bluuebunny/crossref_metadata_2025 huggingface dataset:
Ethanol‐Induced Up‐Regulation of Candidate Plasminogen Receptor Annexin II in Cultured Human Endothelial Cells
Authors: Tabengwa Edlue M. , Abou‐Agag Laila H. , Benza Raymond L. , Torres Jose A. , Aikens Michael L. , Booyse Francois M.
Published: April 2006

Introduction Epidemiological studies indicate that moderate alcohol consumption reduces the risk for coronary heart disease and that this cardioprotective benefit may be mediated, in part, by increased fibrinolysis. Endothelial cells (ECs) synthesize plasminogen activators, tissue‐type plasminogen activator (t‐PA), urokinase‐type plasminogen activator (u‐PA), receptors for plasminogen activators, and a receptor for plasminogen, annexin II (Ann‐II). These receptors localize and facilitate receptor‐bound plasminogen activator‐mediated conversion of receptor‐bound plasminogen to receptor‐bound plasmin on the EC surface, which results in the regulated expression of surface‐localized EC fibrinolytic activity. Ethanol is a systemic factor that affects these components, which increases EC fibrinolysis and hence reduces the risk for thrombosis, coronary heart disease, and myocardial infarction (MI).

Methods: This study was carried out to determine whether low ethanol (0.1% v/v) increased plasminogen receptor, Ann‐II antigen (western blot), messenger ribonucleic acid (mRNA) (reverse transcription polymerase chain reaction; RT‐PCR) expression, activity (ligand binding/Scatchard analysis), and hence fibrinolysis (plasmin generation) in cultured human ECs.

Results: Plasminogen receptor activity increased ∼2‐fold (2.5 vs. 5.6 × 106 sites/cell), as evidenced by increased 125I‐labeled Glu‐plasminogen ligand binding/Scatchard analysis. In addition, western blot analyses indicated an increase in Ann‐II antigen, and mRNA levels increased ∼2‐fold (RT‐PCR). This increase in Ann‐II expression was concomitant with ∼2‐ to 3‐fold sustained increase (∼24 hr) in surface‐localized EC fibrinolytic activity. Nuclear transcription run‐on assays showed an ∼5‐ to 6‐fold increase in new 32P‐labeled Ann‐II mRNA levels, compared with controls (no ethanol).

Conclusions: These results demonstrated that low ethanol increased Ann‐II antigen/mRNA levels and up‐regulated Ann‐II gene expression at the transcriptional level. The results further identify and define the contribution and role of the plasminogen receptor, Ann‐II, in the ethanol‐induced mechanism of increased EC fibrinolysis that may underlie and contribute, in part, to the cardioprotective benefit associated with moderate alcohol consumption.
Dissociation Between the Time Course of Ethanol and Extracellular Dopamine Concentrations in the Nucleus Accumbens After a Single Intraperitoneal Injection
Authors: Yim Hyeon Joo , Robinson Donita L. , White Martha L. , Jaworski Jason N. , Randall Patrick K. , Lancaster Francine E. , Gonzales Rueben A.
Published: April 2006

Background: Dopamine release in the nucleus accumbens has been linked to the reinforcing effects of ethanol, but the time course or relationship of this response to ethanol concentrations in the brain has not been studied.

Methods: Various doses of ethanol (0–2.0 g/kg) were administered intraperitoneally to male Sprague Dawley® rats, and dopamine and ethanol were simultaneously analyzed in dialysate samples from the nucleus accumbens. A separate study to compare the ethanol‐induced dopamine response in male and female rats was carried out by using a 1 g/kg intraperitoneal dose of ethanol.

Results: In male rats, 1 and 2 g/kg ethanol significantly increased dialysate dopamine by 40% over basal, whereas 0.25 and 0.5 g/kg ethanol produced a nonsignificant 20% increase. Dialysate ethanol concentrations exhibited a curvilinear decline after reaching peak levels for the lower doses but showed a linear decrease after 1 and 2 g/kg. There was a dissociation between the time courses of extracellular dopamine and ethanol after 1 and 2 g/kg ethanol treatment. The dopamine response returned to basal within 90 min, whereas the ethanol concentrations remained elevated. In a separate study that compared male and female rats, the ratio of the dopamine response over basal to the dialysate ethanol concentrations was significantly decreased at 60 min after an injection of 1 g/kg. However, there were no differences between males and females.

Conclusions: The dissociation between dopamine and ethanol levels may reflect the development of acute tolerance to ethanol‐induced dopamine release in the nucleus accumbens within the time course of a single acute injection. Given the strong links between dopamine and ethanol reinforcement, our findings may be relevant for understanding the time course of ethanol's reinforcing effects in vivo.
Regional Brain Metabolism During Alcohol Intoxication
Authors: Wang Gene‐Jack , Volkow Nora D. , Franceschi Dinko , Fowler Joanna S , Thanos Panayotis K. , Scherbaum Nobert , Pappas Naomi , Wong Christopher T. , Hitzemann Robert J. , Felder Christoph A.
Published: April 2006

Background: Ethanol has a broad range of actions on many neurotransmitter systems. The depressant actions of ethanol in the brain are related in part to facilitation of γ‐aminobutyric acid (GABA) neurotransmission via its interaction with the benzodiazepine/GABA receptor complex. The purpose of this study was to evaluate the effects of ethanol on regional brain metabolism in 10 healthy right‐handed men. The results were compared with those we previously published in a different group of 16 normal male subjects who received intravenous lorazepam, a benzodiazepine drug that also enhances GABA neutrotranmission.

