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.
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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World Health Organization. Global status report on alcohol and health 2014 (WHO, 2014).
Enoch, M. A. & Goldman, D. Problem drinking and alcoholism: diagnosis and treatment. Am. Fam. Physician 65, 441–448 (2002).
American Psychiatric Association. The Diagnostic and Statistical Manual of Mental Disorders DSM-5 5th edn (American Psychiatric Publishing, 2013).
Koob, G. F. & Volkow, N. D. Neurocircuitry of addiction. Neuropsychopharmacology 35, 217–238 (2010).
Koob, G. F. in Behavioral Neurobiology of Alcohol Addiction (eds Sommer, W. H. & Spanagel, R.) 3–30 (Springer, 2013).
Wise, R. A. & Koob, G. F. The development and maintenance of drug addiction. Neuropsychopharmacology 39, 254–262 (2014).
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).
Torregrossa, M. M., Corlett, P. R. & Taylor, J. R. Aberrant learning and memory in addiction. Neurobiol. Learn. Mem. 96, 609–623 (2011).
Crews, F. T. & Vetreno, R. P. Neuroimmune basis of alcoholic brain damage. Int. Rev. Neurobiol. 118, 315–357 (2014).
Ron, D. & Messing, R. O. in Behavioral Neurobiology of Alcohol Addiction (eds Sommer, W. H. & Spanagel, R.) 87–126 (Springer, 2013).
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).
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).
Abel, T. & Nguyen, P. V. Regulation of hippocampus-dependent memory by cyclic AMP-dependent protein kinase. Prog. Brain Res. 169, 97–115 (2008).
Kandel, E. R. The molecular biology of memory: cAMP, PKA, CRE, CREB-1, CREB-2, and CPEB. Mol. Brain 5, 14 (2012).
Lee, A. M. & Messing, R. O. Protein kinases and addiction. Ann. NY Acad. Sci. 1141, 22–57 (2008).
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).
Maas, J. W. Jr. et al. Calcium-stimulated adenylyl cyclases are critical modulators of neuronal ethanol sensitivity. J. Neurosci. 25, 4118–4126 (2005).
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.
Mailliard, W. S. & Diamond, I. Recent advances in the neurobiology of alcoholism: the role of adenosine. Pharmacol. Ther. 101, 39–46 (2004).
Choi, D. S. et al. The type 1 equilibrative nucleoside transporter regulates ethanol intoxication and preference. Nat. Neurosci. 7, 855–861 (2004).
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).
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).
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).
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).
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).
Ohnishi, H., Murata, Y., Okazawa, H. & Matozaki, T. Src family kinases: modulators of neurotransmitter receptor function and behavior. Trends Neurosci. 34, 629–637 (2011).
Trepanier, C. H., Jackson, M. F. & MacDonald, J. F. Regulation of NMDA receptors by the tyrosine kinase Fyn. FEBS J. 279, 12–19 (2012).
Goebel-Goody, S. M. et al. Therapeutic implications for striatal-enriched protein tyrosine phosphatase (STEP) in neuropsychiatric disorders. Pharmacol. Rev. 64, 65–87 (2012).
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.
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).
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).
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).
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).
Coultrap, S. J. & Bayer, K. U. CaMKII regulation in information processing and storage. Trends Neurosci. 35, 607–618 (2012).
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).
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.
Malinow, R. & Malenka, R. C. AMPA receptor trafficking and synaptic plasticity. Annu. Rev. Neurosci. 25, 103–126 (2002).
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).
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).
Ben Hamida, S. et al. Protein tyrosine phosphatase α in the dorsomedial striatum promotes excessive ethanol-drinking behaviors. J. Neurosci. 33, 14369–14378 (2013).
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).
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).
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).
Feig, L. A. Regulation of neuronal function by Ras-GRF exchange factors. Genes Cancer 2, 306–319 (2011).
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).
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.
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.
Manning, B. D. & Cantley, L. C. AKT/PKB signaling: navigating downstream. Cell 129, 1261–1274 (2007).
Cozzoli, D. K. et al. Binge drinking upregulates accumbens mGluR5–Homer2–PI3K signaling: functional implications for alcoholism. J. Neurosci. 29, 8655–8668 (2009).
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).
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).
Buffington, S. A., Huang, W. & Costa-Mattioli, M. Translational control in synaptic plasticity and cognitive dysfunction. Annu. Rev. Neurosci. 37, 17–38 (2014).
Hoeffer, C. A. & Klann, E. mTOR signaling: at the crossroads of plasticity, memory and disease. Trends Neurosci. 33, 67–75 (2010).
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).
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).
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).
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.
Azzi, A., Boscoboinik, D. & Hensey, C. The protein kinase C family. Eur. J. Biochem. 208, 547–557 (1992).
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.
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).
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).
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).
Lesscher, H. M. et al. Amygdala protein kinase C epsilon controls alcohol consumption. Genes Brain Behav. 8, 493–499 (2009).
