bluuebunny/crossref_metadata_2025 huggingface dataset:
Alcohol and Drug CAGE Screeners for Pregnant, Low‐Income Women: The California Perinatal Needs Assessment
Authors: Midanik Lorraine T. , Zahnd Elaine G. , Klein Dorie
Published: May 2006

The purpose of this study is to evaluate a revised CAGE and a new drug version of the CAGE as screeners for risk of heavier or problem alcohol and/or drug use among a population of low‐income, pregnant women and adolescents (n= 1147) recruited from 19 agencies in two California counties. Two versions of the CAGE were used in this analysis: (1) the 4‐item Alcohol CAGE, using the year before knowing about pregnancy as the timeframe (as opposed to lifetime prevalence), and (2) a newly developed 4‐item Drug CAGE using the same timeframe. The two instruments were assessed on sensitivity, specificity, and area under the receiver operating characteristic curve by using self‐reported periconceptional heavier or problem alcohol and drug use as the criteria for the 12 months before knowing about the pregnancy. The results indicate that, for the Alcohol CAGE, the cut‐point of 1 yielded the highest sensitivity, while maximizing sensitivity and specificity (receiver operating characteristic analysis) for this sample. For heavier drug use, the Drug CAGE had a high sensitivity rate with a cut‐point of 3. The Drug CAGE was not a useful screener for periconceptional lighter drug and marijuana use. These results demonstrate the utility of a revised version of the Alcohol CAGE that incorporates a more specific timeframe (the year before pregnancy) to screen pregnant, low‐income women for at‐risk heavier or problem alcohol use. The Drug CAGE, which uses the same timeframe, seems to be an effective tool for identifying pregnant, low‐income women at risk for heavier drug use only. More psychometric works needs to be done to refine the Drug CAGE for detecting at‐risk use of lighter drugs and marijuana.
Circulating Neutrophils and Liver Injury in Rat Models of Experimental Alcoholic Liver Disease
Authors: Ross Aron D. , Saldivia Victor , Oporto Betzavel , Carmichael Frederick J. , Cameron Ross , Israel Yedy
Published: May 2006

The present study examined the relationship between circulating neutrophils and liver injury in two widely used rat models of chronic ethanol administration. Hematological alterations, liver histopathology, and biochemical indices of liver injury were assessed in rats receiving chronic ethanol by oral liquid diet feeding (Lieber‐DeCarli method) or by continuous intragastric infusion (Tsukamoto‐French method). Oral administration of ethanol did not affect circulating neutrophil counts, but resulted in minimal liver injury characterized by elevated serum alanine aminotransferase (79%), increased liver mass (15%), and moderate steatosis. In contrast, rats receiving ethanol by continuous intragastric infusion showed an ∼ 2‐fold increase in circulating neutrophils, and a moderate degree of liver injury, indicated by a 169% elevation of serum alanine aminotransferase and a 2‐fold increase in liver mass. Liver biopsies from these rats showed severe steatosis and scattered necrotic hepatocytes, and some neutrophil infiltrates. To determine whether an increase in the number of circulating neutrophils could potentiate liver injury induced by oral ethanol feeding, rats were treated with human recombinant granulocyte colony‐stimulating factor at a dose of 100 μg/kg/day (sc) for 4 days. Treatment with granulocyte colony‐stimulating factor resulted in a 6‐ to 9‐fold increase in circulating neutrophil counts. Nevertheless, this change did not enhance the minor degree of ethanol‐induced liver injury in this model. Our results indicate that, whereas neutrophil leukocytosis accompanies more severe manifestations of ethanol hepatotoxicity in rats, this condition per se does not directly induce or exacerbate ethanol‐induced liver injury.
Clamping Breath Alcohol Concentration Reduces Experimental Variance: Application to the Study of Acute Tolerance to Alcohol and Alcohol Elimination Rate
Authors: O'Connor S. , Morzorati S. , Christian J. , Li T.‐K.
Published: May 2006

An oral loading dose was combined with intravenous infusion of 6% alcohol at rates adjusted on‐line to close the gap between measurements of breath alcohol concentration (B,AC) and a target of 50 mg%. The goal was to minimize the deviation from a prescribed course of B,AC over time. In a pilot study of 10 young men, subjects underwent three experimental sessions: twice at 50 mg% and once in a 0 mg% control condition. The pilot study assessed the performance of the B,AC clamp, its potential utility in studies of acute tolerance to alcohol, and the retest reliability of directly measuring the alcohol elimination rate (AER) calculated from the steady‐state infusion rate. Reduced variance was demonstrated in 4 of 5 experimental parameters, compared with results of an earlier approach using a split‐dose oral administration procedure. Subjects' perceptions about alcohol effects were measured in one B,AC clamping session, using Schuckit's Subjective High Assessment Scale: 3 of 15 Schuckit's items demonstrated statistically significant indices of acute tolerance to alcohol. Within‐subject AERs calculated in the steady‐state had a coefficient of variation of 6.5%. Details of the B,AC clamping procedure are provided. The pilot study demonstrated the ability to prescribe experimental parameters of the brain's exposure to alcohol while preserving experimental flexibility in studies of acute tolerance to alcohol and AER.
Regulation of Monocyte Interleukin‐12 Production by Acute Alcohol: A Role for Inhibition by Interleukin‐10
Authors: Girouard Linda , Mandrekar Pranoti , Catalano Donna , Szabo Gyongyi
Published: May 2006

