High-dose Alcohol Research Articles

β-Carotene Increases Activity of Cytochrome P450 2E1 during Ethanol Consumption.

One of the key routes through which ethanol induces oxidative stress appears to be the activation of cytochrome P450 2E1 at different levels of ethanol intake. Our aim was to determine if oral β-carotene intake had an antioxidant effect on CYP2E1 gene expression in mice that had previously consumed ethanol. C57BL/6 mice were used and distributed into: control (C), low-dose alcohol (LA), moderate-dose alcohol (MA), β-carotene (B), low-dose alcohol+β-carotene (LA + B), and moderate-dose alcohol+β-carotene (MA + B). Animals were euthanized at the end of the experiment, and liver tissue was taken from each one. CYP2E1 was measured using qPCR to detect liver damage. The relative expression level of each RNA was estimated using the comparative threshold cycle (Ct) technique (2−ΔΔCT method) by averaging the Ct values from three replicates. The LA+B (2267 ± 0.707) and MA+B (2.307 ± 0.384) groups had the highest CYP2E1 fold change values. On the other hand, the C (1.053 ± 0.292) and LA (1.240 ± 0.163) groups had the lowest levels. These results suggest that ethanol feeding produced a fold increase in CYP2E1 protein in mice as compared to the control group. Increased CYP2E1 activity was found to support the hypothesis that β-carotene might be dangerous during ethanol exposure in animal models. Our findings imply that β-carotene can increase the hepatic damage caused by low and high doses of alcohol. Therefore, the quantity of alcohol ingested, the exposure period, the regulatory mechanisms of alcoholic liver damage, and the signaling pathways involved in the consumption of both alcohol and antioxidant must all be considered.

The effects of alcohol consumption on fetal craniofacial development during gestation: a systematic review/ Os efeitos do consumo de álcool no desenvolvimento craniofacial fetal durante a gestação: uma revisão sistemática

The present study used evidence-based dentistry (EBD) to identify clinical studies that described the effects of alcohol on fetal craniofacial development and qualitatively analyze the results found via this systematic review. This systematic review followed the guidelines “Meta-analysis Of Observational Studies in Epidemiology” (MOOSE). As a research strategy, several medical and scientific platforms were chosen, in which studies were sought using keywords defined from medical subject headings (MeSH), following the criterion of choosing keywords that were most related to the proposed theme. A total of 278 studies (116 studies in humans and 162 studies in animals) were identified and, after screening and analysis based on the inclusion criteria, twenty-six observational studies in humans were chosen for the configuration of this systematic review. Studies have reported fetal alterations related to alcohol consumption by mothers such as in the head shape and size, thin upper lip, hypoplastic philtrumbone, short palpebral fissures, micrognathia, flat nasal bridge, among others. These were more often found in patients whose mothers were alcoholics or those who had ingested high doses of alcohol, especially during the first trimester of gestation. Based on the analysis of the results, the impact of maternal alcohol consumption on fetal craniofacial development was evidenced and, as such, these complications can be harmful to the quality of life of the patient, both in childhood and in adulthood, as well as leading to lifelong sequelae. The results also suggest that to avoid craniofacial anatomical abnormalities related to alcohol, the best course of action is to stop alcohol consumption completely or at least reduce it to a minimum level before conception.

How low working memory demands and reduced anticipatory attentional gating contribute to impaired inhibition during acute alcohol intoxication

High-dose alcohol intoxication is commonly associated with impaired inhibition, but the boundary conditions, as well as associated neurocognitive/neuroanatomical changes have remained rather unclear. This study was motivated by the counterintuitive finding that high-dose alcohol intoxication compromises response inhibition performance when working memory demands were low, but not when they were high. To investigate whether this is more likely to be caused by deficits in cognitive control processes or in attentional processes, we examined event-related (de)synchronization processes in theta and alpha-band activity and performed beamforming analyses on the EEG data of previously published behavioral findings. This yielded two possible explanations: There may be a selective decrease of working memory engagement in case of relatively low demand, which boosts response automatization, ultimately putting more strain on the remaining inhibitory resources. Alternatively, there may be a decrease in proactive preparatory and anticipatory attentional gating processes in case of relatively low demand, hindering attentional sampling of upcoming stimuli. Crucially, both of these interrelated mechanisms reflect differential alcohol effects after the actual motor inhibition process and therefore tend to be processes that serve to anticipate future response inhibition affordances. This provides new insights into how high-dose alcohol intoxication can impair inhibitory control.

