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Molecular mechanisms underlying alcohol-drinking behaviours

Key Points

  • Signal transduction pathways that contribute to synaptic plasticity and to learning and memory processes are key mediators of neuroadaptations underlying the transition from moderate use of alcohol to excessive, uncontrolled alcohol seeking and drinking. These cascades are termed here as 'go pathways'.

  • Endogenous signalling pathways gate the level of alcohol drinking and keep consumption in moderation. These 'stop pathways' also provide clues as to why some individuals become 'problem drinkers' and exhibit phenotypes of alcohol use disorder, whereas the majority of people do not. Excessive alcohol drinking and dependence occur when the stop pathways cease to function.

  • Epigenetic mechanisms that control the conformation of chromatin as well as non-coding RNAs such as microRNAs change the molecular landscape in response to alcohol consumption and serve as molecular hubs that transduce both the go and stop pathways.

  • Alcohol-induced neuroadaptations in the go and stop pathways produce brain region- and cell type-specific alterations, which in turn integrate into functional abnormalities in specific circuits. These molecular- to system-level functional alterations account for the behavioural phenotypes of addiction, such as the binge drinking of alcohol, compulsive alcohol seeking, dependence, negative affect, craving and relapse.

Abstract

The main characteristic of alcohol use disorder is the consumption of large quantities of alcohol despite the negative consequences. The transition from the moderate use of alcohol to excessive, uncontrolled alcohol consumption results from neuroadaptations that cause aberrant motivational learning and memory processes. Here, we examine studies that have combined molecular and behavioural approaches in rodents to elucidate the molecular mechanisms that keep the social intake of alcohol in check, which we term 'stop pathways', and the neuroadaptations that underlie the transition from moderate to uncontrolled, excessive alcohol intake, which we term 'go pathways'. We also discuss post-transcriptional, genetic and epigenetic alterations that underlie both types of pathways.

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Figure 1: Signalling pathways underlying the go pathways.
Figure 2: Signalling pathways underlying the stop pathways.
Figure 3: Signalling, neural circuits and alcohol.

References

  1. 1

    World Health Organization. Global status report on alcohol and health 2014 (WHO, 2014).

  2. 2

    Enoch, M. A. & Goldman, D. Problem drinking and alcoholism: diagnosis and treatment. Am. Fam. Physician 65, 441–448 (2002).

    PubMed  Google Scholar 

  3. 3

    American Psychiatric Association. The Diagnostic and Statistical Manual of Mental Disorders DSM-5 5th edn (American Psychiatric Publishing, 2013).

  4. 4

    Koob, G. F. & Volkow, N. D. Neurocircuitry of addiction. Neuropsychopharmacology 35, 217–238 (2010).

    Article  PubMed  Google Scholar 

  5. 5

    Koob, G. F. in Behavioral Neurobiology of Alcohol Addiction (eds Sommer, W. H. & Spanagel, R.) 3–30 (Springer, 2013).

    Google Scholar 

  6. 6

    Wise, R. A. & Koob, G. F. The development and maintenance of drug addiction. Neuropsychopharmacology 39, 254–262 (2014).

    Article  PubMed  Google Scholar 

  7. 7

    Hyman, S. E., Malenka, R. C. & Nestler, E. J. Neural mechanisms of addiction: the role of reward-related learning and memory. Annu. Rev. Neurosci. 29, 565–598 (2006).

    Article  CAS  PubMed  Google Scholar 

  8. 8

    Torregrossa, M. M., Corlett, P. R. & Taylor, J. R. Aberrant learning and memory in addiction. Neurobiol. Learn. Mem. 96, 609–623 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. 9

    Crews, F. T. & Vetreno, R. P. Neuroimmune basis of alcoholic brain damage. Int. Rev. Neurobiol. 118, 315–357 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  10. 10

    Ron, D. & Messing, R. O. in Behavioral Neurobiology of Alcohol Addiction (eds Sommer, W. H. & Spanagel, R.) 87–126 (Springer, 2013).

    Google Scholar 

  11. 11

    Ahmadiantehrani, S., Warnault, V., Legastelois, R. & Ron, D. in Neurobiology of Alcohol Dependence (eds Nohrona, A., Cui, C., Harris, R. & Crabbe, J.) 155–171 (Elsevier, 2014).

    Book  Google Scholar 

  12. 12

    Rothenfluh, A., Troutwine, B., Ghezzi, A. & Atkinson, N. S. in Neurobiology of Alcohol Dependence (eds Nohrona, A., Cui, C., Harris, R. & Crabbe, J.) 467–494 (Elsevier, 2014).

    Book  Google Scholar 

  13. 13

    Abel, T. & Nguyen, P. V. Regulation of hippocampus-dependent memory by cyclic AMP-dependent protein kinase. Prog. Brain Res. 169, 97–115 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. 14

    Kandel, E. R. The molecular biology of memory: cAMP, PKA, CRE, CREB-1, CREB-2, and CPEB. Mol. Brain 5, 14 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. 15

    Lee, A. M. & Messing, R. O. Protein kinases and addiction. Ann. NY Acad. Sci. 1141, 22–57 (2008).

    Article  CAS  PubMed  Google Scholar 

  16. 16

    Wand, G., Levine, M., Zweifel, L., Schwindinger, W. & Abel, T. The cAMP-protein kinase A signal transduction pathway modulates ethanol consumption and sedative effects of ethanol. J. Neurosci. 21, 5297–5303 (2001).

    Article  CAS  PubMed  Google Scholar 

  17. 17

    Maas, J. W. Jr. et al. Calcium-stimulated adenylyl cyclases are critical modulators of neuronal ethanol sensitivity. J. Neurosci. 25, 4118–4126 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. 18

    Yao, L. et al. βγ dimers mediate synergy of dopamine D2 and adenosine A2 receptor-stimulated PKA signaling and regulate ethanol consumption. Cell 109, 733–743 (2002). This study provided, for the first time, a mechanism for alcohol-induced activation of PKA in the brain. Specifically, the authors used a combination of cell culture and in vivo assays to show that PKA signalling is activated by alcohol through the synergistic actions of D2Rs and A 2A Rs.

    Article  CAS  PubMed  Google Scholar 

  19. 19

    Mailliard, W. S. & Diamond, I. Recent advances in the neurobiology of alcoholism: the role of adenosine. Pharmacol. Ther. 101, 39–46 (2004).

    Article  CAS  PubMed  Google Scholar 

  20. 20

    Choi, D. S. et al. The type 1 equilibrative nucleoside transporter regulates ethanol intoxication and preference. Nat. Neurosci. 7, 855–861 (2004).

    Article  CAS  PubMed  Google Scholar 

  21. 21

    Nam, H. W. et al. Adenosine transporter ENT1 regulates the acquisition of goal-directed behavior and ethanol drinking through A2A receptor in the dorsomedial striatum. J. Neurosci. 33, 4329–4338 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. 22

    Arolfo, M. P., Yao, L., Gordon, A. S., Diamond, I. & Janak, P. H. Ethanol operant self-administration in rats is regulated by adenosine A2 receptors. Alcohol. Clin. Exp. Res. 28, 1308–1316 (2004).

    Article  CAS  PubMed  Google Scholar 

  23. 23

    Thorsell, A., Johnson, J. & Heilig, M. Effect of the adenosine A2a receptor antagonist 3,7-dimethyl-propargylxanthine on anxiety-like and depression-like behavior and alcohol consumption in Wistar rats. Alcohol. Clin. Exp. Res. 31, 1302–1307 (2007).