Acute ethanol treatment results in decreased antigen presentation capacity (Th1‐type immunity) and elevated interleukin IL‐10 (Th2 cytokine) production in human monocytes. Monocytes can contribute to both Th1 (IL‐12) and Th2 (IL‐10) immune responses via production of IL‐12 and IL‐10, respectively. Thus, we tested the hypothesis that acute alcohol treatment might affect Th1/Th2 immune balance by altering monocyte production of IL‐12 and IL‐10. Neither acute ethanol treatment alone (25 to 100 mM) nor its combination with a bacterial challenge Staphylococcal enterotoxin B (SEB) induced IL‐12 production in isolated blood monocytes. In contrast, the same physiological alcohol concentrations increased monocyte IL‐10 levels, suggesting that ethanol can induce a dysbalance of monocyte‐derived mediator production at the expense of Th1 cytokines. However, we found that monocyte activation with interferon‐γ (IFN‐γ) can prevent the preferential IL‐10 induction by ethanol. IFN‐γ (100 units/ml) inhibited monocyte IL‐10 production whether induced by 1/μg/ml of lipopolysaccharide (p < 0.01), 1/μg/ml of SEB (p < 0.02), or a combination of bacterial stimulation + ethanol (lipopolysaccharide: p < 0.01). Furthermore, decreased IL‐10 was concomitant to an increase in IL‐12 production in IFN‐γ‐treated monocytes. Moreover, acute ethanol treatment augmented IL‐12 production in IFN‐γ‐treated monocytes in response to SEB stimulation (25 mM ethanol, p < 0.01; 100 mM ethanol, p < 0.01). Experiments with anti‐IL‐10 neutralizing antibody show that ethanol may prevent monocyte IL‐12 induction via IL‐10. These results suggest that inhibition of ethanol‐induced IL‐10 production by IFN‐γ treatment is permissive for IL‐12 induction by alcohol stimulation in monocytes. Thus, our results imply that the presence or absence of IFN‐γ is critical in determining the effect of acute ethanol treatment on monocyte IL‐12 versus IL‐10 induction.
Prenatal Alcohol Exposure and Development at Preschool Age: Main Results of a French Study
Authors: Larroque Beatrice , Kaminski Monique
Published: May 2006

Very high levels of alcohol consumption during pregnancy are harmful for the central nervous system of the child and affect morphogenesis and growth. The aim of this study was to investigate the effects of moderate prenatal alcohol exposure on development at preschool age in a longitudinal study. Pregnant women were interviewed on their alcohol consumption during pregnancy at their first visit to the maternity hospital of Roubaix, France. The development of their 160 children was assessed at the age of 4½. Multiple regression analyses indicated that consumption of 1.5 oz of absolute alcohol (approximately 3 drinks) or more during pregnancy was significantly related to a decrease of 7 points on the general cognitive index of the McCarthy scales, after controlling for confounders. This level of consumption was also related to a higher score on minor neurological anomalies, a lower height of the child, and a higher score on facial features. This level of 1.5 oz of absolute alcohol/day should not be interpreted as a biological threshold, because the study does not allow conclusions to be drawn regarding the effects of lower levels of alcohol consumption. Alcohol consumption during pregnancy can affect the development of the child, at levels well below those associated with fetal alcohol syndrome.
Neuroanatomical and Neurophysiological Mechanisms Involved in Central Nervous System Dysfunctions Induced by Prenatal Alcohol Exposure
Authors: Guerri Consuelo
Published: May 2006

One of the most severe consequences of maternal ethanol consumption is the damage to the developing central nervous system, which is manifested by long‐term cognitive and behavioral deficits in the offspring. Prenatal exposure to ethanol affects many crucial neurochemical and cellular components of the developing brain. Ethanol interferes with all of the stages of brain development, and the severity of the damage depends on the amount of ethanol intake and level of exposure. Experimental observations also indicate that the toxic effects of ethanol are not uniform: some brain regions are more affected than others and, even within a given region, some cell populations are more vulnerable than others. The neocortex, the hippocampus, and the cerebellum are the regions in which the neurotoxic effects of ethanol have been associated with the behavioral deficits. At the cellular level, ethanol disrupts basic developmental processes, including interference with division and proliferation, cell growth, and differentiation and the migration of maturing cells. Alterations in astroglia development and in neuronalglial interactions may also influence the development of the nervous system. An impairment of several neurotransmitter systems and/or their receptors, as well as changes in the endocrine environment during brain development, are also important factors involved in the behavioral dysfunctions observed after prenatal ethanol exposure. Finally, some molecular mechanisms of ethanol‐induced behavioral dysfunctions will be discussed.
Chronic Ethanol Exposure Impairs Phosphorylation of CREB and CRE‐Binding Activity in Rat Striatum
Authors: Yang Xiaoju , Horn Kristin , Wand Gary S.
Published: May 2006

