Chronic binge alcohol and ovariectomy dysregulate omental adipose tissue metaboproteome in simian immunodeficiency virus-infected female macaques.

Effective antiretroviral therapy (ART) has significantly reduced mortality of people living with HIV (PLWH), and the prevalence of at-risk alcohol use is higher among PLWH. Increased survival and aging of PLWH is associated with increased prevalence of metabolic comorbidities especially among menopausal women, and adipose tissue metabolic dysregulation may be a significant contributing factor. We examined the differential effects of chronic binge alcohol (CBA) administration and ovariectomy (OVX) on the omental adipose tissue (OmAT) proteome in a subset of simian immunodeficiency virus (SIV)-infected macaques of a longitudinal parent study. Quantitative discovery-based proteomics identified 1,429 differentially expressed proteins. Ingenuity Pathway Analysis (IPA) was used to calculate z-scores, or activation predictions, for functional pathways and diseases. Results revealed that protein changes associated with functional pathways centered around the "OmAT metaboproteome profile." Based on z-scores, CBA did not affect functional pathways of metabolic disease but dysregulated proteins involved in adenosine monophosphate-activated protein kinase (AMPK) signaling and lipid metabolism. OVX-mediated proteome changes were predicted to promote pathways involved in glucose- and lipid-associated metabolic disease. Proteins involved in apoptosis, necrosis, and reactive oxygen species (ROS) pathways were also predicted to be activated by OVX and these were predicted to be inhibited by CBA. These results provide evidence for the role of ovarian hormone loss in mediating OmAT metaboproteome dysregulation in SIV and suggest that CBA modifies OVX-associated changes. In the context of OVX, CBA administration produced larger metabolic and cellular effects, which we speculate may reflect a protective role of estrogen against CBA-mediated adipose tissue injury in female SIV-infected macaques.

Pairing Binge Drinking and a High-Fat Diet in Adolescence Modulates the Inflammatory Effects of Subsequent Alcohol Consumption in Mice.

Alcohol binge drinking (BD) and poor nutritional habits are two frequent behaviors among many adolescents that alter gut microbiota in a pro-inflammatory direction. Dysbiotic changes in the gut microbiome are observed after alcohol and high-fat diet (HFD) consumption, even before obesity onset. In this study, we investigate the neuroinflammatory response of adolescent BD when combined with a continuous or intermittent HFD and its effects on adult ethanol consumption by using a self-administration (SA) paradigm in mice. The inflammatory biomarkers IL-6 and CX3CL1 were measured in the striatum 24 h after BD, 3 weeks later and after the ethanol (EtOH) SA. Adolescent BD increased alcohol consumption in the oral SA and caused a greater motivation to seek the substance. Likewise, mice with intermittent access to HFD exhibited higher EtOH consumption, while the opposite effect was found in mice with continuous HFD access. Biochemical analyses showed that after BD and three weeks later, striatal levels of IL-6 and CX3CL1 were increased. In addition, in saline-treated mice, CX3CL1 was increased after continuous access to HFD. After oral SA procedure, striatal IL-6 was increased only in animals exposed to BD and HFD. In addition, striatal CX3CL1 levels were increased in all BD- and HFD-exposed groups. Overall, our findings show that adolescent BD and intermittent HFD increase adult alcohol intake and point to neuroinflammation as an important mechanism modulating this interaction.

Drinking and responses to antidrinking messages among young adults: An fMRI study.

