Alcohol dependence: molecular and behavioral evidence

doi:10.1016/j.tips.2014.04.009

Trends in Pharmacological Sciences

Volume 35, Issue 7, July 2014, Pages 317-323

https://doi.org/10.1016/j.tips.2014.04.009 Get rights and content

Highlights

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Structural, computer modeling, and mutagenesis studies reveal direct sites for alcohol on ligand-gated ion channels (LGICs).
•
Alcohol alters ion channel function indirectly via receptor phosphorylation and trafficking.
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Mutant mice and genetic association studies demonstrate the role of LGICs in alcohol dependence.
•
Combining structural, functional, behavioral, and genomic approaches is crucial for identifying sites of alcohol action.

Alcohol dependence is a complex condition with clear genetic factors. Some of the leading candidate genes code for subunits of the inhibitory GABA_A and glycine receptors. These and related ion channels are also targets for the acute actions of alcohol, and there is considerable progress in understanding interactions of alcohol with these proteins at the molecular and even atomic levels. X-ray structures of open and closed states of ion channels combined with structural modeling and site-directed mutagenesis have elucidated direct actions of alcohol. Alcohol also alters channel function by translational and post-translational mechanisms, including phosphorylation and protein trafficking. Construction of mutant mice with either deletion of key proteins or introduction of alcohol-resistant channels has further linked specific proteins with discrete behavioral effects of alcohol. A combination of approaches, including genome wide association studies in humans, continues to advance the molecular basis of alcohol action on receptor structure and function.

Section snippets

Molecular targets of alcohol

The pathway from an initial drink of alcohol (ethanol) to dependence is a long and complex one. However, in recent years there has been much progress in understanding the complexity and dynamicity of the acute and chronic mechanisms at play. This review describes the acute actions and chronic, persistent adaptations of alcohol, encompassing the structural, protein, intracellular, and genomic targets implicated in alcohol dependence. First, some of the rapid-onset effects of alcohol are probably

Translating protein interactions into behavior

The structural studies discussed above clearly demonstrate molecular sites where ethanol can interact with key brain proteins, particularly ion channels, to alter their function. This raises the key question of which (if any) of these target proteins account for specific behavioral actions of ethanol. Two widely used approaches to link specific proteins with behavior are genetic deletion of a protein in a null mutant or knockout mouse and viral delivery of inhibitory RNAs or other RNAs to

Ethanol modulation via receptor phosphorylation

Although there is structural, molecular, and behavioral evidence for direct actions of alcohol on ion channels, alcohol can also indirectly regulate ion channel function (and presumably behavior) by altering post-translational processing or protein trafficking. For example, ethanol alters the function of the related non-receptor protein tyrosine kinases Src and Fyn, which modulate NMDA receptors and synaptic plasticity [44]. Ethanol inhibits Src in hippocampal neurons, causing internalization

Ethanol modulation of receptor trafficking

Ethanol activates signaling pathways that induce receptor trafficking and can change the composition of receptors at synapses and extrasynaptic sites. For example, a single intoxicating dose of ethanol rapidly decreases extrasynaptic GABA_A receptors that contain α4 and δ subunits in hippocampal pyramidal neurons, which may contribute to acute tolerance to ethanol 57, 58. Several hours later, there is also reduced synaptic GABA_A receptor function that is due to internalization of α1 subunits, a

Concluding remarks

Convergent results from several structural and computational approaches show that alcohol can occupy discrete water-filled cavities in LGICs and thereby alter their function. Cys-loop receptor homologs from lower organisms have proved particularly valuable in modeling structural and functional channel properties in this family in unprecedented detail. A major limitation in characterizing ethanol modulation of LGICs at a molecular level is the absence of high-resolution structural data for human

Acknowledgments

The authors acknowledge funding from the following National Institutes of Health (NIH) grants: AA06399 to R.A.H.; AA018316, AA013588, and AA017072 to R.O.M; and R01AA013378 to J.R.T.