Effect of chronic alcohol consumption on myocardial apoptosis in the rat model of isoproterenol-induced myocardial injury and investigation on the cardioprotective role of calpain inhibitor 1

We investigated the presence of myocardial apoptosis on isoproterenol (ISO)-induced myocardial injury (MI) after long-term high dose alcohol consumption and examined the antiapoptotic role of calpain inhibitor 1. Male Wistar Albino rats (n = 108) were divided into six groups: Control, alcohol (ethanol was given during 30 days for chronic alcohol consumption), MI (150 mg/kg ISO injection at last two days of alcohol consumption), alcohol + MI, alcohol + MI + calpain inhibitor 1 (10 mg/kg inhibitor was injected at 15 min before ISO injections) and Dimethyl Sulfoxide (DMSO) groups. Biochemical, histological, and morphometric methods determined apoptosis levels in the heart tissue of rats. Cytochrome c, caspase 3, and calpain levels were significantly high in alcohol, MI, and alcohol + MI groups. In contrast, mitochondrial cardiolipin content was found to be low in alcohol, MI, and alcohol + MI groups. These parameters were close to the control group in the therapy group. Histological and morphometric data have supported biochemical results. As a result of our biochemical data, myocardial apoptosis was seen in the alcohol, MI, and especially alcohol after MI groups. Calpain inhibitor 1 reduced apoptotic cell death and prevented myocardial tissue injury in these groups. The efficiency of calpain inhibitor was very marked in MI after long-term high dose alcohol consumption.

Effects of alcohol intake on cognitive function and β-amyloid protein in APP/PS1 transgenic mice

To investigate the effects of alcohol intake on cognitive function and β-amyloid protein (Aβ) in APP/PS1 double-transgenic mice with Alzheimer's disease (AD). Sixty APP/PS1 transgenic male mice were randomized into seven groups: control group, 0.5% alcohol group, 1% alcohol group, 2% alcohol group, 3% alcohol group, and 4% alcohol group, with 10 non-transgenic B6C3F1 mice of the same genetic background as the negative control group. All mice were pair-fed a liquid diet containing alcohol before assessment of learning and memory using the Y-maze test, and of Aβ content and related enzyme activity on them. Immunohistochemistry was used to detect the expression of Aβ1–42, Aβ1–40, and β-amyloid precursor protein (β-APP) in the cerebral cortex. 3%, and 4% alcohol intake significantly impaired the learning and memory abilities. 2%, 3%, and 4% alcohol groups indicated a remarkable change in Aβ1–42 content, α-secretase and γ-secretase activities in the hippocampus, and β-APP in the cortex; 3% and 4% alcohol groups showed a significant increase in Aβ1–42 content, β-site amyloid cleavage enzyme 1 (BACE1) activity, and a significant decrease in α-secretase activity in the hippocampus or cortex; 2% and 3% alcohol groups showed a significant increase in Aβ1–40 content in the hippocampus or cortex; and 2%, 3%, and 4% alcohol groups showed an increase in the expression of Aβ1–42, Aβ1–40, and β-APP in the cortex; 1% alcohol groups showed a significant decline in the levels of Aβ1–42, Aβ1–40, β-APP, and BACE1 activity in the hippocampus, and γ-secretase activity in the hippocampus and cortex, and 1% alcohol group showed a significant increase of α-secretase activity in the hippocampus. Besides, 0.5% alcohol showed statistically significant effects on the reduction of BACE1 and γ-secretase activities in the hippocampus. Long-term intake of high-dose alcohol can induce cognitive deficits and improve the activity of β-APP decomposition-related enzymes, increase Aβ content and deposition, and initiate AD progression, while long-term intake of low-dose alcohol can antagonize excessive production of Aβ and slow down AD progression.

The acute effects of alcohol on state rumination in the laboratory

RationaleRumination is a repetitive, negative, self-focused thinking style associated with various forms of psychopathology. Recent studies suggest that rumination increases craving for alcohol and predicts harmful drinking and alcohol-related problems. However, the acute effects of alcohol on rumination have not been previously studied. It is proposed that alcohol may reduce ruminative thinking through decreasing negative mood.ObjectivesIn the present study, we aimed to test the previously unexplored effects of acute alcohol consumption on rumination in a hazardous drinking population.MethodsWe conducted a randomised placebo-controlled laboratory study to examine the effect of low (0.4 g kg−1) and high doses (0.8 g kg−1) of alcohol on state rumination compared to placebo. Participants completed a rumination induction task prior to receiving drinks. We then measured state rumination and mood at repeated time points; 30 min, 60 min and 90 min post-drinks consumption.ResultsWe found a significant decrease in state rumination in the low-dose alcohol group compared to placebo at 30 min post-alcohol consumption, but no difference was observed between the high-dose alcohol and placebo groups. Mediation analysis provided evidence for an indirect effect of alcohol on state rumination through concurrent changes in negative mood.ConclusionsThese findings suggest that acute alcohol consumption can regulate negative mood and concurrently rumination, providing preliminary evidence for the role of rumination in alcohol use disorders. Rumination may be a treatment target in alcohol use disorders.