Methods: The subjects were scanned with positron emission tomography and [F‐18] fluorodeoxyglucose twice: 40 min after the end of placebo (diet soda) or ethanol (0.75 g/kg) oral administration. Image data sets were analyzed by using both the region of interest and the statistical parametric mapping (SPM) approach. SPM was used to generate a difference image between baseline and ethanol, which we compared to the difference image between baseline and lorazepam (30 μg/kg).

Results: Ethanol significantly increased self‐reports of “high” (p≤ 0.0001), dizziness (p≤ 0.004), and intoxication (p≤ 0.0001). Ethanol significantly decreased whole brain (−25 ± 6%, p≤ 0.0001) and regional metabolism. Normalization of the regional measures by whole brain metabolism (relative measures) showed that ethanol decreased relative metabolic activity in occipital cortex (−4.9 ± 4.1%, p≤ 0.006), whereas it increased relative metabolic act in left temporal cortex (+3.5 ± 2.9%, p≤ 0.006) and left basal ganglia (+9 ± 6.3%, p≤ 0.0009). SPM analyses revealed the same pattern of responses as the relative measures, showing decreases in occipital cortex and increases in left temporal cortex. Comparison of the relative measures and the SPM analyses obtained with lorazepam data revealed a similar pattern of effects, with relative decreases in occipital cortex (−7.8 ± 4.8%) and relative increases in left temporal cortex (+3.8 ± 5.7%). Lorazepam, but not ethanol, also decreased thalamic metabolism (−11.2 ± 7.2%).

Conclusions: These results support similar though not identical mechanisms for the effects of alcohol and benzodiazepines on brain glucose metabolism. The fact that lorazepam, but not alcohol, reduced thalamic metabolism, an effect associated with sleepiness, could explain the higher sedative effects of lorazepam than of alcohol.
High Salivary Acetaldehyde After a Moderate Dose of Alcohol in ALDH2‐Deficient Subjects: Strong Evidence for the Local Carcinogenic Action of Acetaldehyde
Authors: Väkeväinen Satu , Tillonen Jyrki , Agarwal Dharam P. , Srivastava Nidhi , Salaspuro Mikko
Published: April 2006

Background: Due to a point mutation, aldehyde dehydrogenase‐2 (ALDH2) isoenzyme is deficient in 30% to 50% of Asians. Among Asian ALDH2‐deficient heavy drinkers, the risk for digestive tract cancers is markedly increased (odds ratio 3.4–54.2). The reason for this is unknown but could be due to the local carcinogenic action of acetaldehyde.

Methods: Salivary and blood acetaldehyde levels were determined in 20 healthy Asians after a moderate dose of alcohol (0.5 g/kg of body weight). Salivary acetaldehyde production capacity from ethanol in vitro was measured also. ALDH2 genotype of the Asians was determined from isolated leukocyte‐deoxyribonucleic acid by polymerase chain reaction/restriction fragment length polymorphism method. Acetaldehyde content of parotid gland saliva was measured in three ALDH2‐deficient Asians and three White subjects with normal ALDH2 after the same dose of ethanol.

Results: Seven of the Asians were heterozygous for the mutant ALDH2*2 allele (flushers). They had two to three times higher salivary acetaldehyde levels than the Asians (n= 13) with normal ALDH2 throughout the follow‐up period of 240 min (p < 0.001). Only in the flushers did the parotid gland contribute to salivary acetaldehyde production. The in vitro capacity of saliva to produce acetaldehyde from ethanol was equal in both groups. The flushers’ blood acetaldehyde levels were only one ninth of the levels in saliva.

Conclusions: By using this human “knockout model” for deficient acetaldehyde removal, we found that in addition to oral microflora, acetaldehyde in saliva may also originate from the oxidation of ethanol in the parotid gland. When combined with earlier epidemiological data, these results offer a strong evidence for the local carcinogenic action of acetaldehyde in humans.
Trajectories of Concurrent Substance Use Disorders: A Developmental, Typological Approach to Comorbidity
Authors: Jackson Kristina M. , Sher Kenneth J. , Wood Phillip K.
Published: April 2006

Background: Although alcohol and tobacco use disorders are highly comorbid, little is known regarding the combined course of these disorders.

Methods: The current study utilized latent class analysis to examine longitudinal patterns of alcohol–tobacco use disorder comorbidity. Participants were 449 young adults (baseline age, 18.5 years; 48% male; 51% with paternal history of alcoholism) assessed five times over 7 years.

Results: Five longitudinal types of alcohol or tobacco use disorder over time were identified: nondiagnosing; developmentally limited alcohol use disorder; chronic alcohol use disorder; chronic tobacco use disorder; and comorbid alcohol and tobacco use disorder. These typologies were distinguishable on the basis of family history of alcoholism status and sex. Etiologically important third variables (alcohol expectancies, behavioral undercontrol, childhood stressors) mediated the relation between family history and the latent classes.

