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Background Prenatal alcohol exposure can kill developing neurons, leading to microencephaly and mental retardation. However, not all fetuses are equally vulnerable to alcohol's neurotoxic effects. While some fetuses are severely affected and are ultimately diagnosed with fetal alcohol syndrome (FAS), others have no evidence of neuropathology and are behaviorally normal. These widely different outcomes among alcohol-exposed fetuses are likely due, in part, to genetic differences. Some fetuses possess genotypes that make them much more vulnerable than others to alcohol's teratogenic effects. However, to date, only 1 gene has been identified whose mutation can worsen alcohol-induced behavioral deficits in an animal model of FAS. That gene is neuronal nitric oxide synthase ( nNOS). The purpose of this study was to determine whether mutation of nNOS can likewise worsen alcohol-induced microencephaly and lead to permanent neuronal deficits. Methods Wild-type and nNOS−/− mice received alcohol (0.0, 2.2, or 4.4 mg/g) daily over postnatal days (PDs) 4 to 9. Beginning on PD 85, the mice underwent a series of behavioral tests; the results of which are reported in the companion paper. The brains were then weighed, and stereological cell counts were performed on the cerebral cortex and hippocampal formation, which are the brain regions that mediate the aforementioned behavioral tasks. Results Alcohol caused dose-dependent microencephaly, but only in the nNOS−/− mice and not in wild-type mice. Alcohol-induced neuronal losses were more severe in the nNOS−/− mice than in the wild-type mice in all of the brain regions examined, including the cerebral cortex, hippocampal CA3 subregion, hippocampal CA1 subregion, and dentate gyrus. Conclusions Targeted mutation of the nNOS gene increases the vulnerability of the developing brain to alcohol-induced growth restriction and neuronal losses. This increased neuropathology is associated with worsened behavioral dysfunction. The results demonstrate the critical importance of genotype in determining the outcome of developmental alcohol exposure. [ABSTRACT FROM AUTHOR]

Background: This paper examines differences in drinking and binge drinking between Mexican Americans living along the U.S.-Mexico border and those living in 2 metropolitan areas away from the border (Houston, Texas and Los Angeles, California). Methods: Respondents in the non-border area (Houston and Los Angeles) constitute a multistage probability sample ( N = 1,288), who were interviewed as part of the 2006 Hispanic Americans Baseline Alcohol Survey (HABLAS). Respondents in the border area ( N = 1,307) constitute a household probability sample of Mexican Americans living on the U.S.-Mexico border. In both surveys, data were collected during computer-assisted interviews conducted in respondents' homes. The HABLAS and the border sample response rates were 76 and 67%, respectively. Results: There were no differences between border and non-border Mexican American men in the proportion of drinkers, the proportion who binge drink at least once a year, and volume of alcohol consumption. However, within each location, there were significant differences in drinking by age, indicating that younger men drank more than men who were older. Border women showed significant differences across age-groups in the proportion of drinkers, in binge drinking, and volume of alcohol consumption, which were not seen among non-border women. Conclusions: Women's drinking seems to be more affected than men's by their residence on or off the U.S.-Mexico border. This is seen most clearly among young women 18 to 29 years old, and it is associated with an increased proportion of drinkers, a higher volume of drinking, and an increased proportion of women who report binge drinking. Increased drinking in this group of younger women seems to be associated with drinking in Mexico. [ABSTRACT FROM AUTHOR]

Background In our companion article, we examined the role of MyD88-dependent signaling in ethanol (EtOH) consumption in mice lacking key components of this inflammatory pathway and observed differential effects on drinking. Here, we studied the role of these same signaling components in the acute sedative, intoxicating, and physiological effects of EtOH. Toll-like receptor 4 (TLR4) has been reported to strongly reduce the duration of EtOH-induced sedation, although most studies do not support its direct involvement in EtOH consumption. We examined TLR4 and other MyD88 pathway molecules to determine signaling specificity in acute EtOH-related behaviors. We also studied other GABAergic sedatives to gauge the EtOH specificity and potential role for GABA in EtOH's sedative and intoxicating effects in the mutant mice. Methods Loss of righting reflex ( LORR) and recovery from motor incoordination were studied following acute injection of EtOH or other sedative drugs in male and female control C57 BL/6J mice versus mice lacking CD14, TLR2, TLR4 (C57 BL/10ScN), or MyD88. We also examined EtOH-induced hypothermia and blood EtOH clearance in these mice. Results Male and female mice lacking TLR4 or MyD88 showed reduced duration of EtOH-induced LORR and faster recovery from EtOH-induced motor incoordination in the rotarod test. MyD88 knockout mice had slightly faster recovery from EtOH-induced hypothermia compared to control mice. None of the mutants differed from control mice in the rate of blood EtOH clearance. All of the mutants showed similar decreases in the duration of gaboxadol-induced LORR, but only mice lacking TLR4 were less sensitive to the sedative effects of pentobarbital. Faster recovery from diazepam-induced motor impairment was observed in CD14, TLR4, and MyD88 null mice of both sexes. Conclusions TLR4 and MyD88 were key mediators of the sedative and intoxicating effects of EtOH and GABAergic sedatives, indicating a strong influence of TLR4-MyD88 signaling on GABAergic function. Despite the involvement of TLR4 in EtOH's acute behaviors, it did not regulate EtOH consumption in any drinking model as shown in our companion article. Collectively, our studies demonstrate differential effects of TLR-MyD88 components in the acute versus chronic actions of EtOH. [ABSTRACT FROM AUTHOR]

Background Treatment for alcohol use disorders (AUDs) has traditionally been abstinence oriented, but new research and regulatory guidelines suggest that low-risk drinking may also be an acceptable treatment outcome. However, little is known about long-term outcomes for patients who become low-risk drinkers posttreatment. This study explores a posttreatment low-risk drinking outcome as a predictor of future drinking and psychosocial outcomes over 9 years. Methods Study participants were adults with AUDs at treatment entry who received follow-up interviews 6 months posttreatment intake ( N = 1,061) in 2 large randomized studies conducted at Kaiser Permanente Northern California, a large private, nonprofit, integrated health system. Six-month drinking status was defined as abstinent, low-risk (nonabstinent, no 5+ drinking days), or heavy drinking (1 or more days of 5+ drinks). Using logistic regression models, we explored the relationship between past 30-day drinking status at 6 months and odds of being abstinent or a low-risk drinker (compared to heavy drinking), and positive Addiction Severity Index psychosocial outcomes over 9 years (9-year follow-up rate of 73%). Results Abstainers and low-risk drinkers at 6 months had higher odds of recent abstinence/low-risk drinking over 9 years than heavy drinkers; abstainers had better drinking outcomes than low-risk drinkers. Additionally, among those with interview data, 95% of abstainers and 94% of low-risk drinkers at 6 months were abstinent/low-risk drinkers at 9 years; surprisingly, 89% of heavy drinkers at 6 months were also abstinent/low-risk drinkers although still significantly fewer than the other groups. Abstainers and low-risk drinkers at 6 months had better psychiatric outcomes, and abstainers had better family/social outcomes than heavy drinkers; medical outcomes did not differ. Low-risk drinkers and abstainers showed no reliable differences across psychosocial measures. Conclusions The findings suggest that a low-risk drinking outcome may be reasonable over the long-term for some alcohol-dependent individuals receiving addiction treatment. [ABSTRACT FROM AUTHOR]

Background New pharmacotherapies to treat alcohol use disorders ( AUD) are needed. Given the complex nature of AUD, there likely exist multiple novel drug targets. We, and others, have shown that the tetracycline drugs, minocycline and doxycycline, reduced ethanol (EtOH) drinking in mice. To test the hypothesis that suppression of high EtOH consumption is a general property of tetracyclines, we screened several derivatives for antidrinking activity using the Drinking-In-the-Dark ( DID) paradigm. Active drugs were studied further using the dose-response relationship. Methods Adult female and male C57 BL/6J mice were singly housed and the DID paradigm was performed using 20% EtOH over a 4-day period. Mice were administered a tetracycline or its vehicle 20 hours prior to drinking. Water and EtOH consumption was measured daily. Body weight was measured at the start of drug injections and after the final day of the experiment. Blood was collected for EtOH content measurement immediately following the final bout of drinking. Results Seven tetracyclines were tested at a 50 mg/kg dose. Only minocycline and tigecycline significantly reduced EtOH drinking, and doxycycline showed a strong effect size trend toward reduced drinking. Subsequent studies with these 3 drugs revealed a dose-dependent decrease in EtOH consumption for both female and male mice, with sex differences in efficacy. Minocycline and doxycycline reduced water intake at higher doses, although to a lesser degree than their effects on EtOH drinking. Tigecycline did not negatively affect water intake. The rank order of potency for reduction in EtOH consumption was minocycline > doxycycline > tigecycline, indicating efficacy was not strictly related to their partition coefficients or distribution constants. Conclusions Due to its effectiveness in reducing high EtOH consumption coupled without an effect on water intake, tigecycline was found to be the most promising lead tetracycline compound for further study toward the development of a new pharmacotherapy for the treatment of AUD. [ABSTRACT FROM AUTHOR]

Background Neurobehavioral consequences of heavy prenatal alcohol exposure are well documented; however, the role of age or sex in these effects has not been studied. The current study examined the effects of prenatal alcohol exposure, sex, and age on neurobehavioral functioning in children. Methods Subjects were 407 youth with prenatal alcohol exposure ( n = 192) and controls ( n = 215). Two age groups (child [5 to 7 years] or adolescent [10 to 16 years]) and both sexes were included. All subjects completed standardized neuropsychological testing, and caregivers completed parent-report measures of psychopathology and adaptive behavior. Neuropsychological functioning, psychopathology, and adaptive behavior were analyzed with separate 2 (exposure history) × 2 (sex) × 2 (age) multivariate analyses of variance (MANOVAs). Significant effects were followed by univariate analyses. Results No 3-way or 2-way interactions were significant. The main effect of group was significant in all 3 MANOVAs, with the control group performing better than the alcohol-exposed group on all measures. The main effect of age was significant for neuropsychological performance and adaptive functioning across exposure groups with younger children performing better than older children on 3 measures (language, communication, socialization). Older children performed better than younger children on a different language measure. The main effect of sex was significant for neuropsychological performance and psychopathology; across exposure groups, males had stronger language and visual spatial scores and fewer somatic complaints than females. Conclusions Prenatal alcohol exposure resulted in impaired neuropsychological and behavioral functioning. Although adolescents with prenatal alcohol exposure may perform more poorly than younger exposed children, the same was true for nonexposed children. Thus, these cross-sectional data indicate that the developmental trajectory for neuropsychological and behavioral performance is not altered by prenatal alcohol exposure, but rather, deficits are consistent across the 2 age groups tested. Similarly, observed sex differences on specific measures were consistent across the groups and do not support sexually dimorphic effects in these domains. [ABSTRACT FROM AUTHOR]