Hnrnph1 is a novel regulator of alcohol reward

BackgroundHnrnph1 is a validated quantitative trait gene for methamphetamine behavioral sensitivity that encodes for heterogeneous nuclear ribonucleoprotein H1 (hnRNP H1). This RNA-binding protein is involved in all stages of RNA metabolism that impacts mesocorticolimbic dopamine neurotransmission to influence addiction-related behavior. MethodsWe characterized the alcohol behavioral phenotypes of mice heterozygous for a deletion in the first coding exon of Hnrnph1 (Hnrnph1+/-). We examined alcohol intake under both continuous- and limited-access procedures, as well as alcohol-induced place-conditioning. Follow-up studies examined genotypic differences in the psychomotor-activating and sedative-hypnotic effects of acute and repeated alcohol, and a behavioral test battery was employed to determine the effects of Hnrnph1 deletion on the manifestation of negative affect during alcohol withdrawal. ResultsRelative to wild-type (WT) controls, Hnrnph1+/- males exhibited blunted intake of high alcohol concentrations under both drinking procedures. Hnrnph1 deletion did not impact the conditioned rewarding properties of low-dose alcohol, but reversed the conditioned place-aversion elicited by higher alcohol doses (2 and 4 g/kg), with more robust effects in male versus female mice. No genotypic differences were observed for alcohol-induced locomotor activity. Hnrnph1+/- mice exhibited a modest increase in sensitivity to alcohol’s sedative-hypnotic effects, but did not differ from WT mice with regard to tolerance to alcohol’s sedative-hypnotic effects or alcohol metabolism, Inconsistent effects of Hnrnph1 deletion were observed in models for withdrawal-induced negative affect. ConclusionsThese data identify Hnrnph1 as a novel, male-selective, driver of alcohol consumption and high-dose alcohol aversion that is potentially relevant to the neurobiology of alcohol abuse and alcoholism.

Chronic Ethanol Consumption Induces Osteopenia via Activation of Osteoblast Necroptosis.

Chronic high-dose alcohol consumption impairs bone remodeling, reduces bone mass, and increases the risk of osteoporosis and bone fracture. However, the mechanisms underlying alcohol-induced osteoporosis are yet to be elucidated. In this study, we showed that excess intake of ethyl alcohol (EtOH) resulted in osteopenia and osteoblast necroptosis in mice that led to necrotic lesions and reduced osteogenic differentiation in bone marrow mesenchymal stem cells (BMMSCs). We found that EtOH treatment led to the activation of the RIPK1/RIPK3/MLKL signaling, resulting in increased osteoblast necroptosis and decreased osteogenic differentiation and bone formation both in vivo and in vitro. We further discovered that excessive EtOH treatment-induced osteoblast necroptosis might partly depend on reactive oxygen species (ROS) generation; concomitantly, ROS contributed to necroptosis of osteoblasts through a positive feedback loop involving RIPK1/RIPK3. In addition, blocking of the RIPK1/RIPK3/MLKL signaling by necrostatin-1 (Nec-1), a key inhibitor of RIPK1 kinase in the necroptosis pathway, or antioxidant N-acetylcysteine (NAC), an inhibitor of ROS, could decrease the activation of osteoblast necroptosis and ameliorate alcohol-induced osteopenia both in vivo and in vitro. Collectively, we demonstrated that chronic high-dose alcohol consumption induced osteopenia via osteoblast necroptosis and revealed that RIPK1 kinase may be a therapeutic target for alcohol-induced osteopenia.

Increased transcription of TSPO, HDAC2, and HDAC6 in the amygdala of males with alcohol use disorder.