This study examined influences of ethanol exposure on phosphorylation of cAMP response element‐binding protein (CREB) and CRE‐binding activity in the striatum of rats. The phosphorylated form of CREB increased 180% during acute intoxication, compared to sham conditions. After chronic ethanol exposure, induction of CREB phosphorylation by an acute ethanol challenge was markedly attenuated (50%) compared with acute ethanol exposure in the pair‐fed condition. Gel retardation assays with oligomers encoding the rat proen‐kephalin CRE‐1 and CRE‐2 were performed to determine the effects of ethanol on CRE‐binding activity. Super‐shift experiments demonstrated that striatal nuclear protein contains CREB and CEBP/3 (CCAAT/enhancer‐binding protein) and that both transcription factors are involved in specifically binding to the DNA sequence. Re‐challenging rats that had been chronically exposed to ethanol with an acute ethanol challenge reduced the CRE/nuclear protein complexes. However, supershift analyses did not show that chronic ethanol exposure altered the dimerization patterns of CREB and CEBPβ within the complexes. Associated with these impairments in CREB binding and CREB phosphorylation was a significant reduction in two CREB‐modulated factors, proenkephalin and c‐fos expression. In summary, acute ethanol exposure activates the phosphorylation of CREB. Neuroadaptation to chronic ethanol exposure includes alterations in CREB physiology that may impair genes that are dependent upon CREB for transcriptional activation.
Differential Effects of Ethanol on Memory in Adolescent and Adult Rats
Authors: Markwiese Barbara J. , Acheson Shawn K. , Levin Edward D. , Wilson Wilkie A. , Swartzwelder H. Scott
Published: May 2006

Previous studies have shown that ethanol inhibits memory‐related synaptic activity and plasticity more potently in hippocampal slices from immature rats, compared with those taken from adults. We therefore hypothesized that ethanol would more potently attenuate the acquisition of spatial memory in adolescents, compared with adult rats. Adult (65 days of age) and adolescent (30 days of age) male rats were given five daily trials on a spatial memory task in a Morris Water Maze. The animals from each age group were subdivided into three subgroups. Each day, thirty minutes before training, the animals in each subgroup were given an intraperitoneal injection of 1.0 g/kg of ethanol, 2.0 g/kg of ethanol, or the saline vehicle. Training continued daily until the control animals had reached a performance criterion. Ethanol treatment significantly impaired spatial memory acquisition in the adolescent rats, but did not impair acquisition in adult rats. A separate experiment with identical treatment groups showed that ethanol did not impair acquisition of a nonspatial memory task in the water maze in animals from either age group. These experiments show that the acquisition of spatial, but not nonspatial, memory is more potently impaired by ethanol in adolescent animals, compared with adults.
Serum and Muscle Levels of α‐Tocopherol, Ascorbic Acid, and Retinol Are Normal in Chronic Alcoholic Myopathy
Authors: Fernández‐Solà J. , Villegas E. , Nicolàs J. M. , Deulofeu R. , Antúnez E. , Sacanella E. , Estruch R. , Urbano‐Márquez A.
Published: May 2006

Some authors have suggested a possible loss of antioxidant factors in alcoholic skeletal myopathy. To assess the relationship between ethanol consumption and serum and muscle levels of α‐tocopherol, ascorbic acid, and retinol in chronic alcoholics with and without skeletal myopathy, a prospective cross‐sectional study was performed in the Alcohol Unit of a 1000‐bed university hospital. Twenty‐five chronic male alcoholic patients (10 with skeletal myopathy) and 15 male controls of similar age were included. Evaluation of daily and lifetime ethanol consumption, assessment of anthropometric and protein nutritional parameters, and open biopsy of the left deltoid muscle were performed, as well as determinations of serum and muscle levels of retinol, α‐tocopherol, and ascorbic acid by HPLC analysis. Ten of the 25 chronic alcoholic patients presented histological criteria of skeletal myopathy. Four alcoholics presented caloric malnutrition and three protein malnutrition. All of the muscle biopsies of the control group were entirely normal, as were their nutritional studies. The serum and muscular levels of α‐tocopherol, ascorbic acid, and retinol were normal and were similar in both alcoholics and controls. Except for serum retinol, these values were also similar in alcoholic patients with or without skeletal myopathy. In the univariate analysis, we identified the total lifetime dose of ethanol (p < 0.003), the muscle arm area (p < 0.05), and serum levels of prealbumin (p < 0.03) and retinol‐binding protein (p < 0.05) as factors influencing the development of alcoholic myopathy. However, in multivariate analysis, the total lifetime dose of ethanol was the only independent factor in relation to alcoholic myopathy (p < 0.003). Serum and muscle levels of the antioxidants α‐tocopherol, ascorbic acid, and retinol do not influence the presence of skeletal myopathy in chronic alcoholic patients.
P‐450 ‐Dependent Metabolism of Laurie Acid in Alcoholic Liver Disease: Comparison between Rat Liver and Kidney Microsomes
Authors: Amet Yolande , Lucas Danièle , Zhang‐Gouillon Zhi‐Qi , French Samuel W.
Published: May 2006

