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Pharmacology of Alcohol and Alcohol Use Disorder

  • Naoyuki HironakaEmail author
Living reference work entry

Abstract

Alcohol (ethanol) is a central nervous system (CNS) depressant drug that, depending on its blood concentration, can induce various manifestations such as relief from anxiety, disinhibition, ataxia, and general anesthesia. Chronic exposure to alcohol can cause persistent structural and functional changes in the brain. Since alcohol is widely abused and alcohol dependence often leads to serious medical and social problems, medication is very important. It is crucial that we understand the complex mechanism of action of alcohol to find better therapeutic alternatives. Alcohol acts on various neurotransmitters such as gamma-aminobutyric acid (GABA), glutamate, dopamine, serotonin, and endogenous opioids. Alcohol is both a GABA agonist and a glutamate N-methyl-d-aspartate (NMDA) receptor antagonist. It also facilitates dopamine release from the nucleus accumbens, although the effect is not potent. Its actions on dopaminergic and opioid peptidergic systems are implicated in the reinforcing effect of alcohol. After chronic exposure, downregulation of GABAergic and upregulation of NMDA glutamatergic systems typically occur. Normalizing this imbalance might be effective in the treatment of alcohol dependence. Antagonism of the μ-opioid system also reduces the motivation to consume alcohol. New animal models of binge alcohol intake, such as the alcohol deprivation effect (ADE) and the “Drinking-in-the-Dark” technique, would help us to develop new treatment methods against alcohol dependence. In this chapter, neurobehavioral effects of both acute and chronic alcohol exposure are described. In addition, some recent advancements in biomedical research are introduced with reference to hepatic and cardiovascular influences of alcohol, factors relevant to the development of alcohol dependence, and biological targets for the treatment of alcohol dependence.

References

  1. al Qatari M, Bouchenafa O, Littleton J. Mechanism of action of acamprosate. Part II. Ethanol dependence modifies effects of acamprosate on NMDA receptor binding in membranes from rat cerebral cortex. Alcohol Clin Exp Res. 1998;22:810–4.PubMedCrossRefPubMedCentralGoogle Scholar
  2. Alongkronrusmee D, Chiang T, van Rijn RM. Delta opioid pharmacology in relation to alcohol behaviors. Handb Exp Pharmacol. 2016;247:199.CrossRefGoogle Scholar
  3. Badanich KA, Fakih ME, Gurina TS, Roy EK, Hoffman JL, Uruena-Agnes AR, Kirstein CL. Reversal learning and experimenter-administered chronic intermittent ethanol exposure in male rats. Psychopharmacology (Berl). 2016;233:3615–26.CrossRefGoogle Scholar
  4. Bahi A. Decreased anxiety, voluntary ethanol intake and ethanol-induced CPP acquisition following activation of the metabotropic glutamate receptor 8 “mGluR8”. Pharmacol Biochem Behav. 2017;155:32–42.PubMedCrossRefPubMedCentralGoogle Scholar
  5. Barker JM, Zhang H, Villafane JJ, Wang TL, Torregrossa MM, Taylor JR. Epigenetic and pharmacological regulation of 5HT3 receptors controls compulsive ethanol seeking in mice. Eur J Neurosci. 2014;39:999–1008.PubMedPubMedCentralCrossRefGoogle Scholar
  6. Bassareo V, Cucca F, Frau R, Di Chiara G. Changes in dopamine transmission in the nucleus accumbens shell and core during ethanol and sucrose self-administration. Front Behav Neurosci. 2017;11:71.PubMedPubMedCentralCrossRefGoogle Scholar
