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1.  CHRONIC METHYLPHENIDATE TREATMENT DURING EARLY LIFE IS ASSOCIATED WITH GREATER ETHANOL INTAKE IN SOCIALLY ISOLATED RATS 
Background
Methylphenidate is a stimulant prescribed to treat Attention Deficit Hyperactivity Disorder. Its primary mechanism of action is in the dopamine system, alterations of which are associated with vulnerability to alcohol abuse. There are concerns that juvenile MPH treatment may influence adult drinking behavior. This study examined the interaction of MPH treatment and environmental rearing conditions, which are known to independently influence ethanol (EtOH) drinking behavior, on anxiety-like behavior and vulnerability to alcohol abuse in a juvenile rodent model.
Methods
Male Sprague Dawley rats were housed in enriched, standard, or isolated conditions for four weeks, starting at postnatal day 21. Rats were concurrently treated with 8 mg/kg/day MPH or saline, delivered via osmotic minipump. Anxiety-like behavior was determined at the end of the treatment session, and 5 weeks later. After MPH treatment, rats were exposed to a two-bottle choice EtOH drinking procedure that lasted three weeks.
Results
Early life chronic MPH treatment was associated with greater EtOH intake and greater EtOH preference, but only in socially isolated animals. Isolated animals had greater levels of anxiety-like behavior than standard-housed or enriched animals after 4 weeks of exposure to the housing conditions, a difference that persisted even after all animals had been individually housed for an additional 5 weeks and exposed to EtOH.
Conclusions
These results suggest that early life MPH treatment may increase vulnerability to EtOH drinking in adulthood in a subset of the population. Additionally, this study highlights the importance of early rearing condition for establishing long-lasting behavioral phenotypes. Environmental histories should be considered when prescribing MPH treatment to young children.
doi:10.1111/acer.12489
PMCID: PMC4145615  PMID: 25156616
Social Isolation; Ethanol Drinking; Methylphenidate; Rearing Environment
2.  A moderating role for gender in racial/ethnic disparities in alcohol services utilization: Results from the 2000-2010 National Alcohol Surveys 
Background
Few nationally representative studies have examined racial/ethnic disparities in alcohol services utilization. Further, little is known about whether racial/ethnic disparities generalize across genders, and what factors account for these disparities. Thus, we aimed to describe the combined impact of race/ethnicity and gender on alcohol services utilization, and to explore roles for social influence factors in explaining racial/ethnic and gender disparities.
Methods
Data were pooled across the 2000, 2005, and 2010 National Alcohol Surveys. Outcomes included lifetime utilization of any services, specialty alcohol treatment, and Alcoholics Anonymous (AA). Social influence factors were assessed as lifetime social pressures (i.e., pressures from a partner, friends, and/or family), legal consequences, and work-related consequences. Core analyses included only those with a lifetime alcohol use disorder (AUD).
Results
Analyses revealed a pattern of lower services utilization among Latinos and Blacks (vs. Whites) and women (vs. men); further, race-by-gender interactions revealed that Black-White differences were limited to women, and provided some evidence of stronger Latino-White disparities among women (vs. men). Illustrating these patterns, among women, only 2.5% of Latinas and 3.4% of Blacks with a lifetime AUD accessed specialty treatment, vs. 6.7% of Whites; among men, corresponding figures were 6.8% for Latinos, 12.2% for Blacks, and 10.1% for Whites. Racial/ethnic differences were typically robust (or stronger) when controlling for demographics and AUD severity. Evidence did not support a role for measured social influence factors in racial/ethnic disparities, but did suggest that these factors contribute to gender disparities, particularly among Whites and Blacks.
Discussion
Findings for substantial Latino-White and Black-White disparities, especially among women, highlight the need for continuing research on explanatory factors and the development of appropriate interventions. Meanwhile, our evidence for persistent gender disparities and for social influence factors as drivers of these disparities tentatively suggests a need for intensified outreach to female heavy drinkers.
doi:10.1111/acer.12500
PMCID: PMC4146628  PMID: 25041173
Hispanic; African American; alcohol treatment; health disparities; social pressures; alcohol dependence
3.  The Relationship between Brand-Specific Alcohol Advertising on Television and Brand-Specific Consumption among Underage Youth 
Background
Being able to investigate the relationship between underage drinkers' preferences for particular brands and their exposure to advertising for those brands would represent a significant advance in alcohol marketing research. However, no previous national study has examined the relationship between underage youth exposure to brand-specific alcohol advertising and consumption of those brands.
Methods
We conducted a cross-sectional, internet-based survey of a national sample of 1,031 youths, ages 13-20, who had consumed at least one drink of alcohol in the past 30 days. We ascertained all alcohol brands consumed by respondents in the past 30 days. The main outcome measure was brand-specific consumption during the past 30 days, measured as a dichotomous variable. The main predictor variable was exposure to brand-specific alcohol advertising on television. The respondents reported which of 20 television shows popular with youth they had watched during the past 30 days. For each respondent, we calculated a standard measure of potential exposure to the brand-specific alcohol advertising that aired on those shows during the preceding 12 months, based on Nielsen (New York, NY) estimates of the youth audience for each show's telecasts.
Results
Compared to no brand-specific advertising exposure, any exposure was associated with an increased likelihood of brand-specific consumption (adjusted odds ratio 3.02; 95% confidence interval: 2.61-3.49) after controlling for several individual- and brand-level variables. When measured as a continuous variable, the relationship between advertising exposure and brand consumption was nonlinear, with a large association at lower levels of exposure and diminishing incremental effects as the level of exposure increased.
Conclusions
There is a robust relationship between youth's brand-specific exposure to alcohol advertising on television and their consumption of those same alcohol brands during the past 30 days. This study provides further evidence of a strong association between alcohol advertising and youth drinking behavior.
doi:10.1111/acer.12488
PMCID: PMC4146644  PMID: 24986257
Advertising; Alcohol; Brand; Underage Drinking; Youth
4.  Aging and alcohol interact to alter hepatic DNA hydroxymethylation 
Background
Aging and chronic alcohol consumption are both modifiers of DNA methylation but it is not yet known whether chronic alcohol consumption also alters DNA hydroxymethylation, a newly discovered epigenetic mark produced by oxidation of methylcytosine. Furthermore, it has not been tested whether aging and alcohol interact to modify this epigenetic phenomenon, thereby having an independent effect on gene expression.