Background: Exposure to ethanol (EtOH) in utero alters the disposition of tangentially migrating GABAergic interneurons in the fetal brain. The medial ganglionic eminence (MGE) gives rise to a large portion of cortical GABAergic interneurons, including the parvalbumin-expressing interneurons that shape and contribute to inhibitory/excitatory (I/E) balance of the intracortical circuit. Here, we investigated in the mouse medial prefrontal cortex (mPFC) the hypothesis that low levels of maternal EtOH consumption from closure of the neural tube embryonic day (E) 9.5 until birth result in an enduring interneuronopathy. Methods: Pregnant mice were subjected to a 2%w/w EtOH consumption regimen starting at neural tube closure and ending at parturition. Neurogenesis in theMGE was assessed by 5-bromo-2-deoxyuridine (BrdU) immunofluorescence at E12.5. The count and distribution of parvalbumin-expressing interneurons were determined in adult animals, and patch clamp electrophysiology was performed to determine GABAergic function and I/E balance. Open-field behavior in adult mice was assessed to determine whether the EtOH-exposed cohort displayed a lasting alteration in exploratory behavior. Results: In embryos exposed to EtOH in utero, we found increased BrdU labeling in the MGE, pointing to increased neurogenesis. Adult mice prenatally exposed to EtOH were hyperactive, and this was associated with an increase in parvalbumin-expressing GABAergic interneurons in the mPFC. In addition, prenatal EtOH exposure altered the balance between spontaneous inhibitory and excitatory synaptic input and attenuated GABAergic tone in layer V mPFC pyramidal neurons in juvenile mice. Conclusions: These findings underscore that altered migration of GABAergic interneurons contributes to the EtOH-induced aberration of cortical development and that these effects persist into adulthood as altered cortical form and function. [ABSTRACT FROM AUTHOR]

Background Prenatal alcohol exposure ( PAE) can result in an array of morphological, behavioral, and neurobiological deficits that can range in their severity. Despite extensive research in the field and a significant progress made, especially in understanding the range of possible malformations and neurobehavioral abnormalities, the molecular mechanisms of alcohol responses in development are still not well understood. There have been multiple transcriptomic studies looking at the changes in gene expression after PAE in animal models; however, there is a limited apparent consensus among the reported findings. In an effort to address this issue, we performed a comprehensive re-analysis and meta-analysis of all suitable, publically available expression data sets. Methods We assembled 10 microarray data sets of gene expression after PAE in mouse and rat models consisting of samples from a total of 63 ethanol (EtOH)-exposed and 80 control animals. We re-analyzed each data set for differential expression and then used the results to perform meta-analyses considering all data sets together or grouping them by time or duration of exposure (pre- and postnatal, acute and chronic, respectively). We performed network and Gene Ontology enrichment analysis to further characterize the identified signatures. Results For each subanalysis, we identified signatures of differential expressed genes that show support from multiple studies. Overall, the changes in gene expression were more extensive after acute EtOH treatment during prenatal development than in other models. Considering the analysis of all the data together, we identified a robust core signature of 104 genes down-regulated after PAE, with no up-regulated genes. Functional analysis reveals over representation of genes involved in protein synthesis, mRNA splicing, and chromatin organization. Conclusions Our meta-analysis shows that existing studies, despite superficial dissimilarity in findings, share features that allow us to identify a common core signature set of transcriptome changes in PAE. This is an important step to identifying the biological processes that underlie the etiology of fetal alcohol spectrum disorders. [ABSTRACT FROM AUTHOR]

Background In the accompanying article, we showed that activation of peroxisome proliferator-activated receptor alpha (PPARα) signaling by fenofibrate and tesaglitazar decreases ethanol (EtOH) consumption in mice. In this study, we determined the role of these PPAR agonists in EtOH-related behaviors and other actions that may be important in regulating EtOH consumption. Methods The effects of fenofibrate (150 mg/kg) and tesaglitazar (1.5 mg/kg) were examined on the following responses in male and female C57BL/6J (B6) and B6 × 129S4 mice: preference for saccharin, EtOH-induced conditioned place preference (CPP), conditioned taste aversion (CTA), loss of righting reflex, and withdrawal, acoustic startle reflex, response to novelty, and EtOH clearance. Because the B6 inbred strain usually displays weak EtOH-induced CPP and weak EtOH-induced acute withdrawal, B6 × 129S4 mice were also studied. Results Fenofibrate and tesaglitazar decreased the novelty response and increased acute EtOH withdrawal severity, and fenofibrate increased EtOH-induced CTA. Two important factors for EtOH consumption (saccharin preference and EtOH-induced CPP) were not altered by fenofibrate or tesaglitazar. EtOH clearance was increased by both fenofibrate and tesaglitazar. Response to novelty, acute withdrawal, and EtOH clearance show sex differences and could contribute to the reduced EtOH consumption following fenofibrate administration. Conclusions These studies indicate the complexity of EtOH-dependent and EtOH-independent behaviors that are altered by PPAR agonists and provide evidence for novel behavioral actions of these drugs that may contribute to PPAR-mediated effects on alcohol drinking. [ABSTRACT FROM AUTHOR]

Background Posttraumatic stress disorder (PTSD) is an important and timely clinical issue particularly for combat veterans. Few pharmacologic options are available to treat PTSD, particularly among military personnel, and they are not based on rational neurobiology. The evidence for noradrenergic dysregulation in PTSD is strong, and the alpha-adrenergic agonist prazosin is one of the most promising medications to treat sleep disturbances associated with PTSD as well as PTSD symptoms among both veterans and civilians. Evidence also implicates noradrenergic dysregulation in the pathophysiology of alcohol dependence (AD); prazosin also may have efficacy in treating this disorder. The use of prazosin represents a rational and compelling approach for the treatment of PTSD and comorbid AD. Given the high rates of comorbid AD in trauma survivors with PTSD, and the enormous impact that these comorbid disorders have on psychosocial function and well-being, finding effective treatments for this population is of high clinical importance. Methods Ninety-six veterans with PTSD and comorbid AD were randomized to receive prazosin (16 mg) or placebo in an outpatient, randomized, double-blind, clinical trial for 13 weeks. Main outcomes included symptoms of PTSD, sleep disturbances, and alcohol use. Results Symptoms of PTSD improved over time, but contrary to the hypothesis, there was no medication effect on PTSD symptoms, or on sleep. Alcohol consumption also decreased over time, but there were no significant differences in outcomes between medication groups. Conclusions Prazosin was not effective in treating PTSD symptoms, improving sleep, or reducing alcohol consumption overall in this dually diagnosed group. This does not support the use of prazosin in an actively drinking population and suggests that the presence of a comorbid condition affects the efficacy of this medication. This study highlights the importance of conducting clinical trials in 'real-world' patients, as results may vary based on comorbid conditions. [ABSTRACT FROM AUTHOR]

Background: The role of neuroimmune activation in withdrawal from chronic alcohol (ethanol) has been established in both adolescent and adult models, but direct comparisons across age are sparse. Studies need to elucidate age-dependent neuroimmune effects of alcohol and to focus research attention on age-dependent mechanisms and outcomes. Methods: Adult and adolescent rats from 2 commonly used strains, Wistar and Sprague Dawley (SD), were maintained on continuous 7%, 5.35%, 4.5%alcohol diet (CAD) or cycled 7%w/v alcohol diet for 15 days. Cortical tissue was collected at 0, 8, 16, and 24 hours postwithdrawal followed by measurement of chemokine (C-C motif) ligand 2 (CCL2), tumor necrosis factor alpha, and interleukin 1 beta mRNA with quantitative real-time polymerase chain reaction. Results: Both age groups and strains showed a strong cytokine mRNA response at 7%CAD. Further, a greater increase in CCL2 mRNA was observed in the cortex of adolescents at 7% CAD, which correlated with higher blood alcohol levels (BALs). Adolescents exposed to 5.35%CAD exhibited similar blood levels and cytokine responses as adults exposed to 7%CAD. Substantial variability in CCL2 mRNA responses was found only in adolescent rats exposed to 7%CAD. In this group, data could be segregated into high-responding and low-responding groups. Moreover, the data from the high-responding group were associated with seizures. Conclusions: Relative to other cytokine mRNAs, CCL2 exhibits a unique response profile during withdrawal from CAD. This profile is shown in adolescents, where CCL2 is uniquely influenced by the effects of seizures. Additionally, this profile is shown by the fact that only CCL2 expression correlated with BAL that transcended age groups. These data emphasize the importance of BALs and treatment regimen on developmental neuroimmune responses and suggest that select components of the neuroimmune system are more responsive to CAD withdrawal and that neurobiological mechanisms differentiating these responses should be further explored. [ABSTRACT FROM AUTHOR]

Background Many alcoholics display moderate to severe cognitive dysfunction accompanied by brain pathology. A factor confounded with prolonged heavy alcohol consumption is poor nutrition, and many alcoholics are thiamine deficient. Thus, thiamine deficiency ( TD) has emerged as a key factor underlying alcohol-related brain damage ( ARBD). TD in humans can lead to Wernicke Encephalitis that can progress into Wernicke-Korsakoff syndrome and these disorders have a high prevalence among alcoholics. Animal models are critical for determining the exact contributions of ethanol (EtOH)- and TD-induced neurotoxicity, as well as the interactions of those factors to brain and cognitive dysfunction. Methods Adult rats were randomly assigned to 1 of 6 treatment conditions: chronic EtOH treatment ( CET) where rats consumed a 20% v/v solution of EtOH over 6 months; severe pyrithiamine-induced TD ( PTD-moderate acute stage); moderate PTD ( PTD-early acute stage); moderate PTD followed by CET ( PTD- CET); moderate PTD during CET ( CET- PTD); and pair-fed (PF) control. After recovery from treatment, all rats were tested on spontaneous alternation and attentional set-shifting. After behavioral testing, brains were harvested for determination of mature brain-derived neurotrophic factor ( BDNF) and thalamic pathology. Results Moderate TD combined with CET, regardless of treatment order, produced significant impairments in spatial memory, cognitive flexibility, and reductions in brain plasticity as measured by BDNF levels in the frontal cortex and hippocampus. These alterations are greater than those seen in moderate TD alone, and the synergistic effects of moderate TD with CET lead to a unique cognitive profile. However, CET did not exacerbate thalamic pathology seen after moderate TD. Conclusions These data support the emerging theory that subclinical TD during chronic heavy alcohol consumption is critical for the development of significant cognitive impairment associated with ARBD. [ABSTRACT FROM AUTHOR]