    Article  CAS  PubMed  Google Scholar 

  24. 24

    Darcq, E. et al. Inhibition of striatal-enriched tyrosine phosphatase 61 in the dorsomedial striatum is sufficient to increased ethanol consumption. J. Neurochem. 129, 1024–1034 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. 25

    Ben Hamida, S. et al. The small G protein H-Ras in the mesolimbic system is a molecular gateway to alcohol-seeking and excessive drinking behaviors. J. Neurosci. 32, 15849–15858 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. 26

    Ohnishi, H., Murata, Y., Okazawa, H. & Matozaki, T. Src family kinases: modulators of neurotransmitter receptor function and behavior. Trends Neurosci. 34, 629–637 (2011).

    Article  CAS  PubMed  Google Scholar 

  27. 27

    Trepanier, C. H., Jackson, M. F. & MacDonald, J. F. Regulation of NMDA receptors by the tyrosine kinase Fyn. FEBS J. 279, 12–19 (2012).

    Article  CAS  PubMed  Google Scholar 

  28. 28

    Goebel-Goody, S. M. et al. Therapeutic implications for striatal-enriched protein tyrosine phosphatase (STEP) in neuropsychiatric disorders. Pharmacol. Rev. 64, 65–87 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. 29

    Wang, J. et al. Long-lasting adaptations of the NR2B-containing NMDA receptors in the dorsomedial striatum play a crucial role in alcohol consumption and relapse. J. Neurosci. 30, 10187–10198 (2010). This paper provided the first indication that alcohol activates signalling cascades in a brain subregion-specific manner. Specifically, it showed that alcohol activates FYN signalling in the DMS but not in other striatal regions even though these regions are composed of the same type of neurons.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. 30

    Gibb, S. L., Hamida, S. B., Lanfranco, M. F. & Ron, D. Ethanol-induced increase in Fyn kinase activity in the dorsomedial striatum is associated with subcellular redistribution of protein tyrosine phosphatase α. J. Neurochem. 119, 879–889 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. 31

    Yaka, R., Phamluong, K. & Ron, D. Scaffolding of Fyn kinase to the NMDA receptor determines brain region sensitivity to ethanol. J. Neurosci. 23, 3623–3632 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. 32

    Xu, J., Kurup, P., Foscue, E. & Lombroso, P. J. Striatal-enriched protein tyrosine phosphatase regulates the PTPα/Fyn signaling pathway. J. Neurochem. 134, 629–641 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. 33

    Bhandari, V., Lim, K. L. & Pallen, C. J. Physical and functional interactions between receptor-like protein-tyrosine phosphatase α and p59fyn. J. Biol. Chem. 273, 8691–8698 (1998).

    Article  CAS  PubMed  Google Scholar 

  34. 34

    Coultrap, S. J. & Bayer, K. U. CaMKII regulation in information processing and storage. Trends Neurosci. 35, 607–618 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. 35

    Salling, M. C. et al. Moderate alcohol drinking and the amygdala proteome: identification and validation of calcium/calmodulin dependent kinase II and AMPA receptor activity as novel molecular mechanisms of the positive reinforcing effects of alcohol. Biol. Psychiatry 79, 430–442 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. 36

    Easton, A. C. et al. αCaMKII autophosphorylation controls the establishment of alcohol drinking behavior. Neuropsychopharmacology 38, 1636–1647 (2013). This study used a genetic approach in mice and provided evidence that the autonomous activation of CaMKII contributes to the go pathways. It also showed that a single-nucleotide polymorphism (SNP) within the coding region of the autonomous activation domain of the kinase is linked with alcohol dependence in humans.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. 37

    Malinow, R. & Malenka, R. C. AMPA receptor trafficking and synaptic plasticity. Annu. Rev. Neurosci. 25, 103–126 (2002).

    Article  CAS  PubMed  Google Scholar 

  38. 38

    Wang, J. et al. Ethanol-mediated facilitation of AMPA receptor function in the dorsomedial striatum: implications for alcohol drinking behavior. J. Neurosci. 32, 15124–15132 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. 39

    Wang, J. et al. Alcohol elicits functional and structural plasticity selectively in dopamine D1 receptor-expressing neurons of the dorsomedial striatum. J. Neurosci. 35, 11634–11643 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. 40

    Ben Hamida, S. et al. Protein tyrosine phosphatase α in the dorsomedial striatum promotes excessive ethanol-drinking behaviors. J. Neurosci. 33, 14369–14378 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. 41

    Legastelois, R., Darcq, E., Wegner, S. A., Lombroso, P. J. & Ron, D. Striatal-enriched protein tyrosine phosphatase controls responses to aversive stimuli: implication for ethanol drinking. PLoS ONE 10, e0127408 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. 42

    Ye, X. & Carew, T. J. Small G protein signaling in neuronal plasticity and memory formation: the specific role of Ras family proteins. Neuron 68, 340–361 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. 43

    Repunte-Canonigo, V. et al. Genome-wide gene expression analysis identifies K-ras as a regulator of alcohol intake. Brain Res. 1339, 1–10 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. 44

    Feig, L. A. Regulation of neuronal function by Ras-GRF exchange factors. Genes Cancer 2, 306–319 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. 45

    Baouz, S. et al. Sites of phosphorylation by protein kinase A in CDC25Mm/GRF1, a guanine nucleotide exchange factor for Ras. J. Biol. Chem. 276, 1742–1749 (2001).

    Article  CAS  PubMed  Google Scholar 

  46. 46

    Mulligan, M. K. et al. Toward understanding the genetics of alcohol drinking through transcriptome meta-analysis. Proc. Natl Acad. Sci. USA 103, 6368–6373 (2006). This large-scale microarray study used mice that were selectively bred to consume large amounts of alcohol and inbred mouse lines that prefer or avoid alcohol. The authors found that the transcripts of genes in specific signalling cascades, including the HRAS–MKK1–ERK1/2 axis, are enriched in the brains of mice that consume high levels of alcohol.

    Article  CAS  PubMed  Google Scholar 

  47. 47

    Stacey, D. et al. RASGRF2 regulates alcohol-induced reinforcement by influencing mesolimbic dopamine neuron activity and dopamine release. Proc. Natl Acad. Sci. USA 109, 21128–21133 (2012). The authors identified a role for the small G protein RAS-GRF2 in alcohol consumption in mice. The authors further provided a link between RAS-GRF2–ERK1/2 signalling and dopamine release. Human studies identified a SNP within the RGS2 gene as a risk factor for alcohol drinking during adolescence.

    Article  PubMed  Google Scholar 

  48. 48

    Manning, B. D. & Cantley, L. C. AKT/PKB signaling: navigating downstream. Cell 129, 1261–1274 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. 49

    Cozzoli, D. K. et al. Binge drinking upregulates accumbens mGluR5–Homer2–PI3K signaling: functional implications for alcoholism. J. Neurosci. 29, 8655–8668 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. 50

    Neasta, J., Ben Hamida, S., Yowell, Q. V., Carnicella, S. & Ron, D. AKT signaling pathway in the nucleus accumbens mediates excessive alcohol drinking behaviors. Biol. Psychiatry 70, 575–582 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. 51

    Liu, F. et al. mTORC1-dependent translation of collapsin response mediator protein-2 drives neuroadaptations underlying excessive alcohol drinking behaviors. Mol. Psychiatry http://dx.doi.org/10.1038/mp.2016.12 (2016).

