acute withdrawal, protracted abstinence and negative affect in alcoholism: are they linked? Addict Biol 15:169–184PubMedCentralPubMedGoogle Scholar
  48. Heilig M, Goldman D, Berrettini W, O’Brien CP (2011) Pharmacogenetic approaches to the treatment of alcohol addiction. Nat Rev Neurosci 12:670–684PubMedCentralPubMedGoogle Scholar
  49. Hermann D, Weber-Fahr W, Sartorius A, Hoerst M, Frischknecht U, Tunc-Skarka N, Perreau-Lenz S, Hansson AC, Krumm B, Kiefer F, Spanagel R, Mann K, Ende G, Sommer WH (2011) Translational Magnetic Resonance Spectroscopy Reveals Excessive Central Glutamate Levels During Alcohol Withdrawal in Humans and Rats. Biol Psychiatry [Epub ahead of print]Google Scholar
  50. Hölter SM, Danysz W, Spanagel R (1996) Evidence for alcohol anti-craving properties of memantine. Eur J Pharmacol 314:R1–R2PubMedGoogle Scholar
  51. Hölter SM, Danysz W, Spanagel R (2000) 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. J Pharmacol Exp Ther 292:545–552PubMedGoogle Scholar
  52. Hundt W, Danysz W, Holter SM, Spanagel R (1998) Ethanol and N-methyl-D-aspartate receptor complex interactions: a detailed drug discrimination study in the rat. Psychopharmacology 135:44–51PubMedGoogle Scholar
  53. Jerlhag E, Egecioglu E, Landgren S, Salomé N, Heilig M, Moechars D, Datta R, Perrissoud D, Dickson SL, Engel JA (2009) Requirement of central ghrelin signaling for alcohol reward. Proc Natl Acad Sci U S A 106:11318–11323PubMedCentralPubMedGoogle Scholar
  54. Jerlhag E, Egecioglu E, Dickson SL, Engel JA (2011) Glutamatergic regulation of ghrelin-induced activation of the mesolimbic dopamine system. Addict Biol 16:82–91PubMedCentralPubMedGoogle Scholar
  55. Kaiser J (2010) National Institutes of Health. Collins endorses merger of U.S. addiction research programs. Science 330:1166Google Scholar
  56. Karpyak VM, Geske JR, Colby CL, Mrazek DA, Biernacka JM (2011) Genetic variability in the NMDA-dependent AMPA trafficking cascade is associated with alcohol dependence. Addict Biol [Epub ahead of print]Google Scholar
  57. Karhuvaara S, Simojoki K, Virta A, Rosberg M, Löyttyniemi E, Nurminen T, Kallio A, Mäkelä R (2007) Targeted nalmefene with simple medical management in the treatment of heavy drinkers: a randomized double-blind placebo-controlled multicenter study. Alcohol Clin Exp Res 31:1179–1187PubMedGoogle Scholar
  58. Kiefer F et al (2003) Comparing and combining naltrexone and acamprosate in relapse prevention of alcoholism: a double-blind, placebo-controlled study. Arch Gen Psychiatry 60:92–99PubMedGoogle Scholar
  59. Kiefer F, Spanagel R (2006) Measuring alcohol consumption in man–it is time for a change. Addiction 101:1215–1216PubMedGoogle Scholar
  60. Kiefer F, Witt SH, Frank J, Richter A, Treutlein J, Lemenager T, Nöthen MM, Cichon S, Batra A, Berner M, Wodarz N, Zimmermann US, Spanagel R, Wiedemann K, Smolka MN, Heinz A, Rietschel M, Mann K (2011) Involvement of the atrial natriuretic peptide transcription factor GATA4 in alcohol dependence, relapse risk and treatment response to acamprosate. Pharmacogenomics J 11:368–374PubMedGoogle Scholar
  61. Kotlinska J, Biala G, Rafalski P, Bochenski M, Danysz W (2004) Effect of neramexane on ethanol dependence and reinforcement. Eur J Pharmacol 503:95–98PubMedGoogle Scholar