Methods
Old (18 months) and young (4 months) male C57BL/6 mice were pair-fed either a Lieber-DeCarli liquid diet with alcohol (18% of energy) or an isocaloricLieber-DeCarli control diet for 5 weeks. Global DNA hydroxymethylation and DNA methylation were analyzed from hepatic DNA using a new LC/MS-MS method. Hepatic mRNA expression of the Tet enzymes and Cyp2e1 were measured via qRTPCR.
Results
In young mice, mild chronic alcohol exposure significantly reduced global DNA hydroxymethylation compared with control mice (0.22%±0.01% vs 0.29±0.06%, p = 0.004). Alcohol did not significantly alter hydroxymethylcytosine levels in old mice. Old mice fed the control diet showed decreased global DNA hydroxymethylation compared with young mice fed the control diet (0.24±0.02% vs 0.29±0.06%, p = 0.04). This model suggests an interaction between aging and alcohol in determining DNA hydroxymethylation (pinteraction = 0.009). Expression of Tet2 and Tet3 enzymes was decreased in the old mice relative to the young (p < 0.005).
Conclusions
The observation that alcohol alters DNA hydroxymethylation indicates a new epigenetic effect of alcohol. This is the first study demonstrating the interactive effects of chronic alcohol consumption and aging on DNA hydroxymethylation.
doi:10.1111/acer.12477
PMCID: PMC4146686  PMID: 25070523
DNA hydroxymethylation; alcohol; aging; liver; mouse
5.  ‘Wired’, yet intoxicated: Modeling binge caffeine and alcohol co-consumption in the mouse 
Background
The combination of highly caffeinated ‘energy drinks’ with alcohol (ethanol) has become popular among young adults and intoxication via such beverages has been associated with an elevated risk for harmful behaviors. However, there are discrepancies in the human literature regarding the effect of caffeine on alcohol intoxication, perhaps due to confounding factors such as personality type, expectancy, and history of exposure. Animal models of co-exposure are resistant to such issues, however, the consequences of voluntary co-consumption have been largely ignored in the animal literature. The primary goal of this work was to characterize a mouse model of binge caffeine and ethanol co-consumption employing the limited-access ‘Drinking-in-the-Dark’ paradigm (DID).
Methods
Caffeine was added to a 20% alcohol solution via DID. Alcohol/caffeine intake, locomotor behavior, ataxia, anxiety-like behavior, and cognitive function were evaluated as a consequence of co-consumption in adult male C57BL/6J mice.
Results
Caffeine did not substantially alter binge alcohol intake or resultant BECs, nor did it alter alcohol’s anxiolytic effects on the elevated plus maze or cognitive interfering effects in a novel object recognition task. However, no evidence of alcohol-induced sedation was observed in co-consumption groups that instead demonstrated a highly stimulated state similar to that of caffeine alone. The addition of caffeine was also found to mitigate alcohol-induced ataxia.
Conclusions
Taken together, our mouse model indicates that binge co-consumption of caffeine and alcohol produces a stimulated, less ataxic and anxious, as well as cognitively altered state; a state that could be of great public health concern. These results appear to resemble the colloquially-identified ‘wide awake drunk’ state that individuals seek via consumption of such beverages. This self-administration model therefore offers the capacity for translationally-valid explorations of the neurobiological consequences of binge co-consumption in order to assess the public health risk of this drug combination.
doi:10.1111/acer.12472
PMCID: PMC4146700  PMID: 24961658
6.  A Longitudinal Study of Insomnia and Other Sleep Complaints in Adolescents with and without Alcohol Use Disorders 
Background
Sleep disturbances are both common and well-characterized in adults with alcohol use disorders (AUDs), but have received little study in adolescents with AUDs. Furthermore, a handful of studies suggest that sleep complaints are a risk factor for AUDs. However, no published studies have yet examined the longitudinal course of sleep complaints in adolescents with AUDs; in particular, it remains unclear how persistent AUD-associated sleep complaints are in this age group, and what types of sleep complaints are most relevant to alcohol use symptoms. We investigated these questions in a 5-year longitudinal study of adolescents with and without AUDs at baseline.
Methods
Participants were 696 adolescents (age 12–19) from a longitudinal study at the Pittsburgh Adolescent Alcohol Research Center. At baseline, 347 participants had a current AUD (AUD+), while 349 had no current or past AUD (AUD−). We examined sleep and alcohol involvement at baseline as well as 1, 3, and 5-year follow-up visits. Sleep variables included self-reported insomnia and hypersomnia, as well as variability in weekday-weekend sleep duration, all at baseline. Covariates included sex, age, current alcohol symptoms, and depression severity.
Results
The AUD+ group reported more overall sleep disturbance at baseline, including greater insomnia and hypersomnia complaints, and greater variability in weekday-weekend sleep duration. Group differences in insomnia and hypersomnia complaints persisted to the 5-year and 3-year follow-ups, respectively. In the AUD− group, greater insomnia complaints at baseline predicted an increase in alcohol symptoms at the 1-year follow-up, while greater variability in sleep duration at baseline predicated an increase in alcohol symptoms at the 3- and 5-year follow-ups.
Conclusions
These results complement previous findings in other samples, indicating that insomnia and other sleep problems are a chronic predicament for adolescents with AUDs. The findings also suggest that sleep disturbances may place adolescents without AUDs at an elevated risk of developing alcohol problems.
doi:10.1111/acer.12474
PMCID: PMC4146702  PMID: 24976511
sleep; alcohol; adolescents; alcohol use disorders
7.  Adolescent Alcohol Abuse and Adverse Adult Outcomes: Evaluating Confounds with Drinking-Discordant Twins 
Background
Adolescent alcohol abuse is associated with adverse outcomes in early adulthood, but differences in familial status and structure and household and community environments correlate with both adolescent drinking and adverse adult outcomes and may explain their association. We studied drinking-discordant twin pairs to evaluate such confounds to ask: Will between-family associations replicate in within-family comparisons?