  7. Bazov I, Sarkisyan D, Kononenko O, Watanabe H, Karpyak VM, Yakovleva T, Bakalkin G. Downregulation of the neuronal opioid gene expression concomitantly with neuronal decline in dorsolateral prefrontal cortex of human alcoholics. Transl Psychiatry. 2018;8:122.PubMedPubMedCentralCrossRefGoogle Scholar
  8. Bell RL, Hauser SR, McClintick J, Rahman S, Edenberg HJ, Szumlinski KK, McBride WJ. Ethanol-associated changes in glutamate reward neurocircuitry: a minireview of clinical and preclinical genetic findings. Prog Mol Biol Transl Sci. 2016;137:41–85.PubMedCrossRefPubMedCentralGoogle Scholar
  9. Belmer A, Patkar OL, Lanoue V, Bartlett SE. 5-HT1A receptor-dependent modulation of emotional and neurogenic deficits elicited by prolonged consumption of alcohol. Sci Rep. 2018;8:2099.PubMedPubMedCentralCrossRefGoogle Scholar
  10. Bilbao A, Robinson JE, Heilig M, Malanga CJ, Spanagel R, Sommer WH, Thorsell A. A pharmacogenetic determinant of mu-opioid receptor antagonist effects on alcohol reward and consumption: evidence from humanized mice. Biol Psychiatry. 2015;77:850–8.PubMedCrossRefGoogle Scholar
  11. Borghese CM, Hicks JA, Lapid DJ, Trudell JR, Harris RA. GABA(A) receptor transmembrane amino acids are critical for alcohol action: disulfide cross-linking and alkyl methanethiosulfonate labeling reveal relative location of binding sites. J Neurochem. 2014;128:363–75.PubMedCrossRefGoogle Scholar
  12. Brevers D, Bechara A, Cleeremans A, Kornreich C, Verbanck P, Noël X. Impaired decision-making under risk in individuals with alcohol dependence. Alcohol Clin Exp Res. 2014;38:1924–31.PubMedPubMedCentralCrossRefGoogle Scholar
  13. Chang GQ, Barson JR, Karatayev O, Chang SY, Chen YW, Leibowitz SF. Effect of chronic ethanol on enkephalin in the hypothalamus and extra-hypothalamic areas. Alcohol Clin Exp Res. 2010;34:761–70.PubMedPubMedCentralCrossRefGoogle Scholar
  14. Ciafrè S, Carito V, Ferraguti G, Greco A, Chaldakov GN, Fiore M, Ceccanti M. How alcohol drinking affects our genes: an epigenetic point of view. Biochem Cell Biol. 2019;97:345–56.PubMedCrossRefGoogle Scholar
  15. Crabbe JC, Kendler KS, Hitzemann RJ. Modeling the diagnostic criteria for alcohol dependence with genetic animal models. Curr Top Behav Neurosci. 2013;13:187–221.PubMedPubMedCentralCrossRefGoogle Scholar
  16. Cunningham CL, Fidler TL, Hill KG. Animal models of alcohol’s motivational effects. Alcohol Res Health. 2000;24:85–92.PubMedPubMedCentralGoogle Scholar
  17. de la Monte SM, Kril JJ. Human alcohol-related neuropathology. Acta Neuropathol. 2014;127:71–90.PubMedCrossRefGoogle Scholar
  18. De Sousa Fernandes Perna EB, Theunissen EL, Kuypers KP, Toennes SW, Ramaekers JG. Subjective aggression during alcohol and cannabis intoxication before and after aggression exposure. Psychopharmacology (Berl). 2016;233:3331–40.CrossRefGoogle Scholar
  19. De Witte P. Imbalance between neuroexcitatory and neuroinhibitory amino acids causes craving for ethanol. Addict Behav. 2004;29:1325–39.PubMedCrossRefGoogle Scholar
  20. den Hartog CR, Beckley JT, Smothers TC, Lench DH, Holseberg ZL, Fedarovich H, Gilstrap MJ, Homanics GE, Woodward JJ. Alterations in ethanol-induced behaviors and consumption in knock-in mice expressing ethanol-resistant NMDA receptors. PLoS One. 2013;8:e80541.CrossRefGoogle Scholar
  21. Di Castelnuovo A, Rotondo S, Iacoviello L, Donati MB, De Gaetano G. Meta-analysis of wine and beer consumption in relation to vascular risk. Circulation. 2002;105:2836–44.PubMedCrossRefGoogle Scholar
  22. Di Chiara G, Imperato A. Ethanol preferentially stimulates dopamine release in the nucleus accumbens of freely moving rats. Eur J Pharmacol. 1985;115:131–2.PubMedCrossRefGoogle Scholar