  62. Kotlinska J, Bochenski M, Danysz W (2006) N-methyl-D-aspartate and group I metabotropic glutamate receptors are involved in the expression of ethanol-induced sensitization in mice. Behav Pharmacol. 17:1–8PubMedGoogle Scholar
  63. Kovacs KM, Szakall I, O’Brien D, Wang R, Vinod KY, Saito M, Simonin F, Kieffer BL, Vadasz C (2005) Decreased oral self-administration of alcohol in kappa-opioid receptor knock-out mice. Alcohol Clin Exp Res 29:730–738PubMedGoogle Scholar
  64. Krystal JH, Petrakis IL, Mason G, Trevisan L, D`Souza DC (2003) N-methyl-D-aspartate glutamate receptors and alcoholism: reward, dependence, treatment, and vulnerability. Pharmacol Ther 99:79–94PubMedGoogle Scholar
  65. Kuhn J, Lenartz D, Huff W, Lee S, Koulousakis A, Klosterkoetter J, Sturm V (2007) Remission of alcohol dependency following deep brain stimulation of the nucleus accumbens: valuable therapeutic implications? J Neurol Neurosurg Psychiatry 78:1152–1153PubMedGoogle Scholar
  66. Kuhn J, Gründler TO, Bauer R, Huff W, Fischer AG, Lenartz D, Maarouf M, Bührle C, Klosterkötter J, Ullsperger M, Sturm V (2011) Successful deep brain stimulation of the nucleus accumbens in severe alcohol dependence is associated with changed performance monitoring. Addict Biol 16:620–623PubMedGoogle Scholar
  67. Kuzmin A et al (2007) The nociceptin/orphanin FQ receptor agonist Ro 64–6198 reduces alcohol self-administration and prevents relapse-like alcohol drinking. Neuropsychopharmacology 32:902–910PubMedGoogle Scholar
  68. Landgren S, Simms JA, Hyytiä P, Engel JA, Bartlett SE, Jerlhag E (2011) Ghrelin receptor (GHS-R1A) antagonism suppresses both operant alcohol self-administration and high alcohol consumption in rats. Addict Biol [Epub ahead of print]Google Scholar
  69. Lee MR, Hinton DJ, Wu J, Mishra PK, Port JD, Macura SI, Choi DS (2011) Acamprosate reduces ethanol drinking behaviors and alters the metabolite profile in mice lacking ENT1. Neurosci Lett 490:90–95PubMedCentralPubMedGoogle Scholar
  70. Leeman RF, Heilig M, Cunningham CL, Stephens DN, Duka T, O’Malley SS (2010) Ethanol consumption: how should we measure it? Achieving consilience between human and animal phenotypes. Addict Biol 15:109–124PubMedCentralPubMedGoogle Scholar
  71. Leggio L, Addolorato G (2010) Pharmacotherapy of alcohol dependence: past, present and future research. Curr Pharm Des 16:2074–2075PubMedGoogle Scholar
  72. Lovinger DM, White G, Weight FF (1989) Ethanol inhibits NMDA-activated ion current in hippocampal neurons. Science 243:1721–1724PubMedGoogle Scholar
  73. Mason BJ, Ritvo EC, Morgan RO, Salvato FR, Goldberg G, Welch B, Mantero-Atienza E (1994) A double-blind, placebo-controlled pilot study to evaluate the efficacy and safety of oral nalmefene HCl for alcohol dependence. Alcohol Clin Exp Res 18:1162–1167PubMedGoogle Scholar
  74. Mason BJ, Salvato FR, Williams LD, Ritvo EC, Cutler RB (1999) A double-blind, placebo-controlled study of oral nalmefene for alcohol dependence. Arch Gen Psychiatry 56:719–724PubMedGoogle Scholar
  75. Mattick RP, Breen C, Kimber J, Davoli M (2009) Methadone maintenance therapy versus no opioid replacement therapy for opioid dependence. Cochrane Database Syst Rev. Jul 8 (3):CD002209Google Scholar
