Trends in Pharmacological Sciences
ReviewAlcohol dependence: molecular and behavioral evidence
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 GABAA 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 GABAA 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)
NMR study of volatile anesthetic binding to nicotinic acetylcholine receptors
Biophys. J.
(2000)Microsecond simulations indicate that ethanol binds between subunits and could stabilize an open-state model of a glycine receptor
Biophys. J.
(2011)Linking GABAA receptor subunits to alcohol-induced conditioned taste aversion and recovery from acute alcohol intoxication
Neuropharmacology
(2013)The role of GABAA receptors in the development of alcoholism
Pharmacol. Biochem. Behav.
(2008)Ethanol alters trafficking and functional N-methyl-D-aspartate receptor NR2 subunit ratio via H-Ras
J. Biol. Chem.
(2005)Protein kinase C epsilon regulates GABAA receptor sensitivity to ethanol and benzodiazepines through phosphorylation of gamma 2 subunits
J. Biol. Chem.
(2007)Endogenous positive allosteric modulation of GABAA receptors by diazepam binding inhibitor
Neuron
(2013)GABA neurons of the VTA drive conditioned place aversion
Neuron
(2012)Ethanol's molecular targets
Sci. Signal.
(2008)Seeking structural specificity: direct modulation of pentameric ligand-gated ion channels by alcohols and general anesthetics
Pharmacol. Rev.
(2014)
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
Cited by (76)
Substitution therapy for patients with alcohol dependence: Mechanisms of action and efficacy
2024, International Review of NeurobiologyGABAergic mechanisms in alcohol dependence
2024, International Review of NeurobiologyReducing the harms of alcohol: nutritional interventions and functional alcohol alternatives
2024, International Review of NeurobiologyFGF21 suppresses alcohol consumption through an amygdalo-striatal circuit
2022, Cell MetabolismCitation Excerpt :However, these homeostatic systems are subject to dysregulation due to genetic or environmental factors, which is evident in the high prevalence of alcohol dependence (Edenberg and Foroud, 2013). Efforts to therapeutically target pathways that contribute to regulation of alcohol consumption (i.e., ethanol metabolism [Haass-Koffler et al., 2017], reward signaling [Koob et al., 1998], or neuropeptide signaling [Thiele, 2017]) with the goal of cessation of alcohol consumption have been limited in their efficacy to effectively treat alcohol use disorder (AUD) (Pomrenze et al., 2017; Swift and Aston, 2015; Trudell et al., 2014). Recently, genome-wide association studies identified multiple SNPs in the genes FGF21 (Soberg et al., 2017) and KLB (Clarke et al., 2017; Jorgenson et al., 2017; Kranzler et al., 2019; Mallard et al., 2021; Sanchez-Roige et al., 2019; Schumann et al., 2016) as being associated with increased alcohol consumption in humans.
Pharmacology of Alcohol Use
2022, Comprehensive Pharmacology