Background Alcohol research may benefit from controlled and validated picture sets. We have constructed the Amsterdam Beverage Picture Set ( ABPS), which was designed for alcohol research in general and cognitive bias measurement and modification in particular. Here, we first formulate a position on alcohol stimulus validity that prescribes that alcohol-containing pictures, compared to nonalcohol-containing pictures, should induce a stronger urge to drink in heavy drinkers than in light drinkers. Because a perceptually simple picture might induce stronger cognitive biases but the presence of a drinking context might induce a stronger urge to drink, the ABPS contains pictures with and without drinking context. By limiting drinking contexts to simple consumption scenes instead of real-life scenes, complexity was minimized. A validation study was conducted to establish validity, to examine ABPS drinking contexts, and to explore the role of familiarity, valence, arousal, and control. Methods Two hundred ninety-one psychology students completed the Alcohol Use Disorders Identification Test, as well as rating and recognition tasks for a subset of the ABPS pictures. Results The ABPS was well-recognized, familiar, and heavy drinkers reported a greater urge to drink in response to the alcohol-containing pictures only. Alcohol presented in drinking context did not elicit a stronger urge to drink but was recognized more slowly than alcohol presented without context. Conclusions The ABPS was found to be valid, although pictures without context might be preferable for measuring cognitive biases than pictures with context. We discuss how an explicit approach to picture construction may aid in creating variations of the ABPS. Finally, we describe how ABPS adoption across studies may allow more reproducible and comparable results across paradigms, while allowing researchers to apply picture selection criteria that correspond to a wide range of theoretical positions. The latter is exemplified by ABPS derivatives and adoptions that are currently under way. [ABSTRACT FROM AUTHOR]

Background Heavy drinking is common during transitions from high school to college. Optimal programs for diminishing risks for high alcohol consumption often tailor the approach to the specific needs of students. This study describes the results of an Internet-based prevention protocol that tailors the information to the risk associated with a pre-existing phenotype, the Low level of Response (Low LR) to alcohol. Methods Using stratified random assignment, 454 freshmen with Low and High LR values were assigned to 2 education groups (LR-based where all examples were given the context of the Low LR model of heavy drinking or a State Of The Art (SOTA) Group where the same lessons were taught but without an emphasis on LR) or a no-intervention Control Group. Individuals in the 2 education groups viewed 50-minute online videos once per week for 4 weeks. Changes in drinking patterns were assessed at Baseline, 4 weeks, and 8 weeks using a 2 (LR status) by 3 (education group) by 3 (time points) analysis of variance, with additional tests for ethnicity and sex. Results Low LR participants tended to decrease their usual ( p < 0.06) and maximum ( p < 0.05) drinks per occasion most prominently when assigned to the LR-based protocol, while those with High LRs improved more in the SOTA Group. The most robust differences were seen when controlling for ethnicity. The effect sizes were small to medium. Conclusions These results support the advantages of carrying out prevention via the Internet and in tailoring the approach to a pre-existing phenotype. [ABSTRACT FROM AUTHOR]

Background Alcohol's effect on sleep electroencephalogram ( EEG) power spectra during late adolescence is of interest given that this age group shows both dramatic increases in alcohol consumption and major sleep-related developmental changes in quantitative EEG measures. This study examined the effect of alcohol on sleep EEG power spectra in 18- to 21-year-old college students. Methods Participants were 24 (12 female) healthy 18- to 21-year-old social drinkers. Participants underwent 2 conditions: presleep alcohol and placebo, followed by standard polysomnography with comprehensive EEG recordings. Results After alcohol, mean breath alcohol concentration at lights-out was 0.084%. Interaction effects indicated simultaneous increases in frontal non-rapid eye movement sleep ( NREM) delta ( p = 0.031) and alpha ( p = 0.005) power in the first sleep cycles following alcohol consumption which was most prominent at frontal scalp sites ( p < 0.001). A decrease in sigma power ( p = 0.001) was also observed after alcohol. Conclusions As hypothesized, alcohol increased slow wave sleep-related NREM delta power. However, there was a simultaneous increase in frontal alpha power. Results suggest that alcohol may exert an arousal influence which may compete with the sleep maintenance influence of increased delta activity. The phenomenon is similar to, or the same as, alpha-delta sleep which has been associated with the presence of disruptive stimuli during sleep. This may have negative implications for the impact of presleep alcohol consumption on sleep and consequent daytime functioning. [ABSTRACT FROM AUTHOR]

Background Alcohol abuse during pregnancy often induces neuropsychological problems in the offspring, including learning disorders, attention deficits, and behavior problems, all of which are prominent components of fetal alcohol spectrum disorders (FASD). However, not all children who were exposed to alcohol in utero are equally affected by it. While some children have major deficits, others are spared. This unequal vulnerability is likely due largely to differences in fetal genetics. Some fetuses appear to have certain genotypes that make them much more prone to FASD. However, to date, no gene has been identified that worsens alcohol-induced brain dysfunction. Nitric oxide (NO) is a gaseous molecule that can protect developing neurons against alcohol-induced death. In the brain, NO is produced by neuronal nitric oxide synthase ( nNOS). In this study, we examined whether homozygous mutation of the nNOS gene in mice worsens the behavioral deficits of developmental alcohol exposure. Methods Wild-type and nNOS−/− mice received alcohol (0.0, 2.2, or 4.4 mg/g) daily over postnatal days (PDs) 4 to 9. Beginning on PD 85, the mice underwent a series of behavioral tests, including open field activity, the Morris water maze, and paired pulse inhibition. Results For the wild-type mice, alcohol impaired performance only in the water maze. In contrast, for the nNOS−/− mice, alcohol impaired performance on all 3 tasks. Furthermore, the nNOS−/− mice were substantially more impaired than wild-type mice in their performance on all 3 of the behavioral tests and at both the low (2.2) and high (4.4) doses of alcohol. Conclusions Targeted disruption of the nNOS gene worsens the behavioral impact of developmental alcohol exposure and allows alcohol-induced learning problems to emerge that are not seen in wild type. This is the first demonstration that a specific genotype can interact with alcohol to worsen functional brain deficits in an animal model of FASD. [ABSTRACT FROM AUTHOR]

Background Anxiety disorders predispose individuals to the development of alcohol dependence in humans. Surprisingly, whether anxiety is a trait influencing the development of alcohol-related behaviors in rodents remains controversial. Here, we addressed the hypothesis of a relationship between basal anxiety levels and the development of ethanol (Et OH)-induced behavioral sensitization ( EIBS), a model of neuroadaptations occurring after repeated Et OH exposure which is proposed to play a role in early and recurring steps of addiction. Methods Et OH-naïve DBA/2J mice were submitted to the elevated plus maze and light/dark box tests to evaluate their basal anxiety levels. Then, mice received daily intraperitoneal injection of saline or 2 g/kg Et OH for 10 days and locomotor activity was immediately monitored. Mice were then split into resistant and sensitized phenotypes based on their increase in locomotion. The relationship between basal anxiety and the development of sensitization was investigated. In addition, we tested the effect of an 8-day-long treatment with 4 mg/kg diazepam, a broad-spectrum benzodiazepine anxiolytic, on the expression of sensitization in both resistant and sensitized mice. Results For the first time, we showed that vulnerability to EIBS is negatively correlated with basal anxiety. Moreover, a diazepam treatment during EIBS procedure increased Et OH-induced hyperlocomotion of resistant mice after 1 week of withdrawal (but not immediately after) without any effect in the group of sensitized mice. Conclusions This study shows that, in mice, basal anxiety predicts the vulnerability to EIBS. Mice exhibiting low basal anxiety will develop higher EIBS than mice with elevated anxiety levels. Modulation of anxiety by a diazepam treatment during the development of EIBS enhances its expression after 1 week postinduction. Altogether, we demonstrated an inverse relationship between basal anxiety-like behaviors and EIBS vulnerability and that resistance to EIBS vanishes after anxiolytic treatment. [ABSTRACT FROM AUTHOR]

Background Fetal alcohol spectrum disorders are the result of alcohol-exposed pregnancies ( AEP) and believed to be the leading known cause of developmental disabilities in the United States. Our objective was to determine whether a culturally targeted Screening, Brief Intervention, and Referral to Treatment ( SBIRT) intervention may reduce risky drinking and vulnerability to AEP among American Indian/Alaska Native ( AIAN) women in Southern California. Methods Southern California AIAN women of childbearing age who completed a survey including questions regarding alcohol consumption and contraceptive use were randomized into intervention or treatment as usual groups where the former group completed an online SBIRT intervention, and were followed up at 1, 3, and 6 months postintervention. Results Of 263 women recruited and 247 with follow-up data, one-third were at high risk of having an AEP at baseline. Both treatment groups decreased self-reported risky drinking behavior (drinks per week, p < 0.001; frequency of heavy episodic [binge] drinking episodes per 2 weeks, p = 0.017 and risk of AEP p < 0.001 at 6 months postintervention) in the follow-up period. There was no difference between treatment groups. Baseline factors associated with decreased risk of an AEP at follow-up included the perception that other women in their peer group consumed a greater number of drinks per week, having reported a greater number of binge episodes in the past 2 weeks, and depression/impaired functionality. Conclusions Participation in assessment alone may have been sufficient to encourage behavioral change even without the web-based SBIRT intervention. Randomization to the SBIRT did not result in a significantly different change in risky drinking behaviors. The importance of perception of other women's drinking and one's own depression/functionality may have implications for future interventions. [ABSTRACT FROM AUTHOR]