Monooxygenase enzymatic activities were measured in liver and kidney microsomes of control and ethanol‐treated rats. Animals were administered alcohol by using a model for alcoholic liver injury. Several in vitro approaches were used to compare the laurate metabolism in liver and kidney microsomes: correlation studies between specific P‐450 catalytic activities, immunoblot analysis, and chemical and immunoinhibitions. Ethanol treatment increased the liver and renal hydroxylations of chlorzoxazone and 4‐nitrophenol. Moreover, lauric acid (ω‐1)‐hydroxylation was found to be significantly increased (∼6‐fold) after ethanol treatment in liver, but not in kidney microsomes. The laurate ω‐1/ω ratio increased from 1.52 ± 0.49 to 4.11 ± 1.01 in liver microsomes of control and ethanol‐treated rats, and from 0.29 ± 0.06 to 0.44 ± 0.07 in kidney microsomes. Immunoblot analysis using polyclonal anti‐cytochrome P‐450 (CYP) 2E1 or CYP4A antibodies showed an increase of CYP2E1 and CYP4A contents in both organs, but the increase was higher in liver than in kidney microsomes. Chemical inhibitions using CYP2E1 competitive inhibitors (such as chlorzoxazone and ethanol) led to a nonsignificant inhibition of the renal (ω‐1)‐hydroxylation of lauric acid. In contrast, 17‐octadecynoic acid (a mechanism‐based inhibitor of ω ‐hy‐droxylase) was able to inhibit both to‐ and (ω ‐1)‐hydroxylations of lauric acid in kidney microsomes. Immunoinhibitions specific to CYP2E1 significantly decreased the (ω ‐1)‐hydroxylation of lauric acid in liver, but not in kidney microsomes, whereas the polyclonal anti‐CYP4A1 antibody inhibited to‐ and (ω ‐1)‐hydroxylations of lauric acid in kidney microsomes. All of these results show that lauric acid hydroxylations in liver and kidney respond in different manners to ethanol treatment. Lauric acid (ω ‐1)‐hydroxylation, a highly specific probe for CYP2E1 in rat and human liver microsomes, is mediated by a CYP4A isoform in rat kidney microsomes.
Influence of Chronic Alcohol Intake on Intestinal Taurine and Antipyrine Transport in Pregnant Rats
Authors: Martín‐Algarra R. V. , Polache A. , Fernández‐Villalba E. , Delfina J. M. Plá , Guerri C.
Published: May 2006

Taurine is a nonessential amino acid that plays a critical role in development. However, biosynthetic capacity is almost negligible in the fetus and must be supplied by the mother. Therefore, when maternal taurine status is depressed during gestation, fetal tissue taurine concentrations can also be compromised. In the present study, the effect of chronic alcohol intake on the intestinal transport of taurine during pregnancy has been investigated by an in vitro technique that allows measurement of the unidirectional influx of the amino acid across the intact rat mid jejunum. The influence of alcohol intake on the passive component of the intestinal transport was also investigated with antipyrine, a model compound for passive diffusion. For chronic alcohol treatment, the rats were fed a liquid diet containing ethanol (36% of calories) or an isocaloric diet (pair‐fed control) for 5 weeks before and during pregnancy. The animals were sacrificed at 21 days of gestation. Results from the kinetic analysis revealed that chronic ethanol treatment significantly decreases the maximum transport (Jm) of taurine, without modifying the Michaelis‐Menten constant (Km), but enhances its diffusion component (ka) compared with that of controls. At the same time, this treatment significantly increased the passive diffusion of antipyrine. These results indicate that although chronic ethanol inhibits the active transport of taurine, passive diffusion is significantly increased. However, because of the predominant passive component in the intestinal absorption of taurine, an overall enhancement in the absorption of this amino acid is observed in alcohol‐fed rats. The biological and practical implications of our results are discussed.
A Model to Examine the Validity of the 6‐Month Abstinence Criterion for Liver Transplantation
Authors: Yates William R. , Martin Maureen , LaBrecque Douglas , Hillebrand Don , Voigt Michael , Pfab Debra
Published: May 2006

Six months of abstinence from alcohol is a commonly used criterion for liver transplantation eligibility for patients with alcoholic cirrhosis. There is limited evidence to document the validity of this criterion with regard to risk of alcoholism relapse. Ninety‐one patients with alcoholic cirrhosis were interviewed for relapse risk using the High Risk Alcoholism Relapse (HRAR) Scale. The HRAR model can be used to predict relapse risk independent of duration of sobriety and therefore can be used to examine the validity of the 6 months of abstinence criteria in this clinical population. The two methods demonstrated poor to fair agreement. Agreement was highest with a cutoff allowing a 5% 6‐month relapse risk when 79% agreement (k= 0.56) was demonstrated between the two methods. Using the 6‐month abstinence criterion alone disallows a significant number of candidates who have a low relapse risk based on their HRAR score. The validity of the 6‐month abstinence criterion is supported somewhat by comparison with the HRAR model. However, use of the 6‐month abstinence criterion alone forces a significant number of patients with a low relapse risk by HRAR to wait for transplant listing. A relapse risk model based on an estimate of alcoholism severity in addition to duration of sobriety may more accurately select patients who are most likely to benefit from liver transplantation.
Trends in Alcohol‐Related Problems among Whites, Blacks, and Hispanics: 1984–1995
Authors: Caetano Raul , Clark Catherine L
Published: May 2006