Conclusions: Characterizations of alcohol use disorders typically fail to consider important sources of heterogeneity such as course or comorbidity. By simultaneously modeling developmental course and comorbidity with tobacco dependence, we were able to identify distinct trajectories of single and concurrent substance use disorders. Such multi‐substance trajectories represent meaningful subtypes that, although sharing substantial common influences, have unique etiologic correlates. Additionally, these subtypes might represent distinct groups from the perspective of intervention strategies.
Comments on Integrating Person‐Centered and Variable‐Centered Research on Problems Associated With the Use of Alcohol
Authors: Horn John L.
Published: April 2006

Abstract: For any sample of m different variables obtained on a sample of n different persons, there is an identity transformation between classifications of persons (types) that are defined with person‐centered methods and classifications of variables (factors) defined with variable‐centered methods: types are manifested in factors and factors are expressed in types. Both kinds of methods analyze the variability—the same variability—in a persons‐by‐variables data matrix. Person‐centered types can be transformed into variable‐centered factors. Thus, at a basic level there is a basis for integrating person‐centered and variable‐centered research.

But there are many different ways to implement person‐centered methods, just as there are many different ways to resolve variables into factors, and generally any model for analysis directed at identifying types will not be the complement of a model selected for analysis leading to factors. Thus, while the results from the two kinds of analysis can be related to one another, the results they produce in applications can be quite different. Also, in practice, one method is used before the other. For example, person‐centered methods might be used to form types, which are then studied with multiple‐group, variable‐centered methods to test hypotheses specifying invariance or differences of relationships across types. There are good reasons to think in terms of types as one contemplates analysis in terms of variables. But the reverse also is true.

In typological analysis, it must be assumed that types exist and that samples of subjects and indicator variables are drawn in ways that can reveal this. Different typologies indicated by person‐centered research are most concretely compared if the different studies use comparable sets of persons, indicator variables, and other variables that can indicate correlates.

Strictly speaking, none of these sets were comparable in the three substantive studies reviewed here. Nevertheless, at an abstract level it was possible to see that the results of the three studies agreed in indicating that there is a type of adolescent and young adult that, by and large, does not have—or at least does not report having—problems associated with the use of alcohol. This type is in the majority, accounting for approximately 60% of the youth sampled in the reviewed studies. The studies agree also in suggesting that types may emerge along a continuum of maladjustment characterized by increasing use of alcohol and other drugs, failures in school, problems at home, interpersonal difficulties, delinquency, and legal problems. Variable‐centered dynamic analyses might further describe phenomena of this kind.
Genetic Control of Acute Ethanol‐Induced Behaviors in Drosophila
Authors: Singh Carol M. , Heberlein Ulrike
Published: April 2006

Background: In most organisms in which acute ethanol exposure has been studied, it leads to similar changes in behavior. Generally, low ethanol doses activate the central nervous system, whereas high doses are sedative. Sensitivity to the acute intoxicating effects of ethanol is in part under genetic control in rodents and humans, and reduced sensitivity in humans predicts the development of alcoholism (Crabbe et al., 1994; Schuckit, 1994). We have established Drosophila melanogaster as a model organism to study the mechanisms that regulate acute sensitivity to ethanol.

Methods: We measured the effects of ethanol vapor on Drosophila locomotor behaviors by using three different assays. Horizontal locomotion was quantified in a locomotor chamber, turning behavior was assayed in narrow tubes, and ethanol‐induced loss of postural control was measured in an inebriometer. Mutants with altered sensitivity to the acute effects of ethanol were generated by treatment with ethyl methane sulfonate and isolated by selection in the inebriometer. We ascertained the effects of these mutations on ethanol pharmacokinetics by measuring ethanol levels in extracts of flies at various times during and after ethanol exposure.

Results: Among nearly 30,000 potentially mutant flies tested, we isolated 19 mutant strains with reduced and 4 strains with increased sensitivity to the acute effects of ethanol as measured in the inebriometer. Of these mutants, four showed changes in ethanol absorption. Two mutants, named barfly and tipsy to reflect their reduced and increased ethanol sensitivity in the inebriometer, respectively, were analyzed for locomotor behaviors. Both mutants exhibited ethanol‐induced hyperactivity that was indistinguishable from wild type. However, barfly and tipsy displayed reduced and increased sensitivity to the sedative effects of ethanol, respectively. Finally, both mutants showed an increased rate of ethanol‐induced turning behavior.

Conclusions: The effects of acute ethanol exposure on Drosophila locomotor behaviors are remarkably similar to those described for mammals. The analysis of mutants with altered sensitivity to ethanol revealed that the genetic pathways which regulate these responses are complex and that single genes can affect hyperactivity, turning, and sedation independently.
Inferior Colliculus Intracellular Response Abnormalities In Vitro Associated With Susceptibility to Ethanol Withdrawal Seizures
Authors: Evans M. Steven , Li Yang , Faingold Carl
Published: April 2006