IntroductionRepeated exposure to high doses of alcohol triggers neuroinflammatory processes that contribute to craving and mood dysfunction in alcohol use disorder (AUD). The upregulation of the translocator protein (TSPO) is considered a biomarker of neuroinflammation, and TSPO ligands have been used as neuroimaging biomarkers of neuroinflammation. Epigenetic mechanisms are also implicated in neuroinflammatory responses to alcohol, and elevated expression of HDAC2 and HDAC6 has been reported in the brain of animals exposed to chronic alcohol.MethodsThe present study examined the transcriptional regulation of TSPO, HDAC2, and HDAC6 in human postmortem brain tissue from males previously diagnosed with AUD (n = 11) compared to age‐matched nondependent males (n = 13) in four brain regions relevant to AUD: prefrontal cortex (PFC), nucleus accumbens (NAc), hippocampus (HPP), and amygdala (AMY).ResultsTranslocator protein mRNA levels in AMY and PFC and HDAC2 and HDAC6 mRNA levels in AMY were upregulated in AUD compared to controls. In AMY, TSPO mRNA levels were positively associated with HDAC2 and HDAC6 mRNA levels, suggesting a possible regulation of TSPO by HDAC2 and HDAC6 in this brain region. In contrast, there were no group differences for TSPO, HDAC2, and HDAC6 in NAc and HPP.ConclusionOur study is the first to find upregulated TSPO mRNA levels in AMY and PFC in postmortem brains from AUD consistent with neuroinflammation, and in the amygdala, they implicate epigenetic regulation of TSPO by HDAC2 and HDAC6.

The Feasibility, Tolerability, and Safety of Administering a Very High Alcohol Dose to Drinkers with Alcohol Use Disorder.

There remains a paucity of research quantifying alcohol's effects in drinkers with alcohol use disorder (AUD), particularly responses to very high alcohol doses (≥0.8g/kg). As drinkers with AUD frequently engage in very heavy drinking (8 to 10 drinks/occasion), doses of ≤0.8g/kg may lack ecological validity. The present study examined the feasibility, tolerability, and safety of administering a very high alcohol dose (1.2g/kg) to non-treatment-seeking AUD participants. Sixty-one young adult AUD drinkers enrolled in the Chicago Social Drinking Project and completed 3 laboratory sessions at which they consumed a beverage with 1.2, 0.8, and 0.0g/kg alcohol. Physiological responses (vital signs, nausea and vomiting, breath alcohol concentrations [BrAC]) were monitored throughout the sessions. After each session, participants completed a next-day survey of substance use, engagement in risky behaviors, and related consequences. Overall, the sample demonstrated good compliance with study procedures; 93% of participants adhered to presession alcohol abstinence requirements (indicated by BrAC<0.003g/dl), with no participants exhibiting serious alcohol withdrawal symptoms at arrival to study visits. The 1.2g/kg alcohol dose achieved an expected mean peak BrAC of 0.13g/dl at 60minutes after drinking, which was well tolerated; the majority of the sample did not experience nausea (70%) or vomiting (93%), and dose effects on vital signs were not clinically significant. Finally, we demonstrated that the 1.2g/kg alcohol dose is safe and not associated with postsession consequences, including reduced sleep time, atypical substance use, accidents or injuries, and severe hangovers. Results support the feasibility, tolerability, and safety of administering a very high alcohol dose to young adult drinkers with AUD within the context of a well-validated laboratory alcohol challenge paradigm. Utilizing an alcohol dose more consistent with naturalistic drinking patterns may foster greater ecological validity of laboratory paradigms for persons with moderate to severe AUD.

Preconception Alcohol Exposure Increases the Susceptibility to Diabetes in the Offspring.

Heavy alcohol drinking alters glucose metabolism, but the inheritability of this effect of alcohol is not well understood. We used an animal model of preconception alcohol exposure in which adult female rats were given free access to 6.7% alcohol in a liquid diet and water for about 4 weeks, went without alcohol for 3 weeks, and then were bred to generate male and female offspring. Control animals were either ad lib-fed rat chow or pair-fed an isocaloric liquid diet during the time of alcohol-feeding in the experimental animals. Our results show that the female rats fed with alcohol in the liquid diet, but not with the isocaloric liquid diet, prior to conception had an altered stress gene network involving glucose metabolism in oocytes when compared with those in ad lib-fed chow diet controls. The offspring born from preconception alcohol-fed mothers showed significant hyperglycemia and hypoinsulinemia when they were adults. These rats also showed increased levels of inflammatory cytokines and cellular apoptosis in the pancreas, altered insulin production and actions in the liver, and a reduced number of proopiomelanocortin neurons in the hypothalamus. Replenishment of proopiomelanocortin neurons in these animals normalized the abnormal glucose to restore homeostasis. These data suggest that preconception alcohol exposures alter glucose homeostasis by inducing proopiomelanocortin neuronal functional abnormalities. Our findings provide a novel insight into the impact of high doses of alcohol on the female gamete that may cause inheritance of an increased susceptibility to diabetes.

