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Alcoholism: Molecular Mechanisms and Treatment Strategies

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Toxicology".

Deadline for manuscript submissions: closed (31 May 2016) | Viewed by 49771

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Special Issue Editor

Dr. Ashok K. Singh

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Guest Editor

Department of Veterinary Population Medicine, College of Veterinary Medicine, University of Minnesota, St. Paul, MN 55108, USA
Interests: nanoparticle synthesis; nanomedicine; nanotoxicology; alcoholism; withdrawal syndrome; inflammation; oxidative stress; puerarin; curcumin; neurotoxicity
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Alcohol is considered the most socially acceptable psychoactive drug in our society. Excessive drinking, including underage drinking and binge drinking, can lead to increased risk of health problems including, but not limited to, addiction (alcoholism), liver diseases, cancer and behavioral disorders. Although some of the adverse effects (liver toxicity, CNS (central nervous system) abnormalities, behavioral abnormalities, etc.) can occur in general population practicing unsafe drinking, not everyone will become an alcoholic (physically dependent on alcohol). Some individuals may have genetic predispositions in their brains that result in a greater tendency to become addicted to alcohol.

The acute effects of alcohol mainly occur via (i) an increase in oxidative stress and (ii) abnormalities in the inhibitory gamma aminobutyric acid (GABA) receptors, the excitatory amino acid (EAA) receptors, and the phosphoinositide (PI) and cyclic nucleotide (cAMP) second messenger systems. The chronic effects of alcohol drinking leading addiction may be due to abnormalities in the brain opioid, dopamine GABA and β-endorphin signaling in genetically predisposed (genetic and epigenetic factors) population. However, the mechanisms that cause one to become alcoholic have not yet been clarified.

Despite serious consequences of alcohol-related health issues, the majority of people with alcohol use disorders go untreated, possibly due to unavailability of medical insurance and/or limited availability, underutilization, or distrust of currently available interventions. A lack of knowledge regarding the therapeutic mechanisms of available treatments hinders strategic development of new interventions.

This Special Issue will focus on the publication of novel research on the molecular mechanisms and treatment strategies of alcoholism. Original manuscripts and critical reviews examining (i) the cellular, molecular, genetic, epigenetic, immunologic, and/or signal transduction mechanisms involved in the development of alcoholism, and (ii) alcohol treatment strategies, are welcome.

Dr. Ashok K. Singh
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

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Keywords

Alcoholism
Addiction
Opioid receptors
GABA receptors
Excitatory amino acid receptors
Phosphoinositide (PI)
Cyclic nucleotide (cAMP)
cAMP responsive element binding protein (CREB)
CREB- gene transcription factor
Genetics
Epigenetics
Alcoholism therapeutic strategies
Detoxification, rehabilitation and maintenance of sobriety
Alternative medicine and pharmacotherapy

Published Papers (6 papers)

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Research

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1708 KiB

Open AccessArticle

The FKBP5 Gene Affects Alcohol Drinking in Knockout Mice and Is Implicated in Alcohol Drinking in Humans

by Bin Qiu, Susan E. Luczak, Tamara L. Wall, Aaron M. Kirchhoff, Yuxue Xu, Mimy Y. Eng, Robert B. Stewart, Weinian Shou, Stephen L. Boehm, Julia A. Chester, Weidong Yong and Tiebing Liang

Int. J. Mol. Sci. 2016, 17(8), 1271; https://doi.org/10.3390/ijms17081271 - 05 Aug 2016