The objective of this study was to report trends in alcohol problems among whites, blacks, and Hispanics between 1984 and 1995. Data were obtained from two nationwide probability samples of U.S. households, the first conducted in 1984 and the second in 1995. The 1984 sample consisted of 1777 whites, 1947 blacks, and 1453 Hispanics. The 1995 sample included 1636 whites, 1582 blacks, and 1585 Hispanics. On both occasions, interviews (average length, 1 hr) were conducted in respondents' homes by trained interviewers. The results indicate that between 1984 and 1995, alcohol problems were stable among white and black men and increased among Hispanic men. The rates of three or more alcohol problems for men of each ethnic group for 1984 and 1995 were: 12% and 11% for white men, 16% and 13% for black men, and 9% and 16% for Hispanic men, respectively. Problem prevalence was stable and relatively low among women in all three ethnic groups. Overall, the prevalence of alcohol problems continues to be high among men in the United States. Even though recent research has shown that rates of frequent heavy drinking among white men have declined, we found no corresponding decrease in problem prevalence. Rates of frequent heavy drinking and alcohol‐related problems between 1984 and 1995 have remained especially high among black and Hispanic men, suggesting that men of these two ethnic groups should be specifically targeted for renewed prevention efforts.
Predicting Relapse to Substance Abuse as a Function of Personality Dimensions
Authors: Fisher Lisa A. , Elias Jeffrey W. , Ritz Kathy
Published: May 2006

The goal of the present study was to determine whether personality traits are related to return to heavy drinking or drug use following treatment for substance abuse. Personality characteristics of one hundred and eight patients residing on an inpatient substance abuse treatment program were assessed. Personality traits were examined using the 5‐factor model of personality as measured by the NEO‐Personality Inventory. These patients were then followed for 1 year after discharge from the treatment program. These substance abuse patients scored higher than the NEO‐Personality Inventory normative sample on the personality domains of Neuroticism and Conscientiousness. A survival analysis showed that Neuroticism and Conscientiousness from the NEO‐Personality Inventory were significant predictors of relapse. Odds ratios showed that the risk of relapsing was greatest for those patients who were both low in conscientiousness and high in neuroticism. The relevance of these two broad personality dimensions to the development and maintenance of addiction is discussed. Treatment implications for patients who possess these personality risk factors are outlined.
Effects of Cues on Memory in Alcoholics and Controls
Authors: Nixon S. J. , Tivis R. D. , Jenkins M. R. , Parsons O. A.
Published: May 2006

This study was conducted to determine whether alcoholics' memory difficulties are due, in part, to access (retrieval) or to availability (retention) deficits. Forty‐four alcoholics (n=20 females) and 44 controls (n=22 females) learned a paired associate list consisting of 12 adjective‐CCC trigram pairs. Half of the subjects in each group learned the list to a low degree of learning (DOL; 4/12 pairs); the remainder to a high DOL (8/12 pairs). Two distinct environmental contexts (providing implicit cues) were used during acquisition. Subjects then completed a cued recall (an explicit cue) test in either the same or a different room. Alcoholics were significantly inferior in the acquisition phase on trials required to reach criterion, regardless of DOL required [F(1,68) = 10.92, p=0.002]. The main effect for implicit cuing was not significant; similarly, there were no significant interactions. In contrast, the explicit cue manipulation produced a significant group × DOL interaction on the number of trigrams correctly recalled [F=(1,77)=6.38, p=0.01]; alcoholics' recall did not benefit from the higher DOL in contrast to a significant improvement in recall by controls. The failure of alcoholics to demonstrate improvement with higher levels of learning is consistent with a deficit in the availability of information. The results confirm previous reports of recovering alcoholics' verbal learning and memory dysfunction, and suggest that these deficits may be attributed, in part, to a deficit in the availability of information (retention).
Intravenous Self‐Administration of Ethanol in β‐Endorphin‐Deficient Mice
Authors: Grahame Nicholas J. , Low Malcolm J. , Cunningham Christopher L.
Published: May 2006

Extensive research on both human alcoholics and in animal models of alcoholism has implicated the release of endogenous opioids in the consumption of ethanol. Various experiments using opioid antagonists have indicated that these drugs cause both humans and animals to decrease their consumption of ethanol. However, it remains unclear exactly which of the endogenous opioids mediates the rewarding effects of ethanol. The present experiment used intravenous self‐administration of ethanol to determine whether β‐endorphin (BE)‐deficient mice differed from wild‐type (WT) mice in ethanol self‐administration. The BE‐deficient mice completely lack BE, but are otherwise similar to the WT mice. By using intravenous self‐administration, we were able to rule out any ability of BE to mediate differences in ethanol consumption via palatability factors alone. Both types of mice were 7 generations backcrossed onto a C57BL/6J inbred strain background. During nine daily, 2‐hr free‐operant sessions, 14 BE‐deficient and 17 WT mice could nosepoke for 75 mg/kg ethanol infusions delivered intravenously on an fixed‐ratio 3 schedule with a 2‐sec time‐out after each reinforcer delivery. Reinforcer delivery occurred following nosepokes in only one of two holes. Contrary to what was expected, BE‐deficient mice acquired selective operant responding for ethanol, whereas WT mice did not. Although the two genotypes did not differ in either operant or locomotor behavior during the first session, by the end of the nine sessions, BE deficient mice were reliably nosepoking for ethanol, whereas WT mice were not. These findings may indicate that BE is not essential for the postingestive reinforcing effects of ethanol in these animals.
Confirmation of Quantitative Trait Loci for Alcohol Preference in Mice
Authors: Tarantino Lisa M. , McClearn Gerald E. , Rodriguez Lawrence A. , Plomin Robert
Published: May 2006