Methods
With longitudinal data from > 3,000 Finnish twins, we associated drinking problems at age 18½ with 13 outcomes assessed at age 25; included were sustained substance abuse, poor health, physical symptoms, early coital debut, multiple sexual partners, life dissatisfaction, truncated education, and financial problems. We assessed associations among twins as individuals with linear regression adjusted for correlated observations; within-family analyses of discordant twin pairs followed, comparing paired means for adult outcomes among co-twins discordant for adolescent problem drinking. Defining discordance by extreme scores on self-reported problem drinking at age 18½ permitted parallel analyses of twins as individuals and discordant twin pairs. Alternate definitions of pair-wise discordance and difference score correlations across the entire twin sample yielded supplementary analyses.
Results
All individual associations were highly significant for all definitions of discordance we employed. Depending on definitions of discordance, 11 to 13 comparisons of all drinking-discordant twin pairs and 3 to 6 comparisons of discordant monozygotic twin pairs replicated between-family associations. For most outcomes, effect size attenuated from individual level analysis to that within discordant MZ twin pairs providing evidence of partial confounding in associations reported in earlier research. The exception was the General Health Questionnaire; at age 25, GHQ-12 had equivalent associations with age 18½ RAPI across all comparisons.
Conclusions
Our analyses control for shared family background, and, partly or fully, for shared genes, to yield within-family replications and more compelling evidence than previously available that adolescent alcohol abuse disrupts transitions into early adulthood.
doi:10.1111/acer.12491
PMCID: PMC4146743  PMID: 25040879
Discordant Twin comparisons; Alcohol Exposure; Adverse Outcomes
8.  Catching a conserved mechanism of ethanol teratogenicity 
Due to its profound impact on human development, ethanol teratogenicity is a field of intense study. The complexity of variables that influence the outcomes of embryonic or prenatal ethanol exposure compels the use of animal models in which these variables can be isolated. Numerous model systems have been used in these studies. The zebrafish is a powerful model system, which has seen a recent increase in usage for ethanol studies. Those using zebrafish for alcohol studies often face two questions: 1) How physiologically relevant are the doses of ethanol administered to zebrafish embryos and 2) Will the mechanisms of ethanol teratogenesis be conserved to other model systems and human? The current manuscript by Flentke et al helps to shed important light on these questions and clearly demonstrates that the zebrafish will be a valuable model system with which to understand ethanol teratogenicity.
doi:10.1111/acer.12484
PMCID: PMC4147959  PMID: 25156611
9.  Methodological biases in estimating the relationship between alcohol consumption and breast cancer: The role of drinker misclassification errors in meta-analytic results 
Background
While alcohol consumption has been linked to breast cancer in women, few studies have controlled for possible biases created by including former or occasional drinkers in the abstainer reference group. We explored the potential for such misclassification errors as sources of bias in estimates of the alcohol-breast cancer relationship.
Methods
Meta-analyses of population case-control, hospital case-control, and cohort studies to examine relationships between level of alcohol use and breast cancer morbidity and/or mortality in groups of studies with and without different misclassification errors.
Results
Of 60 studies identified, only 6 were free of all misclassification errors. The abstainer reference group was biased by the inclusion of former drinkers in 49 studies, occasional drinkers (<10g ethanol per week) in 22 and by both these groups in 18. Occasional drinkers were also mixed with light or hazardous level drinkers in 21 studies. Unbiased estimates of the OR for breast cancer were 1.011 (95% CI: 0.891-1.148) among former drinkers (n = 11) and 1.034 (95% CI: 1.003-1.064) among occasional drinkers (n=17). Hazardous level drinking (>20g<41g ethanol/day) was not significantly associated with breast cancer in studies with occasional drinker bias. However, in studies free from occasional drinker bias, the OR for breast cancer was 1.085 (95% CI: 1.015-1.160) for low level (<21g/day) drinkers (n=17), 1.374 (95% CI: 1.319-1.431) for hazardous level drinkers (n=26) and 1.336 (95% CI: 1.228-1.454) for harmful level (>40g/day) drinkers (n=9).
Conclusions
While the great majority of studies of the alcohol-breast cancer link include misclassification errors, only misclassification of occasional drinkers was found to bias risk estimates significantly. Estimates based on error free studies confirmed that low, hazardous and harmful levels of alcohol use each significantly increase the risk of breast cancer.
doi:10.1111/acer.12479
PMCID: PMC4149760  PMID: 25156617
alcohol; breast cancer; abstainers; methodological bias
10.  Estimating BrAC from Transdermal Alcohol Concentration Data Using the BrAC Estimator Software Program 
Background
Transdermal alcohol sensor (TAS) devices have the potential to allow researchers and clinicians to unobtrusively collect naturalistic drinking data for weeks at a time, but the transdermal alcohol concentration (TAC) data these devices produce do not consistently correspond with breath alcohol concentration (BrAC) data. We present and test the BrAC Estimator software, a program designed to produce individualized estimates of BrAC from TAC data by fitting mathematical models to a specific person wearing a specific TAS device.
Methods
Two TAS devices were worn simultaneously by one participant for 18 days. The trial began with a laboratory alcohol session to calibrate the model and was followed by a field trial with 10 drinking episodes. Model parameter estimates and fit indices were compared across drinking episodes to examine the calibration phase of the software. Software-generated estimates of Peak BrAC, time of peak BrAC, area under the BrAC curve were compared with breath analyzer data to examine the estimation phase of the software.
Results
In this single-subject design with breath analyzer peak BrAC scores ranging from .013 to .057, the software created consistent models for the two TAS devices, despite differences in raw TAC data, and was able to compensate for the attenuation of peak BrAC and latency of the time of peak BrAC that are typically observed in TAC data.