References (66)

Y. Xu
NMR study of volatile anesthetic binding to nicotinic acetylcholine receptors
Biophys. J.
(2000)
S. Murail
Microsecond simulations indicate that ethanol binds between subunits and could stabilize an open-state model of a glycine receptor
Biophys. J.
(2011)
Y.A. Blednov
Linking GABA_A receptor subunits to alcohol-induced conditioned taste aversion and recovery from acute alcohol intoxication
Neuropharmacology
(2013)
M.A. Enoch
The role of GABA_A receptors in the development of alcoholism
Pharmacol. Biochem. Behav.
(2008)
N. Suvarna
Ethanol alters trafficking and functional N-methyl-D-aspartate receptor NR2 subunit ratio via H-Ras
J. Biol. Chem.
(2005)
Z.H. Qi
Protein kinase C epsilon regulates GABA_A receptor sensitivity to ethanol and benzodiazepines through phosphorylation of gamma 2 subunits
J. Biol. Chem.
(2007)
C.A. Christian
Endogenous positive allosteric modulation of GABA_A receptors by diazepam binding inhibitor
Neuron
(2013)
K.R. Tan
GABA neurons of the VTA drive conditioned place aversion
Neuron
(2012)
R.A. Harris
Ethanol's molecular targets
Sci. Signal.
(2008)
R.J. Howard
Seeking structural specificity: direct modulation of pentameric ligand-gated ion channels by alcohols and general anesthetics
Pharmacol. Rev.
(2014)

D.I. Perkins

Charge and geometry of residues in the loop 2 β hairpin differentially affect agonist and ethanol sensitivity in glycine receptors

J. Pharmacol. Exp. Ther.

(2012)

D. Ron et al.

Signaling pathways mediating alcohol effects

Curr. Top. Behav. Neurosci.

(2013)

I. Ponomarev

Gene coexpression networks in human brain identify epigenetic modifications in alcohol dependence

J. Neurosci.

(2012)

G. Gorini

Proteomic approaches and identification of novel therapeutic targets for alcoholism

Neuropsychopharmacology

(2014)

C.M. Borghese

Characterization of two mutations, M287L and Q266I, in the alpha1 glycine receptor subunit that modify sensitivity to alcohols

J. Pharmacol. Exp. Ther.

(2012)

R.J. Howard

Structural basis for alcohol modulation of a pentameric ligand-gated ion channel

Proc. Natl. Acad. Sci. U.S.A.

(2011)

R.J. Howard

Alcohol-binding sites in distinct brain proteins: the quest for atomic level resolution

Alcohol. Clin. Exp. Res.

(2011)

K. Bodhinathan et al.

Molecular mechanism underlying ethanol activation of G-protein-gated inwardly rectifying potassium channels

Proc. Natl. Acad. Sci. U.S.A.

(2013)

G. Weber

Biological specificity and ligand binding. Biological specificity in ligand binding

Protein Interactions

(1992)

J.R. Trudell et al.

Localization of molecular halothane in phospholipid bilayer model nerve membranes

Anesthesiology

(1976)

T.W. Schwartz et al.

Structural biology: a moving story of receptors

Nature

(2008)

E.J. Bertaccini

Effect of cobratoxin binding on the normal mode vibration within acetylcholine binding protein

J. Chem. Inf. Model.

(2008)

R.W. Olsen

Structural models of ligand-gated ion channels: sites of action for anesthetics and ethanol

Alcohol. Clin. Exp. Res.

(2014)

J.R. Trudell

Teaching an old GABA receptor new tricks

Anesth. Analg.

(2012)

L. Sauguet

Structural basis for potentiation by alcohols and anaesthetics in a ligand-gated ion channel

Nat. Commun.

(2013)

S.W. Kruse

Structure of a specific alcohol-binding site defined by the odorant binding protein LUSH from Drosophila melanogaster

Nat. Struct. Biol.

(2003)

E.J. Bertaccini

Normal-mode analysis of the glycine alpha1 receptor by three separate methods

J. Chem. Inf. Model.

(2007)

E.J. Bertaccini

Modeling anesthetic binding sites within the glycine alpha one receptor based on prokaryotic ion channel templates: the problem with TM4

J. Chem. Inf. Model.

(2010)

Y.A. Blednov

Behavioral actions of alcohol: phenotypic relations from multivariate analysis of mutant mouse data

Genes Brain Behav.

(2012)

H. Nie

Extrasynaptic delta-containing GABA_A receptors in the nucleus accumbens dorsomedial shell contribute to alcohol intake

Proc. Natl. Acad. Sci. U.S.A.