Young adults consume most of their alcohol by binge drinking, and more than one-third report binge drinking in the past month. Some will transition out of excessive drinking, while others will maintain or increase alcohol use into adulthood. Public health campaigns depicting negative consequences of drinking have shown some efficacy at reducing this behavior. However, substance use in dependent individuals is governed in part by automatic or habitual responses to drug cues rather than the consequences. This study used functional magnetic resonance imaging to measure neural responses to drinking cues and drinking cues paired with antidrinking messages among young adults who binge drink (N = 30). This study also explored responses to smoking cues and antismoking messages. Neural responses were also compared between drinking/smoking and neutral cues. Self-reported drinking and smoking were collected at baseline, postscan, and 1 month. Results indicate that activity in the ventral striatum-implicated in reward processing-was lower for drinking cues paired with antidrinking messages than drinking cues. This difference was less pronounced in young adults who reported greater baseline past month drinking quantity. Past month drinking quantity decreased from baseline to 1 month. Further, young adults who showed higher activity during antidrinking messages in the medial prefrontal cortex-implicated in processing message self-relevance- reported a greater decrease in past month drinking frequency from baseline to 1 month. Findings may help to identify young adults who are at risk for continued heavy drinking in adulthood and inform interventions aimed to reduce drinking and reward in young adults.

Administration of a putative pro-dopamine regulator, a neuronutrient, mitigates alcohol intake in alcohol-preferring rats.

BACKGROUND: Excessive alcohol intake is a serious but preventable public health problem in the United States and worldwide. Alcohol and other substance use disorders occur co-morbid with more generalized reward deficiency disorders, characterized by a reduction in dopamine (DA) signaling within the reward pathway, and classically associated with increased impulsivity, risk taking and subsequent drug seeking behavior. It is postulated that increasing dopamine availability and thus restoring DA homeostasis in the mesocorticolimbic system could reduce the motivation to seek and consume ethanol. Here, we treated animals with a neuro-nutrient, KB220Z also known as Synaptamine, designed to augment DA signaling. METHOD: KB220Z was administered to genetically alcohol-preferring (P) adult male and female rats by oral gavage (PO), intraperioneally (IP), or subcutaneously (SQ) for 4 consecutive days at a 3.4 mL/Kg rat equivalent dose and compared to saline (SQ, IP) or water (PO) controls. Subsequent to treatment, lever pressing and consumption of 10 % ethanol or control 3% sucrose during operant responding was assessed using a drinking in the dark multiple scheduled access (DIDMSA) binge drinking protocol. Locomotor and elevated zero maze activity, and DRD2 mRNA expression via in situ hybridization (ISH) were assessed independently following 4 days of a SQ regimen of KB220Z. RESULTS: KB220Z administered via IP and SQ markedly and immediately reduced binge drinking of 10 % ethanol in both male and female rats whereas PO administration took at least 3 days to decrease lever pressing for ethanol in both male and female rats. There was no effect of SQ KB220Z on 3% sucrose drinking. Elevated activity in the open field was significantly decreased, and time spent in the open arm of the EZM was moderately reduced. The regimen of SQ KB220Z did not impact the number of DRD2 punctae in neurons of the NAc, but the NAc shell expressed more DRD2 mRNA/cell than NAc core independent of KB220Z. CONCLUSION: KB220Z attenuates ethanol drinking and other RDS behaviors in P rats possibly by acting on the dopaminergic system, but not by effecting an increase in NAc DRD2 mRNA expression.

Is It Good To Be Good? Dispositional Compassion and Health Behaviors.

BACKGROUND: Despite the documented importance of dispositional compassions for a range of health-related outcomes, its role in predicting health behaviors remains unclear. PURPOSE: This study examined the associations between dispositional compassion and three domains of health behavior, including physical activity, alcohol use, and smoking. METHODS: The participants (N = 1,279-1,913) were from the Finnish population-based Young Finns study. We collected self-reports of compassion in 1997 and 2011 and health behaviors in 2001, 2007, and 2011. In addition, an objective pedometer measure of physical activity was collected in 2011. Linear and logistic regression models were fitted to estimate the cross-sectional and longitudinal associations between compassion and the health behavior outcomes. RESULTS: In a cross-sectional analysis, compassion was associated with having never smoked and a reduced likelihood of at-risk alcohol use and binge drinking. There was no robust association between compassion and physical activity. In longitudinal analyses over a 14-year period, the associations remained for at-risk alcohol use and binge drinking. CONCLUSIONS: Dispositional compassion may have a protective effect against unhealthy behaviors, especially excessive alcohol consumption.