  52. 52

    Buffington, S. A., Huang, W. & Costa-Mattioli, M. Translational control in synaptic plasticity and cognitive dysfunction. Annu. Rev. Neurosci. 37, 17–38 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. 53

    Hoeffer, C. A. & Klann, E. mTOR signaling: at the crossroads of plasticity, memory and disease. Trends Neurosci. 33, 67–75 (2010).

    Article  CAS  PubMed  Google Scholar 

  54. 54

    Neasta, J., Barak, S. & Hamida, S. B. & Ron, D. mTOR complex 1: a key player in neuroadaptations induced by drugs of abuse. J. Neurochem. 130, 172–184 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. 55

    Neasta, J., Ben Hamida, S., Yowell, Q., Carnicella, S. & Ron, D. Role for mammalian target of rapamycin complex 1 signaling in neuroadaptations underlying alcohol-related disorders. Proc. Natl Acad. Sci. USA 107, 20093–20098 (2010).

    Article  PubMed  Google Scholar 

  56. 56

    Beckley, J. T., Laguesse, S., Phamluong, K., Wegner, S. A. & Ron, D. The first alcohol drink triggers mTORC1-dependent synaptic plasticity in nucleus accumbens dopamine D1 receptor neurons. J. Neurosci. 36, 701–13 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. 57

    Barak, S. et al. Disruption of alcohol-related memories by mTORC1 inhibition prevents relapse. Nat. Neurosci. 16, 1111–1117 (2013). This was the first study to suggest that a specific signalling pathway (mTORC1 signalling) is activated during reconsolidation of alcohol-associated memories. Furthermore, the authors found that memories can be erased by inhibition of mTORC1 during reconsolidation, leading to long-lasting prevention of relapse.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. 58

    Azzi, A., Boscoboinik, D. & Hensey, C. The protein kinase C family. Eur. J. Biochem. 208, 547–557 (1992).

    Article  CAS  PubMed  Google Scholar 

  59. 59

    Hodge, C. W. et al. Supersensitivity to allosteric GABAA receptor modulators and alcohol in mice lacking PKCε. Nat. Neurosci. 2, 997–1002 (1999). This was the first study to use a transgenic mouse line to study the contribution of a specific signalling molecule to the actions of alcohol in vivo . The authors showed that PKCε has a role in mechanisms underlying alcohol-drinking behaviours and provided the first indication that the kinase lies at the intersection between the effects of stress and alcohol.

    Article  CAS  PubMed  Google Scholar 

  60. 60

    Olive, M. F., Mehmert, K. K., Messing, R. O. & Hodge, C. W. Reduced operant ethanol self-administration and in vivo mesolimbic dopamine responses to ethanol in PKCε-deficient mice. Eur. J. Neurosci. 12, 4131–4140 (2000).

    Article  CAS  PubMed  Google Scholar 

  61. 61

    Choi, D. S., Wang, D., Dadgar, J., Chang, W. S. & Messing, R. O. Conditional rescue of protein kinase C ε regulates ethanol preference and hypnotic sensitivity in adult mice. J. Neurosci. 22, 9905–9911 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. 62

    Cozzoli, D. K. et al. Protein kinase C epsilon activity in the nucleus accumbens and central nucleus of the amygdala mediates binge alcohol consumption. Biol. Psychiatry 79, 443–451 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. 63

    Lesscher, H. M. et al. Amygdala protein kinase C epsilon controls alcohol consumption. Genes Brain Behav. 8, 493–499 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. 64

    Janak, P. H. & Tye, K. M. From circuits to behaviour in the amygdala. Nature 517, 284–292 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. 65

    Hodge, C. W. et al. Decreased anxiety-like behavior, reduced stress hormones, and neurosteroid supersensitivity in mice lacking protein kinase Cε. J. Clin. Invest. 110, 1003–1010 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. 66

    Lesscher, H. M. et al. Amygdala protein kinase C epsilon regulates corticotropin-releasing factor and anxiety-like behavior. Genes Brain Behav. 7, 323–333 (2008).

    Article  CAS  PubMed  Google Scholar 

  67. 67

    Zorrilla, E. P., Logrip, M. L. & Koob, G. F. Corticotropin releasing factor: a key role in the neurobiology of addiction. Front. Neuroendocrinol. 35, 234–244 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. 68

    Bajo, M., Cruz, M. T., Siggins, G. R., Messing, R. & Roberto, M. Protein kinase C epsilon mediation of CRF- and ethanol-induced GABA release in central amygdala. Proc. Natl Acad. Sci. USA 105, 8410–8415 (2008).

    Article  PubMed  Google Scholar 

  69. 69

    Johnson, G. L. & Lapadat, R. Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science 298, 1911–1912 (2002).

    Article  CAS  PubMed  Google Scholar 

  70. 70

    Pascoli, V., Cahill, E., Bellivier, F., Caboche, J. & Vanhoutte, P. Extracellular signal-regulated protein kinases 1 and 2 activation by addictive drugs: a signal toward pathological adaptation. Biol. Psychiatry 76, 917–926 (2014).

    Article  CAS  PubMed  Google Scholar 

  71. 71

    Schroeder, J. P. et al. 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, 546–554 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. 72

    Yoshii, A. & Constantine-Paton, M. Postsynaptic BDNF-TrkB signaling in synapse maturation, plasticity, and disease. Dev. Neurobiol. 70, 304–322 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73

    Airaksinen, M. S. & Saarma, M. The GDNF family: signalling, biological functions and therapeutic value. Nat. Rev. Neurosci. 3, 383–394 (2002).

    Article  CAS  PubMed  Google Scholar 

  74. 74

    McGough, N. N. et al. RACK1 and brain-derived neurotrophic factor: a homeostatic pathway that regulates alcohol addiction. J. Neurosci. 24, 10542–10552 (2004). This paper provided the first evidence suggesting that moderate intake of alcohol stimulates a signalling pathway that in turn keeps alcohol drinking in moderation. Specifically, it showed that moderate alcohol intake increases expression of BDNF in the dorsal striatum and that BDNF signalling in this brain region gates the level of alcohol intake.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. 75

    Logrip, M. L., Janak, P. H. & Ron, D. Escalating ethanol intake is associated with altered corticostriatal BDNF expression. J. Neurochem. 109, 1459–1468 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. 76

    Ahmadiantehrani, S., Barak, S. & Ron, D. GDNF is a novel ethanol-responsive gene in the VTA: implications for the development and persistence of excessive drinking. Addict. Biol. 19, 623–633 (2014).

    Article  CAS  PubMed  Google Scholar 

  77. 77

    Hensler, J. G., Ladenheim, E. E. & Lyons, W. E. Ethanol consumption and serotonin-1A (5-HT1A) receptor function in heterozygous BDNF (+/−) mice. J. Neurochem. 85, 1139–1147 (2003).

