Excessive Ethanol Consumption Research Articles

Methylsulfonylmethane Protects Against Ethanol-Induced Brain Injury in Mice Through the Inhibition of Oxidative Stress, Proinflammatory Mediators and Apoptotic Cell Death

Excessive ethanol consumption causes brain injury through oxidative stress, inflammation and apoptotic cell death. Methylsulfonylmethane (MSM) is a natural compound that has therapeutic effects on oxidative and inflammatory disorders. The aim of this study was to investigate the protective effect and underlying mechanisms of MSM on ethanol-induced brain injury in an experimental model. Male C57BL/6 mice were exposed to binge ethanol (5 g/kg/day, orally) and treated with MSM (200 and 400 mg/kg/day) concomitantly for 12 days. At the end of the experiment brain tissues were removed for biochemical analysis. The results showed that MSM reduced ethanol-mediated oxidative stress by decreasing the levels of malondialdehyde (MDA) and carbonyl protein. The Nrf2/HO-1 pathway and the levels of cytoprotective antioxidants superoxide dismutase (SOD), catalase and glutathione (GSH) were increased by MSM in the brain tissue. MSM treatment reduced the ethanol-induced inflammatory factors including myeloperoxidase (MPO), iNOS/NO, cyclooxygenase (COX)-2, nuclear factor kappa B (NF-κB), NLRP3 inflammasome and proinflammatory cytokines including TNF-α, IL-1β, IL-6 and MCP-1. MSM also decreased the levels of pro-apoptotic caspase-3 and TUNEL positive cells while increased the level of anti-apoptotic Bcl-2 in the brain tissue. Our findings demonstrated that MSM protects against ethanol-induced brain injury by improving anti-oxidant defense mechanism and reducing ethanol-mediated inflammation and apoptosis. Therefore, MSM may be a potential protective approach for brain damage caused by high levels of alcohol.

Gentiopicroside ameliorates ethanol-induced gastritis via regulating MMP-10 and pERK1/2 signaling

Background: Excessive ethanol consumption results in gastric mucosa damage, which could further develop into chronic gastritis, peptic ulcer, and gastric cancer in humans. Gentiopicroside (GPS), a major active component of Gentianae Macrophyllae radix, was reported to play a critical role in anti-inflammation. In the study, we aimed to investigate the functional role and underlying mechanism of GPS in ethanol-induced gastritis. Methods: A model of gastritis was created by ethanol in C57BL/6 mice. Enzyme-linked immunosorbent assay was used to determine the concentration of TNF-α, IL-1β, IL-8, and IL-10. Results: We found that GPS treatment significantly ameliorated ethanol-induced gastritis in mice, with lower production of pro-inflammatory cytokine TNF-α, IL-1β, and IL-8 and higher levels of anti-inflammatory cytokine IL-10. The anti-inflammatory effect of GPS was further confirmed in vitro in ethanol-treated human gastric mucosal GES cells. Mechanistically, we demonstrated that GPS regulated matrix metallopeptidase expression and pERK1/2 signaling. Knockdown of matrix metallopeptidase 10 (MMP-10) greatly improved cell survival and suppressed inflammatory response in ethanol-treated GES cells. Moreover, inhibition of pERK1/2 signaling using U0126 decreased the expression of MMP-10 in ethanol-induced gastritis. U0126 treatment also suppressed the expression of TNF-α, IL-1β, and IL-8, and enhanced IL-10 expression in mice gastric mucosa. Conclusions: Taken together, our findings suggest that GPS ameliorates ethanol-induced gastritis via regulating MMP-10 and pERK1/2 signaling, which might provide a promising therapeutic drug for ethanol-induced gastritis.