Effects of Binge Drinking on the Developing Brain.

Binge drinking is a pattern of alcohol drinking that raises a person's blood alcohol concentration to at least .08%, which amounts to consuming five alcoholic drinks for men and four alcoholic drinks for women in about 2 hours. It is the most common form of alcohol misuse in adolescents and young adults. Heavy drinking includes the same criterion as binge drinking, but with higher frequency (i.e., 5 or more days in the past 30 days). Although binge drinking or heavy drinking alone is insufficient to meet the criteria for an alcohol use disorder (AUD) diagnosis, there are neurobiological changes, as well as an increased risk of developing an AUD later in life, associated with this form of alcohol misuse. This review describes the recent neuroimaging findings in binge drinking and heavy-drinking adolescents and young adults, a developmental period during which significant neuromaturation occurs.

Effects of docosahexaenoic acid on locomotor activity in ethanol-treated HIV-1 transgenic rats.

Binge drinking affects the onset and progression of human immunodeficiency virus (HIV)-associated neurological disorders. The HIV-1 transgenic (HIV-1Tg) rat was created with a gag- and pol-deleted HIV-1 viral genome to mimic HIV-infected patients receiving combination anti-retroviral therapy (cART). Docosahexaenoic acid (DHA) is a marine compound that modulates inflammatory responses. Using HIV-1Tg rats subjected to binge exposure to ethanol (EtOH), this study examined whether DHA could reduce the detrimental neurological effects of EtOH and HIV proteins. Young adult male HIV-1Tg and F344 control rats received 4 mL/kg/day saline as a control (Saline group), 20 mg/kg/day DHA (DHA group), 4.8 g/kg/day 52% w/v EtOH (EtOH group), or 4.8 g/kg/day 52% w/v EtOH and 20 mg/kg/d DHA (DHA + EtOH group) by gavage for 5 weeks (n = 6 per group). EtOH was administrated on days 5, 6, and 7 of each week. Locomotor activity (LMA) was assessed using open field tests before and 45, 90, 135, and 180 min after each treatment. Repeated binge EtOH exposure gradually decreased LMA measured before daily treatments in HIV-1Tg and F344 rats, an effect that was reversed by DHA only in the HIV-1Tg rats. Decreased LMA of rats after treatment and under the influence of EtOH was less pronounced, and the reversal effect of DHA did not reach statistical significance. The plasma endotoxin level was significantly higher in HIV-1Tg rats than in F344 rats. IL-6 and IL-18 expression in the striatum was significantly higher in the HIV-1Tg EtOH group than in the F344 EtOH group. DHA significantly decreased the high levels of IL-6, IL-18, and NF-κB expression observed in the HIV-1Tg EtOH group. DHA appears to ameliorate inflammation and consequently lessen the reductions in LMA produced by the combination of EtOH and HIV-1 viral proteins.

Alcohol consumption and cardiorespiratory fitness in five population-based studies.

Background Poor cardiorespiratory fitness is a risk factor for cardiovascular morbidity. Alcohol consumption contributes substantially to the burden of disease, but its association with cardiorespiratory fitness is not well described. We examined associations between average alcohol consumption, heavy episodic drinking and cardiorespiratory fitness. Design The design of this study was as a cross-sectional population-based random sample. Methods We analysed data from five independent population-based studies (Study of Health in Pomerania (2008-2012); German Health Interview and Examination Survey (2008-2011); US National Health and Nutrition Examination Survey (NHANES) 1999-2000; NHANES 2001-2002; NHANES 2003-2004) including 7358 men and women aged 20-85 years, free of lung disease or asthma. Cardiorespiratory fitness, quantified by peak oxygen uptake, was assessed using exercise testing. Information regarding average alcohol consumption (ethanol in grams per day (g/d)) and heavy episodic drinking (5+ or 6+ drinks/occasion) was obtained from self-reports. Fractional polynomial regression models were used to determine the best-fitting dose-response relationship. Results Average alcohol consumption displayed an inverted U-type relation with peak oxygen uptake ( p-value<0.0001), after adjustment for age, sex, education, smoking and physical activity. Compared to individuals consuming 10 g/d (moderate consumption), current abstainers and individuals consuming 50 and 60 g/d had significantly lower peak oxygen uptake values (ml/kg/min) (ß coefficients = -1.90, ß = -0.06, ß = -0.31, respectively). Heavy episodic drinking was not associated with peak oxygen uptake. Conclusions Across multiple adult population-based samples, moderate drinkers displayed better fitness than current abstainers and individuals with higher average alcohol consumption.