Cited by 24 | Viewed by 10059

Abstract

FKBP5 encodes FK506-binding protein 5, a glucocorticoid receptor (GR)-binding protein implicated in various psychiatric disorders and alcohol withdrawal severity. The purpose of this study is to characterize alcohol preference and related phenotypes in Fkbp5 knockout (KO) mice and to examine the role of FKBP5 in human alcohol consumption. The following experiments were performed to characterize Fkpb5 KO mice. (1) Fkbp5 KO and wild-type (WT) EtOH consumption was tested using a two-bottle choice paradigm; (2) The EtOH elimination rate was measured after intraperitoneal (IP) injection of 2.0 g/kg EtOH; (3) Blood alcohol concentration (BAC) was measured after 3 h limited access of alcohol; (4) Brain region expression of Fkbp5 was identified using LacZ staining; (5) Baseline corticosterone (CORT) was assessed. Additionally, two SNPs, rs1360780 (C/T) and rs3800373 (T/G), were selected to study the association of FKBP5 with alcohol consumption in humans. Participants were college students (n = 1162) from 21–26 years of age with Chinese, Korean or Caucasian ethnicity. The results, compared to WT mice, for KO mice exhibited an increase in alcohol consumption that was not due to differences in taste sensitivity or alcohol metabolism. Higher BAC was found in KO mice after 3 h of EtOH access. Fkbp5 was highly expressed in brain regions involved in the regulation of the stress response, such as the hippocampus, amygdala, dorsal raphe and locus coeruleus. Both genotypes exhibited similar basal levels of plasma corticosterone (CORT). Finally, single nucleotide polymorphisms (SNPs) in FKBP5 were found to be associated with alcohol drinking in humans. These results suggest that the association between FKBP5 and alcohol consumption is conserved in both mice and humans. Full article

(This article belongs to the Special Issue Alcoholism: Molecular Mechanisms and Treatment Strategies)

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1793 KiB

Open AccessArticle

Distinct Effects of Nalmefene on Dopamine Uptake Rates and Kappa Opioid Receptor Activity in the Nucleus Accumbens Following Chronic Intermittent Ethanol Exposure

by Jamie H. Rose, Anushree N. Karkhanis, Björn Steiniger-Brach and Sara R. Jones

Int. J. Mol. Sci. 2016, 17(8), 1216; https://doi.org/10.3390/ijms17081216 - 27 Jul 2016

Cited by 20 | Viewed by 9901

Abstract

The development of pharmacotherapeutics that reduce relapse to alcohol drinking in patients with alcohol dependence is of considerable research interest. Preclinical data support a role for nucleus accumbens (NAc) κ opioid receptors (KOR) in chronic intermittent ethanol (CIE) exposure-induced increases in ethanol intake. Nalmefene, a high-affinity KOR partial agonist, reduces drinking in at-risk patients and relapse drinking in rodents, potentially due to its effects on NAc KORs. However, the effects of nalmefene on accumbal dopamine transmission and KOR function are poorly understood. We investigated the effects of nalmefene on dopamine transmission and KORs using fast scan cyclic voltammetry in NAc brain slices from male C57BL/6J mice following five weeks of CIE or air exposure. Nalmefene concentration-dependently reduced dopamine release similarly in air and CIE groups, suggesting that dynorphin tone may not be present in brain slices. Further, nalmefene attenuated dopamine uptake rates to a greater extent in brain slices from CIE-exposed mice, suggesting that dopamine transporter-KOR interactions may be fundamentally altered following CIE. Additionally, nalmefene reversed the dopamine-decreasing effects of a maximal concentration of a KOR agonist selectively in brain slices of CIE-exposed mice. It is possible that nalmefene may attenuate withdrawal-induced increases in ethanol consumption by modulation of dopamine transmission through KORs. Full article

(This article belongs to the Special Issue Alcoholism: Molecular Mechanisms and Treatment Strategies)

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1154 KiB

Open AccessArticle

Protective Effect of Tyrosol and S-Adenosylmethionine against Ethanol-Induced Oxidative Stress of Hepg2 Cells Involves Sirtuin 1, P53 and Erk1/2 Signaling

by Paola Stiuso, Maria Libera Bagarolo, Concetta Paola Ilisso, Daniela Vanacore, Elisa Martino, Michele Caraglia, Marina Porcelli and Giovanna Cacciapuoti

Int. J. Mol. Sci. 2016, 17(5), 622; https://doi.org/10.3390/ijms17050622 - 26 Apr 2016