Abstract: During ethanol withdrawal (ETX), rats become susceptible to audiogenic seizures in which the inferior colliculus (IC) is known to play a critical role. The present study examined changes in membrane properties that occurred in IC dorsal cortex (ICd) neurons in brain slices from rats after 4 days of three times daily intragastric ethanol, which is proposed to be an analog of binge drinking. Compared with neurons from control animals, ICd neurons during ETX had action potentials (APs) with lower thresholds, a greater incidence of spontaneous APs, a reduced degree of spike firing adaptation, and an increased incidence of anode‐break firing. With synaptic stimulation, epileptiform firing was seen in nearly 50% of ICd neurons during ETX but never was seen in normal ICd neurons except after perfusion of the γ‐aminobutyric acid type A (GABAA) antagonist bicuculline. Paired pulse responses of ICd neurons were also abnormal during ETX. Thus, in 75% of normal rats, paired synaptic stimuli inhibited the second response, but during ETX all neurons tested showed paired pulse facilitation. These aberrant membrane and synaptic properties provide direct evidence for the hyperexcitability of IC neurons during ETX. They may be due, in part, to changes in GABAergic and glutamatergic neurotransmission known to be produced during withdrawal after continued ethanol administration.
Enhanced Clinical Utility of γ‐CDT in a General Population
Authors: Sillanaukee Pekka , Massot Nuria , Jousilahti Pekka , Vartiainen Erkki , Poikolainen Kari , Olsson Ulf , Alho Hannu
Published: April 2006

Background: The use of a combination of markers to detect excessive alcohol consumption has been reported to provide better sensitivity in the diagnosis of alcohol abuse than single markers. However, the optimal combination of markers for the diagnosis of alcohol abuse has not yet been found. The aim of this study was to compare the diagnostic value of carbohydrate‐deficient transferrin (CDT) and γ‐glutamyltransferase (GGT) to discriminate among heavy drinkers (>280 g/week), moderate drinkers (105–280 g/week), and light drinkers (<105 g/week). Their mathematical combination, named γ‐CDT, which has been found to be a strong marker of alcohol abuse in a former study, was also evaluated.

Methods: The study was conducted in a group of 6962 subjects (3974 males and 2988 females), between the ages of 25 and 74 years, who participated in a large cross‐sectional risk factor survey carried out in five geographic areas in Finland. In each study area, an age‐ and gender‐stratified random sample was drawn from the general population. Sensitivity, specificity, positive and negative predictive values, and receiver operating characteristic curves were used to evaluate the performance of CDT, GGT, and γ‐CDT.

Results: For both sexes, the combined marker had the highest specificity (95%) and sensitivity in detecting heavy drinkers. In all cases, γ‐CDT had the highest area under ROC plots. Our results also showed that GGT and CDT have similar, and rather low, sensitivity but high specificity in a general population.

Conclusions: Compared with single markers, a significant improvement of sensitivity was obtained when the combination of both markers was used, especially in females.
Adverse Working Conditions and Alcohol Use in Men and Women
Authors: José B. San , van de Mheen H. , van Oers J. A. M. , Mackenbach J. P. , Garretsen H. F. L.
Published: April 2006

Objective This study examined the association between adverse working conditions and abstinence and heavy drinking.

Methods: The study was a cross‐sectional study within the framework of a general population survey conducted in Eindhoven, The Netherlands (N = 7533). Working conditions were classified into four domains: hazardous physical working conditions, demands at work, level of control over one's job, and support from coworkers and supervisors. Abstainers were compared with drinkers; within drinkers, heavy drinkers were compared with light‐moderate drinkers, and those who reported binge drinking were compared with those who did not report binge drinking.

Results: Respondents who reported adverse working conditions were as likely to be abstainers as they were to be drinkers. Within drinkers, males and females who reported high hazardous physical working conditions were more likely to be heavy drinkers than to be light‐moderate drinkers (light‐moderate is not just an amount, but a combination of amount and frequency) and to report binge drinking (males only). Respondents who reported high demands were also more likely to be heavy drinkers than to be light‐moderate drinkers.

Conclusions: Stressful circumstances, such as adverse working conditions, were associated with high levels of alcohol intake among drinking men and women.
Increased Serum Tissue Polypeptide Specific Antigen (TPS) in Alcoholics: A Possible Marker of Alcoholic Hepatitis
Authors: González‐Quintela A. , Mella C. , Pérez L. F. , Abdulkader I. , Caparrini A. M. , Lojo S.
Published: April 2006

Background: Serum tissue polypeptide specific antigen (TPS) is widely used as a tumor proliferation marker. There is some evidence of an increase in serum TPS in benign liver diseases. The aim of the study was to evaluate serum TPS levels in alcoholics.

Methods: Seventy‐seven alcoholics (64 men and 13 women) admitted to the hospital with ethanol withdrawal syndrome entered the study. Twenty‐three patients were biopsied (12 of them had alcoholic hepatitis and 11 steatosis or fibrosteatosis). Serum TPS was determined by enzyme immunoassay in all cases. Results were compared with those of 24 healthy controls.

Results: Serum TPS levels were significantly increased in alcoholic patients compared with controls (median 365 units/liter and range 41–6400 units/liter versus median 79 units/liter and range 19–235 units/liter, respectively, p < 0.0001). Seventeen alcoholics (22%) had a TPS value 10 times higher than the upper normal threshold level (≥1000 units/liter). Among alcoholics, serum TPS levels were higher in patients with alcoholic hepatitis than in those with steatosis or fibrosteatosis (median 1486 units/liter and range 176‐5023 units/liter versus median 106 units/liter and range 41–221 units/liter, respectively, p= 0.0001), offering a better discriminant value for the diagnosis of alcoholic hepatitis than usual liver function parameters. Serum TPS values showed significant correlation with liver cell necrosis and Mallory's hyaline degeneration. TPS values decreased after alcohol abstinence during hospital admission.

