Moderate Ethanol Intake Research Articles

Liver regeneration and ethanol detoxification: A new link in YAP regulation of ALDH1A1 during alcohol-related hepatocyte damage.

Yes‐associated protein (YAP), a central effector in the Hippo pathway, is involved in the regulation of organ size, stem cell self‐renewal, and tissue regeneration. In this study, we observed YAP activation in patients with alcoholic steatosis, hepatitis, and cirrhosis. Accumulation of this protein in the nucleus was also observed in murine livers that were damaged after chronic‐plus‐single binge or moderate ethanol ingestion combined with carbon tetrachloride intoxication (ethanol/CCl4). To understand the role of this transcriptional coactivator in alcohol‐related liver injury, we knocked out the Yap1 gene in hepatocytes of floxed homozygotes through adeno‐associated virus (AAV8)‐mediated deletion utilizing Cre recombinase. Yap1 hepatocyte‐specific knockouts (KO) exhibited hemorrhage, massive hepatic necrosis, enhanced oxidative stress, elevated hypoxia, and extensive infiltration of CD11b+ inflammatory cells into hepatic microenvironments rich for connective tissue growth factor (Ctgf) during ethanol/CCl4‐induced liver damage. Analysis of whole‐genome transcriptomics indicated upregulation of genes involved in hypoxia and extracellular matrix (ECM) remodeling, whereas genes related to hepatocyte proliferation, progenitor cell activation, and ethanol detoxification were downregulated in the damaged livers of Yap1 KO. Acetaldehyde dehydrogenase (Aldh)1a1, a gene that encodes a detoxification enzyme for aldehyde substrates, was identified as a potential YAP target because this gene could be transcriptionally activated by a hyperactive YAP mutant. The ectopic expression of the human ALDH1A1 gene caused increase in hepatocyte proliferation and decrease in hepatic necrosis, oxidative stress, ECM remodeling, and inflammation during ethanol/CCl4‐induced liver damage. Taken together, these observations indicated that YAP was crucial for liver repair during alcohol‐associated injury. Its regulation of ALDH1A1 represents a new link in liver regeneration and detoxification.

Components of the Mediterranean Diet and Risk of COVID-19.

Adherence to the traditional Mediterranean diet has been customarily assessed with the Mediterranean diet score (MDS or Trichopolou Index), with values of 0 or 1 assigned to each of the nine elements, and with the use of the sex-specific median as the cutoff. The value of persons whose consumption of the six beneficial items (ratio of monounsaturated to saturated fatty acids, vegetables, legumes, fruits and nuts, cereal, and fish) is at or above the median and is assigned a value of 1. Otherwise they receive 0 points. For detrimental elements (meats and dairy products) persons whose consumption is below the median are assigned a value of 1. An additional ninth point is assigned to moderate ethanol intake. We assessed the effect of each of the nine components of the MDS (replacing the fats ratio with olive oil, the main source of monounsaturated fats in the Mediterranean diet) on the risk of COVID-19 infection, symptomatic and severe COVID-19. From March to December 2020, 9,699 participants of the “Seguimiento Universidad de Navarra” (SUN) cohort answered a COVID-19 questionnaire. After excluding doctors and nurses, 5,194 participants were included in the main statistical analyses. Among them, we observed 382 cases of COVID-19 based on symptoms and clinical diagnosis; 167 of them with test confirmation. For the two COVID-19 definitions used, we found a significant decrease in risk for a higher adherence to the Mediterranean diet (OR = 0.64, 95% CI: 0.42–0.98, p for trend = 0.040; and OR = 0.44, 95% CI: 0.22–0.88, p for trend = 0.020, for test-diagnosed cases). A protective effect was also found for symptomatic COVID-19 (OR = 0.64, 95% CI: 0.41–1.00, p for trend = 0.050). Among the different individual food groups, only the consumption of whole dairy products showed a harmful direct association. The Mediterranean diet as a whole seems more important than each of its components in preventing the infection and symptoms of COVID-19.