    Article  CAS  PubMed  Google Scholar 

  78. 78

    Logrip, M. L., Barak, S., Warnault, V. & Ron, D. Corticostriatal BDNF and alcohol addiction. Brain Res. 1628, 60–67 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. 79

    Carnicella, S., Ahmadiantehrani, S., Janak, P. H. & Ron, D. GDNF is an endogenous negative regulator of ethanol-mediated reward and of ethanol consumption after a period of abstinence. Alcohol. Clin. Exp. Res. 33, 1012–1024 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. 80

    Jeanblanc, J. et al. Endogenous BDNF in the dorsolateral striatum gates alcohol drinking. J. Neurosci. 29, 13494–13502 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. 81

    Jeanblanc, J., Logrip, M. L., Janak, P. H. & Ron, D. BDNF-mediated regulation of ethanol consumption requires the activation of the MAP kinase pathway and protein synthesis. Eur. J. Neurosci. 37, 607–612 (2013).

    Article  PubMed  Google Scholar 

  82. 82

    Darcq, E. et al. MicroRNA-30a-5p in the prefrontal cortex controls the transition from moderate to excessive alcohol consumption. Mol. Psychiatry 20, 1219–1231 (2014). This study and reference 96 provided the first link between alcohol-dependent alterations of the expression of miRNAs and alcohol consumption. Specifically, the studies provided independent evidence suggesting that miRNAs that control the expression levels of Bdnf in the mPFC drive excessive alcohol drinking in alcohol-dependent and non-dependent rodents.

    PubMed  PubMed Central  Google Scholar 

  83. 83

    Warnault, V. et al. The BDNF valine 68 to methionine polymorphism increases compulsive alcohol drinking in mice that is reversed by tropomyosin receptor kinase B activation. Biol. Psychiatry 79, 463–473 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. 84

    Pandey, S. C., Roy, A., Zhang, H. & Xu, T. Partial deletion of the cAMP response element-binding protein gene promotes alcohol-drinking behaviors. J. Neurosci. 24, 5022–5030 (2004). In this study, the authors provided the first evidence that malfunctioning of CREB and its downstream effector genes Npy and Bdnf is associated with increased alcohol intake and anxiety-like behaviour in rodents.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. 85

    Pandey, S. C., Zhang, H., Roy, A. & Misra, K. Central and medial amygdaloid brain-derived neurotrophic factor signaling plays a critical role in alcohol-drinking and anxiety-like behaviors. J. Neurosci. 26, 8320–8331 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. 86

    Barak, S. et al. Glial cell line-derived neurotrophic factor (GDNF) is an endogenous protector in the mesolimbic system against excessive alcohol consumption and relapse. Addict. Biol. 20, 629–642 (2015).

    Article  CAS  PubMed  Google Scholar 

  87. 87

    Carnicella, S., Kharazia, V., Jeanblanc, J., Janak, P. H. & Ron, D. GDNF is a fast-acting potent inhibitor of alcohol consumption and relapse. Proc. Natl Acad. Sci. USA 105, 8114–8119 (2008).

    Article  PubMed  Google Scholar 

  88. 88

    Logrip, M. L., Janak, P. H. & Ron, D. Dynorphin is a downstream effector of striatal BDNF regulation of ethanol intake. FASEB J. 22, 2393–2404 (2008).

    Article  CAS  PubMed  Google Scholar 

  89. 89

    Jeanblanc, J. et al. The dopamine D3 receptor is part of a homeostatic pathway regulating ethanol consumption. J. Neurosci. 26, 1457–1464 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. 90

    Moonat, S., Sakharkar, A. J., Zhang, H. & Pandey, S. C. The role of amygdaloid brain-derived neurotrophic factor, activity-regulated cytoskeleton-associated protein and dendritic spines in anxiety and alcoholism. Addict. Biol. 16, 238–250 (2011).

    Article  CAS  PubMed  Google Scholar 

  91. 91

    You, C., Zhang, H., Sakharkar, A. J., Teppen, T. & Pandey, S. C. Reversal of deficits in dendritic spines, BDNF and Arc expression in the amygdala during alcohol dependence by HDAC inhibitor treatment. Int. J. Neuropsychopharmacol. 17, 313–322 (2014).

    Article  CAS  PubMed  Google Scholar 

  92. 92

    Pandey, S. C. et al. Effector immediate-early gene Arc in the amygdala plays a critical role in alcoholism. J. Neurosci. 28, 2589–2600 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. 93

    Stragier, E. et al. Ethanol-induced epigenetic regulations at the Bdnf gene in C57BL/6J mice. Mol. Psychiatry 20, 405–412 (2014).

    Article  CAS  PubMed  Google Scholar 

  94. 94

    Barak, S., Carnicella, S., Yowell, Q. V. & Ron, D. Glial cell line-derived neurotrophic factor reverses alcohol-induced allostasis of the mesolimbic dopaminergic system: implications for alcohol reward and seeking. J. Neurosci. 31, 9885–9894 (2011). This paper used a rodent paradigm to provide support for the allostasis model of addiction described by Koob and Le Moal in reference 165. Specifically, it showed that chronic, excessive alcohol consumption leads to a reduction in dopamine release in the NAc, and that the activation of GDNF signalling in the VTA reduces alcohol consumption by normalizing dopamine levels in the NAc.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. 95

    Barak, S., Ahmadiantehrani, S., Kharazia, V. & Ron, D. Positive autoregulation of GDNF levels in the ventral tegmental area mediates long-lasting inhibition of excessive alcohol consumption. Transl Psychiatry 1, e60 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. 96

    Tapocik, J. D. et al. microRNA-206 in rat medial prefrontal cortex regulates BDNF expression and alcohol drinking. J. Neurosci. 34, 4581–4588 (2014). This study and reference 82 provided the first link between alcohol-dependent alterations of the expression of miRNAs and alcohol consumption.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. 97

    Joe, K. H. et al. Decreased plasma brain-derived neurotrophic factor levels in patients with alcohol dependence. Alcohol. Clin. Exp. Res. 31, 1833–1838 (2007).

    Article  CAS  PubMed  Google Scholar 

  98. 98

    Heberlein, A. et al. BDNF and GDNF serum levels in alcohol-dependent patients during withdrawal. Prog. Neuropsychopharmacol. Biol. Psychiatry 34, 1060–1064 (2010).

    Article  CAS  PubMed  Google Scholar 

  99. 99

    Prakash, A., Zhang, H. & Pandey, S. C. Innate differences in the expression of brain-derived neurotrophic factor in the regions within the extended amygdala between alcohol preferring and nonpreferring rats. Alcohol. Clin. Exp. Res. 32, 909–920 (2008).

    Article  CAS  PubMed  Google Scholar 

  100. 100

    Egan, M. F. et al. The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell 112, 257–269 (2003).

    Article  CAS  PubMed  Google Scholar 

  101. 101

    Chen, Z. Y. et al. Variant brain-derived neurotrophic factor (BDNF) (Met66) alters the intracellular trafficking and activity-dependent secretion of wild-type BDNF in neurosecretory cells and cortical neurons. J. Neurosci. 24, 4401–4411 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. 102

    Matsushita, S. et al. Association study of brain-derived neurotrophic factor gene polymorphism and alcoholism. Alcohol. Clin. Exp. Res. 28, 1609–1612 (2004).

    Article  CAS  PubMed  Google Scholar 

  103. 103

    Wojnar, M. et al. Association between Val66Met brain-derived neurotrophic factor (BDNF) gene polymorphism and post-treatment relapse in alcohol dependence. Alcohol. Clin. Exp. Res. 33, 693–702 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. 104

    Mon, A. et al. Brain-derived neurotrophic factor genotype is associated with brain gray and white matter tissue volumes recovery in abstinent alcohol-dependent individuals. Genes Brain Behav. 12, 98–107 (2013).