Background The long-term consequences of adolescent alcohol abuse that persist into adulthood are poorly understood and have not been widely investigated. We have shown that intermittent exposure to alcohol during adolescence decreased the amplitude of GABAA receptor (GABAAR)-mediated tonic currents in hippocampal dentate granule cells in adulthood. The aim of this study was to investigate the enduring effects of chronic intermittent alcohol exposure during adolescence or adulthood on the expression of hippocampal GABAARs. Methods We used a previously characterized tissue fractionation method to isolate detergent resistant membranes and soluble fractions, followed by Western blots to measure GABAAR protein expression. We also measured mRNA levels of GABAAR subunits using quantitative real-time polymerase chain reaction. Results Although the protein levels of α1-, α4-, and δ-GABAAR subunits remained stable between postnatal day (PD) 30 (early adolescence) and PD71 (adulthood), the α5-GABAAR subunit was reduced across that period. In rats that were subjected to adolescent intermittent ethanol (AIE) exposure between PD30 and PD46, there was a significant reduction in the protein levels of the δ-GABAAR, in the absence of any changes in mRNA levels, at 48 hours and 26 days after the last ethanol (EtOH) exposure. Protein levels of the α4-GABAAR subunit were significantly reduced, but mRNA levels were increased, 26 days (but not 48 hours) after the last AIE exposure. Protein levels of α5-GABAAR were not changed by AIE, but mRNA levels were reduced at 48 hours but normalized 26 days after AIE. In contrast to the effects of AIE, chronic intermittent ethanol (CIE) exposure during adulthood had no effect on expression of any of the GABAAR subunits examined. Conclusions AIE produced both short- and long-term alterations of GABAAR subunits mRNA and protein expression in the hippocampus, whereas CIE produced no long-lasting effects on those measures. The observed reduction of protein levels of the δ-GABAAR, specifically, is consistent with previously reported altered hippocampal GABAAR-mediated electrophysiological responses after AIE. The absence of effects of CIE underscores the emerging view of adolescence as a time of distinctive vulnerability to the enduring effects of repeated EtOH exposure. [ABSTRACT FROM AUTHOR]

Background The effects of stress, including neuroendocrine and behavioral sequelae aimed at maintaining homeostasis, are associated with increased alcohol consumption. Because both stress and drinking are multifactorial, the mechanisms underlying the relationship are difficult to elucidate. We therefore employed an animal model investigating the influence of blocked access to a running wheel on drinking in C57 BL/6J (B6) mice. Methods In the first experiment, naïve, adult male and female subjects were individually housed for 2 weeks with 24-hour access to a running wheel and 12% ethanol (EtOH) in a 2-bottle, free choice paradigm. After determining baseline consumption and preference, experimental subjects had the running wheel placed in a locked position for 6 hours, and the Et OH bottle was removed during the first half of this period. Two subsequent experiments, again in adult, naïve B6 mice, examined the influence of locked running wheels on self-administration of 20% Et OH in a limited access paradigm, and blood Et OH concentrations ( BECs) were determined on the final day of this protocol. Results In all 3 studies, using both between- and within-subject analyses, females showed transient yet reliable increases in alcohol drinking during blocked access to a rotating activity, while drinking in male mice was largely insensitive to this manipulation, although both sexes showed appreciable BECs (>130 mg/dl in females and 80 mg/dl in males) following a 2-hour EtOH access period. Conclusions These data add to a burgeoning literature suggesting that the factors contributing to excessive alcohol use differ between males and females and that females may be especially sensitive to the influence of wheel manipulation. Elucidating the sex-dependent mechanisms mediating differences in alcohol sensitivity and response is critical to understanding the causes of alcoholism and in developing effective treatments and interventions. [ABSTRACT FROM AUTHOR]

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 to 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- 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 predicted 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. [ABSTRACT FROM AUTHOR]

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- De Carli liquid diet with alcohol (18% of energy) or an isocaloric Lieber- De Carli control diet for 5 weeks. Global DNA hydroxymethylation and DNA methylation were analyzed from hepatic DNA using a new liquid chromatography-tandem mass spectrometry method. Hepatic m RNA expression of the Tet enzymes were measured via quantitative real-time polymerase chain reaction. 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 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. [ABSTRACT FROM AUTHOR]

Background Binge alcohol drinking is among 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 postoperative 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 2 subsequent doses (adjusted based on the intoxication level of the rat) approximately 8 hours apart. Sleep-wakefulness was continuously recorded for 3 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 (BAC) was 0, sleep disruptions were observed manifested by a reversal of sleep-wakefulness as evident from insomnia-like symptoms (significant increase in wakefulness; significant reduction in nonrapid eye movement [ 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 BAC is 0. Our results suggest that the reversal of sleep-wakefulness accompanies alcohol hangover after binge alcohol administration. [ABSTRACT FROM AUTHOR]

Background It has been known that ADH1B*2 allele has a protective effect against the development of alcohol dependence. However, the protection mechanism is still unknown. We investigated whether ADH1B gene polymorphism affects ethanol (EtOH) metabolism. Methods In a parent study, we conducted a randomized crossover trials on 24 healthy male subjects who were selected by genotyping: 12 with ALDH2*1/*1 (active form) and 12 with ALDH2*1/*2 (inactive form). In the present study, the 24 subjects were reclassified into 2 groups of 11 with ADH1B*1/*2 and 13 with ADH1B*2/*2 according to the ADH1B genotypes. Each subject was administered 1 of 3 doses of EtOH (0.25, 0.5, 0.75 g/kg) or a placebo in 4 trials. After the administration of alcohol, blood EtOH and acetaldehyde concentrations were measured 9 times over 4 hours. Results In the case of EtOH, the area under the concentration-time curve from 0 to 4 hours ( AUC0-4) and the peak blood concentration of EtOH ( Cmax) in subjects with ADH1B*2/*2 were significantly higher than those in subjects with ADH1B*1/*2 at all 3 dosages before stratifying by ALDH2 genotype. However, after stratifying by ALDH2 genotype, a statistically significant difference between ADH1B*2/*2 and ADH1B*1/*2 was found only at the 0.5 g/kg dosage regardless of ALDH2 genotype. In the case of acetaldehyde, the AUC0-4 and Cmax of acetaldehyde of ADH1B*2/*2 after administration of 0.25 g/kg alcohol and the AUC0-4 of acetaldehyde of ADH1B*2/*2 at 0.5 g/kg were significantly higher than corresponding values of ADH1B*1/*2 only in the group of ALDH2*1/*2. Conclusions Our findings indicate that the blood EtOH concentrations of ADH1B*2/*2 group are higher than those of ADH1B*1/*2 group regardless of ALDH2 genotype, and the blood acetaldehyde concentrations of ADH1B*2/*2 are also higher than those of ADH1B*1/*2 only in the ALDH2*1/*2 group. To our knowledge, this is the first report to demonstrate the association of ADH1B*2 allele with blood EtOH and acetaldehyde levels in humans, and these results suggest that higher blood EtOH and acetaldehyde concentrations in ADH1B*2/*2 may constitute the mechanism of protection against alcoholism by ADH1B*2/*2. [ABSTRACT FROM AUTHOR]

Background Heavy prenatal alcohol exposure and attention-deficit/hyperactivity disorder ( ADHD) are associated with adaptive behavior deficits. This study examined the interaction between these 2 factors on parent ratings of adaptive behavior. Methods As part of a multisite study, primary caregivers of 317 children (8 to 16 years, M = 12.38) completed the Vineland Adaptive Behavior Scales-Second Edition ( VABS- II). Four groups of subjects were included: children with prenatal alcohol exposure with ADHD ( AE+, n = 82), children with prenatal alcohol exposure without ADHD ( AE−, n = 34), children with ADHD ( ADHD, n = 71), and control children ( CON, n = 130). VABS- II domain scores (Communication, Daily Living Skills, Socialization) were examined using separate 2 (Alcohol Exposure [ AE]) × 2 ( ADHD diagnosis) between-subjects analyses of covariance. Results There were significant main effects of AE ( p < 0.001) and ADHD ( p < 0.001) on all VABS- II domains; alcohol-exposed children had lower scores than children without prenatal alcohol exposure and children with ADHD had lower scores than those without ADHD. There was a significant AE × ADHD interaction effect for Communication, F(1, 308) = 7.49, p = 0.007, partial η2 = 0.024, but not Daily Living Skills or Socialization domains ( ps > 0.27). Follow-up analyses in the Communication domain indicated the effects of ADHD were stronger in comparison subjects ( ADHD vs. CON) than exposed subjects ( AE+ vs. AE−), and the effects of alcohol exposure were stronger in subjects without ADHD ( AE− vs. CON) than in subjects with ADHD ( AE+ vs. ADHD). Conclusion As found previously, both prenatal alcohol exposure and ADHD increase adaptive behavior deficits in all domains. However, these 2 factors interact to cause the greatest impairment in children with both prenatal alcohol exposure and ADHD for communication abilities. These results further demonstrate the deleterious effects of prenatal alcohol exposure and broaden our understanding of how ADHD exacerbates behavioral outcomes in this population. [ABSTRACT FROM AUTHOR]

Background This study examined how well students estimate their overall drinker type and the relation between the accuracy of this estimation with alcohol-related consequences. The study also explored the association between psychosocial alcohol variables and underestimation or overestimation of drinker type. Methods College students ( n = 1,895) completed questionnaires at baseline (precollege matriculation) assessing self-reported drinker types ( SI), protective and risky drinking behaviors, drinking expectancies, attitudes, and norms. Postbaseline assessment occurred during the fall semester sophomore year and included the number and type of alcohol consequences experienced during the previous year. Students' SIs were coded as accurate, overestimated, or underestimated relative to their empirically derived latent class analytic drinker class. The association between drinker type accuracy and consequences and membership in the high-risk Multiple and Repeated Consequence group was assessed, as was the relationship between the psychosocial alcohol variables and accuracy. Results Eighteen percent of students underestimated and 10% overestimated their drinker type. Students who under- or overestimated their drinker type reported experiencing more consequences, even after controlling for drinking. Increases in positive alcohol expectancies, protective and risky drinking behaviors, and descriptive peer norms were positively associated with underestimation of drinker type. Only protective and risky drinking behaviors were associated with overestimation. Conclusions This study underscores the importance of accurate estimation of drinker type and the risk of experiencing alcohol consequences. Future research and intervention strategies are discussed. [ABSTRACT FROM AUTHOR]