Impact of evening alcohol consumption on nocturnal autonomic and cardiovascular function in adult men and women: a dose-response laboratory investigation.

To investigate the dose-dependent impact of moderate alcohol intake on sleep-related cardiovascular (CV) function, in adult men and women. A total of 26 healthy adults (30-60 years; 11 women) underwent 3 nights of laboratory polysomnographic (PSG) recordings in which different doses of alcohol (low: 1 standard drink for women and 2 drinks for men; high: 3 standard drinks for women and 4 drinks for men; placebo: no alcohol) were administered in counterbalanced order before bedtime. These led to bedtime average breath alcohol levels of up to 0.02% for the low doses and around 0.05% for the high doses. Autonomic and CV function were evaluated using electrocardiography, impedance cardiography, and beat-to-beat blood pressure monitoring. Presleep alcohol ingestion resulted in an overall increase in nocturnal heart rate (HR), suppressed total and high-frequency (vagal) HR variability, reduced baroreflex sensitivity, and increased sympathetic activity, with effects pronounced after high-dose alcohol ingestion (p's < 0.05); these changes followed different dose- and measure-dependent nocturnal patterns in men and women. Systolic blood pressure showed greater increases during the morning hours of the high-alcohol dose night compared to the low-alcohol dose night and placebo, in women only (p's < 0.05). Acute evening alcohol consumption, even at moderate doses, has marked dose- and time-dependent effects on sleep CV regulation in adult men and women. Further studies are needed to evaluate the potential CV risk of repeated alcohol-related alterations in nighttime CV restoration in healthy individuals and in those at high risk for CV diseases, considering sex and alcohol dose and time effects.

Effect of alcohol on blood pressure.

Alcohol is consumed by over 2 billion people worldwide. It is a common substance of abuse and its use can lead to more than 200 disorders including hypertension. Alcohol has both acute and chronic effects on blood pressure. This review aimedto quantify the acute effects of different doses of alcohol over time on blood pressure and heart rate in an adult population. Primary objective To determine short-term dose-related effects of alcohol versus placebo on systolic blood pressure and diastolic blood pressure in healthy and hypertensive adults over 18 years of age. Secondary objective To determine short-term dose-related effects of alcohol versus placebo on heart rate in healthy and hypertensive adults over 18 years of age. The Cochrane Hypertension Information Specialist searched the following databases for randomised controlled trials up to March 2019: the Cochrane Hypertension Specialised Register; the Cochrane Central Register of Controlled Trials (CENTRAL; 2019, Issue 2), in the Cochrane Library; MEDLINE (from 1946); Embase (from 1974); the World Health Organization International Clinical Trials Registry Platform; and ClinicalTrials.gov. We also contacted authors of relevant articlesregarding further published and unpublished work. These searches had no language restrictions. Randomised controlled trials (RCTs) comparing effects of a single dose of alcohol versus placebo on blood pressure (BP) or heart rate (HR) in adults(≥ 18 years of age). Two review authors (ST and CT) independentlyextracted data and assessed the quality of included studies. We also contacted trial authors for missing or unclear information. Mean difference (MD) from placebo with 95% confidence interval (CI) was the outcome measure, and a fixed-effect model was used to combine effect sizes across studies. MAIN RESULTS: We included 32RCTs involving 767 participants.Most of the study participants were male (N = 642) and were healthy. The mean age of participants was 33 years, and mean body weight was 78 kilograms. Low-dose alcohol (< 14 g) within six hours (2 RCTs, N = 28) did not affect BP but did increase HR by 5.1 bpm (95% CI 1.9 to 8.2) (moderate-certainty evidence). Medium-dose alcohol (14 to 28 g) within six hours (10 RCTs, N = 149) decreasedsystolic blood pressure (SBP) by 5.6 mmHg (95% CI -8.3 to -3.0) anddiastolic blood pressure (DBP) by 4.0 mmHg (95% CI -6.0 to -2.0)and increased HR by 4.6 bpm (95% CI 3.1 to 6.1) (moderate-certainty evidence for all). Medium-dose alcohol within 7 to 12 hours (4 RCTs, N = 54) did not affect BP or HR. Medium-dose alcohol > 13 hours after consumption (4 RCTs, N = 66) did not affect BP or HR. High-dose alcohol (> 30 g) within six hours (16 RCTs, N = 418) decreased SBP by 3.5 mmHg (95% CI -6.0 to -1.0),decreased DBP by 1.9 mmHg (95% CI-3.9 to 0.04), and increased HR by 5.8 bpm (95% CI 4.0 to 7.5).The certainty of evidence was moderate for SBP and HR, and was low for DBP. High-dose alcohol within 7 to 12hours of consumption (3 RCTs, N = 54) decreased SBP by 3.7 mmHg (95% CI -7.0 to -0.5)and DBP by 1.7 mmHg (95% CI -4.6 to 1.8) and increased HR by6.2 bpm (95% CI 3.0 to 9.3). The certainty of evidence was moderate for SBP and HR, and low for DBP. High-dose alcohol ≥ 13hours after consumption (4 RCTs, N = 154) increased SBP by 3.7 mmHg (95% CI 2.3 to 5.1),DBP by 2.4 mmHg (95% CI 0.2 to 4.5), and HR by 2.7 bpm (95% CI 0.8 to 4.6) (moderate-certainty evidence for all). AUTHORS' CONCLUSIONS: High-dose alcohol has a biphasic effect on BP; it decreases BP up to 12 hours after consumption and increases BP > 13 hours after consumption. High-dose alcohol increases HR at all times up to 24 hours. Findingsof this review are relevant mainly to healthy males, as only small numbers of womenwere included in the included trials.