Adolescent Binge Alcohol Exposure Affects the Brain Function Through Mitochondrial Impairment.

In the young population, binge drinking is a pattern of problematic alcohol consumption, characterized by a short period of heavy drinking followed by abstinence which is frequently repeated over time. This drinking pattern is associated with mental problems, use of other drugs, and an increased risk of excessive alcohol intake during adulthood. However, little is known about the effects of binge drinking on brain function in adolescents and its neurobiological impact during the adulthood. In the present study, we evaluated the effects of alcohol on hippocampal memory, synaptic plasticity, and mitochondrial function in adolescent rats after a binge drinking episode in vivo. These effects were analyzed at 1, 3, or 7 weeks post alcohol exposure. Our results showed that binge-like ethanol pre-treated (BEP) rats exhibited early alterations in learning and memory tests accompanied by an impairment of synaptic plasticity that was total and partially compensated, respectively. These changes could be attributed to a rapid increase in oxidative damage and a late inflammatory response induced by post ethanol exposure. Additionally, BEP alters the regulation of mitochondrial dynamics and modifies the expression of mitochondrial permeability transition pore (mPTP) components, such as cyclophilin D (Cyp-D) and the voltage-dependent anion channel (VDAC). These mitochondrial structural changes result in the impairment of mitochondrial bioenergetics, decreasing ATP production progressively until adulthood. These results strongly suggest that teenage alcohol binge drinking impairs the function of the adult hippocampus including memory and synaptic plasticity as a consequence of the mitochondrial damage induced by alcohol and that the recovery of hippocampal function could implicate the activation of alternative pathways that fail to reestablish mitochondrial function.

Interactive effects of ovarian steroid hormones on alcohol use and binge drinking across the menstrual cycle.

Patterns and features of substance use and abuse vary across the menstrual cycle in humans. Yet, little work has systematically examined the within-person relationships between ovarian hormone changes and alcohol use across the menstrual cycle. Our study was the first to examine the roles of within-person levels of estradiol (E2) and progesterone (P4) in relation to daily alcohol use and binge drinking in young women. Participants were 22 naturally cycling women, ages 18-22, recruited through a university subject pool who reported any alcohol use and who completed a screening visit assessing study eligibility, followed by 35 subsequent days of data collection. E2 and P4 were obtained via enzyme immunoassay of saliva samples collected by participants each morning, 30 min after waking. Presence and degree of daily substance use were obtained using an adaptation of the Timeline FollowBack Interview completed daily. Results indicated that elevated E2 in the context of decreased P4 levels were associated with higher risk of drinking and binge drinking. These effects were present only on weekend days. Results are suggestive of a dual risk model in which both ovulatory E2 increases and perimenstrual P4 decreases increase risk for drinking. Differential associations of steroids with drinking across the menstrual cycle may suggest the need for clinical assessment of substance use to take into account hormone dynamics and menstrual cycle phase. (PsycINFO Database Record

Long-Lasting Effects of Chronic Intermittent Alcohol Exposure in Adolescent Mice on Object Recognition and Hippocampal Neuronal Activity.