  23. Edenberg HJ. The genetics of alcohol metabolism: role of alcohol dehydrogenase and aldehyde dehydrogenase variants. Alcohol Res Health. 2007;30:5–13.PubMedPubMedCentralGoogle Scholar
  24. Farokhnia M, Faulkner ML, Piacentino D, Lee MR, Leggio L. Ghrelin: from a gut hormone to a potential therapeutic target for alcohol use disorder. Physiol Behav. 2019;204:49–57.PubMedCrossRefGoogle Scholar
  25. Fein G, Di Sclafani V, Cardenas VA, Goldmann H, Tolou-Shams M, Meyerhoff DJ. Cortical gray matter loss in treatment-naïve alcohol dependent individuals. Alcohol Clin Exp Res. 2002; 26:558–64.PubMedPubMedCentralGoogle Scholar
  26. Feltmann K, Borroto-Escuela DO, Rüegg J, Pinton L, de Oliveira Sergio T, Narváez M, Jimenez-Beristain A, Ekström TJ, Fuxe K, Steensland P. Effects of long-term alcohol drinking on the dopamine D2 receptor: gene expression and heteroreceptor complexes in the striatum in rats. Alcohol Clin Exp Res. 2018;42:338–51.PubMedPubMedCentralCrossRefGoogle Scholar
  27. Flores-Bastías O, Karahanian E. Neuroinflammation produced by heavy alcohol intake is due to loops of interactions between Toll-like 4 and TNF receptors, peroxisome proliferator-activated receptors and the central melanocortin system: a novel hypothesis and new therapeutic avenues. Neuropharmacology. 2018;128:401–7.PubMedCrossRefGoogle Scholar
  28. Flory JD, Pytte CL, Hurd Y, Ferrell RE, Manuck SB. Alcohol dependence, disinhibited behavior and variation in the prodynorphin gene. Biol Psychol. 2011;88:51–6.PubMedPubMedCentralCrossRefGoogle Scholar
  29. Ford MM. Applications of schedule-induced polydipsia in rodents for the study of an excessive ethanol intake phenotype. Alcohol. 2014;48:265–76.PubMedPubMedCentralCrossRefGoogle Scholar
  30. Fortier CB, Leritz EC, Salat DH, Venne JR, Maksimovskiy AL, Williams V, Milberg WP, McGlinchey RE. Reduced cortical thickness in abstinent alcoholics and association with alcoholic behavior. Alcohol Clin Exp Res. 2011;35:2193–201.PubMedPubMedCentralCrossRefGoogle Scholar
  31. Fujiwara A, Iino M, Sasaki M, Hironaka N, Wakasa Y. A new behavioral test for assessment of drug effects on attentional performance and its validity in cynomolgus monkeys. J Toxicol Sci. 2009;34:183–90.PubMedCrossRefPubMedCentralGoogle Scholar
  32. Gawel K, Labuz K, Gibula-Bruzda E, Jenda M, Marszalek-Grabska M, Filarowska J, Silberring J, Kotlinska JH. Cholinesterase inhibitors, donepezil and rivastigmine, attenuate spatial memory and cognitive flexibility impairment induced by acute ethanol in the Barnes maze task in rats. Naunyn Schmiedebergs Arch Pharmacol. 2016;389:1059–71.PubMedPubMedCentralCrossRefGoogle Scholar
  33. GBD 2016 Alcohol Collaborators. Alcohol use and burden for 195 countries and territories, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet. 2018;392:1015–35.PubMedCentralCrossRefGoogle Scholar
  34. Gerlach M, Blum-Degen D, Ransmayr G, Leblhuber F, Pedersen V, Riederer P. Expression, but not activity, of neuronal nitric oxide synthase is regionally increased in the alcoholic brain. Alcohol Alcohol. 2001;36:65–9.PubMedCrossRefPubMedCentralGoogle Scholar
  35. Gotz ME, Janetzky B, Pohli S, Gottschalk A, Gsell W, Tatschner T, Ransmayr G, Leblhuber F, Gerlach M, Reichmann H, Riederer P, Boning J. Chronic alcohol consumption and cerebral indices of oxidative stress: is there a link? Alcohol Clin Exp Res. 2001;25:717–25.PubMedCrossRefPubMedCentralGoogle Scholar
  36. Hartwell EE, Kranzler HR. Pharmacogenetics of alcohol use disorder treatments: an update. Expert Opin Drug Metab Toxicol. 2019;15:553–64.PubMedCrossRefPubMedCentralGoogle Scholar
  37. Heinz AJ, Beck A, Meyer-Lindenberg A, Sterzer P, Heinz A. Cognitive and neurobiological mechanisms of alcohol-related aggression. Nat Rev Neurosci. 2011;12:400–13.PubMedCrossRefPubMedCentralGoogle Scholar