Background Nicotinic acetylcholine receptors (n ACh Rs) may play a critical role in alcohol reinforcement and consumption. The effects of varenicline, an n ACh R partial agonist, on alcohol seeking and self-administration responses were evaluated in 2 groups of baboons trained under a 3-component chained schedule of reinforcement ( CSR). Methods Alcohol (4% w/v; n = 4; alcohol group) or a preferred nonalcoholic beverage ( n = 4; control group) was available for self-administration only in component 3 of the CSR. Responses in component 2, required to gain access to alcohol, provided indices of seeking behavior. Varenicline (0.032 to 0.32 mg/kg; 0.32 mg/kg twice daily [BID]) and vehicle were administered before CSR sessions subchronically (5 consecutive days). Higher doses (0.56, 1.0 mg/kg) were attempted, but discontinued due to adverse effects. Results Subchronic varenicline administration significantly ( p < 0.05) decreased the seeking response rate and increased the time to complete the response requirement to gain access to the daily supply of alcohol at the higher doses (0.32 mg/kg, 0.32 mg/kg BID dosing) in the alcohol group compared with the control group. Mean number of drinks was significantly decreased ( p < 0.05), but effects did not differ between groups. The pattern of drinking was characterized by a high rate during an initial bout. Number of drinks during and duration of the initial bout were significantly decreased in the alcohol group, compared with the control group, at 0.32 mg/kg ( p < 0.05). Conclusions Varenicline may be clinically useful for reducing alcohol-seeking behaviors prior to alcohol exposure. Given the modest effects on drinking itself, varenicline may be better suited as a treatment in combination with a pharmacotherapy that significantly reduces alcohol consumption. [ABSTRACT FROM AUTHOR]

Background Chronic ethanol ( Et OH) exposure produces neuroadaptations in NMDA receptor function and/or abundance and alterations in hypothalamic-pituitary-adrenal ( HPA) axis functioning that contribute to neuronal excitation and neurotoxicity during ethanol withdrawal ( EWD). Both Et OH and corticosterone (CORT) promote synthesis of polyamines, which allosterically potentiate NMDA receptor function at the GluN2B subunit. The current studies investigated the effect of 10-day Et OH and CORT co-exposure on toxicity during EWD in rat hippocampal explants and hypothesized that alterations in function and/or density of GluN2B subunits contribute to the toxicity. Methods Organotypic hippocampal slice cultures were exposed to CORT (0.01-1.0 μM) during 10-day Et OH exposure (50 mM) and 1 day of EWD. Et OH-naïve cultures were exposed to CORT for 11 days. Additional cultures were exposed to a membrane impermeable form of CORT ( BSA- CORT) with and without 10-day Et OH exposure and EWD. Cytotoxicity (uptake of propidium iodide) was assessed in the pyramidal cell layer of the CA1 region. Western blot analysis was employed to assess the density of GluN2B subunits following Et OH and CORT exposure. Results EWD did not produce overt neurotoxicity. However, co-exposure to Et OH/ EWD and CORT produced significant neurotoxicity in the CA1 region pyramidal cell layer. Ifenprodil, a GluN2B polyamine site antagonist, significantly reduced toxicity from Et OH and CORT (0.1 μM) co-exposure during EWD. However, Western blots did not reveal differences in GluN2B subunit density among groups. Exposure to BSA- CORT did not produce toxicity, suggesting that membrane-bound CORT receptors did not significantly contribute to the observed toxicity. Conclusions These data suggest that CORT and Et OH co-exposure result in increased function of polyamine-sensitive GluN2B subunits, but this toxicity does not appear dependent on the abundance of hippocampal NMDA GluN2B subunits or membrane-bound CORT receptor function. [ABSTRACT FROM AUTHOR]

Background Prenatal ethanol ( Et OH) and prenatal stress have both been independently shown to induce learning deficits and anxiety behavior in adult offspring. However, the interactive effects of these 2 developmental teratogens on behavioral outcomes have not been systematically evaluated. Methods We combined an established moderate prenatal Et OH consumption paradigm where Long- Evans rat dams voluntarily consume either a 0 or 5% Et OH solution in 0.066% saccharin water (resulting in a mean peak maternal serum Et OH concentration of 84 mg/dl) with a novel prenatal stress paradigm. Pregnant rats were exposed to 3% 2,3,5-trimethyl-3-thiazoline (TMT) for 20 minutes a day on gestational days 13, 15, 17, and 19. Adult female offspring were evaluated for anxiety-like behavior using an elevated plus-maze and hippocampal-sensitive learning using a 2-trial trace conditioning ( TTTC) task. Results TMT exposure produced a threefold increase in maternal serum corticosterone compared to nonexposed, unhandled controls. Neither prenatal exposure paradigm, either alone or in combination, altered maternal weight gain, Et OH consumption, maternal care of litters, litter size, pup birth weight, or pup weight gain up to weaning. Offspring exposed to prenatal stress displayed significant increases in anxiety-like behavior in the elevated plus maze in terms of open arm entries and time spent on the open arms, with no significant effect of prenatal Et OH exposure and no interaction of the 2 prenatal exposures. Performance in a TTTC task revealed a significant effect of prenatal Et OH exposure on freezing behavior on the testing day, with no significant effect of prenatal stress exposure and no interaction of the 2 prenatal exposures. Conclusions While each prenatal exposure independently produced different behavioral outcomes, the results indicate that there is no significant interaction of prenatal Et OH and prenatal stress exposures on learning or anxiety at the exposure levels employed in this dual exposure paradigm. Subsequent studies will examine whether similar outcomes occur in male offspring and whether other measures of anxiety or learning are differentially impacted by these prenatal exposure paradigms. [ABSTRACT FROM AUTHOR]

Background There is a strong relationship between circadian rhythms and ethanol ( Et OH) responses. EtOH consumption has been shown to disrupt physiological and behavioral circadian rhythms in mammals ( Alcohol Clin Exp Res 2005b, 29, 1550). The Drosophila central circadian pacemaker is composed of proteins encoded by the per, tim, cyc, and Clk genes. Using Drosophila mutant analysis, we asked whether these central components of the circadian clock make the equivalent contribution toward Et OH tolerance and whether rhythmicity itself is necessary for tolerance. Methods We tested flies carrying mutations in core clock genes for the capacity to acquire Et OH tolerance. Tolerance was assayed by comparing the sedation curves of populations during their first and second sedation. Animals that had acquired tolerance sedated more slowly. Movement was also monitored as the flies breathe the Et OH vapor to determine if other facets of the Et OH response were affected by the mutations. Gas chromatography was used to measure internal Et OH concentration. Constant light was used to nongenetically destabilize the PER and TIM proteins. Results A group of circadian mutations, all of which eliminate circadian rhythms, do not disrupt tolerance identically. Mutations in per, tim, and cyc completely block tolerance. However, a mutation in Clk does not interfere with tolerance. Constant light also disrupts the capacity to acquire tolerance. These lines did not differ in Et OH absorption. Conclusions Mutations affecting different parts of the intracellular circadian clock can block the capacity to acquire rapid Et OH tolerance. However, the role of circadian genes in Et OH tolerance is independent of their role in producing circadian rhythmicity. The interference in the capacity to acquire Et OH tolerance by some circadian mutations is not merely a downstream effect of a nonfunctional circadian clock; instead, these circadian genes play an independent role in Et OH tolerance. [ABSTRACT FROM AUTHOR]

Background Early alcohol use is one of the strongest predictors of later alcohol use disorders, with early use usually taking place during puberty. Many researchers have suggested drinking during puberty as a potential biological basis of the age at first drink ( AFD) effect. However, the influence of the pubertal phase at alcohol use initiation on subsequent drinking in later life has not been examined so far. Methods Pubertal stage at first drink ( PSFD) was determined in N = 283 young adults (131 males, 152 females) from an epidemiological cohort study. At ages 19, 22, and 23 years, drinking behavior (number of drinking days, amount of alcohol consumed, hazardous drinking) was assessed using interview and questionnaire methods. Additionally, an animal study examined the effects of pubertal or adult ethanol (EtOH) exposure on voluntary EtOH consumption in later life in 20 male Wistar rats. Results PSFD predicted drinking behavior in humans in early adulthood, indicating that individuals who had their first drink during puberty displayed elevated drinking levels compared to those with postpubertal drinking onset. These findings were corroborated by the animal study, in which rats that received free access to alcohol during the pubertal period were found to consume more alcohol as adults, compared to the control animals that first came into contact with alcohol during adulthood. Conclusions The results point to a significant role of stage of pubertal development at first contact with alcohol for the development of later drinking habits. Possible biological mechanisms and implications for prevention are discussed. [ABSTRACT FROM AUTHOR]

Background Alcohol consumption has been linked to increased tobacco use and craving in both dependent and nondaily smokers, yet the extent to which these relationships depend on interactions involving nicotine remains unclear. This study examined the acute effects of alcohol on the subjective and behavioral responses to nicotine-containing tobacco and denicotinized tobacco in 17 (10 male) dependent daily smokers ( DDS) and 23 (11 male) nondependent nondaily smokers ( NNS). Methods During 4 randomized double-blind sessions, participants assessed the effects of nicotine-containing tobacco or denicotinized tobacco following the administration of a moderately intoxicating dose of alcohol (mean blood alcohol concentration = 0.076 g/dl) or a placebo beverage. They could then self-administer additional puffs of the same type of cigarette sampled over a 60-minute period using a progressive ratio task. Results In NNS, alcohol significantly increased the self-administration of both nicotine-containing and denicotinized cigarettes, and no differences in self-administration were observed between the 2 types of tobacco within either beverage condition. In contrast, in DDS, alcohol was associated with decreased denicotinized tobacco self-administration relative to the placebo beverage condition as well as with increased self-administration of nicotine-containing tobacco relative to denicotinized tobacco. DDS also exhibited relatively elevated craving following the administration of a nicotine-containing cigarette in the alcohol beverage condition. Conclusions Findings suggest that nicotine may be critical to the drinking-smoking relationship in DDS, but that nonnicotine smoking factors may be more important in NNS. [ABSTRACT FROM AUTHOR]