  76. Milton AL, Schramm MJ, Wawrzynski JR, Gore F, Oikonomou-Mpegeti F, Wang NQ, Samuel D, Economidou D, Everitt BJ (2012) Antagonism at NMDA receptors, but not β-adrenergic receptors, disrupts the reconsolidation of pavlovian conditioned approach and instrumental transfer for ethanol-associated conditioned stimuli. Psychopharmacology (Berl) 219:751–761Google Scholar
  77. Molander A, Söderpalm B (2005) Accumbal strychnine-sensitive glycine receptors: an access point for ethanol to the brain reward system. Alcohol Clin Exp Res 29:27–37PubMedGoogle Scholar
  78. Molander A, Lidö HH, Löf E, Ericson M, Söderpalm B (2007) The glycine reuptake inhibitor Org 25935 decreases ethanol intake and preference in male wistar rats. Alcohol Alcohol 42:11–18PubMedGoogle Scholar
  79. Molander A, Vengeliene V, Heilig M, Wurst W, Deussing JM, Spanagel R (2012) Brain-Specific Inactivation of the Crhr1 Gene Inhibits Post-Dependent and Stress-Induced Alcohol Intake, but Does Not Affect Relapse-Like Drinking. Neuropsychopharmacology 37:1047–1056PubMedGoogle Scholar
  80. Mucha RF, Herz A (1985) Motivational properties of kappa and mu opioid receptor agonists studied with place and taste preference conditioning. Psychopharmacology (Berl) 86:274–280Google Scholar
  81. Müller UJ, Sturm V, Voges J, Heinze HJ, Galazky I, Heldmann M, Scheich H, Bogerts B (2009) Successful treatment of chronic resistant alcoholism by deep brain stimulation of nucleus accumbens: first experience with three cases. Pharmacopsychiatry 42:288–291PubMedGoogle Scholar
  82. Nelson EC, Agrawal A, Pergadia ML, Wang JC, Whitfield JB, Saccone FS, Kern J, Grant JD, Schrage AJ, Rice JP, Montgomery GW, Heath AC, Goate AM, Martin NG, Madden PA (2010) H2 haplotype at chromosome 17q21.31 protects against childhood sexual abuse-associated risk for alcohol consumption and dependence. Addict Biol 15:1–11PubMedCentralPubMedGoogle Scholar
  83. Oslin DW, Berrettini W, Kranzler HR, Pettinati H, Gelernter J, Volpicelli JR, O’Brien CP (2003) A functional polymorphism of the mu-opioid receptor gene is associated with naltrexone response in alcohol-dependent patients. Neuropsychopharmacology 28:1546–1552PubMedGoogle Scholar
  84. Pawlak CR, Sanchis-Segura C, Soewarto D, Wagner S, Hrabé de Angelis M, Spanagel R (2008) A phenotype-driven ENU mutagenesis screen for the identification of dominant mutations involved in alcohol consumption. Mamm Genome 19:77–84PubMedGoogle Scholar
  85. Peng X, Neumeyer JL (2007) Kappa receptor bivalent ligands. Curr Top Med Chem 7:363–373PubMedGoogle Scholar
  86. Pfeiffer A, Brantl V, Herz A, Emrich HM (1986) Psychotomimesis mediated by kappa opiate receptors. Science 233:774–776PubMedGoogle Scholar
  87. Pichini S, Farré M, Abanades S, Pacifici R, Zuccaro P, Langohr K, de la Torre R (2010) Immunomodulating properties of gamma-hydroxybutyrate (GHB), flunitrazepam and ethanol in ‘club drugs’ users. Addict Biol 15:336–345PubMedGoogle Scholar
  88. Rammes G, Schierloch A (2006) Neramexane (merz pharmaceuticals/forest laboratories). IDrugs 9:128–135PubMedGoogle Scholar
  89. Rösner S, Hackl-Herrwerth A, Leucht S, Lehert P, Vecchi S, Soyka M (2010) Acamprosate for alcohol dependence. Cochrane Database Syst Rev 9:CD004332Google Scholar