Novel Binge Drinking Model Causes Perturbations in Muscle Metabolism with Refeeding

IntroductionIt is well known that acute alcohol intoxication impairs metabolic signaling within skeletal muscle including suppression of protein synthesis which is at least partially due to inhibition of mTOR activity as assessed by phosphorylation of its downstream substrates p70 ribosomal protein S6 Kinase 1 (S6K1), ribosomal protein S6 (rpS6) and eukaryotic initiation factor 4E (4E‐BP1). The current mouse model used to mimic binge drinking employs either oral gavage or intraperitoneal (IP) injection, both of which are stressful to the animal and in the case of the injection, lack physiological relevance as it bathes all organs in a high dose of alcohol while bypassing normal intestinal metabolism. Therefore, we wanted to determine if an acute ‘dose’ of alcohol incorporated into the food would be sufficient to mimic the binge drinking effects previously reported.MethodsC57BL6 male (n=9) and female mice (n=10) were randomized to receive either control liquid diet food (# 710027, DYETS, Bethlehem, PA), or a calorie (kcal) matched liquid diet containing 32% kcal from alcohol (# 710260, DYETS, Bethlehem, PA). Following a 1 week acclimation period to the control liquid diet, mice were fasted for 16 hours during their light cycle and then, at the onset of the dark cycle, were provided with liquid diet (Con or EtOH) for 30 minutes. The gastrocnemius (GAS) and blood were collected 1.5 hour after the beginning of the refeeding period. Western blots were performed on GAS for protein expression. T‐tests (2 tailed, unpaired) for males (Con vs. EtOH), and females (Con vs. EtOH), or between sexes of the same dietary treatment group, were used for analysis (p&lt;0.05).ResultsDespite the high concentration of alcohol in the liquid diet and its novel introduction to the EtOH group, male mice consumed the same volume of food regardless of treatment group. Control females though, consumed significantly more food than EtOH females (4.5 mL vs. 3.6 mL). Alcohol intake per kg body weight was higher in females than males; however, total alcohol intake (g), and blood alcohol levels (213 vs. 187 mg/dL), were not different between males and females. Alcohol intake decreased AKT S473 phosphorylation in GAS, along with phosphorylation of mTOR S2448 in males and females. Downstream substrates of mTOR were also suppressed by alcohol, including phosphorylation of S6K1 T389 and rpS6 S240/244.ConclusionDespite lower blood alcohol levels (compared to injection), alcohol reversed or prevented the increase in mTOR signaling typically induced by an anabolic stimulus (i.e. nutrient intake). Further, novel findings included the consumption of a high percentage of alcohol in liquid diet form without any prior exposure to a lower dose or acclimation period to alcohol. Future work will continue to characterize this model and lead to optimization of models of alcohol intoxication that best mimic human practice.