Janak, P. H. & Tye, K. M. From circuits to behaviour in the amygdala. Nature 517, 284–292 (2015).
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).
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).
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).
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).
Johnson, G. L. & Lapadat, R. Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science 298, 1911–1912 (2002).
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).
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).
Yoshii, A. & Constantine-Paton, M. Postsynaptic BDNF-TrkB signaling in synapse maturation, plasticity, and disease. Dev. Neurobiol. 70, 304–322 (2010).
Airaksinen, M. S. & Saarma, M. The GDNF family: signalling, biological functions and therapeutic value. Nat. Rev. Neurosci. 3, 383–394 (2002).
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.
Logrip, M. L., Janak, P. H. & Ron, D. Escalating ethanol intake is associated with altered corticostriatal BDNF expression. J. Neurochem. 109, 1459–1468 (2009).
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).
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).
Logrip, M. L., Barak, S., Warnault, V. & Ron, D. Corticostriatal BDNF and alcohol addiction. Brain Res. 1628, 60–67 (2015).
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).
Jeanblanc, J. et al. Endogenous BDNF in the dorsolateral striatum gates alcohol drinking. J. Neurosci. 29, 13494–13502 (2009).
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).
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.
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).
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.
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).
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).
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).
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).
Jeanblanc, J. et al. The dopamine D3 receptor is part of a homeostatic pathway regulating ethanol consumption. J. Neurosci. 26, 1457–1464 (2006).
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).
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).
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).
Stragier, E. et al. Ethanol-induced epigenetic regulations at the Bdnf gene in C57BL/6J mice. Mol. Psychiatry 20, 405–412 (2014).
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.
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).
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.
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).
Heberlein, A. et al. BDNF and GDNF serum levels in alcohol-dependent patients during withdrawal. Prog. Neuropsychopharmacol. Biol. Psychiatry 34, 1060–1064 (2010).
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).
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).
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).
Matsushita, S. et al. Association study of brain-derived neurotrophic factor gene polymorphism and alcoholism. Alcohol. Clin. Exp. Res. 28, 1609–1612 (2004).
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).
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).
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).
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).
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).
Karatsoreos, I. N. Links between circadian rhythms and psychiatric disease. Front. Behav. Neurosci. 8, 162 (2014).
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).
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).
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.
Blomeyer, D. et al. Association of PER2 genotype and stressful life events with alcohol drinking in young adults. PLoS ONE 8, e59136 (2013).
Ozburn, A. R. et al. The role of clock in ethanol-related behaviors. Neuropsychopharmacology 38, 2393–2400 (2013).
Eide, E. J. et al. Control of mammalian circadian rhythm by CKIε-regulated proteasome-mediated PER2 degradation. Mol. Cell. Biol. 25, 2795–2807 (2005).
Perreau-Lenz, S. et al. Inhibition of the casein-kinase-1-epsilon/delta/ prevents relapse-like alcohol drinking. Neuropsychopharmacology 37, 2121–2131 (2012).
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).
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).
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).
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).
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).
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).
Heilig, M. The NPY system in stress, anxiety and depression. Neuropeptides 38, 213–224 (2004).
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).
Bell, R. L. et al. Ibudilast reduces alcohol drinking in multiple animal models of alcohol dependence. Addict. Biol. 20, 38–42 (2015).
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).
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).
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).
Logrip, M. L. & Zorrilla, E. P. Stress history increases alcohol intake in relapse: relation to phosphodiesterase 10A. Addict. Biol. 17, 920–933 (2012).
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).
Lee, A. M. et al. Deletion of Prkcz increases intermittent ethanol consumption in mice. Alcohol. Clin. Exp. Res. 38, 170–178 (2014).
Lee, A. M. et al. Prkcz null mice show normal learning and memory. Nature 493, 416–419 (2013).
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).
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).
Lasek, A. W. et al. An evolutionary conserved role for anaplastic lymphoma kinase in behavioral responses to ethanol. PLoS ONE 6, e22636 (2011).
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).
Bos, J. L., Rehmann, H. & Wittinghofer, A. GEFs and GAPs: critical elements in the control of small G proteins. Cell 129, 865–877 (2007).
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).
Nestler, E. J. Epigenetic mechanisms of drug addiction. Neuropharmacology 76, 259–268 (2014).
Bali, P. & Kenny, P. J. MicroRNAs and drug addiction. Front. Genet. 4, 43 (2013).
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).
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).
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.
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).
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.
Zhang, R. et al. Genome-wide DNA methylation analysis in alcohol dependence. Addict. Biol. 18, 392–403 (2013).
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.
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).
Heberlein, A. et al. Epigenetic down regulation of nerve growth factor during alcohol withdrawal. Addict. Biol. 18, 508–510 (2013).
Heberlein, A. et al. Do changes in the BDNF promoter methylation indicate the risk of alcohol relapse? Eur. Neuropsychopharmacol. 25, 1892–1897 (2015).