Alcohol consumption before pregnancy causes detrimental fetal development and maternal metabolic disorders

Alcohol consumption before or during pregnancy poses serious health risks to the fetus; however, the underlying mechanisms involved remain obscure. Here, we investigated whether ethanol consumption before pregnancy affects maternal or fetal health and whether pharmacological inhibition of CYP2E1, a major ethanol oxidation enzyme, by 4-methylpyrazole (4-MP) has therapeutic effects. We found that ethanol consumption (5%) 2 weeks before pregnancy resulted in a decrease in the number of viable fetuses and abnormal fetal development, and these effects were accompanied by impaired maternal glucose homeostasis and hepatic steatosis during pregnancy. Neonates of ethanol-fed mice had postnatal macrosomia and significantly decreased growth rates during the lactation period. However, treatment with 4-MP, a CYP2E1 inhibitor, markedly ameliorated the reduction in insulin action and glucose disposal responsiveness in the livers of ethanol-fed mice. Blockage of CYP2E1 significantly reduced the alteration in hepatic lipid deposition, fatty acid oxidation, mitochondrial energy status, and macrophage infiltration observed in ethanol-fed mice. Finally, there was a positive correlation between postnatal macrosomia or growth retardation and increased inflammatory responses. Collectively, our study suggests that even moderate ethanol intake may be detrimental to fetal development and may cause growth retardation through maternal metabolic disorders.

Effect of Moderate Intake of Ethanol on Lipid Profile of Wistar-Albino Rats Fed High Fat Diet

Many evidences suggest that light to moderate alcohol drinking may provide some cardiovascular benefits. The present study examined the impact of how moderate ethanol consumption provides a protective effect against high blood cholesterol. Wistar-Albino rats were divided into a control group (I) and test groups (II, III, IV). The test groups (II, III, IV) were administered with a predefined dosage of 10%, 20% and 30% ethanol respectively following twenty days of high fat routine however, control animals were managed with normal saline for the next fifteen days. Significant difference in lipid profile parameters witnessed before and after ethanol administration between the control and test groups. Findings from the study suggests that 10% moderate ethanol is adequately least enough to reduce the risk of cardiovascular disease by improving the blood cholesterol in Wistar-Albino rats.

Moderate chronic ethanol consumption exerts beneficial effects on nonalcoholic fatty liver in mice fed a high-fat diet: possible role of higher formation of triglycerides enriched in monounsaturated fatty acids.

Several clinical studies suggested that light-to-moderate alcohol intake could alleviate nonalcoholic fatty liver disease (NAFLD), but the underlying mechanism is still poorly understood. Mice fed a high-fat diet (HFD) were submitted or not to moderate ethanol intake for 3months (ca. 10g/kg/day) via drinking water. Biochemical, analytical and transcriptomic analyses were performed in serum and liver. Serum ethanol concentrations in ethanol-treated HFD mice comprised between 0.5 and 0.7g/l throughout the experiment. NAFLD improvement was observed in ethanol-treated HFD mice as assessed by reduced serum transaminase activity. This was associated with less microvesicular and more macrovacuolar steatosis, the absence of apoptotic hepatocytes and a trend towards less fibrosis. Liver lipid analysis showed increased amounts of fatty acids incorporated in triglycerides and phospholipids, reduced proportion of palmitic acid in total lipids and higher desaturation index, thus suggesting enhanced stearoyl-coenzyme A desaturase activity. mRNA expression of several glycolytic and lipogenic enzymes was upregulated. Genome-wide expression profiling and gene set enrichment analysis revealed an overall downregulation of the expression of genes involved in collagen fibril organization and leukocyte chemotaxis and an overall upregulation of the expression of genes involved in oxidative phosphorylation and mitochondrial respiratory chain complex assembly. In addition, mRNA expression of several proteasome subunits was upregulated in ethanol-treated HFD mice. Moderate chronic ethanol consumption may alleviate NAFLD by several mechanisms including the generation of non-toxic lipid species, reduced expression of profibrotic and proinflammatory genes, restoration of mitochondrial function and possible stimulation of proteasome activity.

Impact of Genetic Variation in Aldehyde Dehydrogenase 2 and Alcohol Consumption on Coronary Artery Lesions in Chinese Patients with Stable Coronary Artery Disease.