Cited by 34 | Viewed by 7952

Abstract

Oxidative stress plays a major role in ethanol-induced liver damage, and agents with antioxidant properties are promising as therapeutic opportunities in alcoholic liver disease. In the present work, we investigated the effect of S-adenosylmethionine (AdoMet), Tyrosol (Tyr), and their combination on HepG2 cells exposed to ethanol exploring the potential molecular mechanisms. We exposed HepG2 cells to 1 M ethanol for 4 and 48 h; thereafter, we recorded a decreased cell viability, increase of intracellular reactive oxygen species (ROS) and lipid accumulation, and the release into culture medium of markers of liver disease such as triacylglycerol, cholesterol, transaminases, albumin, ferritin, and homocysteine. On the other hand, AdoMet and Tyrosol were able to attenuate or antagonize these adverse changes induced by acute exposure to ethanol. The protective effects were paralleled by increased Sirtuin 1 protein expression and nuclear translocation and increased ERK1/2 phosphorylation that were both responsible for the protection of cells from apoptosis. Moreover, AdoMet increased p53 and p21 expression, while Tyrosol reduced p21 expression and enhanced the expression of uncleaved caspase 3 and 9, suggesting that its protective effect may be related to the inhibition of the apoptotic machinery. Altogether, our data show that AdoMet and Tyrosol exert beneficial effects in ethanol-induced oxidative stress in HepG2 cells and provide a rationale for their potential use in combination in the prevention of ethanol-induced liver damage. Full article

(This article belongs to the Special Issue Alcoholism: Molecular Mechanisms and Treatment Strategies)

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Open AccessArticle

Multiplex Immunoassay of Plasma Cytokine Levels in Men with Alcoholism and the Relationship to Psychiatric Assessments

by Ann M. Manzardo, Albert B. Poje, Elizabeth C. Penick and Merlin G. Butler

Int. J. Mol. Sci. 2016, 17(4), 472; https://doi.org/10.3390/ijms17040472 - 29 Mar 2016

Cited by 25 | Viewed by 6764

Abstract

Chronic alcohol use alters adaptive immunity and cytokine activity influencing immunological and hormone responses, inflammation, and wound healing. Brain cytokine disturbances may impact neurological function, mood, cognition and traits related to alcoholism including impulsiveness. We examined the relationship between plasma cytokine levels and self-rated psychiatric symptoms in 40 adult males (mean age 51 ± 6 years; range 33–58 years) with current alcohol dependence and 30 control males (mean age 48 ± 6 years; range 40–58 years) with no history of alcoholism using multiplex sandwich immunoassays with the Luminex magnetic-bead based platform. Log-transformed cytokine levels were analyzed for their relationship with the Symptom Checklist-90R (SCL-90R), Barratt Impulsivity Scales (BIS) and Alcoholism Severity Scale (ASS). Inflammatory cytokines (interferon γ-induced protein-10 (IP-10); monocyte chemoattractant protein-1 (MCP1); regulated on activation, normal T cell expressed and secreted (RANTES)) were significantly elevated in alcoholism compared to controls while bone marrow-derived hematopoietic cytokines and chemokines (granulocyte-colony stimulating factor (GCSF); soluble CD40 ligand (sCD40L); growth-related oncogene (GRO)) were significantly reduced. GRO and RANTES levels were positively correlated with BIS scales; and macrophage-derived chemokine (MDC) levels were positively correlated with SCL-90R scale scores (p < 0.05). Elevated inflammatory mediators in alcoholism may influence brain function leading to increased impulsiveness and/or phobia. The novel association between RANTES and GRO and impulsivity phenotype in alcoholism should be further investigated in alcoholism and psychiatric conditions with core impulsivity and anxiety phenotypes lending support for therapeutic intervention. Full article

(This article belongs to the Special Issue Alcoholism: Molecular Mechanisms and Treatment Strategies)

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7941 KiB

Open AccessArticle

Alcohol Consumption during Pregnancy: Analysis of Two Direct Metabolites of Ethanol in Meconium

by Arantza Sanvisens, Neus Robert, José María Hernández, Paola Zuluaga, Magí Farré, Wifredo Coroleu, Montserrat Serra, Jordi Tor and Robert Muga