Conclusions: Serum TPS is frequently increased in alcoholics and may be a marker of alcoholic hepatitis. Specificity of this molecule as a tumor marker is limited in alcoholics.
Ethanol in Human Brain by Magnetic Resonance Spectroscopy: Correlation With Blood and Breath Levels, Relaxation, and Magnetization Transfer
Authors: Fein George , Meyerhoff Dieter J.
Published: April 2006

Background: Proton magnetic resonance spectroscopy (1H MRS) allows measurement of alcohol in the human brain after alcohol consumption. However, the quantity of alcohol that can be detected in the brain by 1H MRS pulse sequences has been controversial, with values ranging from about 24% to 94% of the temporally concordant blood alcohol concentrations. The quantitation of brain alcohol is critically affected by the kinetics of alcohol uptake and elimination, by the relaxation times of the protons that give rise to the brain alcohol signal, and by the specifics of both pulse sequence timing and radio frequency pulse applications.

Methods: We investigated these factors in 20 light‐drinking subjects after oral administration of approximately 0.85 g/kg body weight of alcohol by localized 1H MRS and measurements of blood and breath alcohol concentrations obtained at the same time. Specifically, we measured transverse and longitudinal relaxation times of brain alcohol and its signal saturation on application of on‐ or off‐resonance radio frequency pulses. All 1H MRS measurements were performed at a time after brain and blood alcohol concentrations had equilibrated.

Results: 1H MRS measures of brain alcohol were correlated highly with both breath and blood alcohol concentrations after equilibration in brain tissue. The measured 1H MRS relaxation times of brain alcohol were shorter than given in previous reports that were limited by smaller subject numbers, improper use of 1H MRS methods, and estimates rather than measurements. The brain alcohol signal decreased by about 30% on application of on‐ or off‐resonance saturation pulses.

Conclusions: 1H MRS allows direct measurement of brain alcohol, formerly only possible indirectly through inferences from breath alcohol levels. Quantitation of brain alcohol levels need to take into account measured relaxation times and alcohol signal attenuation due to presence and timing of standard radio frequency MRS pulses. Saturation experiments give evidence for the existence of more than one compartment of brain alcohol characterized by different molecular environments. They suggest that a fraction of brain alcohol is invisible to 1H MRS.
Ethanol Decreases Zinc Transfer to the Fetus in Normal but Not Metallothionein‐Null Mice
Authors: Carey Luke C. , Coyle Peter , Philcox Jeffrey C. , Rofe Allan M.
Published: April 2006

Background: Ethanol causes significant teratogenicity in normal (MT+/+) but not metallothionein‐null (MT−/−) fetuses. Impaired maternal fetal zinc (Zn) transfer is indicated, because ethanol significantly reduces plasma Zn concentrations in MT+/+ dams while increasing concentrations in MT−/− dams. In this study we examined maternal‐fetal Zn homeostasis in response to ethanol in MT+/+ and MT−/− mice and the origins of the increase in plasma Zn in MT−/− mice.

Methods and Results: Mice were treated with saline or ethanol (0.015 ml/g intraperitoneally at 0 and 4 hr) on day 12 of gestation. An additional subcutaneous injection of 65Zn tracer was administered after the second ethanol injection before mice were killed 3 hr later. Maternal liver MT levels were not different between ethanol and saline MT+/+ mice. Both liver Zn and 65Zn levels were higher in MT+/+ mice. Plasma Zn concentrations were higher in MT−/− mice, with MT−/− ethanol‐treated mice having levels greater than those of MT−/− saline‐treated controls. MT+/+ ethanol‐treated fetuses exhibited lower 65Zn transfer and whole Zn concentrations compared with MT+/+ and MT−/− saline and MT−/− ethanol fetuses. So we could examine changes in plasma Zn after ethanol treatment, MT+/+ and MT−/− mice were injected with 65Zn 3 days before they received ethanol treatment. Muscle and skin showed a decrease in 65Zn retention in both genotypes over 3 hr. There was a trend toward greater 65Zn release from skin and muscle at an earlier time in MT−/− mice: 24% vs. 2% decrease (MT−/− vs. MT+/+) for muscle and 28% vs. 15% decrease (MT−/− vs. MT+/+) for skin at 2 hr.