The aim of this study is to investigate the impact of aldehyde dehydrogenase 2 (ALDH2) genotype and alcohol consumption on coronary artery lesions in Chinese patients with stable coronary artery disease (CAD). A total of 753 Chinese patients (73.6% male) diagnosed with stable CAD by coronary angiography were included in the sample. The frequency of the mutated type ALDH2*2 (including ALDH2*1/*2 and ALDH2*2/*2) was 44.1% in CAD patients. The mutated ALDH2 carriers were more susceptible to multivessel lesions. Low to moderate alcohol consumption is related to higher plasma HDL-C level and fewer coronary artery lesions in CAD patients with ALDH2 wild genotype, while these effects were not observed in CAD patients with ALDH2 mutated genotype. Furthermore, we divided the mutated group into heterozygous and homozygous subgroups, and no obvious relationships were observed among drinking and HDL-C and coronary lesions. To explore the metabolic effects of ALDH2 modified by alcohol, we examined the impact of ALDH2 genotype and alcohol intake on HDL-C levels in ALDH2 wild type and knockout mice. The results showed HDL-C levels were significantly higher post low to moderate alcohol consumption in wild type rather than in knockout mice. CAD patients with mutated ALDH2 genotype are inclined to suffer with coronary artery lesions than wild type subjects. Low to moderate ethanol intake contributes to fewer multivessel lesions in CAD patients with ALDH2 wild type, which might be related to higher HDL-C level.

Inhibition of potassium currents is involved in antiarrhythmic effect of moderate ethanol on atrial fibrillation

Excessive consumption of alcohol is a well-established risk factor of atrial fibrillation (AF). However, the effects of moderate alcohol drinking remain to be elucidated. This study was designed to determine the effects of moderate ethanol ingestion on atrial fibrillation and the electrophysiological mechanisms. In acetylcholine-induced canine and mouse AF models, the moderate ethanol prevented the generation and persistence of AF through prolonging the latent period of AF and shortening the duration of AF. The action potential duration (APD) was remarkably prolonged under the concentration range of 12.5–50.0mM ethanol in guinea pig atrial myocytes. Ultra-rapid delayed rectified potassium currents (IKv1.5) were markedly inhibited by 12.5–50.0mM ethanol in a concentration-dependent manner. Ethanol with 50.0mM could inhibit rapid delayed rectifier potassium currents (IhERG). Ethanol under 6.25–50.0mM did not affect on inward rectifier potassium currents (IKir2.1). Collectively, the present study provided an evidence that moderate ethanol intake can prolong the APD of atrial myocytes by inhibition of IKv1.5 and IhERG, which contributed to preventing the development and duration of AF.

Low-Dose Ethanol Preconditioning Protects Against Oxygen-Glucose Deprivation/Reoxygenation-Induced Neuronal Injury By Activating Large Conductance, Ca2+-Activated K+ Channels In Vitro.

Increasing evidence suggests that low to moderate ethanol ingestion protects against the deleterious effects of subsequent ischemia/reperfusion; however, the underlying mechanism has not been elucidated. In the present study, we showed that expression of the neuronal large-conductance, Ca2+-activated K+ channel (BKCa) α-subunit was upregulated in cultured neurons exposed to oxygen-glucose deprivation/reoxygenation (OGD/R) compared with controls. Preconditioning with low-dose ethanol (10 mmol/L) increased cell survival rate in neurons subjected to OGD/R, attenuated the OGD/R-induced elevation of cytosolic Ca2+ levels, and reduced the number of apoptotic neurons. Western blots revealed that ethanol preconditioning upregulated expression of the anti-apoptotic protein Bcl-2 and downregulated the pro-apoptotic protein Bax. The protective effect of ethanol preconditioning was antagonized by a BKCa channel inhibitor, paxilline. Inside-out patches in primary neurons also demonstrated the direct activation of the BKCa channel by 10 mmol/L ethanol. The above results indicated that low-dose ethanol preconditioning exerts its neuroprotective effects by attenuating the elevation of cytosolic Ca2+ and preventing neuronal apoptosis, and this is mediated by BKCa channel activation.