BACKGROUND: Binge drinking is popular and highly prevalent in teenagers. However, the long-term cognitive and neurobiological consequences of such practices are not yet fully understood. In this context, we therefore assessed in mice whether a chronic intermittent alcohol (CIA) exposure in adolescence had long-term consequences on object discrimination and memory performances, emotional behaviors, brain activity, and morphology. METHODS: C57BL/6JRj mice were treated with either saline or ethanol (EtOH) (2 g/kg/d, i.p., from postnatal days [PND] 30 to PND 44 every other day). The day following the last administration or later in adulthood (PND 71) mice were tested for different behavioral tests (novel object recognition, spontaneous alternation, light-dark box, elevated plus-maze, actimeter test), to assess object recognition, working memory performances, anxiety-like behavior, and locomotor activity. We also investigated neuronal activation of hippocampus, prefrontal and perirhinal cortices, and anatomical changes using immediate-early gene expression and longitudinal brain magnetic resonance imaging. RESULTS: Our results showed that adolescent mice exposed to CIA present a critical and persistent impairment of short-term object recognition performances. By contrast, spatial working memory was not impaired, nor was anxiety-like behavior. This altered object discrimination was associated with a biphasic change in neuronal activity in the hippocampus but without morphological changes. Indeed, c-Fos expression was specifically increased in the dorsal dentate gyrus (DG) of the hippocampus after the binge exposure, but then became significantly lower in adulthood both in the DG and the CA1 part of the hippocampus compared with adult saline pretreated mice. CONCLUSIONS: These findings provide evidence for adolescent vulnerability to the effects of intermittent binge EtOH exposure on object discrimination and hippocampal activity with long-lasting consequences.

Learning and Memory in Adolescent Moderate, Binge, and Extreme-Binge Drinkers.

BACKGROUND: Binge drinking has been linked to neurocognitive disadvantages in youth, but it is unclear whether drinking at particularly heavy levels uniquely affects neurocognitive performance. This study prospectively examined (1) whether initiating moderate, binge, or extreme-binge drinking in adolescence differentially influences subsequent learning and memory performances, and (2) whether dosage of alcohol consumption is linearly associated with changes in learning and memory over 6 years of adolescence. METHODS: Participants, who later transitioned into drinking, were administered verbal learning and memory (VLM) assessments at project intake prior to the onset of substance use (age 12 to 16 years), and at follow-up approximately 6 years later (N = 112). Participants were grouped based on alcohol involvement at follow-up as follows: moderate (≤4 drinks per occasion), binge (5+ drinks per occasion), or extreme-binge (10+ drinks per occasion) drinkers. RESULTS: Despite equivalent performances prior to onset of drinking, extreme-binge drinkers performed worse than moderate drinkers on verbal learning, and cued and free short delayed recall (ps < 0.05); binge drinkers did not differ from the other groups. No distinct thresholds in alcohol quantity to differentiate the 3 groups were detected, but estimated peak blood alcohol concentrations were linearly associated with verbal learning (ß^ = -0.24), and immediate (ß^ = -0.27), short delay free (ß^ = -0.28) and cued (ß^ = -0.30), and long delay free (ß^ = -0.24) and cued (ß^ = -0.27) recall (ps < 0.05). CONCLUSIONS: Drinking quantity during adolescence appears to adversely affect VLM in a dose-dependent manner. The acquisition of new verbal information may be particularly affected, notably for those who initiated drinking 10+ drinks in an occasion. Although classification of drinkers into categories remains critical in the study of alcohol, it is important to consider that subtle differences may exist within drinking categories.

Relationships Between Current and Past Binge Drinking and Systolic Blood Pressure in Young Adults.