Conclusions
This software program represents an important initial step for making it possible for non-mathematician researchers and clinicians to obtain estimates of BrAC from TAC data in naturalistic drinking environments. Future research with more participants and greater variation in alcohol consumption levels and patterns, as well as examination of gain scheduling calibration procedures and nonlinear models of diffusion, will help to determine how precise these software models can become.
doi:10.1111/acer.12478
PMCID: PMC4159387  PMID: 25156615
transdermal alcohol sensor; transdermal alcohol concentration; real-time assessment; ecological momentary assessment; BrAC estimation
11.  Nicotine Modulates Alcohol-Seeking and Relapse by Alcohol-Preferring (P) Rats in a Time Dependent Manner 
Background
Alcohol is frequently co-abused with smoking. In humans, nicotine use can increase alcohol craving and consumption. The objectives of the current study were to assess the acute effects of nicotine on alcohol seeking and relapse at two different time points.
Method
Adult female alcohol-preferring (P) rats were trained in 2-lever operant chambers to self-administer 15% EtOH (v/v) and water on a concurrent fixed-ratio 5 – fixed-ratio 1 (FR5-FR1) schedule of reinforcement in daily 1-hr sessions. Following 10 weeks of daily 1-hr sessions, rats underwent 7 extinction sessions, followed by 2 weeks in their home cages. Rats were then returned to the operant chambers without EtOH or water being present for 4 sessions (Pavlovian Spontaneous Recovery [PSR]). Rats were then given a week in their home cage before being returned to the operant chambers with access to EtOH and water (relapse). Nicotine (0, 0.1, 0.3, or 1.0 mg/kg) was injected s.c. immediately or 4-hr prior to PSR or relapse testing.
Results
Injections of nicotine immediately prior to testing reduced (5–10 responses PSR; 50–60 responses relapse), whereas injections of nicotine 4-hr prior to testing increased (up to 150 responses for PSR; up to 400 responses for relapse with 1.0 mg/kg dose) responses on the EtOH lever during PSR and relapse tests.
Discussion
The results of this study demonstrate that acute effects of nicotine on EtOH-seeking and relapse behaviors may be time-dependent, with the immediate effects being a result of nicotine possibly acting as a substitute for EtOH whereas, with a delay of 4-hr, priming effects of nicotine alterations in nicotinic receptors, and/or the effects of nicotine’s metabolites (i.e., cotinine, nornicotine) may enhance the expression of EtOH-seeking and relapse behaviors.
doi:10.1111/j.1530-0277.2011.01579.x
PMCID: PMC4520427  PMID: 21689122
Ethanol-seeking; Ethanol-relapse; Pavlovian Spontaneous Recovery; nicotine; alcohol preferring rat
12.  Size of Mamillary Bodies in Health and Disease: Useful Measurements in Neuroradiological Diagnosis of Wernicke's Encephalopathy 
Background
As the resolution of noninvasive neuroimaging techniques improves, small structures such as the mamillary bodies can be visualized and measured. The mamillary bodies are pathologically small in a number of neurological disorders, the most common and important is chronic Wernicke's encephalopathy (WE), or the Wernicke-Korsakoff syndrome (WKS), as it is often called. This disorder is caused by vitamin Bl deficiency (thiamin) and is seen most commonly in people who drink excessive amounts of alcohol. The disorder is easily preventable by using oral or parenteral thiamin. The aim of this study was to establish a range for the volume of the mamillary bodies in normal and in various disease states, particularly WE.
Methods
Brains were taken from 2212 sequential autopsies performed at the New South Wales Institute of Forensic Medicine from 1996 through 1997. After fixation in 10% formalin, the brains were sectioned coronally and a block containing the mamillary bodies was dissected. The maximum vertical and transverse diameters of the mamillary bodies were measured using Mitutoyo vernier callipers and the volume calculated (V = 4/3 (a2b), where a and b are the vertical and transverse radii, respectively).
Results
There were 164 cases with significant pathological changes in the mamillary bodies. These included cases with WE (25), Alzheimer's disease (10), infarction (11), and trauma (55). All but two of the WE cases were chronic or acute on chronic. The mean volume of the mamillary bodies was reduced by 60% in cases with chronic WE and by 25% in cases with Alzheimer's disease. In normal cases, there was a significant age-related reduction in volume, and males had larger mamillary bodies than females. Cases with alcoholic cirrhosis of the liver had normal mamillary body volumes.
Conclusions
There is a gross shrinkage of the mamillary bodies in cases of chronic WE, but clinicians need to consider other diagnoses, such as Alzheimer's disease, which can also result in shrinkage. These quantitative data will be helpful in the neuroradiological diagnosis of some of these disorders, particularly WE.
PMCID: PMC4519197  PMID: 10549994
Mamillary Body; Volume; Wernicke's Encephalopathy; Alcohol; Neuroradiology
13.  Ethanol in Human Brain by Magnetic Resonance Spectroscopy: Correlation With Blood and Breath Levels, Relaxation, and Magnetization Transfer 
Background
Proton magnetic resonance spectroscopy (1H MRS) allows measurement of alcohol in the human brain after alcohol consumption. However, the quantity of alcohol that can be detected in the brain by 1H MRS pulse sequences has been controversial, with values ranging from about 24% to 94% of the temporally concordant blood alcohol concentrations. The quantitation of brain alcohol is critically affected by the kinetics of alcohol uptake and elimination, by the relaxation times of the protons that give rise to the brain alcohol signal, and by the specifics of both pulse sequence timing and radio frequency pulse applications.
Methods
We investigated these factors in 20 light-drinking subjects after oral administration of approximately 0.85 g/kg body weight of alcohol by localized 1H MRS and measurements of blood and breath alcohol concentrations obtained at the same time. Specifically, we measured transverse and longitudinal relaxation times of brain alcohol and its signal saturation on application of on- or off-resonance radio frequency pulses. All 1H MRS measurements were performed at a time after brain and blood alcohol concentrations had equilibrated.
Results
1H MRS measures of brain alcohol were correlated highly with both breath and blood alcohol concentrations after equilibration in brain tissue. The measured 1H MRS relaxation times of brain alcohol were shorter than given in previous reports that were limited by smaller subject numbers, improper use of 1H MRS methods, and estimates rather than measurements. The brain alcohol signal decreased by about 30% on application of on- or off-resonance saturation pulses.