Chronic moderate ethanol intake differentially regulates vitamin D hydroxylases gene expression in kidneys and xenografted breast cancer cells in female mice

Factors affecting vitamin D metabolism may preclude anti-carcinogenic effects of its active metabolite calcitriol. Chronic ethanol consumption is an etiological factor for breast cancer that affects vitamin D metabolism; however, the mechanisms underlying this causal association have not been fully clarified. Using a murine model, we examined the effects of chronic moderate ethanol intake on tumoral and renal CYP27B1 and CYP24A1 gene expression, the enzymes involved in calcitriol synthesis and inactivation, respectively. Ethanol (5% w/v) was administered to 25-hydroxyvitamin D3-treated or control mice during one month. Afterwards, human breast cancer cells were xenografted and treatments continued another month. Ethanol intake decreased renal Cyp27b1 while increased tumoral CYP24A1 gene expression.Treatment with 25-hydroxyvitamin D3 significantly stimulated CYP27B1 in tumors of non-alcohol-drinking mice, while increased both renal and tumoral CYP24A1. Coadministration of ethanol and 25-hydroxyvitamin D3 reduced in 60% renal 25-hydroxyvitamin D3–dependent Cyp24a1 upregulation (P<0.05). We found 5 folds higher basal Cyp27b1 than Cyp24a1 gene expression in kidneys, whereas this relation was inverted in tumors, showing 5 folds more CYP24A1 than CYP27B1. Tumor expression of the calcitriol target cathelicidin increased only in 25-hydroxyvitamin D3-treated non-ethanol drinking animals (P<0.05). Mean final body weight was higher in 25-hydroxyvitamin D3 treated groups (P<0.001). Overall, these results suggest that moderate ethanol intake decreases renal and tumoral 25-hydroxyvitamin D3 bioconversion into calcitriol, while favors degradation of both vitamin D metabolites in breast cancer cells. The latter may partially explain why alcohol consumption is associated with vitamin D deficiency and increased breast cancer risk and progression.

Brain plasticity and cognitive functions after ethanol consumption in C57BL/6J mice.

Acute or chronic administrations of high doses of ethanol in mice are known to produce severe cognitive deficits linked to hippocampal damage. However, we recently reported that chronic and moderate ethanol intake in C57BL/6J mice induced chromatin remodeling within the Bdnf promoters, leading to both enhanced brain-derived neurotrophic factor (BDNF) expression and hippocampal neurogenesis under free-choice protocol. We performed here a series of cellular and behavioral studies to analyze the consequences of these modifications. We showed that a 3-week chronic free-choice ethanol consumption in C57BL/6J mice led to a decrease in DNA methylation of the Bdnf gene within the CA1 and CA3 subfields of the hippocampus, and upregulated hippocampal BDNF signaling pathways mediated by ERK, AKT and CREB. However, this activation did not affect long-term potentiation in the CA1. Conversely, ethanol intake impaired learning and memory capacities analyzed in the contextual fear conditioning test and the novel object recognition task. In addition, ethanol increased behavioral perseveration in the Barnes maze test but did not alter the mouse overall spatial capacities. These data suggested that in conditions of chronic and moderate ethanol intake, the chromatin remodeling leading to BDNF signaling upregulation is probably an adaptive process, engaged via epigenetic regulations, to counteract the cognitive deficits induced by ethanol.

Effects of Chronic Ethanol Consumption on Biochemical Parameters and Oxidative Stress on Rat