  38. Helms CM, Rogers LS, Grant KA. Antagonism of the ethanol-like discriminative stimulus effects of ethanol, pentobarbital, and midazolam in cynomolgus monkeys reveals involvement of specific GABA(A) receptor subtypes. J Pharmacol Exp Ther. 2009;331:142–52.PubMedPubMedCentralCrossRefGoogle Scholar
  39. Hermann D, Hirth N, Reimold M, Batra A, Smolka MN, Hoffmann S, Kiefer F, Noori HR, Sommer WH, Reischl G, la Fougère C, Mann K, Spanagel R, Hansson AC. Low μ-opioid receptor status in alcohol dependence identified by combined positron emission tomography and post-mortem brain analysis. Neuropsychopharmacology. 2017;42:606–14.PubMedCrossRefPubMedCentralGoogle Scholar
  40. Heyser CJ, Moc K, Koob GF. Effects of naltrexone alone and in combination with acamprosate on the alcohol deprivation effect in rats. Neuropsychopharmacology. 2003;28:1463–71.PubMedCrossRefGoogle Scholar
  41. Hironaka N. Psychopharmacological effects of smoking and alcohol intake. Alcohol Biomed Res. 2005;25:16–22. [in Japanese].Google Scholar
  42. Hölter SM, Danysz W, Spanagel R. 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. 2000; 292:545–52.PubMedPubMedCentralGoogle Scholar
  43. Hopf FW, Chang SJ, Sparta DR, Bowers MS, Bonci A. Motivation for alcohol becomes resistant to quinine adulteration after 3 to 4 months of intermittent alcohol self-administration. Alcohol Clin Exp Res. 2010;34:1565–73.PubMedPubMedCentralCrossRefGoogle Scholar
  44. Hughes BA, Woodward JJ. Disruption of S2-M4 linker coupling reveals novel subunit-specific contributions to N-methyl-d-aspartate receptor function and ethanol sensitivity. Neuropharmacology. 2016;105:96–105.PubMedCrossRefPubMedCentralGoogle Scholar
  45. Hui X, Li J, Lao Y, Jia B, Hou L, Lu Z, Gu Q, Niu J, Bao H, Yan P, Yao L. Association between alcohol consumption and mild cognitive impairment: a protocol of dose-response meta-analysis. Medicine (Baltimore). 2019;98:e16098.CrossRefGoogle Scholar
  46. Justice M, Ferrugia A, Beidler J, Penprase JC, Cintora P, Erwin D, Medrano O, Brasser SM, Hong MY. Effects of moderate ethanol consumption on lipid metabolism and inflammation through regulation of gene expression in rats. Alcohol Alcohol. 2019;54:5–12.PubMedCrossRefPubMedCentralGoogle Scholar
  47. Karlsson O, Roman E. Dose-dependent effects of alcohol administration on behavioral profiles in the MCSF test. Alcohol. 2016;50:51–6.PubMedCrossRefPubMedCentralGoogle Scholar
  48. Kirpich IA, Warner DR, Feng W, Joshi-Barve S, McClain CJ, Seth D, Zhong W, Zhou Z, Osna NA, Kharbanda KK. Mechanisms, biomarkers and targets for therapy in alcohol-associated liver injury: from genetics to nutrition: summary of the ISBRA 2018 symposium. Alcohol. 2019. pii: S0741–8329(19)30069-2.Google Scholar
  49. Kobayashi T, Ikeda K, Kojima H, Niki H, Yano R, Yoshioka T, Kumanishi T. Ethanol opens G-protein-activated inwardly rectifying K+ channels. Nat Neurosci. 1999;2:1091–7.PubMedCrossRefPubMedCentralGoogle Scholar
  50. Koob G, LeMoal M. Neurobiology of addiction. Amsterdam: Elsevier; 2005. p. 176.Google Scholar
  51. Linden AM, Schmitt U, Leppä E, Wulff P, Wisden W, Lüddens H, Korpi ER. Ro 15-4513 antagonizes alcohol-induced sedation in mice through αβγ2-type GABA(A) receptors. Front Neurosci. 2011;5:3.  https://doi.org/10.3389/fnins.2011.00003.CrossRefPubMedPubMedCentralGoogle Scholar
  52. Makris N, Oscar-Berman M, Jaffin SK, Hodge SM, Kennedy DN, Caviness VS, Marinkovic K, Breiter HC, Gasic GP, Harris GJ. Decreased volume of the brain reward system in alcoholism. Biol Psychiatry. 2008;64:192–202.PubMedPubMedCentralCrossRefGoogle Scholar