Background Behavioral sensitization induced by repeated ethanol ( Et OH) exposure may play a critical role in the development of alcohol dependence. Because recent data demonstrate that histone deacetylase inhibitor ( HDACi) may be of interest in the treatment of addiction, we explored the effect of the HDACi sodium butyrate ( Na B) on Et OH-induced behavioral sensitization ( EIBS) in DBA/2 J mice. We also investigated gene regulations in the striatum of sensitized mice using epigenetic- and signal transduction-related PCR arrays. Methods Mice were injected with saline or Et OH (0.5 to 2.5 g/kg) once a day for 10 days. Mice received Na B (200 to 600 mg/kg) 30 minutes before each injection (prevention protocol) or once daily between days 11 and 16 (reversal protocol). At day 17, brains were removed 30 minutes after a saline or Et OH challenge to assess gene and proteins levels. Results Only the intermediate Et OH doses (1.0 and 2.0 g/kg) were effective in inducing EIBS, and both doses were associated with specific gene regulations in the striatum. The induction of sensitization by 1.0 g/kg (but not 2.0 g/kg) Et OH was dose-dependently prevented or reversed by Na B. Among the 168 studied genes, EIBS blockade was associated with specific gene regulations ( bcl-2, bdnf, hdac4, pak1, penk, tacr1, vip...) and changes in brain-derived neurotrophic factor in both striatum and prefrontal cortex. Conclusions These results indicate that EIBS is associated with specific gene regulations in the striatum depending on the Et OH dose and that Na B can be useful in blocking some long-lasting neuro-adaptations to repeated Et OH administrations. [ABSTRACT FROM AUTHOR]

Background The prevalence of alcohol use during adolescence is concerning given that early age of alcohol initiation is correlated with the development of alcohol-related problems later in life. The purpose of this series of studies was to assess whether voluntary ethanol ( Et OH) exposure during adolescence would influence Et OH drinking behavior in adulthood using an animal model. Methods Pair-housed Sprague- Dawley adolescent (postnatal day [P] 28 to 42) rats of both sexes were given single bottle access to 1 of 3 solutions in their home cages-10% Et OH in 'supersac' (0.125% saccharin and 3% sucrose) ( Et OH/ SS), supersac without Et OH ( SS), or water-for 30 minutes every other day for a total of 8 drinking days or were left nonmanipulated ( NM). Animals were NM thereafter until adulthood ( P70) at which time they were given 1-bottle, 30 minute limited access tests with 20% Et OH every other day (Exp 1), 10% Et OH in SS (Exp 2), or SS without Et OH (Exp 3). Results Adolescent Et OH/ SS exposure increased adulthood consumption of Et OH/ SS (Exp 2), but not 20% unsweetened Et OH (Exp 1) or SS (Exp 3), with this increase most pronounced at the beginning of the 8 intake day procedure. Access to SS (without Et OH) during adolescence produced an analogous effect, with increased adult SS consumption during the first 2 intake days, but no increases in either of the Et OH test solutions. Conclusions Solution-specific increases in adulthood intake after adolescent exposure are most likely associated with solution acceptance due to familiarity. This is an important consideration for future intake studies assessing the influence of Et OH exposure during adolescence on intake of Et OH in adulthood. [ABSTRACT FROM AUTHOR]

Background Nearly 40% of adults aged 65 and older in the United States consume alcohol. Research in older adults has largely examined potential health effects of a moderate drinking lifestyle. Examination of acute effects in this population is generally lacking. To investigate alcohol-induced alteration of electrophysiological correlates of attention in this population, we employed a covert attentional task. We hypothesized that moderate alcohol administration as well as older age would reduce P3 amplitude and increase latency. We anticipated an interaction such that, relative to their age-matched controls, older adults receiving alcohol would be more affected than their younger counterparts. Methods Participants included healthy older (aged 50 to 67; n = 20; 9 men) and younger (aged 25 to 35; n = 12; 5 men) moderate drinkers. Participants received either a moderate dose of alcohol (breath alcohol concentration ∼50 mg/dl) or a placebo beverage. Following absorption, the task was administered and neurophysiological measures were obtained. P3 amplitude and latency were separately subjected to ANOVA across cue conditions using age and dose as independent variables. Results As predicted, P3 amplitude in older adults was significantly lower than in younger adults across cue conditions. An age by alcohol interaction was detected, revealing that older adults receiving alcohol showed lower P3 amplitudes than any other group. An age effect for P3 latency was found, with older adults having longer latencies than their younger counterparts. A significant age by alcohol interaction for P3 latency was detected, revealing that older adults receiving alcohol displayed delayed P3 latencies relative to older adults receiving placebo. In contrast, younger adults receiving alcohol had reduced latency compared to those receiving placebo, although this effect did not reach significance. Conclusions Results suggest that older adults demonstrated alcohol-related shifts in P3 characteristics during an intentional attention task, whereas younger adults failed to demonstrate this pattern. [ABSTRACT FROM AUTHOR]

Background Heavy prenatal exposure to alcohol leads to widespread cognitive deficits, including problems with attention and response inhibition. This study examined blood oxygen level-dependent response in children with and without histories of heavy prenatal alcohol exposure during a task of response inhibition consisting of cued and noncued trials. Methods Children and adolescents (ages 8 to 18 years) with (alcohol-exposed [AE] = 20) and without (control [CON] = 15) histories of heavy prenatal exposure to alcohol underwent functional magnetic resonance imaging while performing a go/no-go task. Unbeknownst to subjects, a predictive cue preceded the no-go stimulus in 87% of trials. Results Groups were matched on demographic variables and did not differ on most measures of task performance. However, following cued stimuli, the AE group demonstrated a lower hit rate to go stimuli and more conservative response bias than the CON group. AE participants demonstrated more activation during no-go trials (inhibition) relative to go trials in the left precuneus, cingulate gyrus, anterior cingulate, and right medial frontal gyrus. During cue-dependent response inhibition, the AE group demonstrated less activation in the left precentral and postcentral gyrus compared to the CON group. Conclusions Consistent with previous studies of response inhibition, the AE group demonstrated greater frontal and parietal activation when attempting to inhibit prepotent responses than the CON group, despite similar rates of commission errors. This study further demonstrated that the AE group had impaired behavioral performance on cued trials and demonstrated less activation in precentral and postcentral gyri relative to the CON group on these trials. This investigation provides evidence of impaired behavioral and neural processing of sequential information in fetal alcohol spectrum disorders, which can help improve inhibition in typical populations. [ABSTRACT FROM AUTHOR]

Background This study examined prevalence of psychiatric disorders and behavioral problems in children with and without prenatal alcohol exposure ( AE) and attention-deficit/hyperactivity disorder ( ADHD). Methods Primary caregivers of 344 children (8 to 16 years, M = 12.28) completed the Computerized Diagnostic Interview Schedule for Children- IV ( C- DISC-4.0) and the Child Behavior Checklist ( CBCL). Subjects comprised 4 groups: AE with ADHD ( AE+, n = 85) and without ADHD ( AE−, n = 52), and nonexposed with ADHD ( ADHD, n = 74) and without ADHD ( CON, n = 133). The frequency of specific psychiatric disorders, number of psychiatric disorders (comorbidity), and CBCL behavioral scores were examined using chi-square and analysis of covariance techniques. Results Clinical groups had greater frequency of all psychiatric disorders, except for anxiety, where the AE- and CON groups did not differ. There was a combined effect of AE and ADHD on conduct disorder. For comorbidity, children with ADHD had increased psychiatric disorders regardless of AE, which did not have an independent effect on comorbidity. For CBCL scores, there were significant main effects of AE and ADHD on all scores and significant AE × ADHD interactions for Withdrawn/ Depressed, Somatic Complaints, Attention, and all Summary scores. There was a combined effect of AE and ADHD on Externalizing, Total Problems, and Attention Problems. Conclusions Findings indicate that ADHD diagnosis elevates children's risk of psychiatric diagnoses, regardless of AE, but suggest an exacerbated relation between AE and ADHD on conduct disorder and externalizing behavioral problems in children. Findings affirm a poorer behavioral prognosis for alcohol-exposed children with ADHD and suggest that more than 1 neurobehavioral profile may exist for individuals with AE. [ABSTRACT FROM AUTHOR]

Background Children with heavy prenatal alcohol exposure often meet criteria for attention-deficit/hyperactivity disorder ( ADHD). ADHD research has examined subtype differences in symptomatology, including sluggish cognitive tempo ( SCT). This construct is defined by behavioral symptoms including hypoactivity and daydreaming and has been linked to increased internalizing behaviors. The current study examined whether similar findings are displayed in children with prenatal alcohol exposure. Methods As part of a multisite study, caregivers of 272 children (8 to 16 years) completed the SCT Scale and Child Behavior Checklist ( CBCL). Four groups were included: alcohol-exposed children with ADHD ( ALC+; n = 75), alcohol-exposed children without ADHD ( ALC−; n = 35), nonexposed children with ADHD ( ADHD; n = 60), and nonexposed children without ADHD ( CON; n = 102). SCT and CBCL scores were analyzed using 2 (exposure) × 2 ( ADHD) analyses of variance. Pearson's correlations measured the relationships between SCT, CBCL, and Full Scale IQ ( FSIQ). Discriminant function analysis examined whether SCT items could accurately classify groups. Results Analyses revealed significant main effects of exposure and ADHD on SCT and internalizing and externalizing scores and significant interaction effects on SCT and internalizing scores. SCT significantly correlated with internalizing, externalizing, and attention ratings in all groups and with FSIQ in ALC+. Discriminant function analysis indicated that specific SCT items could distinguish ALC− from CON. Conclusions Alcohol-exposed children exhibited elevated SCT scores. Elevations were related to increased parent ratings of internalizing and externalizing behaviors and attention. These findings are observed in alcohol-exposed children regardless of ADHD symptoms and specific SCT items proved useful in distinguishing exposed children, suggesting clinical utility for this measure in further defining the neurobehavioral profile related to prenatal alcohol exposure. [ABSTRACT FROM AUTHOR]