Bile Acid Membrane Receptor TGR5 Inhibits Alcohol‐Induced Liver Steatosis

Alcoholic liver disease (ALD) is one of the leading causes of liver failure in the world. It progresses from alcoholic fatty liver (AFL) to alcoholic steatohepatitis (ASH), which is characterized with hepatic inflammation. Chronic ASH will result in fibrosis, cirrhosis and hepatocellular cancer (HCC) eventually. However, very few treatment options for ALD are available currently. Therefore, there is an urgent unmet medical need to better understand the molecular mechanisms underneath the development of ALD and develop effective treatment approaches. Bile acid signaling in the liver‐gastrointestinal tract axis is important for the integrated regulation of lipid, glucose, and energy metabolism. Dysregulated bile acid signaling is associated with ALD due to the fact that alcohol significantly alters bile acids pool and composition in humans and rodents. G‐protein‐coupled bile acid receptor, Gpbar1 (TGR5), is a membrane bound bile acid receptor. It is more broadly expressed, but its hepatic expression is limited to Kupffer cells, macrophages and sinusoidal endothelial cells. Little information regarding the effects of TGR5 in the pathological development of ALD has been reported before. In this study, we use C57BL/6(WT) and TGR5 knockout (TGR5−/−) mice to study the potential role of TGR5 in alcohol‐induced liver disease. Mice were challenged with chronic 5% ethanol feeding (10 days) plus a binge dose of alcohol by oral gavage (5 g/kg body weight) or with acute high dose alcohol gavage. The results showed that the liver/body weight ratio was increased in both WT and TGR5−/− ethanol fed mice, while it was significant higher in ethanol fed TGR5−/− mice than WT mice. The liver injury marker serum alanine transaminase (ALT) and aspartate aminotransferase (AST) were both increased. Alcohol feeding altered gene expression in bile acid homeostasis. The hepatic triglycerides were upregulated almost 30% higher in TGR5−/− mice than WT group. The haematoxylin Eosin (H&amp;E) and Oil Red O staining showed more fat vacuoles in the liver of ethanol fed TGR5−/− mice than that in WT mice. We also treat the mice with a novel potent TGR5 agonist ligand and found protective effects on ALD in WT but not TGR5−/− mice. Collectively, these results suggest that TGR5 may prevent the development of ALD and represent a novel target for ALD treatment.Support or Funding InformationCity of Hope Departmental Internal funding

Effects of oral alcohol administration on heat pain threshold and ratings of supra-threshold stimuli.

Background and aims Evidence for analgesic effects of oral alcohol consumption on heat pain has recently been documented in a placebo-controlled, randomized and double-blind design. We aimed at further investigating these effects and now set the focus on pain threshold and the ratings of supra-threshold pain to cover most of the pain range. Moreover, we now firstly evaluated sex differences in these effects. Methods We investigated 41 healthy participants (22 females) in a randomized, double-blind and placebo-controlled design and targeted two different moderate breath-alcohol levels of 0.06% and 0.08%. Before and after an alcoholic or placebo drink, contact heat was applied at the forearm. Subjects evaluated pain threshold (method of adjustment) and rated pain intensity and pain unpleasantness of supra-threshold stimuli (intensity: threshold +3 °C; duration: 5 s). Results Analgesic effects taking the form of increased pain thresholds were found after both alcohol doses, surprisingly with more pronounced effects for the lower dose. While the high alcohol dose exerted small analgesic effects on pain intensity ratings (i.e. decrease), slightly increased ratings of pain intensity and pain unpleasantness after the low alcohol dose rather suggest pain enhancement. Alcohol did not affect intensity vs. unpleasantness ratings differentially. We found no evidence for sex differences in any of these effects. Conclusions Overall, acute alcohol effects on pain were subtle. Our findings suggest that while low alcohol doses already exert analgesic effects on pain threshold, stronger doses are required for pain reduction on supra-threshold pain levels. Furthermore, sex differences could not be detected within our experimental paradigm but should be further explored in future research. Implications Analgesic effects of sub-toxic alcohol doses - as normally occurring during social drinking - might be weak; however, susceptibility to pain relieving effects of alcohol might be a risk factor for the use of alcohol as self-medication in acute pain states.

Prenatal alcohol exposure and developmental programming of mental illness

It is well established that high-dose alcohol consumption during pregnancy increases the risk for a plethora of adverse offspring outcomes. These include neurodevelopmental, cognitive and social deficits, as well as psychiatric illnesses, such as depression and anxiety. However, much less evidence is available on the effects of low- and early-dose alcohol exposure on mental health outcomes, regardless of the accumulating evidence that mental health outcomes should be considered in the context of the Developmental Origins of Health and Disease hypothesis. This review will discuss the evidence that indicates low-dose and early prenatal alcohol exposure can increase the risk of mental illness in offspring and discuss the mechanistic pathways that may be involved.