Calcitriol alleviates ethanol-induced hepatotoxicity via AMPK/mTOR-mediated autophagy

Excessive ethanol consumption causes cellular damage, leading to fetal alcohol syndrome and alcohol liver diseases, which are frequently seen with vitamin D (VD) deficiency. A great deal of progress has been achieved in the mechanisms of ethanol-induced hepatocyte damage. However, there are limited intervention means to reduce or rescue hepatocytes damage caused by ethanol. On the basis of our preliminary limited screen process, calcitriol showed a positive effect on protecting hepatocyte viability. Therefore, the molecular basis is worth elucidating. We found that calcitriol pretreatment markedly improved the cell viability, decreased cell apoptosis and oxidative stress and alleviated the abnormal mitochondrial morphology and membrane potential of hepatocytes induced by ethanol. Notably, autophagy was significantly enhanced by calcitriol, as evident by the increasing number of autophagosomes and autolysosomes, upregulated LC3B-Ⅱ and ATG5 levels, and promotion of p62 degradation. Furthermore, calcitriol pretreatment increased the colocalization of GFP-LC3-labeled autophagosomes with mitochondria, suggesting that calcitriol effectively promoted ethanol-induced mitophagy in hepatocytes. In addition, the inhibition of autophagy attenuated the protective and preventive effect of calcitriol. Furthermore, the effect of calcitriol on autophagy was regulated by AMPK/mTOR signaling, and signaling transduction was dependent on the Vitamin D receptor (VDR). In conclusion, calcitriol ameliorates ethanol-induced hepatocyte damage by enhancing autophagy. It may offer a convenient preventive and hepatoprotective mean for people on occasional social drink.

Dendropanax morbifera Leaf Extracts Improved Alcohol Liver Injury in Association with Changes in the Gut Microbiota of Rats.

This study evaluated the protective effects of Dendropanax morbifera leaf (DML) extracts in the liver due to excessive ethanol consumption. Our results showed that the ethanol extract had better antioxidant activity than the water extract, likely due to the higher levels of total flavonoid and phenolic compounds in the former. We found that the main phenolic acid was chlorogenic acid and the major flavonoid was rutin. Results from the animal model experiment showed concentration-dependent liver protection with the distilled water extract showing better liver protection than the ethanol extract. Gut microbiota dysbiosis induced by alcohol consumption was significantly shifted by DML extracts through increasing mainly Bacteroides and Allobaculum. Moreover, predicted metabolic activities of biosynthesis of beneficial monounsaturated fatty acids such as oleate and palmitoleate were enhanced. Our results suggest that these hepatoprotective effects are likely due to the increased activities of antioxidant enzymes and partially promoted by intestinal microbiota shifts.

The risk of developing psoriasis in alcohol-dependent patients and possible therapeutic strategies

Excessive alcohol consumption significantly contributes to the damage of the nervous, cardiovascular and digestive systems. According to the latest scientific reports, excessive ethanol consumption might also contribute to an increased risk of developing skin diseases such as rosacea, porphyria cutanea tarda or psoriasis. The risk of developing psoriasis in alcohol-dependent patients is estimated at 3.1-3.4%. Among these people, in addition to the use of traditional therapeutic strategies, therapy with drugs acting on the neurotransmitter systems may constitute a potential treatment. Chronic alcohol consumption increases the activation of T lymphocytes as well as the level of tumor necrosis factor-α (TNF-α) and also stimulates the excessive proliferation of keratinocytes. These factors dysregulate the immune system, predisposing to the risk of developing psoriasis. Alcohol also interferes with signaling through neurotransmission affecting dopaminergic and serotonergic systems, which may affect the immune processes in the pathogenesis of psoriasis. The results of the research showed that the daily consumption of alcohol in an amount greater than 80 grams significantly reduces the effectiveness of treatment in psoriatic patients. Moreover, traditional drugs used in the course of psoriasis (retinoids, methotrexate, cyclosporine) may show reduced activity or even lead to toxic side effects (liver fibrosis) if alcohol is not discontinued during therapy. Treatment of psoriatic patients and coexisting alcohol dependence is a separate therapeutic problem. In addition to traditional methods, drugs that affect the neurotransmitter system may become a chance, mainly due to the influence of alcohol on these systems and modulation of the immune response, which is important in the development of psoriasis.

Phenotypic and gene expression features associated with variation in chronic ethanol consumption in heterogeneous stock collaborative cross mice

Of the more than 100 studies that have examined relationships between excessive ethanol consumption and the brain transcriptome, few rodent studies have examined chronic consumption. Heterogeneous stock collaborative cross mice freely consumed ethanol vs. water for 3 months. Transcriptional differences were examined for the central nucleus of the amygdala, a brain region known to impact ethanol preference. Early preference was modestly predictive of final preference and there was significant escalation of preference in females only. Genes significantly correlated with female preference were enriched in annotations for the primary cilium and extracellular matrix. A single module in the gene co-expression network was enriched in genes with an astrocyte annotation. The key hub node was the master regulator, orthodenticle homeobox 2 (Otx2). These data support an important role for the extracellular matrix, primary cilium and astrocytes in ethanol preference and consumption differences among individual female mice of a genetically diverse population.