    Article  CAS  PubMed  Google Scholar 

  105. 105

    Agoglia, A. E. et al. Alcohol alters the activation of ERK1/2, a functional regulator of binge alcohol drinking in adult C57BL/6J mice. Alcohol. Clin. Exp. Res. 39, 463–475 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. 106

    Faccidomo, S., Salling, M. C., Galunas, C. & Hodge, C. W. Operant ethanol self-administration increases extracellular-signal regulated protein kinase (ERK) phosphorylation in reward-related brain regions: selective regulation of positive reinforcement in the prefrontal cortex of C57BL/6J mice. Psychopharmacology 232, 3417–3430 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. 107

    Faccidomo, S., Besheer, J., Stanford, P. C. & Hodge, C. W. Increased operant responding for ethanol in male C57BL/6J mice: specific regulation by the ERK1/2, but not JNK, MAP kinase pathway. Psychopharmacology 204, 135–147 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. 108

    Karatsoreos, I. N. Links between circadian rhythms and psychiatric disease. Front. Behav. Neurosci. 8, 162 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  109. 109

    Spanagel, R., Rosenwasser, A. M., Schumann, G. & Sarkar, D. K. Alcohol consumption and the body's biological clock. Alcohol. Clin. Exp. Res. 29, 1550–1557 (2005).

    Article  PubMed  Google Scholar 

  110. 110

    Dong, L. et al. Effects of the circadian rhythm gene period 1 (Per1) on psychosocial stress-induced alcohol drinking. Am. J. Psychiatry 168, 1090–1098 (2011).

    Article  PubMed  Google Scholar 

  111. 111

    Spanagel, R. et al. The clock gene Per2 influences the glutamatergic system and modulates alcohol consumption. Nat. Med. 11, 35–42 (2005). This study revealed, for the first time, a role for circadian rhythm genes in AUD. The authors demonstrated that deficits in PER2 function increase alcohol intake and showed that a mutation in PER2 in humans dampens the severity of alcoholism.

    Article  CAS  PubMed  Google Scholar 

  112. 112

    Blomeyer, D. et al. Association of PER2 genotype and stressful life events with alcohol drinking in young adults. PLoS ONE 8, e59136 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. 113

    Ozburn, A. R. et al. The role of clock in ethanol-related behaviors. Neuropsychopharmacology 38, 2393–2400 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. 114

    Eide, E. J. et al. Control of mammalian circadian rhythm by CKIε-regulated proteasome-mediated PER2 degradation. Mol. Cell. Biol. 25, 2795–2807 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. 115

    Perreau-Lenz, S. et al. Inhibition of the casein-kinase-1-epsilon/delta/ prevents relapse-like alcohol drinking. Neuropsychopharmacology 37, 2121–2131 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. 116

    Kim, K. S., Kim, H., Baek, I. S., Lee, K. W. & Han, P. L. Mice lacking adenylyl cyclase type 5 (AC5) show increased ethanol consumption and reduced ethanol sensitivity. Psychopharmacology 215, 391–398 (2011).

    Article  CAS  PubMed  Google Scholar 

  117. 117

    Thiele, T. E. et al. High ethanol consumption and low sensitivity to ethanol-induced sedation in protein kinase A-mutant mice. J. Neurosci. 20, RC75 (2000).

    Article  CAS  PubMed  Google Scholar 

  118. 118

    Pandey, S. C. The gene transcription factor cyclic AMP-responsive element binding protein: role in positive and negative affective states of alcohol addiction. Pharmacol. Ther. 104, 47–58 (2004).

    Article  CAS  PubMed  Google Scholar 

  119. 119

    Pandey, S. C., Roy, A. & Zhang, H. The decreased phosphorylation of cyclic adenosine monophosphate (cAMP) response element binding (CREB) protein in the central amygdala acts as a molecular substrate for anxiety related to ethanol withdrawal in rats. Alcohol. Clin. Exp. Res. 27, 396–409 (2003).

    Article  CAS  PubMed  Google Scholar 

  120. 120

    Pandey, S. C., Zhang, H., Roy, A. & Xu, T. Deficits in amygdaloid cAMP-responsive element-binding protein signaling play a role in genetic predisposition to anxiety and alcoholism. J. Clin. Invest. 115, 2762–2773 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  121. 121

    Moonat, S., Starkman, B. G., Sakharkar, A. & Pandey, S. C. Neuroscience of alcoholism: molecular and cellular mechanisms. Cell. Mol. Life Sci. 67, 73–88 (2010).

    Article  CAS  PubMed  Google Scholar 

  122. 122

    Heilig, M. The NPY system in stress, anxiety and depression. Neuropeptides 38, 213–224 (2004).

    Article  CAS  PubMed  Google Scholar 

  123. 123

    Thiele, T. E., Marsh, D. J., Ste Marie, L., Bernstein, I. L. & Palmiter, R. D. Ethanol consumption and resistance are inversely related to neuropeptide Y levels. Nature 396, 366–369 (1998).

    Article  CAS  PubMed  Google Scholar 

  124. 124

    Bell, R. L. et al. Ibudilast reduces alcohol drinking in multiple animal models of alcohol dependence. Addict. Biol. 20, 38–42 (2015).

    Article  CAS  PubMed  Google Scholar 

  125. 125

    Wen, R. T. et al. The phosphodiesterase-4 (PDE4) inhibitor rolipram decreases ethanol seeking and consumption in alcohol-preferring Fawn-Hooded rats. Alcohol. Clin. Exp. Res. 36, 2157–2167 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. 126

    Franklin, K. M. et al. Reduction of alcohol drinking of alcohol-preferring (P) and high-alcohol drinking (HAD1) rats by targeting phosphodiesterase-4 (PDE4). Psychopharmacology 232, 2251–2262 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. 127

    Logrip, M. L., Vendruscolo, L. F., Schlosburg, J. E., Koob, G. F. & Zorrilla, E. P. Phosphodiesterase 10A regulates alcohol and saccharin self-administration in rats. Neuropsychopharmacology 39, 1722–1731 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. 128

    Logrip, M. L. & Zorrilla, E. P. Stress history increases alcohol intake in relapse: relation to phosphodiesterase 10A. Addict. Biol. 17, 920–933 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. 129

    Logrip, M. L. & Zorrilla, E. P. Differential changes in amygdala and frontal cortex Pde10a expression during acute and protracted withdrawal. Front. Integr. Neurosci. 8, 30 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. 130

    Lee, A. M. et al. Deletion of Prkcz increases intermittent ethanol consumption in mice. Alcohol. Clin. Exp. Res. 38, 170–178 (2014).

    Article  CAS  PubMed  Google Scholar 

  131. 131

    Lee, A. M. et al. Prkcz null mice show normal learning and memory. Nature 493, 416–419 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. 132

    Volk, L. J., Bachman, J. L., Johnson, R., Yu, Y. & Huganir, R. L. PKM-ζ is not required for hippocampal synaptic plasticity, learning and memory. Nature 493, 420–423 (2013).