Background Prenatal exposure to ethanol ( Et OH) elicits a range of neuro-developmental abnormalities, microcephaly to behavioral deficits. Impaired protein synthesis has been connected to pathogenesis of Et OH-induced brain damage and abnormal neuron development. However, mechanisms underlying these impairments of protein synthesis are not known. In this study, we illustrate the effects of Et OH on programmed cell death protein 4 ( PDCD4), a tumor and translation repressor. Methods Primary cortical neurons ( PCNs) were treated with 2.5 and 4 mg/ml Et OH for different time points (4 to 24 hours), and PDCD4 expression was detected by Western blotting. Protein synthesis was determined using [35S] methionine incorporation assay. Methyl cap pull-down assay was performed to establish the effect of Et OH on association of eukaryotic initiation factor 4A (eIF4A) with capped mRNA. Luciferase assay was performed to determine the in vivo translation. A 2-day acute 5-dose binge model with Et OH (4 g/kg body wt, 25% v/v) was performed in Sprague- Dawley rats at 12-hour intervals and analyzed for PDCD4, eIF4 A, and eIF4 A-methyl cap association. Results Et OH increased PDCD4 expression in a time- and dose-dependent manner in PCNs, which inhibited the association of eIF4 A with methyl cap. Et OH and ectopic PDCD4 expression suppressed in vivo translation in PCNs and RNAi targeting of PDCD4 blocked the inhibitory effect of Et OH on protein synthesis. In utero exposure of pregnant rats to Et OH resulted in a significant increase in PDCD4 in fetal cerebral cortex along with the inhibition of methyl cap-associated eIF4 A, compared with isocaloric controls. Increased PDCD4 also occurred in pooled fractions of remaining brain regions. Conclusions Our data, for the first time, illustrate that PDCD4 mediates inhibitory effects of Et OH on protein synthesis in PCNs and developing brain. [ABSTRACT FROM AUTHOR]

Background Several lines of evidence link cannabinoid ( CB) type 1 ( CB1) receptor-mediated endogenous CB (e CB) signaling to the etiology of alcohol dependence ( AD). However, to date, only peripheral measures of e CB function have been collected in living humans with AD and no human in vivo data on the potentially critical role of the brain CB1 receptor in AD have been published. This is an important gap in the literature, because recent therapeutic developments suggest that these receptors could be targeted for the treatment for AD. Methods Medication-free participants were scanned during early abstinence 4 weeks after their last drink. Using positron emission tomography ( PET) with a high-resolution research tomograph and the CB1 receptor selective radiotracer [11 C] OMAR, we determined [11 C] OMAR volume of distribution ( VT) values, a measure of CB1 receptor density, in a priori selected brain regions in men with AD ( n = 8, age 37.4 ± 7.9 years; 5 smokers) and healthy control ( HC) men ( n = 8, age 32.5 ± 6.9 years; all nonsmokers). PET images reconstructed using the MOLAR algorithm with hardware motion correction were rigidly aligned to the subject-specific magnetic resonance ( MR) image, which in turn was warped to an MR template. Time-activity curves ( TACs) were extracted from the dynamic PET data using a priori selected regions of interest delineated in the MR template space. Results In AD relative to HC, [11 C] OMAR VT values were elevated by approximately 20% ( p = 0.023) in a circuit, including the amygdala, hippocampus, putamen, insula, anterior and posterior cingulate cortices, and orbitofrontal cortex. Age, body mass index, or smoking status did not influence the outcome. Conclusions These findings agree with preclinical evidence and provide the first, albeit still preliminary in vivo evidence suggesting a role for brain CB1 receptors in AD. The current study design does not answer the important question of whether elevated CB1 receptors are a preexisting vulnerability factor for AD or whether elevations develop as a consequence of AD. [ABSTRACT FROM AUTHOR]

Background Many children with heavy exposure to alcohol in utero display characteristic alterations in brain size and structure. However, the long-term effects of low-to-moderate alcohol exposure on these outcomes are unknown. Methods Using voxel-based morphometry and region-of-interest analyses, we examined the influence of lower doses of alcohol on gray and white matter composition in a prospectively recruited, homogeneous, well-characterized cohort of alcohol-exposed ( n = 11, age 19.5 ± 0.3 years) and control ( n = 9, age 19.6 ± 0.5 years) young adults. A large proportion of the exposed individuals were born to mothers whose alcohol consumption during pregnancy was in the low-to-moderate range. Results There were no differences in total brain volume or total gray or white matter volume between the exposed and control groups. However, gray matter volume was reduced in alcohol-exposed individuals in several areas previously reported to be affected by high levels of exposure, including the left cingulate gyrus, bilateral middle frontal gyri, right middle temporal gyrus, and right caudate nucleus. Notably, this gray matter loss was dose dependent, with higher exposure producing more substantial losses. Conclusions These results indicate that even at low doses, alcohol exposure during pregnancy impacts brain development and that these effects persist into young adulthood. [ABSTRACT FROM AUTHOR]

Background Ethanol (EtOH) exposure during gestation and lactation induces an oxidative stress in offspring. In kidney, the oxidative damage is the primary pathway to alcohol-induced injury. In this study, we have demonstrated that a diet supplemented with selenium (Se) (0.5 ppm) or with Se (0.5 ppm) + folic acid (8 ppm) administered to EtOH-exposed (20% v/v) dams during gestation and lactation prevents the oxidative EtOH-provoked effects in their offspring's kidneys. Methods All the studies were performed on 21-day-old pups. Serum, urine, and kidney Se levels were assessed by graphite-furnace atomic absorption spectrometry. Se and creatinine clearance, antioxidant enzyme activities, and lipid and protein peroxidation were determined by a spectrophotometric method in kidney. Results Dietary supplementation treatments used could not improve the glomerular filtration function altered by EtOH exposure during gestation and lactation; however, they did improve renal Se deposits, renal development, and renal protein content while decreasing lipid and protein oxidation and modifying antioxidant enzymes' activity. Conclusions Se or Se + folic acid supplementations improve renal development and protein content and modify antioxidant enzymes' activity, decreasing lipid and protein oxidation after EtOH exposure. In this context, a double-supplemented diet appears to reduce protein peroxidation more efficiently than the Se-only-supplemented one, probably via superoxide dismutase and catalase. [ABSTRACT FROM AUTHOR]

Background Perhaps the most difficult thing to ascertain concerning the behavior of another animal is its motivation. The motivation underlying the preference of Drosophila melanogaster for ethanol ( EtOH)-rich food has long been ascribed to its value as a food. A recently introduced idea is that, as in humans, the pharmacological effects of EtOH also motivate the fly to choose EtOH-rich food over nonalcoholic food. Methods Flies are given a choice between pipets that contain liquid food and liquid food supplemented with EtOH. In some experiments, carbohydrates are added to the non- EtOH-containing food to balance the calories for EtOH. Results We confirm that D. melanogaster indeed prefer food that is supplemented with EtOH. However, if the alternative food choice is isocaloric, D. melanogaster usually do not show any preference for a 10% EtOH solution. Even after EtOH preference has been established, it can be completely reversed if the alternative food is calorically supplemented. This occurs even when the carbohydrate solution used to balance calories is not gustatorily attractive. Furthermore, if the alternative food contains more calories than the EtOH food, the flies will prefer the non- EtOH food. We go on to show that during the preference assay that EtOH in the fly does not exceed 4 mM, which in mammals is a nonintoxicating dose. Conclusions We conclude that preference for EtOH in this assay arises not from the pharmacological effects of EtOH but rather because of its nutritive value. [ABSTRACT FROM AUTHOR]

Background Adolescent alcohol abuse remains a serious public health concern, with nearly a third of high school seniors reporting heavy drinking in the previous month. Methods Using the high ethanol-consuming C57 BL/6 J mouse strain, we examined the effects of ethanol (3.75 g/kg, IP, daily for 45 days) on body weight and brain region mass (cerebral cortex, cerebellum, corpus callosum) during peri-adolescence (postnatal day [P]25 to 70) or adulthood ( P180 to 225) of both males and females. Results In control peri-adolescent animals, body weight gain was greater in males compared with females. In the peri-adolescent exposure group, ethanol significantly reduced body weight gain to a similar extent in both male and female mice (82 and 84% of controls, respectively). In adult animals, body weight gain was much less than that of the peri-adolescent mice, with ethanol having a small but significant effect in males but not females. Between the control peri-adolescent and adult cohorts (measurements taken at P70 and 225, respectively), there were no significant differences in the mass of the cerebral cortex or the cerebellum from either male or female mice, although the rostro-caudal length of the corpus callosum increased slightly but significantly (6.1%) between these time points. Conclusions Ethanol treatment significantly reduced the mass of the cerebral cortex in peri-adolescent (−3.1%), but not adult, treated mice. By contrast, ethanol significantly reduced the length of the corpus callosum in adult (−5.4%), but not peri-adolescent, treated mice. Future studies at the histological level may yield additional details concerning ethanol and the peri-adolescent brain. [ABSTRACT FROM AUTHOR]

Background The identification of individuals exposed prenatally to alcohol can be challenging, with only those having the characteristic pattern of facial features, central nervous system abnormality, and growth retardation receiving a clinical diagnosis of fetal alcohol syndrome ( FAS). Methods Seventeen anthropometric measurements were obtained at 5 and 9 years from 125 Cape Town, South African children, studied since birth. The children were divided into 3 groups: FAS or partial FAS ( PFAS), heavily exposed nonsyndromal ( HE), and non-alcohol-exposed controls ( C). Anthropometric measurements were evaluated for mean group differences. Logistic regression models were used to identify the subset of anthropometric measures that best predicted group membership. Anthropometric measurements were examined at the 2 ages in relation to prenatal alcohol exposure obtained prospectively from the mothers during pregnancy. Correlation of these facial measurements with key neurobehavioral outcomes including Wechsler Intelligence Scales for Children-IV IQ and eyeblink conditioning was used to assess their utility as indicators of alcohol-related central nervous system impairment. Results Significant group differences were found for the majority of the anthropometric measures, with means of these measures smaller in the FAS/ PFAS compared with HE or C. Upper facial widths, ear length, lower facial depth, and eye widths were consistent predictors distinguishing those exposed to alcohol from those who were not. Using longitudinal data, unique measures were identified that predicted facial anomalies at one age but not the other, suggesting the face changes as the individual matures. And 41% of the FAS/ PFAS group met criteria for microtia at both ages. Three of the predictive anthropometric measures were negatively related to measures of prenatal alcohol consumption, and all were positively related to at least 1 neurobehavioral outcome. Conclusions The analysis of longitudinal data identified a common set of predictors, as well as some that are unique at each age. Prenatal alcohol exposure appears to have its primary effect on brain growth, reflected by smaller forehead widths, and may suppress neural crest migration to the branchial arches, reflected by deficits in ear length and mandibular dimensions. These results may improve diagnostic resolution and enhance our understanding of the relation between the face and the neuropsychological deficits that occur. [ABSTRACT FROM AUTHOR]