An F2 intercross derived from C57BL/6 and DBA/2 progenitor inbred strains was used to test for replication of quantitative trait loci (QTLs) for alcohol preference nominated by a previous study using BXD recombinant inbred (RI) strains (Rodriguez et al., Alcohol. Clin. Exp. Res. 19:367–379, 1995). Fourteen provisional QTLs were nominated in the original RI study with a p < 0.05 criterion. In the present study, a genome scan (101 microsatellite markers) was conducted on an F2 population (n ‐ 218). Three significant QTLs were detected on chromosomes 1, 4, and 9, and three suggestive QTLs were detected on chromosomes 2, 3, and 10. Of these six QTLs, four were consistent with the previous RI nominations. The replication rate of 28.6% (4 of 14) is in agreement with the results of simulation studies performed by Belknap et al. (Behav. Genet. 26:149–160, 1996) and supports the methodological argument for a multistage research design for nominating and replicating QTLs.
Role of Catalase in In Vitro Acetaldehyde Formation by Human Colonic Contents
Authors: Tillonen J. , Kaihovaara P. , Jousimies‐Somer H. , Heine R. , Salaspuro M.
Published: May 2006

Ingested ethanol is transported to the colon via blood circulation, and intracolonic ethanol levels are equal to those of the blood ethanol levels. In the large intestine, ethanol is oxidized by colonic bacteria, and this can lead to extraordinarily high acetaldehyde levels that might be responsible, in part, for ethanol‐associated carcinogenicity and gastrointestinal symptoms. It is believed that bacterial acetaldehyde formation is mediated via microbial alcohol dehydrogenases (ADHs). However, almost all cytochrome‐containing aerobic and facultative anaerobic bacteria possess catalase activity, and catalase can, in the presence of hydrogen peroxide (H2O2, use several alcohols (e.g., ethanol) as substrates and convert them to their corresponding aldehydes. In this study we demonstrate acetaldehyde production from ethanol in vitro by colonic contents in a reaction catalyzed by both bacterial ADH and catalase. The amount of acetaldehyde produced by the human colonic contents was proportional to the ethanol concentration, the amount of colonic contents, and the length of incubation time, even in the absence of added nicotinamide adenine dinucleotide or H2O2. The catalase inhibitors sodium azide and 3‐amino‐1,2,4‐triazole (3‐AT) markedly reduced the amount of acetaldehyde produced from 22 mM ethanol in a concentration dependent manner compared with the control samples (0.1 mM sodium azide to 73% and 10 mM 3‐AT to 67% of control). H202 generating system [β‐D(+)‐glucose + glucose oxidase] and nicotinamide adenine dinucleotide induced acetaldehyde formation up to 6‐ and 5‐fold, respectively, and together these increased acetaldehyde formation up to 11‐fold. The mean supernatant catalase activity was 0.53 ± 0.1 jumol/min/mg protein after the addition of 10 mM H202, and there was a significant (p < 0.05) correlation between catalase activity and acetaldehyde production after the addition of the hydrogen peroxide generating system. Our results demonstrate that colonic contents possess catalase activity, which probably is of bacterial origin, and indicate that in addition to ADH, part of the acetaldehyde produced in the large intestine during ethanol metabolism can be catalase dependent.
In Vivo Induction of Tyrosylprotein Sulfotransferase by Ethanol: Role of Increased Enzyme Synthesis
Authors: Ramaprasad Patalapati , Kasinathan Chinnaswamy
Published: May 2006

Tyrosine sulfation is a posttranslational modification involved in the synthesis, secretion, and biological activity of proteins and peptides. Our previous studies have demonstrated that the enzyme activity was induced by ethanol. In the present work, the induction was studied in detail. Initial experiments were conducted to examine the time course of tyrosylprotein sulfotransferase (TPST) induction in rats pair‐fed liquid diets containing either ethanol or carbohydrate substitute (controls). Marked elevation of TPST activity (3‐fold) was measured on day 10 in the liver and gastric mucosa of ethanol‐fed rats. Ethanol‐mediated enhancement was also noticed by Western‐blot analysis with anti‐TPST antibody in both the liver and gastric mucosa on days 5 and 10. We then determined the steady‐state TPST protein turnover in ethanol‐fed and control animals that were given 35S‐methionine after 10 days of pair‐feeding with liquid diet. The rates of TPST synthesis assessed by measuring initial rates of incorporation of 35S‐methionine into TPST was increased in the liver and gastric mucosa of animals fed with ethanol. Monophasic exponential decay curves showed that TPST protein half‐lives for liver (control: 34 hr, ethanol: 32 hr) and gastric mucosa (control: 52 hr, ethanol: 48 hr) did not differ between control and ethanol groups. Our overall results indicate that the in vivo induction of TPST by ethanol involves increased enzyme synthesis rather than decreased enzyme degradation.
Quantitation of the Mass of Fatty Acid Ethyl Esters Synthesized by Hep G2 Cells Incubated with Ethanol
Authors: Dan Li , Cluette‐Brown Joanne E. , Kabakibi Ayman , Laposata Michael
Published: May 2006