PURPOSE: Heavy episodic (i.e., "binge") drinking (i.e., ≥five drinks/occasion) is highly prevalent among young adults; those who binge do so four times per month on average, consuming nine drinks on average on each occasion. Although it is well established that chronic heavy drinking (≥two alcoholic beverages per day) increases the risk of hypertension, the relationship between binge drinking and blood pressure is not well described. Our aim was to describe the relationship between frequency of binge drinking, both current (at age 24 years) and past (at age 20 years), and systolic blood pressure (SBP) at age 24 years. METHODS: Participants (n = 756) from the longitudinal Nicotine Dependence in Teens study reported alcohol consumption at ages 20 and 24 years and had SBP measured at age 24 years. We examined the association between binge drinking and SBP using multiple linear regression, controlling for sex, race/ethnicity, education, monthly drinking in high school, cigarette smoking, and body mass index. RESULTS: Compared to nonbinge drinkers, SBP at age 24 years was 2.61 [.41, 4.82] mm Hg higher among current monthly bingers and 4.03 [1.35, 6.70] mm Hg higher among current weekly bingers. SBP at age 24 years was 2.90 [.54, 5.25] mm Hg higher among monthly bingers at age 20 years and 3.64 [.93, 6.35] mm Hg higher among weekly bingers at age 20 years, compared to nonbinge drinkers. CONCLUSIONS: Frequent binge drinking at ages 20 and 24 years is associated with higher SBP at age 24 years and may be implicated in the development of hypertension.

Chronic alcohol binging injures the liver and other organs by reducing NAD⁺ levels required for sirtuin's deacetylase activity.

NAD(+) levels are markedly reduced when blood alcohol levels are high during binge drinking. This causes liver injury to occur because the enzymes that require NAD(+) as a cofactor such as the sirtuin de-acetylases cannot de-acetylate acetylated proteins such as acetylated histones. This prevents the epigenetic changes that regulate metabolic processes and which prevent organ injury such as fatty liver in response to alcohol abuse. Hyper acetylation of numerous regulatory proteins develops. Systemic multi-organ injury occurs when NAD(+) is reduced. For instance the Circadian clock is altered if NAD(+) is not available. Cell cycle arrest occurs due to up regulation of cell cycle inhibitors leading to DNA damage, mutations, apoptosis and tumorigenesis. NAD(+) is linked to aging in the regulation of telomere stability. NAD(+) is required for mitochondrial renewal. Alcohol dehydrogenase is present in every visceral organ in the body so that there is a systemic reduction of NAD(+) levels in all of these organs during binge drinking.

Exploratory Analysis of Power Spectrum and Functional Connectivity During Resting State in Young Binge Drinkers: A MEG Study.

Binge Drinking (BD) is a pattern of intermittent intensive alcohol intake which has spread among young adults over the last decades. Adolescence constitutes a critical neuromaturation period in which the brain is particularly sensitive to the effects of alcohol. However, little is known about how BD affects the brain activity. This study aimed to characterize the brain's functional organization in BD and non-BD young population by means of analyzing functional connectivity (FC) and relative power spectra (PS) profiles measured with magnetoencephalography (MEG) during eyes-closed resting state. Our sample composed 73 first-year university students (35 BDs and 38 controls). Results showed that the BD subjects displayed a decreased alpha FC in frontal-parietal regions, and conversely, an enhanced FC in the delta, theta and beta bands in fronto-temporal networks. Besides the FC differences, the BD group showed a decreased PS within alpha range and an increased PS within theta range in the brain's occipital region. These differences in FC and PS measurements provide new evidence of the neurophysiological alterations related to the alcohol neurotoxicity and could represent an initial sign of an anomalous neural activity caused by a BD pattern of alcohol consumption during youth.

Apoptotic cell death and temporal expression of apoptotic proteins Bcl-2 and Bax in the hippocampus, following binge ethanol in the neonatal rat model.