Conclusions: The results show (a) that ethanol interferes with the transfer of Zn to the fetus, and that this is MT dependent, and (b) that the increase in plasma Zn seen in MT−/− mice after ethanol administration is a result of Zn release from the skin and muscle, in the absence of hepatic Zn sequestration.
Treatment of Older Women With Alcohol Problems: Meeting the Challenge for a Special Population
Authors: Blow Frederic C.
Published: April 2006

As a larger proportion of the U.S. population reaches late life, there are new challenges to providing quality health care services for this group. Record numbers of adults over 60 are seeking health care for acute and chronic conditions. Older women represent the largest single group of health care users in this country. Twelve percent of older women regularly drink in excess of recommended guidelines (no more than one drink per day or seven drinks per week) and can be considered at‐risk drinkers. Problems related to alcohol use and misuse can seriously affect many of the health concerns common among older women, including chronic illnesses and depression. Older women have specific risks and vulnerabilities to alcohol use, which include a swifter progression to alcohol‐related illness. However, women in later life who have alcohol problems are underscreened and underdiagnosed, have significant barriers in accessing health care, and respond differentially to standard specialized treatment protocols. To date, research on these topics has been limited. Furthermore, there is a paucity of research focused on treatment outcomes for elderly adults with alcohol problems, with almost no emphasis on women. This paper presents the state of knowledge about alcohol health services for older women and provides recommendations for necessary future health services research on this vulnerable population.
Barriers to and Need for Alcohol Services for Women in Rural Populations
Authors: Booth Brenda M. , McLaughlin Yvonne S.
Published: April 2006

Background: This article reviews and summarizes the research on alcohol problems and issues related to alcohol services for rural women.

Methods: We discuss the prevalence of alcohol problems, help‐seeking behavior and barriers to help‐seeking for rural women and suggest directions for future research for rural women with alcohol problems. We also address key methodological issues in measuring rurality that must be considered when designing research on rural women.

Results: Little is known about these topics, specifically for rural women, and much has to be currently inferred either from studies of psychiatric disorders in rural populations, from studies of urban or suburban women, or from general research about rural life.

Conclusions: Increased knowledge regarding specific issues for women with alcohol problems in rural areas, particularly about gender‐specific barriers to obtaining services and gender‐specific needs for particular services, will be beneficial for developing programs designed to meet the unique needs of this group of women.
Allelic Variation in the GABAA Receptor γ2 Subunit Is Associated With Genetic Susceptibility to Ethanol‐Induced Motor Incoordination and Hypothermia, Conditioned Taste Aversion, and Withdrawal in BXD/Ty Recombinant Inbred Mice
Authors: Hood Heather M. , Buck Kari J.
Published: April 2006

Background: Behavioral genomics has made dramatic progress toward mapping quantitative trait loci (QTLs) that contain genes responsible for phenotypic differences in a variety of behavioral responses to alcohol (ethanol). We previously identified a QTL on mouse Chromosome 11 that affects genetic predisposition to acute alcohol withdrawal. Among mice derived from the C57BL/6J (B6) and DBA/2J (D2) inbred strains, this QTL (Alcw3) accounts for 12% of the genetic variability in withdrawal liability. Candidate genes within this QTL encode the γ‐aminobutyric acid type A (GABAA) receptor γ2, α1, α6, and β2 subunits. We recently identified a coding sequence polymorphism between the B6 and D2 strains for the GABAA receptor γ2 subunit gene (Gabrg2). In this study, we expand our analysis to a panel of BXD strains derived from the B6 and D2 progenitor strains. These BXD strains provide 26 fixed recombinant genotypes that can be used to examine genetic correlations, for example, between a phenotype of interest and allelic variation in a candidate gene.

Methods: Gabrg2 was cloned and sequenced from the 26 BXD recombinant inbred strains. We analyzed genetic correlations between allelic variation in Gabrg2 and alcohol phenotypes previously measured in the BXD strain means.

Results: Allelic variation in Gabrg2 is correlated genetically with predisposition to acute alcohol withdrawal and may underlie the Alcw3 locus. In addition, Gabrg2 is associated with ethanol‐conditioned taste aversion, ethanol‐induced motor incoordination, and ethanol‐induced hypothermia. A trend is observed for chronic ethanol withdrawal, ethanol‐induced loss of righting reflex, and tolerance to ethanol‐induced hypothermia and ataxia.

Conclusions: Functionally relevant variation in Gabrg2, or a closely linked gene, is correlated genetically with some, but not all, behavioral responses to alcohol. The alcohol‐related phenotypes associated with Gabrg2 generally may be characterized as debilitating or motivationally negative.
Effects of Allopregnanolone on the EEG of Alcohol‐Preferring and Alcohol‐Nonpreferring Rats
Authors: Slawecki C. J. , Purdy R. H. , Li T‐K. , Walpole T. , Ehlers C. L.
Published: April 2006

Background: Alcohol preferring (P) and alcohol‐nonpreferring (NP) rats have been shown to have differing behavioral and electrophysiological responses to drugs that are positive modulators of the γ‐aminobutyric acid type A (GABA‐A) receptor complex, such as ethanol and benzodiazepines. The neuroactive steroid allopregnanolone is also a positive modulator of GABA‐A receptors; therefore, we hypothesized that P and NP rats would respond differently to intraperitoneally administered allopregnanolone.

Methods: Male P and NP rats were implanted with screw electrodes that overlay the frontal and parietal cortices and with a depth electrode aimed at the amygdala. Allopregnanolone (0.0–10.0 mg/kg ip) was administered 10 min before recording the EEG.

Results: Allopregnanolone increased high‐frequency power (8–32 Hz) in the cortex and amygdala of both P rats and NP rats. In addition, allopregnanolone increased the predominant frequency of the cortical EEG in the 8 to 16 Hz bandwidth, decreased the predominant frequency in the 32 to 50 Hz bandwidth, and increased EEG variability (16–50 Hz). The effects of allopregnanolone were qualitatively similar in P and NP rats. However, P rats were more sensitive to low doses of allopregnanolone in cortex, whereas NP rats responded to lower doses of allopregnanolone in the amygdala.