    Article  CAS  PubMed  Google Scholar 

  133. 133

    Savarese, A., Zou, M. E., Kharazia, V., Maiya, R. & Lasek, A. W. Increased behavioral responses to ethanol in Lmo3 knockout mice. Genes Brain Behav. 13, 777–783 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. 134

    Lasek, A. W. et al. An evolutionary conserved role for anaplastic lymphoma kinase in behavioral responses to ethanol. PLoS ONE 6, e22636 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. 135

    Lasek, A. W., Giorgetti, F., Berger, K. H., Tayor, S. & Heberlein, U. Lmo genes regulate behavioral responses to ethanol in Drosophila melanogaster and the mouse. Alcohol. Clin. Exp. Res. 35, 1600–1606 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. 136

    Bos, J. L., Rehmann, H. & Wittinghofer, A. GEFs and GAPs: critical elements in the control of small G proteins. Cell 129, 865–877 (2007).

    Article  CAS  PubMed  Google Scholar 

  137. 137

    Repunte-Canonigo, V. et al. Nf1 regulates alcohol dependence-associated excessive drinking and gamma-aminobutyric acid release in the central amygdala in mice and is associated with alcohol dependence in humans. Biol. Psychiatry 77, 870–879 (2015).

    Article  CAS  PubMed  Google Scholar 

  138. 138

    Nestler, E. J. Epigenetic mechanisms of drug addiction. Neuropharmacology 76, 259–268 (2014).

    Article  CAS  PubMed  Google Scholar 

  139. 139

    Bali, P. & Kenny, P. J. MicroRNAs and drug addiction. Front. Genet. 4, 43 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  140. 140

    Krishnan, H. R., Sakharkar, A. J., Teppen, T. L., Berkel, T. D. & Pandey, S. C. The epigenetic landscape of alcoholism. Int. Rev. Neurobiol. 115, 75–116 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  141. 141

    Warnault, V., Darcq, E., Levine, A., Barak, S. & Ron, D. Chromatin remodeling — a novel strategy to control excessive alcohol drinking. Transl Psychiatry 3, e231 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. 142

    Pandey, S. C., Ugale, R., Zhang, H., Tang, L. & Prakash, A. Brain chromatin remodeling: a novel mechanism of alcoholism. J. Neurosci. 28, 3729–3737 (2008). This study was the first to suggest a role for epigenetic mechanisms in AUD. Specifically, the authors provided a link between deficits in histone acetylation and alcohol withdrawal-induced anxiety-like behaviour in rodents.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. 143

    Moonat, S., Sakharkar, A. J., Zhang, H., Tang, L. & Pandey, S. C. Aberrant histone deacetylase2-mediated histone modifications and synaptic plasticity in the amygdala predisposes to anxiety and alcoholism. Biol. Psychiatry 73, 763–773 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. 144

    Barbier, E. et al. DNA methylation in the medial prefrontal cortex regulates alcohol-induced behavior and plasticity. J. Neurosci. 35, 6153–6164 (2015). In this study, the authors showed that DNA methylation in the mPFC contributes to persistent molecular and behavioural adaptations associated with a history of alcohol dependence.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. 145

    Zhang, R. et al. Genome-wide DNA methylation analysis in alcohol dependence. Addict. Biol. 18, 392–403 (2013).

    Article  CAS  PubMed  Google Scholar 

  146. 146

    Ponomarev, I., Wang, S., Zhang, L., Harris, R. A. & Mayfield, R. D. Gene coexpression networks in human brain identify epigenetic modifications in alcohol dependence. J. Neurosci. 32, 1884–1897 (2012). Using a large-scale transcriptomic approach, in this study the authors showed that DNA hypomethylation and levels of histone H3 lysine 4 trimethylation are higher in the cortex of humans with alcoholism than in individuals without alcoholism, supporting the possibility that epigenetic mechanisms have a crucial role in AUD.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. 147

    Ruggeri, B. et al. Association of protein phosphatase PPM1G with alcohol use disorder and brain activity during behavioral control in a genome-wide methylation analysis. Am. J. Psychiatry 172, 543–552 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  148. 148

    Heberlein, A. et al. Epigenetic down regulation of nerve growth factor during alcohol withdrawal. Addict. Biol. 18, 508–510 (2013).

    Article  CAS  PubMed  Google Scholar 

  149. 149

    Heberlein, A. et al. Do changes in the BDNF promoter methylation indicate the risk of alcohol relapse? Eur. Neuropsychopharmacol. 25, 1892–1897 (2015).

    Article  CAS  PubMed  Google Scholar 

  150. 150

    Bothwell, M. in Neurotrophic Factors (eds Lewin, G. R. & Carter, B. D.) 3–15 (Springer, 2014).

    Book  Google Scholar 

  151. 151

    Miranda, R. C. et al. MicroRNAs: master regulators of ethanol abuse and toxicity? Alcohol. Clin. Exp. Res. 34, 575–587 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. 152

    Most, D., Workman, E. & Harris, R. A. Synaptic adaptations by alcohol and drugs of abuse: changes in microRNA expression and mRNA regulation. Front. Mol. Neurosci. 7, 85 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. 153

    Nunez, Y. O. & Mayfield, R. D. Understanding alcoholism through microRNA signatures in brains of human alcoholics. Front. Genet. 3, 43 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. 154

    Pietrzykowski, A. Z. et al. Posttranscriptional regulation of BK channel splice variant stability by miR-9 underlies neuroadaptation to alcohol. Neuron 59, 274–287 (2008). This was the first study to suggest that miRNAs have an important role in the actions of alcohol in neurons.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. 155

    Li, J. et al. MicroRNA expression profile and functional analysis reveal that miR-382 is a critical novel gene of alcohol addiction. EMBO Mol. Med. 5, 1402–1414 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. 156

    Beech, R. D. et al. Stress-related alcohol consumption in heavy drinkers correlates with expression of miR-10a, miR-21, and components of the TAR-RNA-binding protein-associated complex. Alcohol. Clin. Exp. Res. 38, 2743–2753 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. 157

    Tapocik, J. D. et al. Coordinated dysregulation of mRNAs and microRNAs in the rat medial prefrontal cortex following a history of alcohol dependence. Pharmacogenomics J. 13, 286–296 (2013).

    Article  CAS  PubMed  Google Scholar 

  158. 158

    Lewohl, J. M. et al. Up-regulation of microRNAs in brain of human alcoholics. Alcohol. Clin. Exp. Res. 35, 1928–1937 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. 159

    Most, D., Leiter, C., Blednov, Y. A., Harris, R. A. & Mayfield, R. D. Synaptic microRNAs coordinately regulate synaptic mRNAs: perturbation by chronic alcohol consumption. Neuropsychopharmacology 41, 538–548 (2016).

    Article  CAS  PubMed  Google Scholar 

  160. 160

    Pickens, C. L. et al. Neurobiology of the incubation of drug craving. Trends Neurosci. 34, 411–420 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. 161

    Berridge, K. C. & Kringelbach, M. L. Pleasure systems in the brain. Neuron 86, 646–664 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. 162

    Volkow, N. D. & Morales, M. The brain on drugs: from reward to addiction. Cell 162, 712–725 (2015).

    Article  CAS  PubMed  Google Scholar 

  163. 163

    Gonzales, R. A., Job, M. O. & Doyon, W. M. The role of mesolimbic dopamine in the development and maintenance of ethanol reinforcement. Pharmacol. Ther. 103, 121–146 (2004).

    Article  CAS  PubMed  Google Scholar 

  164. 164

    Pierce, R. C. & Kumaresan, V. The mesolimbic dopamine system: the final common pathway for the reinforcing effect of drugs of abuse? Neurosci. Biobehav. Rev. 30, 215–238 (2006).