(2011)

M. Rewal

Alpha4-containing GABA_A receptors in the nucleus accumbens mediate moderate intake of alcohol

J. Neurosci.

(2009)

Y.A. Blednov

Loss of ethanol conditioned taste aversion and motor stimulation in knockin mice with ethanol-insensitive alpha2-containing GABA_A receptors

J. Pharmacol. Exp. Ther.

(2011)

C.R. den Hartog

Alterations in ethanol-induced behaviors and consumption in knock-in mice expressing ethanol-resistant NMDA receptors

PLoS ONE

(2013)

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Trends in Pharmacological Sciences

ReviewAlcohol dependence: molecular and behavioral evidence

Highlights

Section snippets

Molecular targets of alcohol

Translating protein interactions into behavior

Ethanol modulation via receptor phosphorylation

Ethanol modulation of receptor trafficking

Concluding remarks

Acknowledgments

Biophys. J.

Biophys. J.

Neuropharmacology

Pharmacol. Biochem. Behav.

J. Biol. Chem.

J. Biol. Chem.

Neuron

Neuron

Ethanol's molecular targets

Sci. Signal.

Seeking structural specificity: direct modulation of pentameric ligand-gated ion channels by alcohols and general anesthetics

Pharmacol. Rev.

Charge and geometry of residues in the loop 2 β hairpin differentially affect agonist and ethanol sensitivity in glycine receptors

J. Pharmacol. Exp. Ther.

Signaling pathways mediating alcohol effects

Curr. Top. Behav. Neurosci.

Gene coexpression networks in human brain identify epigenetic modifications in alcohol dependence

J. Neurosci.

Proteomic approaches and identification of novel therapeutic targets for alcoholism

Neuropsychopharmacology

Characterization of two mutations, M287L and Q266I, in the alpha1 glycine receptor subunit that modify sensitivity to alcohols

J. Pharmacol. Exp. Ther.

Structural basis for alcohol modulation of a pentameric ligand-gated ion channel

Proc. Natl. Acad. Sci. U.S.A.

Alcohol-binding sites in distinct brain proteins: the quest for atomic level resolution

Alcohol. Clin. Exp. Res.

Molecular mechanism underlying ethanol activation of G-protein-gated inwardly rectifying potassium channels

Proc. Natl. Acad. Sci. U.S.A.

Biological specificity and ligand binding. Biological specificity in ligand binding

Protein Interactions

Localization of molecular halothane in phospholipid bilayer model nerve membranes

Anesthesiology

Structural biology: a moving story of receptors

Nature

Effect of cobratoxin binding on the normal mode vibration within acetylcholine binding protein

J. Chem. Inf. Model.

Structural models of ligand-gated ion channels: sites of action for anesthetics and ethanol

Alcohol. Clin. Exp. Res.

Teaching an old GABA receptor new tricks

Anesth. Analg.

Structural basis for potentiation by alcohols and anaesthetics in a ligand-gated ion channel

Nat. Commun.

Structure of a specific alcohol-binding site defined by the odorant binding protein LUSH from Drosophila melanogaster

Nat. Struct. Biol.

Normal-mode analysis of the glycine alpha1 receptor by three separate methods

J. Chem. Inf. Model.

Modeling anesthetic binding sites within the glycine alpha one receptor based on prokaryotic ion channel templates: the problem with TM4

J. Chem. Inf. Model.

Behavioral actions of alcohol: phenotypic relations from multivariate analysis of mutant mouse data

Genes Brain Behav.

Extrasynaptic delta-containing GABAA receptors in the nucleus accumbens dorsomedial shell contribute to alcohol intake

Proc. Natl. Acad. Sci. U.S.A.

Alpha4-containing GABAA receptors in the nucleus accumbens mediate moderate intake of alcohol

J. Neurosci.

Loss of ethanol conditioned taste aversion and motor stimulation in knockin mice with ethanol-insensitive alpha2-containing GABAA receptors

J. Pharmacol. Exp. Ther.

Alterations in ethanol-induced behaviors and consumption in knock-in mice expressing ethanol-resistant NMDA receptors

PLoS ONE

Review
Alcohol dependence: molecular and behavioral evidence

Extrasynaptic delta-containing GABA_A receptors in the nucleus accumbens dorsomedial shell contribute to alcohol intake

Alpha4-containing GABA_A receptors in the nucleus accumbens mediate moderate intake of alcohol

Loss of ethanol conditioned taste aversion and motor stimulation in knockin mice with ethanol-insensitive alpha2-containing GABA_A receptors