BACKGROUND: Binge-like ethanol (EtOH) exposure during the early rat neonatal period results in acute cell loss in specific brain regions, but such acute cell death has not been well established in the hippocampus. Binge alcohol exposure can also result in protein expression changes in the cerebellum that could alter cell fate, but this has not been reported for the hippocampal subregions. This study investigates acute apoptotic cell death in hippocampal regions CA1, CA3, and dentate gyrus (DG) following a binge EtOH exposure on postnatal day (PN) 6, PN8, or PN6 + 8 and the alteration in pro- and anti-apoptotic proteins following a single EtOH binge on PN6. METHODS: Apoptotic cell death was quantified 12 hours after EtOH binge exposure using the optical fractionator method. Western blot analysis determined expression of pro-apoptotic Bax and anti-apoptotic Bcl-2, 12, 24, and 48 hours after binge EtOH exposure on PN6. The Bcl-2:Bax ratio was used as a measure of vulnerability to apoptosis. RESULTS: Acute apoptosis increased significantly 12 hours following PN6 or 8 EtOH exposure in CA1, CA3, and DG, but the magnitude of apoptotic cell death was significantly greater in CA1 than in CA3 and DG, which did not differ. Significant cell death was not detected when a PN8 EtOH exposure was preceded by exposure on PN6. Binge EtOH exposure on PN6 resulted in a significant increase in expression of Bcl-2 and the Bcl-2:Bax ratio in the CA1/DG region at 24 hours after EtOH exposure on PN6. The Bcl-2:Bax ratio in the CA3 region was not altered. CONCLUSIONS: This study shows that repeated binge exposure does not have a cumulative effect on the magnitude of acute apoptotic cell death. This finding may be explained in part by changes in the Bcl-2:Bax ratio after a single binge EtOH exposure.

Chronic binge alcohol exposure during pregnancy impairs rat maternal uterine vascular function.

BACKGROUND: Alcohol exposure during pregnancy results in an array of structural and functional abnormalities called fetal alcohol spectrum disorders (FASD). Alcohol dysregulates the exquisite coordination and regulation of gestational adaptations at the level of the uterine vasculature. We herein hypothesized that chronic binge-like alcohol results in uterine vascular dysfunction and impairs maternal uterine artery reactivity to vasoconstrictors and dilators. METHODS: We utilized a once-daily binge alcohol (4.5 g/kg body weight) exposure paradigm (gestational day 7 to 17) in a pregnant rat model system and investigated primary uterine artery function in response to vasoconstrictors and vasodilators utilizing wire myography. RESULTS: Alcohol (peak blood alcohol concentration, 216 mg/dl) produced uterine vascular dysfunction. Alcohol did not produce altered uterine vascular reactivity to α1 adrenergic agonist phenylephrine or the prostanoid thromboxane. However, alcohol specifically impaired acetylcholine (ACh)-mediated uterine artery vasodilation but exogenous endothelium-independent vasodilators like sodium nitroprusside exhibited no alcohol effect; ACh significantly decreased vessel relaxation (p = 0.003; ↓pD2 [negative log molar ACh concentration producing the half maximum response], -7.004 ± 0.215 vs. -6.310 ± 0.208; EMax [maximal ACh response], 92% vs. 75%). CONCLUSIONS: We conclude that moderate alcohol exposure impairs uterine vascular function in pregnant mothers. Alcohol specifically impairs agonist-induced uterine artery vasodilation. In summary, the maternal uterine compartment may play a significant role in the pathogenesis of FASD. Thus, the mechanistic targets of alcohol at the level of both the mother and the fetus need to be considered in order to develop effective therapeutic treatment strategies for FASD.

Luteolin alleviates alcoholic liver disease induced by chronic and binge ethanol feeding in mice.