  90. Rösner S, Hackl-Herrwerth A, Leucht S, Vecchi S, Srisurapanont M, Soyka M (2010) Opioid antagonists for alcohol dependence. Cochrane Database Syst Rev 12:CD001867Google Scholar
  91. Rossetti ZL, Carboni S (1995) Ethanol withdrawal is associated with increased extracellular glutamate in the rat striatum. Eur J Pharmacol 283:177–183PubMedGoogle Scholar
  92. Schiller D, Monfils MH, Raio CM, Johnson DC, Ledoux JE, Phelps EA (2010) Preventing the return of fear in humans using reconsolidation update mechanisms. Nature 463:49–53PubMedCentralPubMedGoogle Scholar
  93. Schmid B, Blomeyer D, Treutlein J, Zimmermann US, Buchmann AF, Schmidt MH, Esser G, Rietschel M, Banaschewski T, Schumann G, Laucht M (2010) Interacting effects of CRHR1 gene and stressful life events on drinking initiation and progression among 19-year-olds. Int J Neuropsychopharmacol 13:703–714PubMedGoogle Scholar
  94. Schroeder JP, Spanos M, Stevenson JR, Besheer J, Salling M, Hodge CW (2008) Cue-induced reinstatement of alcohol-seeking behavior is associated with increased ERK1/2 phosphorylation in specific limbic brain regions: blockade by the mGluR5 antagonist MPEP. Neuropharmacology 55:546–554PubMedCentralPubMedGoogle Scholar
  95. Schumann G, Frank J, Preuss U, Dahmen N, Laucht M, Rujescu D, Hinckers A, Depner M, Wellek S, Treutlein J, Szegedi A, Giegling I, Blomeyer D, Heinz A, Lathrop M, Soyka M, Spanagel R, Mann K (2008) Systematic analysis of glutamatergic neurotransmission genes in alcohol dependence and adolescent risk drinking behaviour. Arch Gen Psychiatry 65:826–838PubMedGoogle Scholar
  96. Schumann G et al (2011) Genome-wide association and genetic functional studies identify autism susceptibility candidate 2 gene (AUTS2) in the regulation of alcohol consumption. Proc Natl Acad Sci U S A 108:7119–7124. Epub 2011 Apr 6. Erratum in: Proc Natl Acad Sci U S A (2011) 108:9316Google Scholar
  97. Shippenberg TS, Zapata A, Chefer VI (2007) Dynorphin and the pathophysiology of drug addiction. Pharmacol Ther 116:306–321PubMedCentralPubMedGoogle Scholar
  98. Sillaber I, Rammes G, Zimmermann S, Mahal B, Zieglgänsberger W, Wurst W, Holsboer F, Spanagel R (2002) Enhanced and delayed stress-induced alcohol drinking in mice lacking functional CRH1 receptors. Science 296:931–933PubMedGoogle Scholar
  99. Sofuoglu M, Sewell RA (2009) Norepinephrine and stimulant addiction. Addict Biol 14:119–129PubMedCentralPubMedGoogle Scholar
  100. Sommer WH, Rimondini R, Hansson AC et al (2008) Upregulation of Voluntary Alcohol Intake, Behavioral Sensitivity to Stress, and Amygdala Crhr1 Expression Following a History of Dependence. Biol Psychiatry 63:139–145PubMedGoogle Scholar
  101. Spence J, Liang T, Foroud T, Lo D, Carr L (2005) Expression profiling and QTL analysis: a powerful complementary strategy in drug abuse research. Addict Biol 10:47–51PubMedGoogle Scholar
  102. Spanagel R (2009) Alcoholism: a systems approach from molecular physiology to addictive behavior. Physiol Rev 89:649–705PubMedGoogle Scholar
  103. Spanagel R, Hölter SM (1999) Long-term alcohol self-administration with repeated alcohol deprivation phases: An animal model of alcoholism? Alcohol Alcohol 34:231–243PubMedGoogle Scholar