Background: The biochemical effect of chronic alcohol consumption has been rarely studied although, most of the human population drinks moderate ethanol. The aims of this study was described some biochemical effects induced by moderate ethanol ingestion on rats in four and 12 weeks duration. Methods: Eighteen adult male albino Wistar rats (175 to 210 g) were fed with ethanol (1.6 ml/kg body weight/day) for 4 and 12 weeks. Animals randomly divided into 3 groups (1 to 3) comprised 6 animals each as following: Control group as group (1): Received orally drinking water. Group II: Treated orally with 1.6 g diluted ethanol/ kg body weight daily for 28 successive days. Group III:Treated orally with 1.6 g diluted ethanol/ kg body weight daily for 84 successive days. Blood samples were collected from retero-orbital plexus of animals before to start the ethanol administration (0 week), and at the end of 4 and 12 weeks of ethanol treatment. The serum was used for biochemical tests such as Blood Urea Nitrogen (BUN), Creatinine, Total protein, Albumin, Alanine Amino transferases (ALT), Aspartate Amino transferases (AST), Alkaline Phosphatases (ALP), Glutamyl transpeptidase (GGT) and Nitrite concentration. Reduced Glutathione (GSH), Mallondialdehyde (MDA) content, Catalase, Superoxide Dismutase (SOD) and Glutathione Peroxidase (GPH) activities were estimated on homogenized samples. For Analysis of data paired t-student test was used. Results: Ethanol exposure initially affects liver function followed by renal function. Chronic ethanol ingestion increased hepatocellular enzyme markers such as ALT, AST, ALP, GGT and MDA and nitrate concentration; while decreased total protein, albumin, GSH, ascorbic acid contents and SOD and catalase activities compare to control group. Conclusion: Long-term ethanol exposure induced toxicity which revealed by increase insystemic, local oxidative stress markers and hepatic enzyme indicators.

PP.34.28

Objective: Mediterranean Diet that is characterized by a high intake of fruit and nuts, vegetables, legumes, cereals, fish and seafood; a low intake of dairy products, meat and meat products; and a moderate ethanol intake mainly in the form of wine and during meals, has become the standard for healthy eating. We conducted a retrospective study to evaluate the association between Mediterranean Diet adherence evaluated by means the calculation of Mediterranean Diet Score (MDS), stroke subtype and severity indexes and outcome of ischemic stroke. Design and method: The primary outcome in this study was differences in mean Mediterranean diet score between patients with acute ischemic stroke and subjects without acute ischemic stroke; Secondary outcomes were evaluation of a relationship between TOAST subtypes of ischemic stroke and mean Mediterranean Diet Score and between severity indexes of acute ischemic stroke and mean Mediterranean diet score. The type of acute ischemic stroke was classified according to the TOAST classification. We administered to all patients admitted with acute ischemic stroke or to their relatives a a 137-item validated food-frequency questionnaire (17) adapted to Sicilian population. A scale indicating the degree of adherence to the traditional Mediterranean diet was constructed by Trichopoulou et al Results: We enrolled 198 subjects with acute ischemic stroke and 100 control subjects without acute ischemic stroke. Among stroke patients we observed a significant correlation between MED diet score and female sex (R: 0.165; p = 0.023), atrial fibrillation (R: 0.152; p = 0.037), and SSS score (R: 0.306; P < 0.0005) whereas we observed a negative relationship between med diet score and CAD (R: -0.146; p = 0.045), NIHSS (R: -0.296; p < 0.0005) and Rankin scores (R:-0.229; p < 0.0005). Among stroke patients, lacunar subtype showed a higher mean Mediterranean diet (5.41 ± 1.51) score compared to LAAS subtype (3.59 ± 1.41) but not compared to cardioembolic (5.98 ± 1.83). Conclusions: We reported that patients with lower adherence to a Mediterranean Diet profile are more likely to have an atherosclerotic (LAAS) subtype of stroke, a worse clinical presentation of ischemic stroke with a higher mean NIHSS and a dependency with higher rankin score at admission.

Consequências da ingestão moderada de etanol na discriminação de notas musicais

O objetivo deste estudo foi avaliar se existe relacao entre a ingestao moderada de etanol e a discriminacao das notas musicais RE, FA, e LA, em adultos jovens. Essas notas apresentam frequencias fundamentais respectivamente de 293,665 Hz, 349,228 Hz e 440 Hz, de temperamento igual, escolhidas devido estarem em localizacao central na escala musical ocidental padrao. Participaram do estudo 40 voluntarios de 18 a 29 anos, nao musicos, saudaveis, nao usuarios de farmacos ou outras substâncias toxicas, exceto o etanol de forma moderada e aguda. Por meio do softwarePsysounds, criado especificamente para esse estudo, esses voluntarios tiveram de escolher, entre duas notas musicais, uma das notas teste apresentada inicialmente. Os dados foram tratados com um teste X2 de aderencia para comparar as frequencias de acertos das notas musicais de teste nas condicoes de ingestao e de nao ingestao de alcool. As analises mostraram diferencas significantes nas frequencias de acertos para todas as notas utilizadas, sugerindo que a ingestao de etanol prejudica a discriminacao das notas musicais RE, FA e LA.