Bothwell, M. in Neurotrophic Factors (eds Lewin, G. R. & Carter, B. D.) 3–15 (Springer, 2014).
Miranda, R. C. et al. MicroRNAs: master regulators of ethanol abuse and toxicity? Alcohol. Clin. Exp. Res. 34, 575–587 (2010).
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).
Nunez, Y. O. & Mayfield, R. D. Understanding alcoholism through microRNA signatures in brains of human alcoholics. Front. Genet. 3, 43 (2012).
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.
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).
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).
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).
Lewohl, J. M. et al. Up-regulation of microRNAs in brain of human alcoholics. Alcohol. Clin. Exp. Res. 35, 1928–1937 (2011).
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).
Pickens, C. L. et al. Neurobiology of the incubation of drug craving. Trends Neurosci. 34, 411–420 (2011).
Berridge, K. C. & Kringelbach, M. L. Pleasure systems in the brain. Neuron 86, 646–664 (2015).
Volkow, N. D. & Morales, M. The brain on drugs: from reward to addiction. Cell 162, 712–725 (2015).
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).
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).
Koob, G. F. & Le Moal, M. Drug addiction, dysregulation of reward, and allostasis. Neuropsychopharmacology 24, 97–129 (2001).
Wise, R. A. Roles for nigrostriatal—not just mesocorticolimbic—dopamine in reward and addiction. Trends Neurosci. 32, 517–524 (2009).
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).
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).
Heimer, L. & Alheid, G. F. in The Basal Forebrain (eds Napier, T. C., Kalivas, P. W. & Hanin, I.) 1–42 (Springer, 1991).
Koob, G. F. Brain stress systems in the amygdala and addiction. Brain Res. 1293, 61–75 (2009).
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).
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).
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).
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).
Doupe, D. P. & Perrimon, N. Visualizing and manipulating temporal signaling dynamics with fluorescence-based tools. Sci. Signal. 7, re1 (2014).
Wend, S. et al. Optogenetic control of protein kinase activity in mammalian cells. ACS Synth. Biol. 3, 280–285 (2014).
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.
Trudell, J. R., Messing, R. O., Mayfield, J. & Harris, R. A. Alcohol dependence: molecular and behavioral evidence. Trends Pharmacol. Sci. 35, 317–323 (2014).
Holmes, A., Spanagel, R. & Krystal, J. H. Glutamatergic targets for new alcohol medications. Psychopharmacology 229, 539–554 (2013).
Allen, J. A., Halverson-Tamboli, R. A. & Rasenick, M. M. Lipid raft microdomains and neurotransmitter signalling. Nat. Rev. Neurosci. 8, 128–140 (2007).
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).
Chin, J. H. & Goldstein, D. B. Electron paramagnetic resonance studies of ethanol on membrane fluidity. Adv. Exp. Med. Biol. 85A, 111–122 (1977).
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).
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).
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).
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).
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).
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).
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).
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).
Millan, E. Z., Furlong, T. M. & McNally, G. P. Accumbens shell–hypothalamus interactions mediate extinction of alcohol seeking. J. Neurosci. 30, 4626–4635 (2010).
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).
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.
Carnicella, S. et al. Cabergoline decreases alcohol drinking and seeking behaviors via glial cell line-derived neurotrophic factor. Biol. Psychiatry 66, 146–153 (2009).
Dancey, J. mTOR signaling and drug development in cancer. Nat. Rev. Clin. Oncol. 7, 209–219 (2010).
Sanchis-Segura, C. & Spanagel, R. Behavioural assessment of drug reinforcement and addictive features in rodents: an overview. Addict. Biol. 11, 2–38 (2006).
Carnicella, S., Ron, D. & Barak, S. Intermittent ethanol access schedule in rats as a preclinical model of alcohol abuse. Alcohol 48, 243–252 (2014).
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).
Griffin, W. C. III. Alcohol dependence and free-choice drinking in mice. Alcohol 48, 287–293 (2014).
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).
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).
Vendruscolo, L. F. & Roberts, A. J. Operant alcohol self-administration in dependent rats: focus on the vapor model. Alcohol 48, 277–286 (2014).
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).
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).
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).
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).
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).
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.
Ojelade, S. A. et al. Rsu1 regulates ethanol consumption in Drosophila and humans. Proc. Natl Acad. Sci. USA 112, E4085–E4093 (2015).
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).
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).
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).
Kitamura, T. et al. Regulation of VEGF-mediated angiogenesis by the Akt/PKB substrate Girdin. Nat. Cell Biol. 10, 329–337 (2008).
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).
Kadrmas, J. L. & Beckerle, M. C. The LIM domain: from the cytoskeleton to the nucleus. Nat. Rev. Mol. Cell Biol. 5, 920–931 (2004).
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).
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).
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.
The authors declare no competing financial interests.
- 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.
(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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