Differential sensitivity of alcohol drinking and partner preference to a CRFR1 antagonist in prairie voles and mice

Available pharmacotherapies to treat alcohol use disorder (AUD) show limited efficacy. Preclinical studies in mice and rats suggested that antagonists of the corticotropin releasing factor receptor 1 (CRFR1) could be more efficacious for such treatment. However, clinical trials with CRFR1 antagonists were not successful. While a number of potential explanations for this translational failure have been suggested, we hypothesized that the lack of success in clinical trials could be in part due to different neuroanatomical organization of the CRFR1 system in mice and rats versus humans. The CRF system in prairie voles (Microtus ochrogaster), a socially monogamous rodent species, also shows differences in organization from mice and rats. To test our hypothesis, we compared the efficacy of a potent CRFR1 antagonist, CP-376,395, to modulate alcohol drinking in male and female prairie voles versus male and female C57BL/6J mice using an almost identical 2-bottle choice drinking procedure. CP-376,375 (10 and 20 mg/kg, i.p.) significantly decreased alcohol intake (but not alcohol preference) in mice, but not prairie voles. Furthermore, administration of this antagonist (20 mg/kg, i.p.) prior to the partner preference test (PPT) decreased partner preference (PP) in male prairie voles. These findings support our hypothesis that the greater efficacy of CRFR1 antagonists to suppress alcohol consumption in mice and rats versus other mammalian species could be due to the differences in organization of the CRFR1 system between species. They further indicate that activity of the CRFR1 system is necessary for the formation of pair-bonds, but not consumption of high doses of alcohol. Overall, we suggest that testing potential pharmacotherapies should not rely only on studies in mice and rats.

Анальгетический эффект кардиотонических стероидов на фоне алкогольной нейропатии у крыс

The present study aimed to assess the possible antinociceptive effect of cardiotonic steroids during the development of alcoholic neuropathy. The pathology was formed in rodents by means of forced alcohol consumption in increasing concentration. The force consumption of high doses of alcohol for 8 weeks allowed us to model a symptomatic complex typical for alcoholic neuropathy. During consequent modelling of the acute alcohol withdrawal syndrome, it was established that on the second day after the withdrawal there was an increase in the renal excretion of marinobufagenin, an alpha-1 isoform inhibitor of Na/K-ATPase, with a simultaneous increase in the threshold of tactile allodynia; that indicated the involvement of cardiotonic steroids in the process of nociception in alcohol dependence. The concentration of marinobufagenin in urine was measured by enzyme-linked immunoassay. It was also demonstrated that intraperitoneally administered ouabain, an alpha-3 isoform inhibitor of Na/K-ATPase, significantly increased the threshold of tactile allodynia, indicating a pronounced analgesic effect of the steroid. These data suggest that the system of Na/K-ATPase and its endogenous ligands has therapeutic potential against the development of chronic pain associated with alcohol dependence.

Dose-dependent alcohol effects on electroencephalogram: Sedation/anesthesia is qualitatively distinct from sleep

Alcohol is commonly used as a sleep inducer/aid by humans. However, individuals diagnosed with alcohol use disorders have sleep problems. Few studies have examined the effect of ethanol on physiological features of sedation and anesthesia, particularly at high doses. This study used polysomnography and a rapid, unbiased scoring of vigilance states with an automated algorithm to provide a thorough characterization of dose-dependent acute ethanol effects on sleep and electroencephalogram (EEG) power spectra in C57BL/6J male mice. Ethanol had a narrow dose-response effect on sleep. Only a high dose (4.0 g/kg) produced a unique, transient state that could not be characterized in terms of canonical sleep-wake states, so we dubbed this novel state Drug-Induced State with a Characteristic Oscillation in the Theta Band (DISCO-T). After this anesthetic effect, the high dose of alcohol promoted NREM sleep by increasing the duration of NREM bouts while reducing wake. REM sleep was differentially responsive to the circadian timing of ethanol administration. EEG power spectra proved more sensitive to ethanol than sleep measures as there were clear effects of ethanol at 2.0 and 4.0 g/kg doses. Ethanol promoted delta oscillations and suppressed faster frequencies, but there were clear, differential effects on wake and REM EEG power based on the timing of the ethanol injection. Understanding the neural basis of the extreme soporific effects of high dose ethanol may aid in treating acute toxicity brought about by patterns of excessive binge consumption commonly observed in young people.