Role of toll-like receptor 7 (TLR7) in voluntary alcohol consumption

Overactivation of neuroimmune signaling has been linked to excessive ethanol consumption. Toll-like receptors (TLRs) are a major component of innate immune signaling and initiate anti- and pro-inflammatory responses via intracellular signal transduction cascades. TLR7 is upregulated in post-mortem brain tissue from humans with alcohol use disorder (AUD) and animals with prior exposure to ethanol. Despite this evidence, the role of TLR7 in the regulation of voluntary ethanol consumption has not been studied. We test the hypothesis that TLR7 activation regulates voluntary ethanol drinking behavior by administering a TLR7 agonist (R848) during an intermittent access drinking procedure in mice. Acute activation of TLR7 reduced ethanol intake, preference, and total fluid intake due, at least in part, to an acute sickness response. However, chronic pre-treatment with R848 resulted in tolerance to the adverse effects of the drug and a subsequent increase in ethanol consumption. To determine the molecular machinery that mediates these behavioral changes, we evaluated gene expression after acute and chronic TLR7 activation. We found that acute TLR7 activation produces brain region specific changes in expression of immune pathway genes, whereas chronic TLR7 activation causes downregulation of TLRs and blunted cytokine induction, suggesting molecular tolerance. Our results demonstrate a novel role for TLR7 signaling in regulating voluntary ethanol consumption. Taken together, our findings suggest TLR7 may be a viable target for development of therapies to treat AUD.

Effect of melatonin on antioxidation in the PC12 cell line after exposure to ethanol

Excessive ethanol consumption may increase the production of reactive oxygen species (ROS), which results in the oxidative damage of tissues. The purpose of this study was to evaluate the effects of melatonin on the antioxidative status in the PC12 cell line after exposure to ethanol. In this study, the PC12 cells were treated with the different concentrations of melatonin for 24 hr. Subsequently, the cells were incubated with a fresh medium containing 150 mM of ethanol for 4 hr. To observe the oxidative damage and evaluate the antioxidative status after acute exposure to ethanol, cell viability, percentage of lactate dehydrogenase released (% LDH released), glutathione (GSH) level, activities of superoxide dismutase (SOD) and glutathione reductase (GRx), and concentrations of the protein carbonyls were assayed. The results showed that cell viability and GSH were increased, whereas the ethanol-induced cytotoxicity and protein carbonyl concentration decreased when the PC12 cells were treated with 10, 100 and 1000 μM melatonin. In contrary, there was no significant difference in the activity of SOD in the ethanol-treated group. In addition, there were no significant differences in the activity of GRx in the groups with the treatment of 10 and 100 μM melatonin; however, GRx activity decreased in the cells treated with 1000 μM melatonin. In conclusion, melatonin of moderate concentration may be a protective agent to alleviate acute ethanol-induced oxidative damage by the generation of GSH in the PC12 cell line.

Ethanol-Induced Changes in Brain of Transgenic Mice Overexpressing DYRK1A.

Alcoholism is a chronic relapsing disorder defined by loss of control over excessive consumption of ethanol despite damaging effects on the liver and brain. We previously showed that the overexpression in mice of Dyrk1A (TgDyrk1A, for dual-specificity tyrosine (Y) phosphorylation-regulated kinase 1A) reduces the severity of alcohol mediated liver injury. Ethanol consumption has also been associated with increased brain glutamate concentration that led to therapies targeting glutamatergic receptors and normalization of glutamatergic neurotransmission. Interestingly, mice overexpressing Dyrk1A (TgDyrk1A mice) present a reduction of glutamatergic brain transmission, which we propose could be protective against alcohol intake. To answer this question, we investigated the ethanol preference in TgDyrk1A mice using a two-bottle choice paradigm. TgDyrk1A mice showed a non-significant decrease of voluntary ethanol intake and ethanol preference compared with wild-type mice. At the peripheral level, mice overexpressing Dyrk1A show lower ethanol plasma levels, indicating a faster ethanol metabolism. At the end of the protocol, lasting 21days, brains were extracted for protein analysis. Ethanol reduced levels of the synaptic protein PSD-95 and increased the glutamate decarboxylase GAD65, specifically in the cortex of TgDyrk1A mice. Our results suggest that overexpression of DYRK1A may cause different ethanol-induced changes in the brain.