Moderate ethanol administration accentuates cardiomyocyte contractile dysfunction and mitochondrial injury in high fat diet-induced obesity

Light to moderate drinking confers cardioprotection although it remains unclear with regards to the role of moderate drinking on cardiac function in obesity. This study was designed to examine the impact of moderate ethanol intake on myocardial function in high fat diet intake-induced obesity and the mechanism(s) involved with a focus on mitochondrial integrity. C57BL/6 mice were fed low or high fat diet for 16 weeks prior to ethanol challenge (1g/kg/d for 3 days). Cardiac contractile function, intracellular Ca2+ homeostasis, myocardial histology, and mitochondrial integrity [aconitase activity and the mitochondrial proteins SOD1, UCP-2 and PPARγ coactivator 1α (PGC-1α)] were assessed 24h after the final ethanol challenge. Fat diet intake compromised cardiomyocyte contractile and intracellular Ca2+ properties (depressed peak shortening and maximal velocities of shortening/relengthening, prolonged duration of relengthening, dampened intracellular Ca2+ rise and clearance without affecting duration of shortening). Although moderate ethanol challenge failed to alter cardiomyocyte mechanical property under low fat diet intake, it accentuated high fat diet intake-induced changes in cardiomyocyte contractile function and intracellular Ca2+ handling. Moderate ethanol challenge failed to affect fat diet intake-induced cardiac hypertrophy as evidenced by H&E staining. High fat diet intake reduced myocardial aconitase activity, downregulated levels of mitochondrial protein UCP-2, PGC-1α, SOD1 and interrupted intracellular Ca2+ regulatory proteins, the effect of which was augmented by moderate ethanol challenge. Neither high fat diet intake nor moderate ethanol challenge affected protein or mRNA levels as well as phosphorylation of Akt and GSK3β in mouse hearts. Taken together, our data revealed that moderate ethanol challenge accentuated high fat diet-induced cardiac contractile and intracellular Ca2+ anomalies as well as mitochondrial injury.

Ethanol-induced epigenetic regulations at the Bdnf gene in C57BL/6J mice.

High ethanol intake is well known to induce both anxiolytic and anxiogenic effects, in correlation with chromatin remodeling in the amygdaloid brain region and deficits in cell proliferation and survival in the hippocampus of rodents. Whether only moderate but chronic ethanol intake in C57BL/6J mice could also have an impact on chromatin remodeling and neuroplasticity was addressed here. Chronic ethanol consumption in a free choice paradigm was found to induce marked changes in the expression of genes implicated in neural development and histone post-translational modifications in the mouse hippocampus. Transcripts encoding neural bHLH activators and those from Bdnf exons II, III and VI were upregulated, whereas those from Bdnf exon VIII and Hdacs were downregulated by ethanol compared with water consumption. These ethanol-induced changes were associated with enrichment in both acetylated H3 at Bdnf promoter PVI and trimethylated H3 at PII and PIII. Conversely, acetylated H3 at PIII and PVIII and trimethylated H3 at PVIII were decreased in ethanol-exposed mice. In parallel, hippocampal brain-derived neurotrophic factor (BDNF) levels and TrkB-mediated neurogenesis in the dentate gyrus were significantly enhanced by ethanol consumption. These results suggest that, in C57BL/6J mice, chronic and moderate ethanol intake produces marked epigenetic changes underlying BDNF overexpression and downstream hippocampal neurogenesis.