  53. Martinez D, Gil R, Slifstein M, Hwang DR, Huang Y, Perez A, Kegeles L, Talbot P, Evans S, Krystal J, Laruelle M, Abi-Dargham A. Alcohol dependence is associated with blunted dopamine transmission in the ventral striatum. Biol Psychiatry. 2005;58:779–86.PubMedCrossRefGoogle Scholar
  54. Matsumoto A. The bidirectional effect of defective ALDH2 polymorphism and disease prevention. Adv Exp Med Biol. 2019;1193:69–87.PubMedCrossRefGoogle Scholar
  55. McMillan DE, Leander JD. Effects of drugs on schedule-controlled behavior. In: Glick SD, Goldfarb J, editors. Behavioral pharmacology. Saint Louis: The C.V. Mosby Company; 1976. p. 85–139.Google Scholar
  56. Meda SA, Narayanan B, Chorlian D, Meyers JL, Gelernter J, Hesselbrock V, Bauer L, Calhoun VD, Porjesz B, Pearlson GD. Multivariate analyses reveal biological components related to neuronal signaling and immunity mediating electroencephalograms abnormalities in alcohol-dependent individuals from the collaborative study on the genetics of alcoholism cohort. Alcohol Clin Exp Res. 2019;43:1462–77.PubMedCrossRefGoogle Scholar
  57. Miczek KA, de Boer SF, Haller J. Excessive aggression as model of violence: a critical evaluation of current preclinical methods. Psychopharmacology (Berl). 2013;226:445–58.PubMedCentralCrossRefPubMedGoogle Scholar
  58. Mitchell JM, O’Neil JP, Janabi M, Marks SM, Jagust WJ, Fields HL. Alcohol consumption induces endogenous opioid release in the human orbitofrontal cortex and nucleus accumbens. Sci Transl Med. 2012;4:116ra6.PubMedCrossRefGoogle Scholar
  59. Miyata H, Hironaka N, Takada K, Miyasato K, Nakamura K, Yanagita T. Psychosocial withdrawal characteristics of nicotine compared with alcohol and caffeine. Ann N Y Acad Sci. 2008; 1139:458–65.PubMedCrossRefGoogle Scholar
  60. Mori T, Rahmadi M, Yoshizawa K, Itoh T, Shibasaki M, Suzuki T. Inhibitory effects of SA4503 on the rewarding effects of abused drugs. Addict Biol. 2014;19:362–9.PubMedCrossRefGoogle Scholar
  61. Mrejeru A, Martí-Prats L, Avegno EM, Harrison NL, Sulzer D. A subset of ventral tegmental area dopamine neurons responds to acute ethanol. Neuroscience. 2015;290:649–58.PubMedPubMedCentralCrossRefGoogle Scholar
  62. Nagy J. Alcohol related changes in regulation of NMDA receptor functions. Curr Neuropharmacol. 2008;6:39–54.PubMedPubMedCentralCrossRefGoogle Scholar
  63. Nutt DJ. The role of the opioid system in alcohol dependence. J Psychopharmacol. 2014;28:8–22.PubMedCrossRefGoogle Scholar
  64. Park SQ, Kahnt T, Beck A, Cohen MX, Dolan RJ, Wrase J, Heinz A. Prefrontal cortex fails to learn from reward prediction errors in alcohol dependence. J Neurosci. 2010;30:7749–53.PubMedPubMedCentralCrossRefGoogle Scholar
  65. Pastor R, Font L, Miquel M, Phillips TJ, Aragon CM. Involvement of the beta-endorphin neurons of the hypothalamic arcuate nucleus in ethanol-induced place preference conditioning in mice. Alcohol Clin Exp Res. 2011;35:2019–29.PubMedPubMedCentralCrossRefGoogle Scholar
  66. Pettinati HM, Anton RF, Willenbring ML. The COMBINE Study: an overview of the largest pharmacotherapy study to date for treating alcohol dependence. Psychiatry (Edgmont). 2006; 3:36–9.Google Scholar
  67. Phillips TJ, Reed C, Pastor R. Preclinical evidence implicating corticotropin-releasing factor signaling in ethanol consumption and neuroadaptation. Genes Brain Behav. 2015;14(1):98–135.PubMedPubMedCentralCrossRefGoogle Scholar
  68. Phillips SA, Osborn K, Hwang CL, Sabbahi A, Piano MR. Ethanol induced oxidative stress in the vasculature: friend or foe. Curr Hypertens Rev. 2019.  https://doi.org/10.2174/1573402115666190325124622.