Conclusions
1H MRS allows direct measurement of brain alcohol, formerly only possible indirectly through inferences from breath alcohol levels Quantitation of brain alcohol levels need to take into account measured relaxation times and alcohol signal attenuation due to presence and timing of standard radio frequency MRS pulses. Saturation experiments give evidence for the existence of more than one compartment of brain alcohol characterized by different molecular environments. They suggest that a fraction of brain alcohol is invisible to 1H MRS.
PMCID: PMC4511813  PMID: 10968662
Magnetic Resonance Spectroscopy; Brain; Ethanol; T1; T2; Magnetization Transfer
14.  Ethanol Impairs Activation of Retinoic Acid Receptors in Cerebellar Granule Cells in a Rodent Model of Fetal Alcohol Spectrum Disorders 
Background
Ethanol is the main addictive and neurotoxic constituent of alcohol. Ethanol exposure during embryonic development causes dysfunction of the central nervous system (CNS) and leads to fetal alcohol spectrum disorders. The cerebellum is one of the CNS regions that are particularly vulnerable to ethanol toxic effects. Retinoic acid (RA) is a physiologically active metabolite of vitamin A that is locally synthesized in the cerebellum. Studies have shown that RA is required for neuronal development, but it remains unknown if ethanol impairs RA signaling and thus induces neuronal malformations. In this study, we tested the hypothesis that ethanol impairs the expression and activation of RA receptors in cerebellum and in cerebellar granule cells.
Methods
The cerebellum of ethanol unexposed and exposed pups was used to study the expression of retinoic acid receptors (RARs or RXRs) by immunohistochemistry and by Western blot analysis. We also studied the effect of ethanol on expression of RA receptors in the cerebellar granule cells. Activation of RA receptors (DNA-binding activities) in response to high-dose ethanol was determined by electrophoretic mobility shift and supershift assays.
Results
Findings from these studies demonstrated that ethanol exposure reduced the expression of RARα/γ while it increased the expression of RXRα/γ in the cerebellum and in cerebellar granule neurons. Immuno-histological studies further strengthened the expression pattern of RA receptors in response to ethanol. The DNA-binding activity of RARs was reduced, while DNA-binding activity of RXRs was increased in response to ethanol exposure.
Conclusion
For the first time, our studies have demonstrated that high-dose ethanol affects the expression and activation of RA receptors, which could impair the signaling events and induce harmful effects on the survival and differentiation of cerebellar granule cells. Taken together, these findings could provide insight into the treatment options for brain defects caused by excessive ethanol exposure, such as in Fetal Alcohol Spectrum Disorders.
doi:10.1111/j.1530-0277.2010.01166.x
PMCID: PMC4502960  PMID: 20201933
Fetal Alcohol Spectrum Disorders; Cerebellum; Ethanol; Neurotoxicity; Retinoic Acid
15.  How Acute and Chronic Alcohol Consumption Affects Brain Networks: Insights from Multimodal Neuroimaging 
Background
Multimodal imaging combining 2 or more techniques is becoming increasingly important because no single imaging approach has the capacity to elucidate all clinically relevant characteristics of a network.
Methods
This review highlights recent advances in multimodal neuroimaging (i.e., combined use and interpretation of data collected through magnetic resonance imaging [MRI], functional MRI, diffusion tensor imaging, positron emission tomography, magnetoencephalography, MR perfusion, and MR spectroscopy methods) that leads to a more comprehensive understanding of how acute and chronic alcohol consumption affect neural networks underlying cognition, emotion, reward processing, and drinking behavior.
Results
Several innovative investigators have started utilizing multiple imaging approaches within the same individual to better understand how alcohol influences brain systems, both during intoxication and after years of chronic heavy use.
Conclusions
Their findings can help identify mechanism-based therapeutic and pharmacological treatment options, and they may increase the efficacy and cost effectiveness of such treatments by predicting those at greatest risk for relapse.
doi:10.1111/j.1530-0277.2012.01831.x
PMCID: PMC4500115  PMID: 22577873
Multimodal Neuroimaging; Acute and Chronic Alcohol
16.  Effects of Combined Alcohol and Anti-HIV Drugs on Cellular Stress Responses in Primary Hepatocytes and Hepatic Stellate and Kupffer Cells 
Background
Certain anti-HIV drugs alone or in combination are often associated with liver damages, which are frequently worsened by alcohol consumption. We previously found an endoplasmic reticulum (ER) stress mechanism for the drug- and alcohol-induced hepatic injuries in animal models and in vitro hepatocytes. However, it is unknown whether anti-HIV drugs and alcohol induce similar cellular stress responses and injuries in liver nonparenchymal cells.
Methods
Primary mouse hepatocytes (PMH), kupffer cells (KC), and hepatocellular stellate cells (HSC) were freshly isolated from mouse liver and treated with DMSO, stress-inducing pharmaceutical agents, alcohol alone, or in combination with antiviral ritonavir (RIT), lopinavir (LOP), or efavirenz (EFV). Expression of cellular stress markers, protein colocalization, and cell death were analyzed with immunoblotting, immunocytochemistry, and positive double staining with Sytox green and Hoechst blue, respectively.
Results
Expression of the ER stress markers of BiP, CHOP, and SERCA and the autophagy marker LC3 was significantly changed in PMH in response to combined alcohol, RIT, and LOP, which was companied by increased cell death compared with control. In contrast, although pharmaceutical agents induced ER stress and cell death, no significant ER stress or cell death was found in KC treated with alcohol, RIT, LOP, and EFV singly or in combination. In HSC, alcohol, RIT, LOP, or EFV induced BiP, but not CHOP, SERCA, or cell death compared with vehicle control. Further in PMH, RIT and LOP or in combination with alcohol-induced dose-dependent inhibition of β-actin. Inhibition of β-actin by RIT and LOP was companied with an inhibited nuclear expression of the antioxidant response regulator Nrf2 and reduced GST downstream of Nrf2. Ascorbic acid treatment reduced the alcohol-, RIT-, and LOP-induced cell death.