Background Prenatal exposure to alcohol often results in disruption to discrete cognitive and behavioral domains, including executive function ( EF) and adaptive functioning. In the current study, the relation between these 2 domains was examined in children with histories of heavy prenatal alcohol exposure, nonexposed children with a diagnosis of attention-deficit/hyperactivity disorder ( ADHD), and typically developing controls. Methods As part of a multisite study, 3 groups of children (8 to 18 years, M = 12.10) were tested: children with histories of heavy prenatal alcohol exposure ( ALC, n = 142), nonexposed children with ADHD ( ADHD, n = 82), and typically developing controls ( CON, n = 133) who did not have ADHD or a history of prenatal alcohol exposure. Children completed subtests of the Delis- Kaplan Executive Function System ( D- KEFS), and their primary caregivers completed the Vineland Adaptive Behavior Scales- II. Data were analyzed using regression analyses. Results Analyses showed that EF measures were predictive of adaptive abilities, and significant interactions between D- KEFS measures and group were present. For the ADHD group, the relation between adaptive abilities and EF was more general, with 3 of the 4 EF measures showing a significant relation with adaptive score. In contrast, for the ALC group, this relation was specific to the nonverbal EF measures. In the CON group, performance on EF tasks did not predict adaptive scores over the influence of age. Conclusions These results support prior research in ADHD, suggesting that EF deficits are predictive of poorer adaptive behavior and extend this finding to include children with heavy prenatal exposure to alcohol. However, the relation between EF and adaptive ability differed by group, suggesting unique patterns of abilities in these children. These results provide enhanced understanding of adaptive deficits in these populations, as well as demonstrate the ecological validity of laboratory measures of EF. [ABSTRACT FROM AUTHOR]

Background: Hyperreactivity and impaired sensory gating of the acoustic startle response in alcohol dependence has been suggested to reflect a residual effect of previous detoxifications, increasing the severity of subsequent withdrawal episodes. Previous studies on the acoustic startle only included early-onset alcohol-dependent patients. The observed abnormalities may therefore also be specific for this subtype of alcohol dependence. We investigated the acoustic startle response in alcohol-dependent patients and healthy controls and hypothesized that (i) early-onset alcohol-dependent patients show increased acoustic startle responses compared with late-onset alcohol-dependent patients and healthy controls, and (ii) the duration of alcohol dependence or the number of prior detoxifications would not explain the differences in the acoustic startle between early- and late-onset alcohol dependence. Methods: The acoustic startle reflex was assessed in detoxified, male alcohol-dependent patients ( N = 83) and age-matched healthy male controls ( N = 86). Reflex eye blink responses to an auditory startle stimulus were measured by means of electromyographic recordings over the right orbicularis oculi muscle. Reflex amplitudes and levels of prepulse inhibition ( PPI) were analyzed. Results: There was no association between number of previous withdrawals and the startle response or PPI. Early-onset alcohol-dependent patients showed higher acoustic startle amplitudes compared with late-onset alcohol-dependent patients and healthy controls [75/105 dB: F(2, 166) = 9.2, p < 0.001; 85/105 dB: F(2, 166) = 12.1, p < 0.001; 95 dB: F(2, 166) = 8.2, p < 0.001; 105 dB: F(2, 166) = 9.7, p < 0.001], and there were no differences in PPI. Conclusions: Increased acoustic startle response in detoxified early-onset alcohol-dependent patients may reflect a trait marker specifically involved in early-onset alcohol dependence. The findings of the current study do not support the hypothesis that the increased startle response is a residual state marker. [ABSTRACT FROM AUTHOR]

Background: Tight junctions form a continuous belt-like structure between cells and act to regulate paracellular signaling. Protein kinase C (PKC) has been shown to regulate tight junction assembly and disassembly and is activated by alcohol. Previous research has shown that alcohol increases the permeability of tight junctions in lung alveolar cells. However, little is known about alcohol's effect on tight junctions in epithelium of the conducting airways. We hypothesized that long-term alcohol exposure reduces zonula occluden-1 (ZO-1) and claudin-1 localization at the cell membrane and increases permeability through a PKC-dependent mechanism. Methods: To test this hypothesis, we exposed normal human bronchial epithelial (NHBE) cells, cells from a human bronchial epithelial transformed cell line (Beas-2B), and Beas-2B expressing a PKCα dominant negative (DN) to alcohol (20, 50, and 100 mM) for up to 48 hours. Immunofluorescence was used to assess changes in ZO-1, claudin-1, claudin-5, and claudin-7 localization. Electric cell-substrate impedance sensing was used to measure the permeability of tight junctions between monolayers of NHBE, Beas-2B, and DN cells. Results: Alcohol increased tight junction permeability in a concentration-dependent manner and decreased ZO-1, claudin-1, claudin-5, and claudin-7 localization at the cell membrane. To determine a possible signaling mechanism, we measured the activity of PKC isoforms (alpha, delta, epsilon, and zeta). PKCα activity significantly increased in Beas-2B cells from 1 to 6 hours of 100 mM alcohol exposure, while PKCζ activity significantly decreased at 1 hour and increased at 3 hours. Inhibiting PKCα with Gö-6976 prevented the alcohol-induced protein changes in both ZO-1 and claudin-1 at the cell membrane. PKCα DN Beas-2B cells were resistant to alcohol-induced protein alterations. Conclusions: These results suggest that alcohol disrupts ZO-1, claudin-1, claudin-5, and claudin-7 through the activation of PKCα, leading to an alcohol-induced 'leakiness' in bronchial epithelial cells. Such alcohol-induced airway-leak state likely contributes to the impaired airway host defenses associated with acute and chronic alcohol ingestion. [ABSTRACT FROM AUTHOR]

Background: It has been estimated that approximately 12% of women consume alcohol at some time during their pregnancy, and as many as 5% of children born in the United States are impacted by prenatal alcohol exposure (PAE). The range of physical, behavioral, emotional, and social dysfunctions that are associated with PAE are collectively termed fetal alcohol spectrum disorder (FASD). Methods: Using a saccharin-sweetened ethanol solution, we developed a limited access model of PAE. C57BL/6J mice were provided access to a solution of either 10% (w/v) ethanol and 0.066% (w/v) saccharin or 0.066% (w/v) saccharin (control) for 4 h/d. After establishing consistent drinking, mice were mated and continued drinking during gestation. Following parturition, solutions were decreased to 0% in a stepwise fashion over a period of 6 days. Characterization of the model included measurements of maternal consumption patterns, blood ethanol levels, litter size, pup weight, maternal care, and the effects of PAE on fear-conditioned and spatial learning, and locomotor activity. Results: Mothers had mean daily ethanol intake of 7.17 ± 0.17 g ethanol/kg body weight per day, with average blood ethanol concentrations of 68.5 ± 9.2 mg/dl after 2 hours of drinking and 88.3 ± 11.5 mg/dl after 4 hours of drinking. Food and water consumption, maternal weight gain, litter size, pup weight, pup retrieval times, and time on nest did not differ between the alcohol-exposed and control animals. Compared with control offspring, mice that were exposed to ethanol prenatally displayed no difference in spontaneous locomotor activity but demonstrated learning deficits in 3 hippocampal-dependent tasks: delay fear conditioning, trace fear conditioning, and the delay nonmatch to place radial-arm maze task. Conclusions: These results indicate that this model appropriately mimics the human condition of PAE and will be a useful tool in studying the learning deficits seen in FASD. [ABSTRACT FROM AUTHOR]

Background: Brief interventions have the potential to reduce heavy drinking in young adults who present to the emergency department (ED), but require time and resources rarely available. Text-messaging (TM) may provide an effective way to collect drinking data from young adults after ED discharge as well as to provide immediate feedback and ongoing support for behavior change. The feasibility of screening young adults in the ED, recruiting them for a TM-based interventional trial, collecting weekly drinking data through TM, and the variance in drinking outcomes remains unknown. Methods: Young adults in 3 urban EDs ( n = 45; aged 18 to 24 years, 54% women) identified as hazardous drinkers by the Alcohol Use Disorders Identification Test-Consumption score were randomly assigned to weekly TM-based feedback with goal setting (Intervention), weekly TM-based drinking assessments without feedback (Assessment), or control. Participants in the Intervention group who reported ≥5 (for men) and ≥4 (for women) maximum drinks during any one 24-hour period were asked whether they would set a goal to reduce their drinking the following week. We describe the interaction with TM and goal setting. We also describe the heavy drinking days (HDDs), drinks per drinking day (DPDD) using timeline follow-back procedure at baseline and 3 months. Results: We screened 109 young adults over 157 hours across 24 unique days and 52 (48%; 95% CI 38 to 50) screened positive for hazardous drinking. Of these, 45 (87%; 95% CI 74 to 94) met inclusion criteria, were enrolled and randomized, and 6 (13%; 95% CI 5 to 27) did not complete 3-month web-based follow-up; 88% (95% CI 84 to 91) of weekly TM-based drinking assessments were answered, with 77% (95% CI 58 to 90) of participants responding to all 12 weeks. Agreeing to set a goal was associated with a repeat HDD 36% (95% CI 17 to 55) of the time compared with 63% (95% CI 44 to 81) when not willing to set a goal. At 3 months, participants that were exposed to the TM-based intervention had 3.4 (SD 5.4) fewer HDDs in the last month and 2.1 (SD 1.5) fewer DPDD when compared to baseline. Conclusions: TM can be used to assess drinking in young adults and can deliver brief interventions to young adults discharged from the ED. TM-based interventions have the potential to reduce heavy drinking among young adults but larger studies are needed to establish efficacy. [ABSTRACT FROM AUTHOR]