  104. Spanagel R, Mann K (2005) Drugs for relapse prevention of alcoholism. Milestones in Drug Therapy. Birkhäuser, BaselGoogle Scholar
  105. Spanagel R, Kiefer F (2008) Drugs for Relapse Prevention of Alcoholism—10 Years of Progress. Trends Pharmacol Sci 29:109–115PubMedGoogle Scholar
  106. Spanagel R, Herz A, Shippenberg TS (1992) Opposing tonically active endogenous opioid systems modulate the mesolimbic dopaminergic pathway. Proc Natl Acad Sci U S A 89:2046–2050PubMedCentralPubMedGoogle Scholar
  107. Spanagel R, Almeida OF, Shippenberg TS (1994) Evidence that nor-binaltorphimine can function as an antagonist at multiple opioid receptor subtypes. Eur J Pharmacol 264:157–162PubMedGoogle Scholar
  108. Spanagel R, Pendyala G, Abarca C, Zghoul T, Sanchis-Segura C, Magnone MC, Lascorz J, Depner M, Holzberg D, Soyka M, Schreiber S, Matsuda F, Lathrop M, Schumann G, Albrecht U (2005) The clock gene Per2 influences the glutamatergic system and modulates alcohol consumption. Nat Med 11:35–42PubMedGoogle Scholar
  109. Spanagel R, Bartsch D, Brors B, Dahmen N, Deussing J, Eils R, Ende G, Gallinat J, Gebicke-Haerter P, Heinz A, Kiefer F, Jager W, Mann K, Matthaus F, Nothen M, Rietschel M, Sartorius A, Schutz G, Sommer WH, Sprengel R, Walter H, Wichmann E, Wienker T, Wurst W, Zimmer A (2010) An integrated genome research network for studying the genetics of alcohol addiction. Addict Biol 15:369–379PubMedGoogle Scholar
  110. Sturgess JE, George TP, Kennedy JL, Heinz A, Müller DJ (2011) Pharmacogenetics of alcohol, nicotine and drug addiction treatments. Addict Biol 16:357–376PubMedGoogle Scholar
  111. Taqi MM, Bazov I, Watanabe H, Sheedy D, Harper C, Alkass K, Druid H, Wentzel P, Nyberg F, Yakovleva T, Bakalkin G (2011) Prodynorphin CpG-SNPs associated with alcohol dependence: elevated methylation in the brain of human alcoholics. Addict Biol 16:499–509PubMedCentralPubMedGoogle Scholar
  112. Treutlein J, Kissling C, Frank J, Wiemann S, Dong L, Depner M, Saam C, Lascorz J, Soyka M, Preuss UW, Rujescu D, Skowronek MH, Rietschel M, Spanagel R, Heinz A, Laucht M, Mann K, Schumann G (2006) Genetic association of the human corticotropin releasing hormone receptor 1 (CRHR1) with binge drinking and alcohol intake patterns in two independent samples. Mol Psychiatry 11:594–602PubMedGoogle Scholar
  113. Treutlein J, Cichon S, Ridinger M, Wodarz N, Soyka M, Zill P, Maier W, Moessner R, Gaebel W, Dahmen N, Fehr C, Scherbaum N, Steffens M, Ludwig KU, Frank J, Wichmann HE, Schreiber S, Dragano N, Sommer WH, Leonardi-Essmann F, Lourdusamy A, Gebicke-Haerter P, Wienker TF, Sullivan PF, Nöthen MM, Kiefer F, Spanagel R, Mann K, Rietschel M (2009) Genome-wide association study of alcohol dependence. Arch Gen Psychiatry 66:773–784PubMedGoogle Scholar
  114. Tsai GC, Coyle JT (1998) The role of glutamatergic neurotransmission in the pathophysiology of alcoholism. Ann Rev Med 49:173–184PubMedGoogle Scholar
  115. Tsai G, Gastfriend DR, Coyle JT (1995) The glutamatergic basis of human alcoholism. Am J Psychiatry 152:332–340Google Scholar