Back to the future: The Mediterranean diet paradigm

The Mediterranean diet was introduced to the scientific community by the classic Seven Countries study. Since then data on the association between this diet and cardiovascular disease, cancer and other chronic diseases have been accumulating. The Mediterranean diet is characterized by a high intake of olive oil, plant products, fish and seafood; a low intake of dairies, meat and meat products; and a moderate ethanol intake. The Mediterranean diet has been operationalized through various computational scores (e.g. the Mediterranean diet score for adults and the KIDMED index for children) which are all based on the dietary components that capture its essence. Next to evidence generated through both observational studies and intervention trials on the inverse association between Mediterranean diet and several risk factors, inflammatory markers and mortality or incidence of disease, there is increasing evidence that Mediterranean populations are abandoning their traditional eating habits. Publications presenting changes over time in the diet of populations participating in the Seven Countries Study point towards an increase in the intake of processed foods and saturated fat and a decrease in the intake of plant foods and monounsaturated fatty acids. Findings are alarming, particularly in relation to younger generations. Studies among children and adolescents in the Mediterranean region clearly indicate that the largest proportions of these populations poorly adhere to their traditional diet. Mediterraneans have clearly not been the major benefactors in the research on the effects of the Mediterranean lifestyle and younger populations in the regions are already following the wrong path.

P.4.006 Reward processing in unaffected siblings of schizophrenia patients: a functional magnetic resonance imaging study

free ethanol consumption, using qRT-PCR, chromatin immunoprecipitation and immunohistochemistry approaches. Increased expression of bHLH transcription factors implicated in neural proliferation and maturation and BDNF occurred concomitantly with increased neurogenesis after free ethanol intake in mice (10% ethanol in drinking water for 3 weeks). In addition, MeCP2 expression was increased at both mRNA and protein levels in the DG and CA3 areas, and upregulation of acetylated histone H4 (H4Ac) and trimethylated histone H3 (H3K4me3) was also noted in these hippocampal areas in ethanol-exposed mice. Thorough analysis of bdnf gene evidenced ethanol-induced modifications at transcription level associated with changes in H3Ac and H3K4me3 at bdnf promoter. Differential expression of bdnf exons appeared causally linked to ethanol-induced increase in BDNF protein in the hilus and CA3 area of the hippocampus. Altogether, these results suggest that chronic moderate ethanol intake under free choice conditions promotes neurogenesis in the DG in C57BL/6J mice by stimulating the expression of neural factors and BDNF. Epigenetic mechanisms involving histone modifications at the level of bdnf gene play probably a key role in ethanol-induced BDNF upregulation in the mouse hippocampus.

Effect of Moderate Ethanol Administration on Biochemical Indices in Streptozotocin-diabetic Wistar Rats

This study was designed to evaluate the effect of moderate ethanol administration on the biochemical indices in streptozotocin (STZ)-diabetic rats. Twenty-four male Wistar rats were divided into four groups of six animals each. Groups one and two contained non-diabetic normal rats and normal rats treated with ethanol, respectively. Group three was untreated STZ-diabetic rats and group four was made up of ethanol-treated STZ-diabetic rats. Diabetes was induced by a single intraperitoneal injection of STZ (35 mg/kg), while ethanol (100%v/v) was given at a dose 2 g/kg thrice per week for three weeks. After the last dose of ethanol and an overnight fasting, rats were sacrificed by cervical dislocation. Blood was collected by syringe from the heart into plain centrifuge tubes. Moderate ethanol administration to STZ-diabetic rats caused a significant (p < 0.05) increase in relative weight of liver relative to normal. Ethanol intake in STZ-diabetic rats produced an insignificant (p > 0.05) effect on the levels of fasting blood glucose (FBG) and HbA1c relative to the untreated-diabetic group. Moderately, ethanol administration to STZ-diabetic rats produced a marked and significant (p < 0.05) increase in the levels of serum total cholesterol, triglycerides, low-density lipoprotein (LDL)-cholesterol and the activities of alanine aminotransferase relative to untreated diabetic rats. Ethanol-treated diabetic rats had significantly (p < 0.05) lower high-density lipoprotein (HDL)-cholesterol levels, while the activities of lactate dehydrogenase and alpha-amylase were insignificantly (p > 0.05) affected. There were no significant (p > 0.05) differences in all the biochemical indices in normal rats relative to ethanol-treated normal rats. Moderate ethanol administration did not affect FBG and HbA1c, but altered the lipid profile of STZ-diabetic rats. Moderate ethanol intake may further increase the risk of complications in diabetes.