  69. Pian JP, Criado JR, Walker BM, Ehlers CL. Differential effects of acute alcohol on EEG and sedative responses in adolescent and adult Wistar rats. Brain Res. 2008;1194:28–36.PubMedCrossRefGoogle Scholar
  70. Quadir SG, Cottone P, Sabino V. Role of sigma receptors in alcohol addiction. Front Pharmacol. 2019;10:687.PubMedPubMedCentralCrossRefGoogle Scholar
  71. Radke AK, Jury NJ, Delpire E, Nakazawa K, Holmes A. Reduced ethanol drinking following selective cortical interneuron deletion of the GluN2B NMDA receptors subunit. Alcohol. 2017;58:47–51.PubMedCrossRefPubMedCentralGoogle Scholar
  72. Rao PS, Bell RL, Engleman EA, Sari Y. Targeting glutamate uptake to treat alcohol use disorders. Front Neurosci. 2015;9:144.PubMedPubMedCentralCrossRefGoogle Scholar
  73. Ren H, Honse Y, Peoples RW. A site of alcohol action in the fourth membrane-associated domain of the N-methyl-d-aspartate receptor. J Biol Chem. 2003;278:48815–20.PubMedCrossRefPubMedCentralGoogle Scholar
  74. Richard JM, Fields HL. Mu-opioid receptor activation in the medial shell of nucleus accumbens promotes alcohol consumption, self-administration and cue-induced reinstatement. Neuropharmacology. 2016;108:14–23.PubMedPubMedCentralCrossRefGoogle Scholar
  75. Ritz L, Lannuzel C, Boudehent C, Vabret F, Bordas N, Segobin S, Eustache F, Pitel AL, Beaunieux H. Validation of a brief screening tool for alcohol-related neuropsychological impairments. Alcohol Clin Exp Res. 2015;39:2249–60.PubMedCrossRefPubMedCentralGoogle Scholar
  76. Sarkisyan D, Hussain MZ, Watanabe H, Kononenko O, Bazov I, Zhou X, Yamskova O, Krishtal O, Karpyak VM, Yakovleva T, Bakalkin G. Downregulation of the endogenous opioid peptides in the dorsal striatum of human alcoholics. Front Cell Neurosci. 2015;9:187.PubMedPubMedCentralCrossRefGoogle Scholar
  77. Serrano A, Pavon FJ, Buczynski MW, Schlosburg J, Natividad LA, Polis IY, Stouffer DG, Zorrilla EP, Roberto M, Cravatt BF, Martin-Fardon R, Rodriguez de Fonseca F, Parsons LH. Deficient endocannabinoid signaling in the central amygdala contributes to alcohol dependence-related anxiety-like behavior and excessive alcohol intake. Neuropsychopharmacology. 2018.  https://doi.org/10.1038/s41386-018-0055-3.PubMedPubMedCentralCrossRefGoogle Scholar
  78. Sharko AC, Kaigler KF, Fadel JR, Wilson MA. Ethanol-induced anxiolysis and neuronal activation in the amygdala and bed nucleus of the stria terminals. Alcohol. 2016;50:19–25.PubMedCrossRefPubMedCentralGoogle Scholar
  79. Shokri-Kojori E, Tomasi D, Wiers CE, Wang GJ, Volkow ND. Alcohol affects brain functional connectivity and its coupling with behavior: greater effects in male heavy drinkers. Mol Psychiatry. 2017;22:1185–95.PubMedCrossRefPubMedCentralGoogle Scholar
  80. Silva JBS, Cristino ED, Almeida NL, Medeiros PCB, Santos NAD. Effects of acute alcohol ingestion on eye movements and cognition: a double-blind, placebo-controlled study. PLoS One. 2017;12:e0186061.PubMedPubMedCentralCrossRefGoogle Scholar
  81. Spanagel R, Putzke J, Stefferl A, Schöbitz B, Zieglgänsberger W. Acamprosate and alcohol: II. Effects on alcohol withdrawal in the rat. Eur J Pharmacol. 1996;305:45–50.PubMedCrossRefGoogle Scholar
  82. Sripada CS, Angstadt M, McNamara P, King AC, Phan KL. Effects of alcohol on brain responses to social signals of threat in humans. Neuroimage. 2011;55:371–80.PubMedCrossRefGoogle Scholar