  116. Umhau JC, Momenan R, Schwandt ML, Singley E, Lifshitz M, Doty L, Adams LJ, Vengeliene V, Spanagel R, George DT, Hommer D, Heilig M (2010) Effect of acamprosate on magnetic resonance spectroscopy measures of central glutamate in detoxified alcohol-dependent individuals: a randomized controlled experimental medicine study. Arch Gen Psychiatry 67:1069–1077PubMedCentralPubMedGoogle Scholar
  117. Vengeliene V, Bachteler D, Danysz W, Spanagel R (2005) The role of the NMDA receptor in alcohol relapse: a pharmacological mapping study using the alcohol deprivation effect. Neuropharmacology 48:822–829PubMedGoogle Scholar
  118. Vengeliene V, Leonardi-Essmann F, Perreau-Lenz S, Gebicke-Haerter P, Drescher K, Gross G, Spanagel R (2006) The dopamine D3 receptor plays an essential role in alcohol-seeking and relapse. FASEB J 20:2223–2233PubMedGoogle Scholar
  119. Vengeliene V, Kiefer F, Spanagel R (2008) D-cycloserine facilitates extinction of conditioned alcohol-seeking behaviour in rats. Alcohol Alcohol 43:626–629PubMedGoogle Scholar
  120. Vengeliene V, Celerier E, Chaskiel L, Penzo F, Spanagel R (2009) Compulsive drug and food taking behaviour in rodents. Addict Biol 14:384–396PubMedGoogle Scholar
  121. Vengeliene V, Leonardi-Essmann F, Sommer WH, Marston HM, Spanagel R (2010) Glycine transporter-1 blockade leads to persistently reduced relapse-like alcohol drinking in rats. Biol Psychiatry 68:704–711PubMedGoogle Scholar
  122. Vollstädt-Klein S, Loeber S, Kirsch M, Bach P, Richter A, Bühler M, von der Goltz C, Hermann D, Mann K, Kiefer F (2011) Effects of cue-exposure treatment on neural cue reactivity in alcohol dependence: a randomized trial. Biol Psychiatry 69:1060–1066PubMedGoogle Scholar
  123. von der Goltz C, Vengeliene V, Bilbao A, Perreau-Lenz S, Pawlak CR, Kiefer F, Spanagel R (2009) Cue-induced alcohol-seeking behaviour is reduced by disrupting the reconsolidation of alcohol-related memories. Psychopharmacology 20:389–397Google Scholar
  124. Walker BM, Koob GF (2008) Pharmacological evidence for a motivational role of kappa-opioid systems in ethanol dependence. Neuropsychopharmacology 33:643–652PubMedCentralPubMedGoogle Scholar
  125. Walker BM, Zorrilla EP, Koob GF (2011) Systemic κ-opioid receptor antagonism by nor-binaltorphimine reduces dependence-induced excessive alcohol self-administration in rats. Addict Biol 16:116–119PubMedCentralPubMedGoogle Scholar
  126. Wee S, Koob GF (2010) The role of the dynorphin-kappa opioid system in the reinforcing effects of drugs of abuse. Psychopharmacology 210:121–135PubMedCentralPubMedGoogle Scholar
  127. Williams TJ, LaForge KS, Gordon D, Bart G, Kellogg S, Ott J, Kreek MJ (2007) Prodynorphin gene promoter repeat associated with cocaine/alcohol codependence. Addict Biol 12:496–502PubMedGoogle Scholar
  128. Xuei X, Dick D, Flury-Wetherill L, Tian HJ, Agrawal A, Bierut L, Goate A, Bucholz K, Schuckit M, Nurnberger J Jr, Tischfield J, Kuperman S, Porjesz B, Begleiter H, Foroud T, Edenberg HJ (2006) Association of the kappa-opioid system with alcohol dependence. Mol Psychiatry 11:1016–1024PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  1. 1.Institute of Psychopharmacology, Central Institute of Mental Health, Medical Faculty MannheimUniversity of HeidelbergMannheimGermany

Personalised recommendations