Ethanol drinking reduces extracellular dopamine levels in the posterior ventral tegmental area of nondependent alcohol-preferring rats

Moderate ethanol exposure produces neuroadaptive changes in the mesocorticolimbic dopamine (DA) system in nondependent rats and increases measures of DA neuronal activity in vitro and in vivo. Moreover, moderate ethanol drinking and moderate systemic exposure elevates extracellular DA levels in mesocorticolimbic projection regions. However, the neuroadaptive changes subsequent to moderate ethanol drinking on basal DA levels have not been investigated in the ventral tegmental area (VTA). In the present study, adult female alcohol-preferring (P) rats were divided into alcohol-naive, alcohol-drinking, and alcohol-deprived groups. The alcohol-drinking group had continuous access to water and ethanol (15%, vol/vol) for 8 weeks. The alcohol-deprived group had 6 weeks of access followed by 2 weeks of ethanol deprivation, 2 weeks of ethanol re-exposure, followed again by 2 weeks of deprivation. The deprived rats demonstrated a robust alcohol deprivation effect (ADE) on ethanol reinstatement. The alcohol-naïve group had continuous access to water only. In the last week of the drinking protocol, all rats were implanted with unilateral microdialysis probes aimed at the posterior VTA and no-net-flux microdialysis was conducted to quantify extracellular DA levels and DA clearance. Results yielded significantly lower basal extracellular DA concentrations in the posterior VTA of the alcohol-drinking group compared with the alcohol-naive and alcohol-deprived groups (3.8 ± 0.3 nM vs. 5.0 ± 0.5 nM [ P < .02] and 4.8 ± 0.4 nM, [ P < .05], respectively). Extraction fractions were significantly ( P < .0002) different between the alcohol-drinking and alcohol-naive groups (72 ± 2% vs. 46 ± 4%, respectively) and not significantly different ( P = .051) between alcohol-deprived and alcohol-naive groups (61 ± 6% for the alcohol-deprived group). The data indicate that reductions in basal DA levels within the posterior VTA occur after moderate chronic ethanol intake in nondependent P rats. This reduction may result, in part, from increased DA uptake and may be important for the maintenance of ethanol drinking. These adaptations normalize with ethanol deprivation and may not contribute to the ADE.

Interaction Between Family History of Alcoholism and Locus of Control in the Opioid Regulation of Impulsive Responding Under the Influence of Alcohol

Naltrexone (NTX) is an opioid antagonist indicated for the treatment of alcoholism, which is not universally effective. Thus, identifying individual predictors of NTX's behavioral effects is critical to optimizing its therapeutic use. Moreover, given the high rate of relapse during treatment for alcoholism, understanding NTX's behavioral effects when combined with moderate ethanol intake is important. Our previous study of abstinent alcoholics and control subjects showed that a more internal Locus of Control score predicted increased impulsive choice on NTX (Mitchell et al., 2007, Neuropsychopharmacology 32:439-449). Here, we tested whether this predictive relationship remains in the context of moderate alcohol intake. In this study, we tested the effect of acute NTX (50 mg) on impulsive choice, motor inhibition, and attentional bias after ingestion of moderate ethanol (∼0.3 g/kg, n = 30 subjects). Subjects included those recruited from a pool of ∼1,200 UC Berkeley undergraduates on the basis of scores on the Barratt Impulsiveness Scale (BIS). Impulsive choice was positively correlated with breath alcohol concentration in placebo sessions. Locus of Control was again the sole predictor of NTX's effect on decision making among subjects with a family history of alcoholism. We also found a weak interaction between BIS scores and NTX's effect on impulsive choice. Our results reinforce the predictive relationship between Locus of Control and NTX's effect on decision making in those with a family history of alcoholism, suggesting a possible biological basis to this relationship.