7,8-Dihydroxyflavone Attenuates Alcohol-Related Behavior in Rat Models of Alcohol Consumption via TrkB in the Ventral Tegmental Area.

Alcohol use disorder (AUD) is a ubiquitous substance use disorder in the world, of which neural mechanisms remain unclear. Alcohol consumption induces neuro-adaptations in the dopaminergic system originating from the ventral tegmental area (VTA), an important brain region for the reward function in AUD. Endogenous brain-derived neurotrophic factor (BDNF)-TrkB implicated in the development of neuroplasticity, including long-term potentiation of GABAergic synapses (LTPGABA). We previously found that ethanol blocks LTPGABA in the VTA, either in vivo or in vitro. 7,8-dihydroflavone (7,8-DHF), a BDNF-mimicking small compound, was recently found to penetrate the blood–brain barrier to mimic the biological role of BDNF-TrkB. In this study, we demonstrate that repeated ethanol consumption (including intermittent and continuous ethanol exposure) results in low expression of BDNF in rat VTA. The amount of ethanol intake enhances significantly in rats with intermittent ethanol exposure after 72 h abstinence. Withdrawal signs emerge in rats with continuous ethanol exposure within 3 days after abstinence. Using behavioral tests, intraperitoneal injection of 7,8-DHF can reduce excessive ethanol consumption and preference as well as withdrawal signs in rats with repeated ethanol exposure. Interestingly, microinjection of K252a, an antagonist of TrkB, into the VTA blocks the effects of 7,8-DHF on ethanol-related behaviors. Furthermore, direct microinjection of BDNF into the VTA mimics the effect of 7,8-DHF on ethanol related behaviors. Taken together, 7,8-DHF attenuates alcohol-related behaviors in rats undergoing alcohol consumption via TrkB in the VTA. Our findings suggest BDNF-TrkB in VTA is a part of regulating signals for opposing neural adaptations in AUD, and 7,8-DHF may serve as a potential candidate for treating alcoholism.

Alcohol induces mitochondrial fragmentation and stress responses to maintain normal muscle function in Caenorhabditis elegans.

Chronic excessive ethanol consumption has distinct toxic and adverse effects on a variety of tissues. In skeletal muscle, ethanol causes alcoholic myopathy, which is characterized by myofiber atrophy and the loss of muscle strength. Alcoholic myopathy is more prevalent than all inherited muscle diseases combined. Current evidence indicates that ethanol directly impairs muscle organization and function. However, the underlying mechanism by which ethanol causes toxicity in muscle is poorly understood. Here, we show that the nematode Caenorhabditis elegans exhibits the key features of alcoholic myopathy when exposed to ethanol. As in mammals, ethanol exposure impairs muscle strength and induces the expression of protective genes, including oxidative stress response genes. In addition, ethanol exposure causes the fragmentation of mitochondrial networks aligned with myofibril lattices. This ethanol-induced mitochondrial fragmentation is dependent on the mitochondrial fission factor DRP-1 (dynamin-related protein 1) and its receptor proteins on the outer mitochondrial membrane. Our data indicate that this fragmentation contributes to the activation of the mitochondrial unfolded protein response (UPR). We also found that robust, perpetual mitochondrial UPR activation effectively reduces muscle weakness caused by ethanol exposure. Our results strongly suggest that the modulation of mitochondrial stress responses may provide a method to ameliorate alcohol toxicity and damage to muscle.

Alcohol consumption and employment: a cross-sectional study of office workers and unemployed people.