Ethanol consumption can lead to hepatic steatosis that contributes to late-stage liver diseases such as cirrhosis and hepatocellular carcinoma. In this study, we investigated the potential protective effect of a flavonoid, luteolin, on ethanol-induced fatty liver development and liver injury. Six-wk-old male C57BL/6 mice were divided into 3 groups: a control group; a group exposed to alcohol by using a chronic and binge ethanol feeding protocol (EtOH); and a group that was administered daily 50 mg/kg of luteolin in addition to ethanol exposure (EtOH + Lut). A chronic and binge ethanol feeding protocol was used, including chronic ethanol consumption (1%, 2%, and 4% for 3 d, and 5% for 9 d) and a binge (30% ethanol) on the last day. Compared with the control group, the EtOH group had a significant elevation in serum concentrations of alanine aminotransferase (ALT) (561%), triglyceride (TG) (47%), and LDL cholesterol (95%), together with lipid accumulation in the liver. Compared with the EtOH group, the EtOH + Lut group had significant reductions in serum concentrations of ALT (43%), TG (22%), LDL cholesterol (52%), and lipid accumulation in the liver. Ethanol elevated liver expression of lipogenic genes including sterol regulatory element-binding protein 1c (Srebp1c) (560%), fatty acid synthase (Fasn) (190%), acetyl-CoA carboxylase (Acc) (48%), and stearoyl-CoA desaturase 1 (Scd1) (286%). Luteolin reduced ethanol-induced expression of these genes in the liver: Srebp1c (79%), Fasn (80%), Acc (60%), and Scd1 (89%). In cultured hepatocytes, luteolin prevented alcohol-induced lipid accumulation and increase in the expression of lipogenic genes. The transcriptional activity of the master regulator of lipid synthesis, sterol regulatory element-binding protein (SREBP), was enhanced by ethanol treatment (160%) and reduced by luteolin administration (67%). In addition, ethanol-induced reduction of AMP-activated protein kinase and SREBP-1c phosphorylation was abrogated by luteolin. Collectively, our study indicates that luteolin is effective in ameliorating ethanol-induced hepatic steatosis and injury.

Acute binge drinking increases serum endotoxin and bacterial DNA levels in healthy individuals.

Binge drinking, the most common form of alcohol consumption, is associated with increased mortality and morbidity; yet, its biological consequences are poorly defined. Previous studies demonstrated that chronic alcohol use results in increased gut permeability and increased serum endotoxin levels that contribute to many of the biological effects of chronic alcohol, including alcoholic liver disease. In this study, we evaluated the effects of acute binge drinking in healthy adults on serum endotoxin levels. We found that acute alcohol binge resulted in a rapid increase in serum endotoxin and 16S rDNA, a marker of bacterial translocation from the gut. Compared to men, women had higher blood alcohol and circulating endotoxin levels. In addition, alcohol binge caused a prolonged increase in acute phase protein levels in the systemic circulation. The biological significance of the in vivo endotoxin elevation was underscored by increased levels of inflammatory cytokines, TNFα and IL-6, and chemokine, MCP-1, measured in total blood after in vitro lipopolysaccharide stimulation. Our findings indicate that even a single alcohol binge results in increased serum endotoxin levels likely due to translocation of gut bacterial products and disturbs innate immune responses that can contribute to the deleterious effects of binge drinking.

Evolution of the binge drinking pattern in college students: neurophysiological correlates.

It is well known that alcohol impairs response inhibition and that adolescence is a critical period of neuromaturation where cognitive processes such as inhibitory control are still developing. In recent years, growing evidence has shown the negative consequences of alcohol binge drinking on the adolescent and young human brain. However, the effects of cessation of binge drinking on brain function remain unexplored. The objective of the present study was to examine brain activity during response execution and inhibition in young binge drinkers in relation to the progression of their drinking habits over time. Event-related potentials (ERPs) elicited by a Go/NoGo task were recorded twice within a 2-year interval in 57 undergraduate students (25 controls, 22 binge drinkers, and 10 ex-binge drinkers) with no personal or family history of alcoholism or psychopathological disorders. The results showed that the amplitude of NoGo-P3 over the frontal region correlated with an earlier age of onset of regular drinking as well as with greater quantity and speed of alcohol consumption. Regression analysis showed that NoGo-P3 amplitude was significantly predicted by the speed of alcohol intake and the age of onset of regular drinking. The group comparisons showed that, after maintaining a binge drinking pattern for at least 2 years, binge drinkers displayed significantly larger NoGo-P3 amplitudes than controls, whereas ex-binge drinkers were in an intermediate position between the two other groups (with no significant differences with respect to controls or binge drinkers). These findings suggest that binge drinking in young people may impair the neural functioning related to inhibitory processes, and that the cessation of binge drinking may act as a brake on the neurophysiological impairments related to response inhibition.