Conclusions
The data suggest for the first time that sensitivities of hepatocytes and nonparenchymal cells to alcohol and anti-HIV drugs in vitro are different in terms of cellular stress response and cell death injury. Oxidative stress mediated by Nrf2 contributes to the alcohol- and drug-induced toxicity in the hepatocytes.
doi:10.1111/acer.12608
PMCID: PMC4495895  PMID: 25623401
Alcohol; Antivirals; Liver Parenchymal Cells Versus Nonparenchymal Cells; Hepatotoxicity
17.  Comparing Alcohol Screening Measures Among HIV Infected and Uninfected Men 
Background
Brief measures of unhealthy alcohol use have not been well-validated among people with HIV. We compared the Alcohol Use Disorders Identification Test (AUDIT) to reference standards for unhealthy alcohol use based on 30 day Timeline Follow Back (TLFB) and Composite International Diagnostic Interview - Substance Abuse Module (CIDI-SAM), among 873 male HIV infected and uninfected patients in the Veterans Aging Cohort Study.
Methods
Three reference standards were: 1)Risky drinking - based on TLFB: >14 drinks over 7 consecutive days or >4 drinks on one day; 2)Alcohol dependence - based on a CIDI-SAM diagnosis; and 3)Unhealthy alcohol use - risky drinking or a CIDI-SAM diagnosis of abuse or dependence. Various cutoffs for the AUDIT, AUDIT-C, and heavy episodic drinking were compared to the reference standards.
Results
Mean age of patients was 52 years, 53% (444) were HIV infected, and 53% (444) were African-American. Among HIV infected and uninfected patients, the prevalence of risky drinking (14% vs. 12% respectively), alcohol dependence (8% vs. 7%), and unhealthy alcohol use (22% vs. 20%) was similar. For risky drinking and alcohol dependence, multiple cutoffs of AUDIT, AUDIT-C, and heavy episodic drinking provided good sensitivity (>80%) and specificity (>90%). For unhealthy alcohol use, few cutoffs provided sensitivity >80%; however, many cutoffs provided good specificity. For all three alcohol screening measures, sensitivity improved when heavy episodic drinking was included with the cutoff. Sensitivity of measures for risky drinking and unhealthy alcohol use were lower in HIV infected than in uninfected patients.
Conclusions
For identifying risky drinking, alcohol dependence, and unhealthy alcohol use, AUDIT-C performs as well as AUDIT and similarly in HIV infected and uninfected patients. Cutoffs should be based on the importance of specific operating characteristics for the intended research or clinical use. Incorporating heavy episodic drinking increased sensitivity for detecting alcohol dependence and unhealthy alcohol use.
doi:10.1111/j.1530-0277.2012.01937.x
PMCID: PMC4492202  PMID: 23050632
18.  THE ROLE OF IMMIGRATION AGE ON ALCOHOL AND DRUG USE AMONG BORDER AND NON-BORDER MEXICAN AMERICANS 
Background
To determine the age of immigration at which the marked increase in risk for alcohol- and drug use problems in adulthood is observed among Mexican American adults residing in two distinct contexts: the U.S.-Mexico border, and cities not proximal to the border.
Methods
We used two samples of Mexican American adults; specifically, 1,307 who resided along the U.S.-Mexico border, and 1,288 non-border adults who were interviewed as a part of the 2006 Hispanic Americans Baseline Alcohol Survey study. Survey logistic and Zero-Inflated Poisson methods were used to examine how immigration age during adolescence is related to alcohol and drug use behavior in adulthood.
Results
We found that participants who immigrate to the U.S. prior to age 12 have qualitatively different alcohol- and drug-related outcomes compared to those who immigrate later in life. Adults who immigrated at younger ages have alcohol and drug use patterns similar to those who were U.S.-born. Similarly, adults who immigrated at younger ages and live along the U.S.-Mexico border are at greater risk for alcohol and drug use than those who live in non-border contexts.
Conclusions
Immigration from Mexico to the U.S. before age 12 results in alcohol and drug-related behavior that mirrors the behavior of U.S.-born residents.
doi:10.1111/acer.12440
PMCID: PMC4106976  PMID: 24846850
immigration; Hispanic; Mexican American; alcohol
19.  Social Contexts of Remission from DSM-5 Alcohol Use Disorder in a High-Risk Sample 
Background
Measures of social context, such as marriage and religious participation, are associated with remission from alcohol use disorders (AUD) in population-based and treatment samples, but whether these associations hold among individuals at high familial risk for AUD is unknown. This study tests associations of measures of social context and treatment with different types of remission from DSM-5 AUD in a high-risk sample.
Methods
Subjects were 686 relatives of probands (85.7% first-degree) who participated in a high-risk family study of alcohol dependence. All subjects met criteria for AUD at baseline and were re-interviewed 5 years later. Follow-up status was categorized as persistent AUD, high-risk drinking, remitted low-risk drinking, and abstinence. Social context measures were defined as stable or changing from baseline to follow-up, and their bivariate and multivariate associations with follow-up status were tested.
Results
At follow-up, 62.8% of subjects had persistent AUD, 6.4% were high-risk drinkers, 22.2% were remitted low-risk drinkers, and 8.6% were abstinent. Birth of first child during the interval was the only measure of social context associated with remitted low-risk drinking and was significant for women only. Abstinent remission was characterized by being stably separated or divorced for women, new marriage for both sexes, experiencing low levels of family support and high levels of friend support, and receiving treatment. High-risk drinkers were more likely than individuals with persistent AUD to have a stable number of children and to have been recently unemployed.
Conclusions
The social contexts accompanying different types of remission in this high-risk sample resemble those found in population-based and clinical samples. Low-risk drinkers resemble natural remitters from population-based samples who change their drinking habits with life transitions. Abstainers resemble clinical samples in marital context, support from friends, and treatment. High-risk drinkers appear to continue to experience negative consequences of heavy drinking.
doi:10.1111/acer.12434
PMCID: PMC4107016  PMID: 24942361
alcohol use disorder; social context; treatment; remission; recovery
20.  Acute ethanol alters multiple histone modifications at model gene promoters in the cerebral cortex 
BACKGROUND
Ethanol (EtOH) exposure alters gene expression in the cerebral cortex (CCx); however, mechanisms of EtOH-induced gene regulation are not well understood. We hypothesized that EtOH regulates gene expression by differentially altering histone modifications at gene promoters that are up- and down-regulated by EtOH. Such epigenetic mechanisms may ultimately contribute to EtOH-induced neuro-adaptations that underlie tolerance, dependence, and EtOH use disorders.