BackgroundAlcohol is a psychoactive substance with toxic and addictive properties. Biomarkers like GGT, AST, ALT and MCV are influenced by excessive ethanol consumption. Alcohol consumption represents a health risk and it has been linked to unemployment. The aim of this study how working status predict alcohol consumption through a cross sectional study comparing alcohol-related biomarkers levels in office workers and unemployed people.MethodsThis study includes 157 office workers and 157 unemployed people, who were recruited from January to December 2018. A propensity score matching procedure was applied to obtain two homogenous groups in terms of age and gender. A non-parametric analysis was performed on serum biomarkers that are generally altered by alcohol consumption. Logistic regression models were designed to evaluate how working status predict abnormal biomarker levels related with alcohol consumption.ResultsNo differences in median biomarker values were found between groups. Logistic regression analysis showed that office work is a negative predictor of pathological biomarker levels. Office workers had a significant relation with the levels of GGT (OR 0.48; 95% CI [0.28–0.84]), AST (OR 0.42; 95% CI [0.22–0.78]), ALT (OR 0.39; 95% CI [0.23–0.66]), and MCV (OR 0.37; 95% CI [0.19–0.70]).ConclusionOffice workers had lower absolute frequencies of pathological values of alcohol consumption biomarkers, after matching for age and gender compared with unemployed people. In addition, a significant negative association between office work is a negative predictor of biomarker levels of alcohol consumption. These results showed that work is an important determinant of health and that can represent a benefit for workers in terms of reducing the risk of consuming alcohol.

Chicory vs. Zinc: The Protective Role in Alcohol-Induced Acute Liver Injury

Background: Ethanol is a natural product of plant fermentation. It is used as an antibacterial substance, food addictive, and alcoholic beverages. Excessive consumption of ethanol can lead to degenerative effects in many organs. Aim: T0 compare between the effect of zinc and chicory (Cichorium intybus) as protective agents in alcohol-induced liver damage. Material and Methods: Forty male albino rats (150-200g) were divided into four groups (10 rats each):group1(control group), group 2:rats were treated with 1ml /kg/BW of 70% ethanol orally by stomach gavage, group 3: rats were treated with 1ml/kg/BW of 70% ethanol and 5 mg/kg/day of zinc sulfate orally by stomach gavage for and, group 4: rats treated with 1ml/kg/BW of 70% ethanol orally by stomach gavage and chicory within the diet for consecutive 5 days. The animals will be anesthetized and subjected to intracardiac normal saline 0.9% NaCl. Liver specimens were extracted for further processing. Results: vasodilatation in portal vein congestion of the hepatic sinusoids and degenerative changes of the hepatocytes. In group III, there was no inflammatory signs, but more damage was detected in hepatic parenchyma. Chicory treated samples had no signs of inflammation. hepatic parenchyma had a mild degree of degeneration. Conclusion: excessive consumption of alcohol lead to acute liver damage and both zinc and chicory had a protective role in decreasing signs of liver damage, but chicory was more protective than zinc in the preservation of liver tissue against damage.

Alcohol ingestion induces pancreatic islet dysfunction and apoptosis via mediation of FGF21 resistance.

BackgroundDisruption of β-cell insulin secretion and viability caused by excessive ethanol consumption increases type 2 diabetes mellitus (T2DM) pathogenesis risk. Fibroblast growth factor 21 (FGF21) plays a significant role in regulating lipid and glucose homeostasis. Recently, FGF21, best known for its role in lipid and glucose homeostasis regulation, and its obligate co-receptor β-klotho have been shown to inhibit ethanol ingestion and metabolism. It remains unclear whether heavy ethanol intake modulates islet FGF21 expression and function. This study investigated the relationship between ethanol exposure, FGF21, and islet function in vivo/ex vivo islet and in vitro cell models.MethodsMice were gavaged with 3.5 g/kg ethanol or saline for 1–3 weeks (long-term exposure). Human MIN6 cells and isolated islets were cultured and treated with 80 mM ethanol for 24 h (short-term exposure) to mimic excessive ethanol consumption. We applied the oral glucose tolerance test (OGTT), blood glucometry, enzyme-linked immunosorbent assay (ELISAs) for insulin and FGF21, glucose stimulated insulin secretion (GSIS) testing, reverse-transcription (RT)-polymerase chain reaction (PCR), and western blot experiments.ResultsLong-term ethanol treatment induced FGF21 resistance in mouse pancreatic islets. Moreover, ethanol exposure damaged insulin secretory ability and glucose homeostasis. In vitro and ex vivo experiments showed that short-term ethanol treatment upregulated the expression of FGF21 signaling pathway-related genes and proteins, without affecting β-cell survival or function.ConclusionsLong-term ethanol consumption induces FGF21 resistance-mediated pancreatic β-cell dysfunction, and thus diabetes pathogenesis risk.