  83. Sugaya N, Ogai Y, Kakibuchi Y, Senoo E, Ikeda K. Influence of GIRK channel inhibition on relapse risk in Japanese alcohol-dependent inpatients. Nihon Shinkei Seishin Yakurigaku Zasshi. 2012;32:165–7. [Japanese].PubMedGoogle Scholar
  84. Tarren JR, Lester HA, Belmer A, Bartlett SE. Acute ethanol administration upregulates synaptic α4-subunit of neuronal nicotinic acetylcholine receptors within the nucleus accumbens and amygdala. Front Mol Neurosci. 2017;10:338.PubMedPubMedCentralCrossRefGoogle Scholar
  85. Thiele TE, Crabbe JC, Boehm SL 2nd. “Drinking in the Dark” (DID): a simple mouse model of binge-like alcohol intake. Curr Protoc Neurosci. 2014;68:9.49.1–12.CrossRefGoogle Scholar
  86. Thome J, Foley P, Gsell W, Davids E, Wodarz N, Wiesbeck GA, Boning J, Riederer P. Increased concentrations of manganese superoxide dismutase in serum of alcohol-dependent patients. Alcohol Alcohol. 1997a;32:65–9.PubMedCrossRefPubMedCentralGoogle Scholar
  87. Thome J, Zhang J, Davids E, Foley P, Weijers HG, Wiesbeck GA, Boning J, Riederer P, Gerlach M. Evidence for increased oxidative stress in alcohol-dependent patients provided by quantification of in vivo salicylate hydroxylation products. Alcohol Clin Exp Res. 1997b; 21:82–5.PubMedCrossRefPubMedCentralGoogle Scholar
  88. Thome J, Weijers HG, Wiesbeck GA, Sian J, Nara K, Boning J, Riederer P. Dopamine D3 receptor gene polymorphism and alcohol dependence: relation to personality rating. Psychiatr Genet. 1999;9:17–21.PubMedCrossRefPubMedCentralGoogle Scholar
  89. Van Skike CE, Diaz-Granados JL, Matthews DB. Chronic intermittent ethanol exposure produces persistent anxiety in adolescent and adult rats. Alcohol Clin Exp Res. 2015;39:262–71.PubMedPubMedCentralCrossRefGoogle Scholar
  90. Van’t Veer A, Smith KL, Cohen BM, Carlezon WA Jr, Bechtholt AJ. Kappa-opioid receptors differentially regulate low and high levels of ethanol intake in female mice. Brain Behav. 2016;6:e00523.CrossRefGoogle Scholar
  91. Vengeliene V, Bilbao A, Spanagel R. The alcohol deprivation effect model for studying relapse behavior: a comparison between rats and mice. Alcohol. 2014;48:313–20.PubMedCrossRefGoogle Scholar
  92. Wall TL, Luczak SE, Hiller-Sturmhöfel S. Biology, genetics, and environment: underlying factors influencing alcohol metabolism. Alcohol Res. 2016;38:59–68.PubMedPubMedCentralGoogle Scholar
  93. Yoder KK, Albrecht DS, Dzemidzic M, Normandin MD, Federici LM, Graves T, Herring CM, Hile KL, Walters JW, Liang T, Plawecki MH, O’Connor S, Kareken DA. Differences in IV alcohol-induced dopamine release in the ventral striatum of social drinkers and nontreatment-seeking alcoholics. Drug Alcohol Depend. 2016;160:163–9.PubMedPubMedCentralCrossRefGoogle Scholar
  94. Yu J, Peng J, Luan Z, Zheng F, Su W. MicroRNAs as a novel tool in the diagnosis of liver lipid dysregulation and fatty liver disease. Molecules. 2019;24:pii: E230.PubMedCentralCrossRefPubMedGoogle Scholar
  95. Zahr NM, Pfefferbaum A. Alcohol’s effects on the brain: neuroimaging results in humans and animal models. Alcohol Res. 2017;38:183–206.PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  1. 1.Department of Pharmacology, Drug Development Service SegmentLSI Medience Corporation (Panasonic Health Care)Kanazawa-ku, YokohamaJapan

Section editors and affiliations

  • Toshikazu Saito
    • 1
  1. 1.The International College of NeuropsychopharmacologyEast KilbrideScotland, UK

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