Conclusions: These data indicate that P and NP rats differ in their sensitivity to the EEG effects of allopregnanolone in the cortex and amygdala, which suggests that differences in GABAergic systems between P and NP rats may contribute to some of the differences observed in their behavioral repertoire.
Serum 6‐Beta‐Naltrexol Levels Are Related to Alcohol Responses in Heavy Drinkers
Authors: McCaul Mary E. , Wand Gary S. , Rohde Charles , Lee Shing M.
Published: April 2006

Background: There is strong evidence for the role of the endogenous opioid system in alcohol reinforcement and consumption; however, recent human laboratory studies and clinical trials have reported mixed effects of naltrexone (a nonselective opioid antagonist) on alcohol‐related behaviors. This paper reports a secondary data analysis of a human laboratory study that examines the relationship between serum levels of 6‐beta‐naltrexol, the major, biologically active metabolite of naltrexone, and subjective effects of alcohol.

Methods: The study used a within‐subjects design to examine the effects of naltrexone (0, 50, and 100 mg/day) on subjective responses to alcohol (none, moderate, and high dose) in heavy drinkers (n= 23). Each subject received three doses of naltrexone in random order; each naltrexone dose was administered over an 8 day period on an inpatient unit, with a 1 week outpatient washout between doses. After stabilization at each of the naltrexone doses, subjects participated in three alcohol challenge sessions (none, moderate, and high dose) in random order; thus, each subject participated in a total of nine alcohol administration sessions.

Results: Doubling the naltrexone dose (50 vs. 100 mg/day) doubled the mean serum 6‐beta‐naltrexol levels. At each naltrexone dose, there was a 4‐fold range in 6‐beta‐naltrexol levels across subjects. Before alcohol administration, higher 6‐beta‐naltrexol levels were associated with higher ratings of sedation. After high‐dose alcohol administration, higher 6‐beta‐naltrexol levels were associated with significantly lower ratings of liking and best effects.

Conclusions: These findings provide further evidence of the involvement of the opioid system in the modulation of alcohol effects and suggest that serum 6‐beta‐naltrexol concentrations may be important in predicting therapeutic response to naltrexone.
Objective Diagnosis of Alcohol Abuse: Compared Values of Carbohydrate‐Deficient Transferrin (CDT), γ‐Glutamyl Transferase (GGT), and Mean Corpuscular Volume (MCV)
Authors: Reynaud Michel , Schellenberg François , Loisequx‐Meunier Marie‐Nadia , Schwan Raymund , Maradeix Bertrand , Planche François , Gillet Claudine
Published: April 2006

Background: Alcohol abuse is roughly twice as common as alcohol dependence. Subjects with alcohol problems are usually diagnosed only when medical complications are present. Therefore, both doctors and patients need a method for early diagnosis of alcohol abuse.

Methods: The mean corpuscular volume, γ‐glutamyl transferase, and carbohydrate‐deficient transferrin in alcohol abusers, alcohol‐dependent patients, and “nonalcohol hospital” individuals were compared.

Results: For objective diagnosis of alcohol abuse, we found a sensitivity of 24%, a specificity of 96%, and a global predictive value of 63% for mean corpuscular volume; a sensitivity of 42%, a specificity of 76%, and a global predictive value of 61% for γ‐glutamyl transferase; and a sensitivity of 67%, a specificity of 97%, and a global predictive value of 84% for carbohydrate‐deficient transferrin.

Conclusions: Carbohydrate‐deficient transferrin proves to be the best marker of alcohol abuse. It allows objective detection so that therapeutic action can be started early, which is easier and more effective than in alcohol dependence.
Victim Impact Panels: Who Is Sentenced To Attend? Does Attendance Affect Recidivism of First‐Time DWI Offenders?
Authors: Baca Janet C’de , Lapham Sandra C. , Paine Susan , Skipper Betty J.
Published: April 2006

Background: Victim Impact Panels (VIPs) have been implemented widely in the United States by judges as a deterrent to drinking and driving, but there is little evidence of their utility in preventing recidivism.

Objectives The objectives of this study were to examine judges’ referral patterns to the VIPs among a multiethnic population of convicted first‐time driving while impaired (DWI) offenders and to compare 5‐year recidivism rates of those mandated and not mandated to attend the VIP.

Methods: Study participants included 5238 convicted first‐time DWI offenders who were referred to a screening program in Bernalillo County, New Mexico, and who completed a personal interview with a master's‐level counselor between April 1989 and October 1995. Logistic regression analysis was used to evaluate judges’ preferences in mandating offenders to attend a VIP. The percent of subjects reoffending in the 5 years following their referral for screening was calculated by standard life‐table analyses. Cox proportional hazards analysis was used to test the effects of known independent predictors for recidivism. Separate models were developed for the entire population, non‐Hispanic offenders, and Hispanic/Mexican national subgroups.

Results: Female judges who regularly adjudicated DWI offenders were more likely to refer offenders to a VIP. Judges were less likely to refer men and offenders with less than 12 years of education and an unknown arrest blood alcohol concentration (BAC), and of Hispanic/Mexican national or other race/ethnicity. Judges were more likely to refer unmarried offenders to a VIP. After controlling for multiple risk factors, referral to VIP was not a strong predictor of recidivism in Hispanic and non‐Hispanic ethnic groups, with 95% confidence limits ranging from 0.8 to 1.0, compared to those not referred.