Chronic Voluntary Ethanol Drinking in Cynomolgus Macaques Elicits Gene Expression Changes in Prefrontal Cortical Area 46.

BackgroundGenome‐wide profiling to examine brain transcriptional features associated with excessive ethanol (EtOH) consumption has been applied to a variety of species including rodents, nonhuman primates (NHPs), and humans. However, these data were obtained from cross‐sectional samples which are particularly vulnerable to individual variation when obtained from small outbred populations typical of human and NHP studies. In the current study, a novel within‐subject design was used to examine the effects of voluntary EtOH consumption on prefrontal cortex (PFC) gene expression in a NHP model.MethodsTwo cohorts of cynomolgus macaques (n = 23) underwent a schedule‐induced polydipsia procedure to establish EtOH self‐administration followed by 6 months of daily open access to EtOH (4% w/v) and water. Individual daily EtOH intakes ranged from an average of 0.7 to 3.7 g/kg/d. Dorsal lateral PFC area 46 (A46) brain biopsies were collected in EtOH‐naïve and control monkeys; contralateral A46 biopsies were collected from the same monkeys following the 6 months of fluid consumption. Gene expression changes were assessed using RNA‐Seq paired analysis, which allowed for correction of individual baseline differences in gene expression.ResultsA total of 675 genes were significantly down‐regulated following EtOH consumption; these were functionally enriched for immune response, cell adhesion, plasma membrane, and extracellular matrix. A total of 567 genes that were up‐regulated following EtOH consumption were enriched in microRNA target sites and included target sites associated with Toll‐like receptor pathways. The differentially expressed genes were also significantly enriched in transcription factor binding sites.ConclusionsThe data presented here are the first to use a longitudinal biopsy strategy to examine how chronic EtOH consumption affects gene expression in the primate PFC. Prominent effects were seen in both cell adhesion and neuroimmune pathways; the latter contained both pro‐ and antiinflammatory genes. The data also indicate that changes in miRNAs and transcription factors may be important epigenetic regulators of EtOH consumption.

Sex differences in cognitive performance and alcohol consumption in High Alcohol-Drinking (HAD-1) rats

Excessive alcohol (ethanol) consumption negatively impacts social, emotional, as well as cognitive function and well-being. Thus, identifying behavioral and/or biological predictors of excessive ethanol consumption is important for developing prevention and treatment strategies against alcohol use disorders (AUDs). Sex differences in alcohol consumption patterns are observed in humans, primates, and rodents. Selectively bred high alcohol-drinking rat lines, such as the “HAD-1” lines are recognized animal models of alcoholism. The present work examined sex differences in alcohol consumption, object recognition, and exploratory behavior in male and female HAD-1 rats. Naïve male and female HAD-1 rats were tested in an object recognition test (ORT) prior to a chronic 24 h intermittent ethanol access procedure for five weeks. Object recognition parameters measured included exploratory behavior, object investigation, and time spent near objects. During the initial training trial, rearing, active object investigation and amount of time spent in the object-containing section was significantly greater in female HAD-1 rats compared to their male counterparts. During the subsequent testing trial, time spent in the object-containing section was greater in female, compared to male, rats; but active object investigation and rearing did not statistically differ between females and males. In addition, female HAD-1 rats consumed significantly more ethanol than their male counterparts, replicating previous findings. Moreover, across all animals there was a significant positive correlation between exploratory behavior in ORT and ethanol consumption level. These results indicate there are significant sex differences in cognitive performance and alcohol consumption in HAD-1 rats, which suggests neurobiological differences as well.

An evaluation of genetic causes and environmental risks for bilateral optic atrophy.