METHODS
Eight-week-old, male C57BL/6J mice were treated with 3 g/kg EtOH (i.p.) or saline and sacrificed 6 hours after injection; the CCx and hippocampus (HC) were immediately removed and flash frozen. Chromatin immunoprecipitation (ChIP) was used to study the association of model gene promoters with histone modifications. Western blot was used to detect global changes in the histone modifications studied. We also used a PCR array was used to identify changes in expression of chromatin modifying enzymes.
RESULTS
In CCx, acute EtOH decreased expression of Gad1, Hdac2, and Hdac11, which was associated with decreased histone acetylation at the Gad1 and Hdac2 promoters; we also identified increased expression of Mt1, Mt2, Egr1, which was associated with increased H3K4me3 levels at the Mt2 promoter and decreased H3K27me3 levels at the Mt1 promoter. We identified an increase in global levels of H3K4me3 in CCx as well as a global increase in H3K9ac and H3K14ac in HC. The PCR array identified decreased expression of Csrp2bp, Hdac2, and Hdac11 as well as increased expression of Kat2b in CCx.
CONCLUSIONS
Acute EtOH induces chromatin remodeling at model up- and down-regulated genes in CCx. Different patterns of histone modifications at these gene promoters indicate that EtOH may be acting through multiple histone modifying enzymes to alter gene expression; in particular, differential expression of Kat2b, Hdac2, Hdac11, and Csrp2bp in CCx may mediate EtOH-induced chromatin remodeling. Additional studies are necessary to determine the relationship between EtOH-induced changes in histone modifying enzymes, specific EtOH-induced histone modifications, and gene expression.
doi:10.1111/acer.12465
PMCID: PMC4107049  PMID: 24942484
epigenetics; ethanol; alcohol; chromatin immunoprecipitation; histones
21.  Binge alcohol consumption in emerging adults: anterior cingulate cortical ‘thinness’ is associated with alcohol use patterns 
Background
The brain undergoes dynamic and requisite changes into the early twenties that are associated with improved cognitive efficiency, particularly in prefrontal regions that are still undergoing neuromaturation. As alcohol consumption is typically initiated and progresses to binge drinking during this time, the objective of the present study was to investigate the impact of binge alcohol consumption on frontal lobe cortical thickness in emerging adults.
Methods
Twenty-three binge drinking (BD; 11 females, mean age 21.5 ± 1.4) and thirty-one light drinking (LD; 15 females, mean age 21.9 ± 1.6) emerging adults underwent high-resolution magnetic resonance imaging at 3 Tesla. Cortical surface reconstruction and thickness estimation were performed using Freesurfer for three a priori brain regions of interest: bilateral anterior cingulate cortex (ACC), posterior cingulate cortex (PCC) and parieto-occipital sulcus (POS). Cortical thickness measurements were then compared between BD and LD groups.
Results
Cortical thickness was significantly lower in BD than LD in the right middle ACC (mid-ACC; p≤0.05) and in the left dorsal PCC (dPCC; p≤0.01). No significant differences in cortical thickness were observed in the POS. Cortical thickness in the mid-ACC correlated negatively with higher quantity and frequency of drinks consumed (p<0.01), and positively with the number of days elapsed since most recent use (p<0.05). Furthermore, less cortical thickness in the mid-ACC in the BD group alone correlated with reported patterns of high quantity and frequency of alcohol consumption (p≤0.05).
Conclusions
Findings suggest that past and recent patterns of intermittent heavy alcohol consumption are associated with less frontal cortical thickness (i.e. ‘thinness’) of the right mid-ACC and left dPCC in emerging adults, but not the POS. While cortical thinness could have predated binge drinking, this pattern of maladaptive consumption may have acute neurotoxic effects that interfere with the finalization of neuromaturational processes in the vulnerable frontal cortex, resulting in increased microarchitectural pruning.
doi:10.1111/acer.12475
PMCID: PMC4107054  PMID: 24961871
cortical thickness; anterior cingulate cortex; binge alcohol drinking; young adults; synaptic pruning
22.  Acute binge alcohol administration reverses sleep-wake cycle in Sprague Dawley rats 
Background
Binge alcohol drinking is amongst the most common pattern of alcohol consumption in our society. Binge alcohol consumption has serious negative consequence on mental and physical health. Although alcohol consumption is known to have profound impact on sleep, it is yet unknown as to how binge alcohol affects/alters sleep-wakefulness. The objective of this study was to examine the effect of acute binge alcohol administration on sleep-wakefulness.
Methods
Male Sprague-Dawley rats were used in the study. Under standard aseptic surgical conditions, rats (N=7) were implanted with sleep recording electrodes. After post-operative recovery and habituation, baseline sleep-wakefulness was recorded. Subsequently, rats were exposed to binge alcohol treatment as follows: One hour before light onset, a priming dose of 5 g/Kg of alcohol was administered followed by two subsequent doses (adjusted based on the intoxication level of the rat) approximately 8 hours apart. Sleep-wakefulness was continuously recorded for three days post-binge.
Results
Acute binge alcohol administration had no significant effect on sleep-wakefulness on post-binge Day 1. However, on post-binge Day 2, after blood alcohol concentration was zero, sleep disruptions were observed manifested by a reversal of sleep-wakefulness as evident from insomnia-like symptoms (significant increase in wakefulness; significant reduction in NREM sleep) during the normal sleep (light) period and excessive sleep (significant increase in NREM sleep) during the normal active (dark) period similar to excessive daytime sleepiness in humans. All sleep-wakefulness changes were normalized on day 3 post-binge.