Conclusions: Female judges were more likely than male judges to refer offenders to a VIP, and referral patterns varied by offender characteristics. The VIP referral did not increase rearrest rates but lowered them marginally to not at all. This study should be followed up with a randomized design to control for referral patterns and to further define the impact of mandating offenders to the VIP.
Chronic Ethanol Consumption Alters Recovery of Spontaneously Active Medial Septal/Diagonal Band of Broca Neurons From GABA‐Microiontophoresis
Authors: Matthews Douglas B. , Criswell Hugh E. , Grobin A. Chistina , Morrow A. Leslie
Published: April 2006

Background: Acute ethanol administration increases GABA‐mediated inhibition in a variety of cerebral cortical preparations. Furthermore, chronic ethanol administration blunts ethanol‐induced increases in GABA‐mediated inhibition and alters GABAA receptor subunit mRNA and peptide expression in the cerebral cortex. The sedative hypnotic effects of ethanol are believed to be modulated by GABA‐induced inhibition in medial septum/diagonal band of Broca (MS/DB) neurons, a brain region where acute ethanol administration increases GABA‐mediated inhibition of spontaneously active neurons. Chronic ethanol administration produces tolerance to the sedative effects of ethanol. However, it is unknown if chronic ethanol consumption produces alterations in GABA‐mediated inhibition in the MS/DB in a manner similar to that found in the cerebral cortex.

Methods: Animals either consumed ethanol chronically for 14 days via a liquid diet or were pair‐fed an equicaloric dextrose‐containing control diet. Spontaneously active MS/DB neurons were recorded using multibarrel glass micropipettes while the effect of GABA‐microiontophoresis was investigated. The total amount of GABA‐mediated inhibition at four ejection currents was analyzed, as was the recovery to spontaneous neural firing rates following GABA inhibition. In a separate group of animals, the medial septum was microdissected, and the relative expression of GABAA receptor α1 and α4 subunit peptide were analyzed via Western blot analysis.

Results: Chronic ethanol consumption altered recovery of spontaneous neural activity of MS/DB neurons following GABA‐microiontophoresis compared to premicroiontophoresis levels. Specifically, the recovery of spontaneous neural activity of MS/DB neurons recorded from animals that chronically consumed ethanol was slower following GABA‐microiontophoresis compared to neurons recorded from control animals. This effect was temporary and reversible. Furthermore, the alteration in recovery of spontaneous neural activity was not due to changes in the total amount of inhibition produced by GABA. Finally, there was no significant change in GABAA receptor α1 and α4 subunit peptide levels in the MS/DB.

Conclusions: Chronic ethanol consumption alters the frequency of spontaneous MS/DB neural activity following GABA microiontophoresis compared to premicroiontophoresis levels. These data suggest that the kinetics of GABAA receptors in the MS/DB are altered by chronic ethanol consumption independent of changes in the total amount of inhibition or alterations in GABAA receptor α1 and α4 subunit peptide expression.
Nursing Experiences With an Alcohol‐Intoxicated Rat Dam Counteract Appetitive Conditioned Responses Toward Alcohol
Authors: Pepino Marta Yanina , Spear Norman E. , Molina Juan Carlos
Published: April 2006

Background: Infant rats detect small amounts of alcohol (175 mg%) that are present in maternal milk whenever the dam is moderately intoxicated with alcohol. Interaction with an alcohol‐intoxicated mother during the first 2 weeks of life facilitates the preweanling's subsequent discrimination of alcohol's orosensory attributes and produces conditioned aversion to alcohol. The present study further analyzed the hedonic content of infantile alcohol memories established in the nursing context by testing the interaction between experiences with an alcohol‐intoxicated dam and learning procedures aimed at establishing an appetitive conditioned response toward alcohol.

Methods: Experiment 1 was to determine appropriate parameters to establish a reliable conditioned preference for alcohol in 16‐day‐old infants. For conditioning, intraorally infused sucrose solution (appetitive reinforcer) was paired with alcohol's orosensory cues derived from an acute state of alcohol intoxication (3 g/kg). Two control groups included an unpaired condition and a group given sucrose after water intubation. Infants then were evaluated in an alcohol intake test. Relative to control animals, a reliable conditioned preference for alcohol was registered in paired pups. In experiment 2, these conditioning procedures were applied to infant rats which, before conditioning, suckled from dams subjected to a 2.5 g/kg alcohol dose (intragastric) or from water‐treated females during postpartum days 3, 5, 7, 9, 11, and 13.

Results: Experiment 2 showed that maternal treatment significantly affected the establishment of conditioned preferences for alcohol. Whereas pups reared by control dams exhibited reliable appetitive conditioning to alcohol, infants raised by alcohol dams completely failed to develop appetitive conditioning.

Conclusions: The present results suggest that alcohol‐related memories generated via infantile interactions with an intoxicated dam counteract subsequent conditioning of alcohol ingestion. In conjunction with prior studies, it is concluded that alcohol‐related nursing experiences are capable of promoting alcohol memories with a negative hedonic content.