Int. J. Mol. Sci. 2016, 17(3), 417; https://doi.org/10.3390/ijms17030417 - 22 Mar 2016

Cited by 9 | Viewed by 6972

Abstract

Alcohol consumption in young women is a widespread habit that may continue during pregnancy and induce alterations in the fetus. We aimed to characterize prevalence of alcohol consumption in parturient women and to assess fetal ethanol exposure in their newborns by analyzing two direct metabolites of ethanol in meconium. This is a cross-sectional study performed in September 2011 and March 2012 in a series of women admitted to an obstetric unit following childbirth. During admission, socio-demographic and substance use (alcohol, tobacco, cannabis, cocaine, and opiates) during pregnancy were assessed using a structured questionnaire and clinical charts. We also recorded the characteristics of pregnancy, childbirth, and neonates. The meconium analysis was performed by liquid chromatography—tandem mass spectrometry (LC-MS/MS) to detect the presence of ethyl glucuronide (EtG) and ethyl sulfate (EtS). Fifty-one parturient and 52 neonates were included and 48 meconium samples were suitable for EtG and EtS detection. The median age of women was 30 years (interquartile range (IQR): 26–34 years); EtG was present in all meconium samples and median concentration of EtG was 67.9 ng/g (IQR: 36.0–110.6 ng/g). With respect to EtS, it was undetectable (<0.01 ng/g) in the majority of samples (79.1%). Only three (6%) women reported alcohol consumption during pregnancy in face-to-face interviews. However, prevalence of fetal exposure to alcohol through the detection of EtG and EtS was 4.2% and 16.7%, respectively. Prevention of alcohol consumption during pregnancy and the detection of substance use with markers of fetal exposure are essential components of maternal and child health. Full article

(This article belongs to the Special Issue Alcoholism: Molecular Mechanisms and Treatment Strategies)

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Review

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627 KiB

Open AccessReview

New Treatment Strategies for Alcohol-Induced Heart Damage

by Joaquim Fernández-Solà and Ana Planavila Porta

Int. J. Mol. Sci. 2016, 17(10), 1651; https://doi.org/10.3390/ijms17101651 - 29 Sep 2016

Cited by 30 | Viewed by 7431

Abstract

High-dose alcohol misuse induces multiple noxious cardiac effects, including myocyte hypertrophy and necrosis, interstitial fibrosis, decreased ventricular contraction and ventricle enlargement. These effects produce diastolic and systolic ventricular dysfunction leading to congestive heart failure, arrhythmias and an increased death rate. There are multiple, dose-dependent, synchronic and synergistic mechanisms of alcohol-induced cardiac damage. Ethanol alters membrane permeability and composition, interferes with receptors and intracellular transients, induces oxidative, metabolic and energy damage, decreases protein synthesis, excitation-contraction coupling and increases cell apoptosis. In addition, ethanol decreases myocyte protective and repair mechanisms and their regeneration. Although there are diverse different strategies to directly target alcohol-induced heart damage, they are partially effective, and can only be used as support medication in a multidisciplinary approach. Alcohol abstinence is the preferred goal, but control drinking is useful in alcohol-addicted subjects not able to abstain. Correction of nutrition, ionic and vitamin deficiencies and control of alcohol-related systemic organ damage are compulsory. Recently, several growth factors (myostatin, IGF-1, leptin, ghrelin, miRNA, and ROCK inhibitors) and new cardiomyokines such as FGF21 have been described to regulate cardiac plasticity and decrease cardiac damage, improving cardiac repair mechanisms, and they are promising agents in this field. New potential therapeutic targets aim to control oxidative damage, myocyte hypertrophy, interstitial fibrosis and persistent apoptosis In addition, stem-cell therapy may improve myocyte regeneration. However, these strategies are not yet approved for clinical use. Full article

(This article belongs to the Special Issue Alcoholism: Molecular Mechanisms and Treatment Strategies)

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