Conclusions
Alcohol hangover is defined as the presence of unpleasant symptoms that peak when blood alcohol concentration is zero. Our results suggest that the reversal of sleep-wakefulness accompanies alcohol hangover after binge alcohol administration.
doi:10.1111/acer.12463
PMCID: PMC4107063  PMID: 24930893
Binge; Rat; Sleep; Hangover
23.  Dysmorphogenic effects of first trimester equivalent ethanol exposure in mice: a magnetic resonance microscopy-based study 
Background
The first trimester of human development and the equivalent developmental period in animal models is a time when teratogenic ethanol exposure induces the major structural birth defects that fall within Fetal Alcohol Spectrum Disorder (FASD). Previous FASD research employing an acute high dose maternal intraperitoneal ethanol treatment paradigm has identified sensitive periods for a number of these defects. Extending this work, this investigation utilized high resolution magnetic resonance imaging (MRM)-based analyses to examine the dysmorphology resulting from maternal dietary ethanol intake occurring during selected first trimester-equivalent time periods.
Methods
Female C57Bl/6J mice were acclimated to a liquid 4.8% ethanol (v/v)-containing diet, then bred while on standard chow. Dams were again provided the ethanol-containing liquid diet for a period that extended either from the beginning of gestational day (GD) 7 to the end of GD 11 or from the beginning of GD 12 to the end of GD 16. On GD 17, a subset of fetuses was selected for MRM-based analyses. Group comparisons were made for litter characteristics and gross dysmorphology, as well as whole and regional brain volumes.
Results
Ethanol-induced stage of exposure-dependent structural brain abnormalities were observed. The GD 7–11 ethanol-exposed group presented with a significant decrease in cerebellar volume and an increase in septal volume, while GD 12–16 ethanol treatment resulted in a reduction in right hippocampal volume accompanied by enlarged pituitaries. Additionally, the GD 12–16 ethanol exposure caused a high incidence of edema/fetal hydrops.
Conclusions
These results illustrate the teratogenic impact of maternal dietary ethanol intake occurring at time periods approximately equivalent to weeks 3 through 6 (GD 7–11 in mice) and weeks 7 through 12 (GD 12–16 in mice) of human gestation, further documenting ethanol’s stage of exposure-dependent neuroteratogenic endpoints and highlighting the vulnerability of selected brain regions during the first trimester. Additionally they suggest that clinical attention should be paid to fetal hydrops as a likely component of FASD.
doi:10.1111/acer.12464
PMCID: PMC4107075  PMID: 24931007
Fetal Alcohol Spectrum Disorder; Magnetic Resonance Imaging; Mouse; Brain; Ethanol
24.  Combined Alcohol and Energy Drink Use: Hedonistic Motives, Adenosine, and Alcohol Dependence 
Consumption of alcohol mixed with energy drinks (AmED) has been associated with both short and long-term risks beyond those observed with alcohol alone. AmED use has been associated with heavy episodic (binge) drinking, risky behaviors, and risk of alcohol dependence. Laboratory research has demonstrated that AmED beverages lead to greater motivation to drink versus the same amount of alcohol consumed alone. However, the reason consumers find AmED beverages particularly appealing has been unclear. A recent report by Droste and colleagues (2014) is the first study to investigate motivations related to AmED consumption and to determine which motives predict AmED consumption patterns, experience of drinking-related harms, and risk of alcohol dependence. The findings of this study significantly enhance our understanding of why AmED consumption is related to the risk of alcohol dependence and change our understanding of why consumers chose AmED beverages. The authors report that hedonistic motives strongly predicted AmED use and the harms associated with use. While intoxication-reduction motives predicted self-reported accidents and injuries, these motives did not predict AmED consumption patterns and risk of dependence. The risk of alcohol dependence may arise from repeated experiences when drinking alcohol is more pleasurable when energy drinks are consumed with the alcohol. This commentary will focus on why energy drinks might increase the rewarding properties of alcohol in social drinkers. In addition, discussion is provided explaining why more research on the neurotransmitter, adenosine, may actually inform us about the mechanisms contributing to the development of alcohol dependence.
doi:10.1111/acer.12493
PMCID: PMC4107304  PMID: 25040590
Alcohol; Dependence; Energy Drinks; Caffeine; Adenosine
25.  Alcoholics have more Tryptophan Hydroxylase 2 mRNA and Protein in the Dorsal and Median Raphe Nuclei 
Background
Chronic alcohol use depletes brain serotonin (5-HT), yet we previously found more tryptophan hydroxylase 2 (TPH2), the rate-limiting biosynthetic enzyme for 5-HT, in the dorsal raphe nucleus (DRN) of alcoholics. We sought to determine whether the increase in amount of TPH2 enzyme is associated with more TPH2 mRNA gene expression in the DRN of a new cohort of alcoholics and controls.
Methods
TPH2 mRNA and protein were measured by in situ hybridization and immunoautoradiography, respectively, in the DRN and median raphe nucleus (MRN) of ageand sex- matched pairs (n=16) of alcoholics and non-psychiatric controls. Alcohol use disorder (AUD) diagnosis and medical, psychiatric and family histories were obtained by psychological autopsy. Age and sex were covariates in the analyses.
Results
TPH2 mRNA in alcoholics was greater in the DRN and MRN compared to controls (DRN: Controls: 3.6±1.6, Alcoholics: 4.8±1.8 nCi/mg of tissue, F= 4.106, p=0.02; MRN: Controls: 2.6±1.2, Alcoholics: 3.5±1.1 nCi/mg of tissue, F=3.96, p=0.024). The difference in TPH2 mRNA was present in all DRN subnuclei (DRd: 135%, DRif: 139%, DRv: 135%, DRvl: 136% percent of control p<0.05) except the caudal subnucleus. Alcoholics also had more TPH2 protein in the DRN and MRN than controls (DRN: Controls: 265±47, Alcoholics: 318±47 μCi/g, F=8.72, p=0.001; MRN: Controls: 253±33, Alcoholics: 345±39 μCi/g, F=7.78, p=0.001). There is a positive correlation between TPH2 protein and mRNA expression in the DRN (r=0.815, p<0.001), suggesting that the higher amount of TPH2 protein is due to an increase in TPH2 gene expression.
Conclusions
These findings suggest that greater TPH2 gene expression is the basis for more TPH2 protein in the DRN and MRN in alcoholics.
doi:10.1111/acer.12414
PMCID: PMC4107109  PMID: 24942188
5-HT; serotonin; human; postmortem; raphe; family history

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