Fatty acid ethyl esters (FAEE), esterification products of fatty acids and ethanol, have been increasingly implicated as mediators of ethanol‐induced organ damage. The first goal of this study was to determine the mass of FAEE synthesized by Hep G2 cells exposed to a given dose of ethanol. The second goal was to determine whether all fatty acids in cells are equally available for FAEE synthesis. Hep G2 cells and essential fatty acid deficient Hep G2 cells (Hep G2‐EFD) were used to study the synthesis of FAEE upon exposure to ethanol. A two‐pool fatty acid model was created: (1) a “previously incorporated pool” formed by incubating the cells with 14C‐labeled fatty acids for 24 hr; and (2) a “newly incorporated pool” formed by incubating cells with 3H‐labeled fatty acids for 0.5 hr. The FAEE production from each pool was then determined. The total production of FAEE within 3 hr by Hep G2 cells in culture was 150 to 250 pmol/mg cell protein. The fatty acids most recently incorporated into the cells were preferred as substrates for FAEE synthesis because a higher percentage of fatty acids from the newly incorporated pool was used for FAEE synthesis than from the previously incorporated pool. Furthermore, a dose‐response relationship was observed between the amount of fatty acid in the newly incorporated pool and FAEE production, but not between the amount of fatty acid in the previously incorporated pool and FAEE synthesis. Taken together, the results indicate that a relatively small amount of endogenously synthesized FAEE is generated from specific intracellular pools of fatty acid since not all fatty acids are equally available for FAEE synthesis. This indicates that if endogenous FAEE are toxic, they exert their toxic effect at very low intracellular FAEE concentrations.
Electrophysiological Characterization of Cerebellar Neurons from Adult Rats Exposed to Ethanol during Development
Authors: Bäckman Cristina , West James R. , Mahoney Jolonda C. , Palmer Michael R.
Published: May 2006

The purpose of this study was to investigate the spontaneous activity of mature rat cerebellar neurons that had been exposed to ethanol (EtOH) during postnatal days 4 to 10, which corresponds to the third trimester in humans. Newborn Sprague‐Dawley rats were implanted with gastric feeding tubes and were artificially reared from postnatal days 4 to 10 with two different diets. The experimental group received 4.5 g/kg/day of EtOH delivered in a milk solution. Controls received similar feeding with an isocaloric supplement replacing the EtOH. Electrophysiological evaluations were performed after an EtOH‐free rearing period. Although lobules IX and X of the cerebellar vermis appeared morphologically smaller in the animals neonatally exposed to EtOH, compared with controls, extracellular recordings from both Purkinje cells and Golgi interneurons in adult rats showed no differences in spontaneous activity or firing pattern between the control and EtOH‐exposed animals. Similarly, excitations and inhibitions of Purkinje neuron activity evoked by parallel pathway stimulation appeared unaffected by the developmental EtOH exposure. However, we did observe a significant decrease in the proportion of Purkinje neurons generating complex spike bursts in the group exposed to EtOH neonatally. These data suggest that, although fewer Purkinje neurons may survive the brain growth spurt if exposed to EtOH during this critical period of development, those that do survive appear to function normally. The observed abnormality in complex spike production may result from EtOH effects on developing neurons in the inferior olive that give rise to the climbing fibers that cause this bursting pattern in Purkinje neurons.
Mechanism of Action of Acamprosate. Part II. Ethanol Dependence Modifies Effects of Acamprosate on NMDA Receptor Binding in Membranes from Rat Cerebral Cortex
Authors: al Qatari Mona , Bouchenafa Ouahiba , Littleton John
Published: May 2006

Acamprosate is a putative anticraving drug used to maintain abstinence in alcohol‐dependent patients. Its mechanism of action is uncertain, but the drug is thought to interact with neuronal NMDA receptors and calcium channels, and these proteins are implicated in the induction of alcohol dependence. In these experiments, the effects of acamprosate were studied on the binding of the NMDA receptor ligand [3H]dizocilpine to rat brain membranes under nonequilibrium conditions; 10 μM glutamate and 1 μM glycine were present in the binding assays to partially activate the receptor. At clinically relevant concentrations (in the micromolar range), acamprosate significantly enhanced [3H]dizocilpine binding to cortical membranes from control animals (suggesting that acamprosate may increase the rate of association of the radioligand), whereas at higher concentrations binding was inhibited. This effect is consistent with a partial agonist effect of acamprosate on the NMDA receptor protein. However, when rats were made dependent on ethanol (exposure to the drug for 10 days by inhalation) and cortical membranes were prepared from these animals, acamprosate in vitro no longer produced any enhancement of [3H]dizocilpine binding. Similar results were obtained when membranes were used from rats that had received 400 mg/kg/day of acamprosate in their drinking water with or without concurrent ethanol inhalation for 10 days. Thus, in brain membranes from all these treatment groups, acamprosate in vitro caused inhibition of [3H]dizocilpine binding only. The results suggest that acamprosate may have excitatory or inhibitory effects on NMDA receptors, depending on the experimental conditions. The effects of the drug on this system appear to be shifted toward inhibition in alcohol dependence, and this finding may be important to its clinical mechanism.
Sex Differences in Voluntary Drinking by Long Evans Rats following Early Stress
Authors: Lancaster Francine E.
Published: May 2006