    Article  CAS  PubMed  Google Scholar 

  165. 165

    Koob, G. F. & Le Moal, M. Drug addiction, dysregulation of reward, and allostasis. Neuropsychopharmacology 24, 97–129 (2001).

    Article  CAS  PubMed  Google Scholar 

  166. 166

    Wise, R. A. Roles for nigrostriatal—not just mesocorticolimbic—dopamine in reward and addiction. Trends Neurosci. 32, 517–524 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. 167

    Everitt, B. J. & Robbins, T. W. From the ventral to the dorsal striatum: devolving views of their roles in drug addiction. Neurosci. Biobehav. Rev. 37, 1946–1954 (2013).

    Article  PubMed  Google Scholar 

  168. 168

    Corbit, L. H., Nie, H. & Janak, P. H. Habitual alcohol seeking: time course and the contribution of subregions of the dorsal striatum. Biol. Psychiatry 72, 389–395 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  169. 169

    Heimer, L. & Alheid, G. F. in The Basal Forebrain (eds Napier, T. C., Kalivas, P. W. & Hanin, I.) 1–42 (Springer, 1991).

    Book  Google Scholar 

  170. 170

    Koob, G. F. Brain stress systems in the amygdala and addiction. Brain Res. 1293, 61–75 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. 171

    Zhang, H. & Pandey, S. C. Effects of PKA modulation on the expression of neuropeptide Y in rat amygdaloid structures during ethanol withdrawal. Peptides 24, 1397–1402 (2003).

    Article  CAS  PubMed  Google Scholar 

  172. 172

    Do-Monte, F. H., Quinones-Laracuente, K. & Quirk, G. J. A temporal shift in the circuits mediating retrieval of fear memory. Nature 519, 460–463 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. 173

    Kaplan, G. B., Heinrichs, S. C. & Carey, R. J. Treatment of addiction and anxiety using extinction approaches: neural mechanisms and their treatment implications. Pharmacol. Biochem. Behav. 97, 619–625 (2011).

    Article  CAS  PubMed  Google Scholar 

  174. 174

    Toettcher, J. E., Weiner, O. D. & Lim, W. A. Using optogenetics to interrogate the dynamic control of signal transmission by the Ras/Erk module. Cell 155, 1422–1434 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. 175

    Doupe, D. P. & Perrimon, N. Visualizing and manipulating temporal signaling dynamics with fluorescence-based tools. Sci. Signal. 7, re1 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. 176

    Wend, S. et al. Optogenetic control of protein kinase activity in mammalian cells. ACS Synth. Biol. 3, 280–285 (2014).

    Article  CAS  PubMed  Google Scholar 

  177. 177

    Lobo, M. K. et al. ΔFosB induction in striatal medium spiny neuron subtypes in response to chronic pharmacological, emotional, and optogenetic stimuli. J. Neurosci. 33, 18381–18395 (2013). In this study, the authors used optogenetics to dissect the role of ΔFOSB in a select population of neurons in limbic brain regions that send synaptic inputs to the NAc.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. 178

    Trudell, J. R., Messing, R. O., Mayfield, J. & Harris, R. A. Alcohol dependence: molecular and behavioral evidence. Trends Pharmacol. Sci. 35, 317–323 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. 179

    Holmes, A., Spanagel, R. & Krystal, J. H. Glutamatergic targets for new alcohol medications. Psychopharmacology 229, 539–554 (2013).

    Article  CAS  PubMed  Google Scholar 

  180. 180

    Allen, J. A., Halverson-Tamboli, R. A. & Rasenick, M. M. Lipid raft microdomains and neurotransmitter signalling. Nat. Rev. Neurosci. 8, 128–140 (2007).

    Article  CAS  PubMed  Google Scholar 

  181. 181

    Eisenberg, S., Shvartsman, D. E., Ehrlich, M. & Henis, Y. I. Clustering of raft-associated proteins in the external membrane leaflet modulates internal leaflet H-Ras diffusion and signaling. Mol. Cell. Biol. 26, 7190–7200 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. 182

    Chin, J. H. & Goldstein, D. B. Electron paramagnetic resonance studies of ethanol on membrane fluidity. Adv. Exp. Med. Biol. 85A, 111–122 (1977).

    Article  CAS  PubMed  Google Scholar 

  183. 183

    Chin, J. H., Parsons, L. M. & Goldstein, D. B. Increased cholesterol content of erythrocyte and brain membranes in ethanol-tolerant mice. Biochim. Biophys. Acta 513, 358–363 (1978).

    Article  CAS  PubMed  Google Scholar 

  184. 184

    Pascual-Lucas, M., Fernandez-Lizarbe, S., Montesinos, J. & Guerri, C. LPS or ethanol triggers clathrin- and rafts/caveolae-dependent endocytosis of TLR4 in cortical astrocytes. J. Neurochem. 129, 448–462 (2014).

    Article  CAS  PubMed  Google Scholar 

  185. 185

    Tobin, S. J. et al. Nanoscale effects of ethanol and naltrexone on protein organization in the plasma membrane studied by photoactivated localization microscopy (PALM). PLoS ONE 9, e87225 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. 186

    Petit-Paitel, A. et al. Prion protein is a key determinant of alcohol sensitivity through the modulation of N-methyl-d-aspartate receptor (NMDAR) activity. PLoS ONE 7, e34691 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. 187

    Bettinger, J. C., Leung, K., Bolling, M. H., Goldsmith, A. D. & Davies, A. G. Lipid environment modulates the development of acute tolerance to ethanol in Caenorhabditis elegans. PLoS ONE 7, e35192 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. 188

    Vilpoux, C., Warnault, V., Pierrefiche, O., Daoust, M. & Naassila, M. Ethanol-sensitive brain regions in rat and mouse: a cartographic review, using immediate early gene expression. Alcohol. Clin. Exp. Res. 33, 945–969 (2009).

    Article  CAS  PubMed  Google Scholar 

  189. 189

    Barson, J. R., Ho, H. T. & Leibowitz, S. F. Anterior thalamic paraventricular nucleus is involved in intermittent access ethanol drinking: role of orexin receptor 2. Addict. Biol. 20, 469–481 (2015).

    Article  CAS  PubMed  Google Scholar 

  190. 190

    Dayas, C. V., Liu, X., Simms, J. A. & Weiss, F. Distinct patterns of neural activation associated with ethanol seeking: effects of naltrexone. Biol. Psychiatry 61, 979–989 (2007).

    Article  CAS  PubMed  Google Scholar 

  191. 191

    Millan, E. Z., Furlong, T. M. & McNally, G. P. Accumbens shell–hypothalamus interactions mediate extinction of alcohol seeking. J. Neurosci. 30, 4626–4635 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. 192

    Cruz, F. C. et al. New technologies for examining the role of neuronal ensembles in drug addiction and fear. Nat. Rev. Neurosci. 14, 743–754 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. 193

    Finegersh, A. & Homanics, G. E. Paternal alcohol exposure reduces alcohol drinking and increases behavioral sensitivity to alcohol selectively in male offspring. PLoS ONE 9, e99078 (2014). This study suggested that parental exposure to alcohol affects offspring alcohol-drinking behaviours via epigenetic mechanisms.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. 194

    Carnicella, S. et al. Cabergoline decreases alcohol drinking and seeking behaviors via glial cell line-derived neurotrophic factor. Biol. Psychiatry 66, 146–153 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. 195

    Dancey, J. mTOR signaling and drug development in cancer. Nat. Rev. Clin. Oncol. 7, 209–219 (2010).

