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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.

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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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