To assess the clinical utility of next-generation sequencing (NGS) for the diagnosis of patients with optic atrophy (OA). Retrospective cohort study. 97 patients were referred to the McMaster University Medical Center (Hamilton, Ontario) for evaluation of bilateral OA. All patients were sent for NGS including a 22 nuclear gene panel and/or complete mitochondrial DNA (mtDNA) sequencing. Positive genetic test results and abnormal vibration sensation were compared in patients +/- environmental exposures or a family history. 19/94 (20.2%) had a positive nuclear variant, of which 15/19 (78.9%) were in the OPA1 gene. No positive mtDNA variants were identified. The detection of a positive genetic variant was significantly different in patients who reported excessive ethanol use, but not in patients who smoke (0/19 (0%) vs. 19/78 (24.4%), P = 0.0164 and 4/22 (18.2%) vs. 15/74 (20.3%), P = 0.829, respectively). Patients with a positive family history were more likely to have a positive genetic variant compared to patients with a negative family history (P = 0.0112). There were significantly more excessive drinkers with an abnormal vibration sensation (P = 0.026), and with a similar trend in smokers (P = 0.074). All positive genetic variants were identified in nuclear genes. We identified a potential independent pathophysiological link between a history of excessive ethanol consumption and bilateral OA. Further investigations should evaluate and identify potential environmental risk factors for OA.

Effect of lacosamide on ethanol induced conditioned place preference and withdrawal associated behavior in mice: Possible contribution of hippocampal CRMP-2.

Excessive consumption of ethanol is known to activate the mTORC1 pathway and to enhance the Collapsin Response Mediator Protein-2 (CRMP-2) levels in the limbic region of brain. The latter helps in forming microtubule assembly that is linked to drug taking or addiction-like behavior in rodents. Therefore, in this study, we investigated the effect of lacosamide, an antiepileptic drug and a known CRMP-2 inhibitor, which binds to CRMP-2 and inhibits the formation of microtubule assembly, on ethanol-induced conditioned place preference (CPP) in mice. The behavior of mice following ethanol addiction and withdrawal was assessed by performing different behavioral paradigms. Mice underwent ethanol-induced CPP training with alternate dose of ethanol (2 g/kg, po) and saline (10 ml/kg, po). The effect of lacosamide on the expression of ethanol-induced CPP and on ethanol withdrawal associated anxiety and depression-like behavior was evaluated. The effect of drug on locomotor activity was also assessed and hippocampal CRMP-2 levels were measured. Ethanol-induced CPP was associated with enhanced CRMP-2 levels in the hippocampus. Lacosamide significantly reduced the expression of ethanol-induced CPP and alleviated the levels of hippocampal CRMP-2 but aggravated withdrawal-associated anxiety and depression in mice. The present study demonstrated the beneficial effect of lacosamide in attenuation of expression of ethanol induced conditioned place preference via reduction of hippocampal CRMP-2 level. These findings suggest that lacosamide may be investigated further for ethanol addiction but not for managing withdrawal.

Intermittent-Excessive and Chronic-Moderate Ethanol Intake during Adolescence Impair Spatial Learning, Memory and Cognitive Flexibility in the Adulthood

Intermittent and excessive ethanol consumption over very short periods of time, known as binge drinking, is common in the adolescence, considered a vulnerable period to the effects of alcohol in terms of cognitive performance. One of the brain functions most drastically affected by ethanol in adolescent individuals seems to be spatial learning and memory dependent on the hippocampus. In the current study we have focused on the long-lasting effects on spatial learning and memory of intermittent and excessive alcohol consumption compared to chronic and moderate alcohol exposure during adolescence. Five-week old male Wistar rats consumed ethanol for 24 days following two different self-administration protocols that differed in the intake pattern. Spatial learning and memory were evaluated in the radial arm maze. Hippocampal synaptic plasticity was assessed by measuring field excitatory postsynaptic potentials. Hippocampal expression of AMPA and NMDA receptor subunits as well as levels of phosphorylated Ser9-GSK3β (the inactive form of GSK3β) were also quantified. Our results show that both patterns of ethanol intake during adolescence impair spatial learning, memory and cognitive flexibility in the adulthood in a dose-dependent way. Nevertheless, changes in synaptic plasticity, gene expression and levels of inactive GSK3β depended on the pattern of ethanol intake.

Correction: Time-Course Analysis of Brain Regional Expression Network Responses to Chronic Intermittent Ethanol and Withdrawal: Implications for Mechanisms Underlying Excessive Ethanol Consumption

[This corrects the article DOI: 10.1371/journal.pone.0146257.].