    Article  CAS  PubMed  Google Scholar 

  196. 196

    Sanchis-Segura, C. & Spanagel, R. Behavioural assessment of drug reinforcement and addictive features in rodents: an overview. Addict. Biol. 11, 2–38 (2006).

    Article  PubMed  Google Scholar 

  197. 197

    Carnicella, S., Ron, D. & Barak, S. Intermittent ethanol access schedule in rats as a preclinical model of alcohol abuse. Alcohol 48, 243–252 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. 198

    Hwa, L. S. et al. Persistent escalation of alcohol drinking in C57BL/6J mice with intermittent access to 20% ethanol. Alcohol. Clin. Exp. Res. 35, 1938–1947 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  199. 199

    Griffin, W. C. III. Alcohol dependence and free-choice drinking in mice. Alcohol 48, 287–293 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  200. 200

    Thiele, T. E. & Navarro, M. “Drinking in the dark” (DID) procedures: a model of binge-like ethanol drinking in non-dependent mice. Alcohol 48, 235–241 (2014).

    Article  CAS  PubMed  Google Scholar 

  201. 201

    Roberts, A. J., Heyser, C. J., Cole, M., Griffin, P. & Koob, G. F. Excessive ethanol drinking following a history of dependence: animal model of allostasis. Neuropsychopharmacology 22, 581–594 (2000).

    Article  CAS  PubMed  Google Scholar 

  202. 202

    Vendruscolo, L. F. & Roberts, A. J. Operant alcohol self-administration in dependent rats: focus on the vapor model. Alcohol 48, 277–286 (2014).

    Article  CAS  PubMed  Google Scholar 

  203. 203

    Griffin, W. C. III, Lopez, M. F. & Becker, H. C. Intensity and duration of chronic ethanol exposure is critical for subsequent escalation of voluntary ethanol drinking in mice. Alcohol. Clin. Exp. Res. 33, 1893–1900 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. 204

    Vengeliene, V., Bilbao, A. & Spanagel, R. The alcohol deprivation effect model for studying relapse behavior: a comparison between rats and mice. Alcohol 48, 313–320 (2014).

    Article  PubMed  Google Scholar 

  205. 205

    Shaham, Y., Shalev, U., Lu, L., De Wit, H. & Stewart, J. The reinstatement model of drug relapse: history, methodology and major findings. Psychopharmacology 168, 3–20 (2003).

    Article  CAS  PubMed  Google Scholar 

  206. 206

    Costin, B. N., Dever, S. M. & Miles, M. F. Ethanol regulation of serum glucocorticoid kinase 1 expression in DBA2/J mouse prefrontal cortex. PLoS ONE 8, e72979 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  207. 207

    Wolen, A. R. et al. Genetic dissection of acute ethanol responsive gene networks in prefrontal cortex: functional and mechanistic implications. PLoS ONE 7, e33575 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  208. 208

    Sommer, W. et al. Differential expression of diacylglycerol kinase iota and L18A mRNAs in the brains of alcohol-preferring AA and alcohol-avoiding ANA rats. Mol. Psychiatry 6, 103–108 (2001). In this study, the authors provided the first indication that signalling genes are differentially expressed in alcohol-preferring or -avoiding rats, suggesting that specific gene expression levels may be linked to resistance or susceptibility to developing AUD.

    Article  CAS  PubMed  Google Scholar 

  209. 209

    Ojelade, S. A. et al. Rsu1 regulates ethanol consumption in Drosophila and humans. Proc. Natl Acad. Sci. USA 112, E4085–E4093 (2015).

    Article  CAS  PubMed  Google Scholar 

  210. 210

    Gelernter, J. et al. Genome-wide association study of alcohol dependence: significant findings in African- and European-Americans including novel risk loci. Mol. Psychiatry 19, 41–49 (2014).

    Article  CAS  PubMed  Google Scholar 

  211. 211

    Le Roy, F., Silhol, M., Salehzada, T. & Bisbal, C. Regulation of mitochondrial mRNA stability by RNase L is translation-dependent and controls IFNα-induced apoptosis. Cell Death Differ. 14, 1406–1413 (2007).

    Article  CAS  PubMed  Google Scholar 

  212. 212

    von der Goltz, C. et al. Cue-induced alcohol-seeking behaviour is reduced by disrupting the reconsolidation of alcohol-related memories. Psychopharmacology 205, 389–397 (2009).

    Article  CAS  PubMed  Google Scholar 

  213. 213

    Kitamura, T. et al. Regulation of VEGF-mediated angiogenesis by the Akt/PKB substrate Girdin. Nat. Cell Biol. 10, 329–337 (2008).

    Article  CAS  PubMed  Google Scholar 

  214. 214

    Mathies, L. D. et al. SWI/SNF chromatin remodeling regulates alcohol response behaviors in Caenorhabditis elegans and is associated with alcohol dependence in humans. Proc. Natl Acad. Sci. USA 112, 3032–3037 (2015).

    Article  CAS  PubMed  Google Scholar 

  215. 215

    Kadrmas, J. L. & Beckerle, M. C. The LIM domain: from the cytoskeleton to the nucleus. Nat. Rev. Mol. Cell Biol. 5, 920–931 (2004).

    Article  CAS  PubMed  Google Scholar 

  216. 216

    Kapoor, M. et al. A meta-analysis of two genome-wide association studies to identify novel loci for maximum number of alcoholic drinks. Hum. Genet. 132, 1141–1151 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  217. 217

    Guevara-Aguirre, J. et al. Growth hormone receptor deficiency is associated with a major reduction in pro-aging signaling, cancer, and diabetes in humans. Sci. Transl Med. 3, 70ra13 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors thank the members of the Ron laboratory and F. W. Hops for thoughtful input and B. Dorn for technical assistance. This Review is supported by the US National Institute on Alcohol Abuse and Alcoholism (NIAAA) of the National Institutes of Health (NIH-NIAAA RO1 AA016848, NIAAA R37 AA016848, NIH-NIAAAP50 AA017072, R01AA014366 and U01AA023489) to D.R. and by the Israel Science Foundation (ISF 968–13 and 1916–13), the Brain & Behavior Research Foundation (NARSAD 19114), the German Israel Foundation (GIF I-2348-105.4/2014) and the National Institute of Psychobiology in Israel (NIPI 110-14-15) to S.B.

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Correspondence to Dorit Ron.

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Glossary

Binge drinking

A drinking pattern in which high quantities of alcohol are consumed in a short amount of time (typically four drinks for women or five drinks for men consumed over approximately 2 hours) that brings blood alcohol concentration (BAC) levels to 80 mg per 100 ml.

MicroRNAs

(miRNAs). Single-stranded non-coding RNA molecules that are about 21–23 nucleotides in length and bind to and target mRNAs for degradation or repress protein translation.

Lipid rafts

Cholesterol- and glycosphingolipid-enriched microdomains within the cell membrane that organize signalling cascades by including or excluding component proteins in response to external stimuli; in the CNS, lipid rafts contribute to the trafficking, clustering and function of neurotransmitter G protein-coupled receptors and ionotropic receptors.

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Ron, D., Barak, S. Molecular mechanisms underlying alcohol-drinking behaviours. Nat Rev Neurosci 17, 576–591 (2016). https://doi.org/10.1038/nrn.2016.85

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