Models for early stress and voluntary drinking were used to determine the contribution of early stress to increased intake of alcoholic beverages during puberty and adulthood. Newborn litters of Long Evans rats were: (1) stressed by daily separation from the mother for 15 midday on days 1 to 7 of life [“handled” (H)]; or (2) left untouched with the mother on days 1 to 7 of life [“nonhandled” (NH)]. All animals were weaned on day 22, separated by sex (M and F), and caged individually with an assignment of 10 animals per sex per treatment group (H and NH). From 25 to 85 days of age, all animals were given free access to beer containing 5% ethanol (v/v), water, and regular laboratory food. Beer, food, and water intake was measured daily at the same time each day, and animals were weighed weekly. HM had greater ethanol intake and preference for ethanol during the peripu‐bertal period (days 32 to 45), compared with all other groups. There were no differences in ethanol intake between NHF and NHM. HM had greater ethanol preference than HF on 22 of the 60 drinking days. HF consumed the same amount of water as the males and significantly greater amounts of water than NHF on 28 of the 60 drinking days. HM had greater ethanol preference than NHM on 8 of the 60 drinking days. From day 75 to day 85, HF had greater ethanol intake than HM, and NHF had greater ethanol intake than NHM. There were no differences in body weights of HF and NHF throughout the study. Growth of HM lagged behind NHM into adulthood. Early stress of males was linked to increased ethanol intake during the peripubertal and adult periods and stunted body growth into adulthood. Early stress of females was linked to polydipsia (water) throughout development and continuing into adulthood, and to increased alcohol intake in adulthood.
A Quantitative Trait Locus for Alcohol Consumption in Selectively Bred Rat Lines
Authors: Carr Lucinda G. , Foroud Tatiana , Bice Paula , Gobbett Troy , Ivashina Julia , Edenberg Howard , Lumeng Lawrence , Li Ting‐Kai
Published: May 2006

Selective breeding for high and low alcohol consumption led to the establishment of alcohol‐preferring (P) and alcohol‐nonpreferring (NP) rat lines that differ greatly in their alcohol consumption. These lines were inbred and F2 intercross progenies were generated to detect quantitative trait loci (QTLs) influencing alcohol consumption. A QTL on chromosome 4 was identified with a maximum lod score of 8.6. This QTL acts in an additive fashion and accounts for 11% of the total phenotypic variability and approximately one‐third of the genetic variability. Neuropeptide Y, an endogenous anxiolytic and neu‐romodulator, has been mapped to this same region of chromosome 4. This study is an advance in genome analyses, demonstrating that crosses between divergent, selectively bred rat lines can be used to identify QTLs. Localization of a gene influencing alcohol consumption may have important implications for the etiology of alcohol abuse and alcoholism in humans.
Association Studies of Polymorphisms of CYP2E1 Gene in Alcoholics with Cirrhosis, Antisocial Personality, and Normal Controls
Authors: Parsian Abbas , Cloninger C. Robert , Zhang Zhen Hua
Published: May 2006

To determine the role of CYP2E1 gene in susceptibility to alcoholism and alcohol cirrhosis, we gentoyped a sample of alcoholics with and without cirrhosis, alcoholics with antisocial personality, alcoholic families, and normal controls with Rsal, Pstl, and Dral polymorphisms in the gene. Relative risk and haplotype relative risk approaches were used in genotype data analysis. The Pstl polymorphism data were excluded from further analysis due to strong linkage disequilibrium with Rsal. For the Rsal polymorphism, comparison of total alcoholics, alcoholics with and without cirrhosis, and alcoholics with antisocial personality with normal controls were negative. The results of the same analysis with the above groups for Dral were also negative. Using the haplotype relative risk method, the result for Dral was positive, meaning that the mutated allele (D2) was significantly more transmitted than nontransmitted. However, the result of the same analysis for the Rsal polymorphism was not statistically significant. We conclude that the CYP2E1 gene plays no substantial role in susceptibility to alcohol cirrhosis or alcoholism.
Activated Lymphocytes (CD25+ CD69+ Cells) and Decreased CD19+ Cells in Well‐Nourished Chronic Alcoholics without Ethanol‐Related Diseases
Authors: Sacanella E. , Estruch R. , Gayà A. , Fernández‐Solà J. , Antúnez E. , Urbano‐Márquez A.
Published: May 2006

To assess lymphocyte subsets and expression of activation antigens in peripheral blood lymphocytes (PBLs) in chronic alcoholism, a cross‐sectional study with 30 well‐nourished chronic alcoholics and 30 controls was performed. Studies included detailed clinical and laboratory evaluation, nutritional status assessment, and determination of lymphocyte subpopulations, as well as activation antigens. A significant decrease of B cells (CD19+) was observed in chronic alcoholics, compared with controls (p < 0.001). A significant increase of PBLs expressing CD69 and CD25 (p < 0.01, both) in chronic alcoholics was also detected, whereas CD71 expression was unaffected. In addition, T lymphocytes expressing HLA‐DR were significantly higher in chronic alcoholics than controls (p < 0.05). The serum level of soluble interleukin‐2 receptor was also significantly higher in the alcoholic group, compared with controls (p= 0.04). Moreover, the estimated total lifetime dose of ethanol consumed correlated positively with the percentage of PBLs expressing CD25 (r= 0.48; p= 0.01) and negatively with PBLs expressing CD71 (r= ‐0.39;p= 0.04). By contrast, the changes were not related to age, nutritional status, or the presence of other ethanol‐related diseases. In conclusion, chronic alcoholics present a significant decrease of B cells and an “incomplete activation state” of PBLs that depends on the dose of ethanol consumed.
Effects of Nicotine and Mecamylamine Microinjections into the Nucleus Accumbens on Ethanol and Sucrose Self‐Administration
Authors: Nadal R. , Chappell A. M. , Samson H. H.
Published: May 2006

Nicotine (NIC) and ethanol (ETOH) are both drugs of abuse that can affect similar pathways in the central nervous system. However, the role of nicotinic processes in ETOH's reinforcing actions is unclear. Although the mesolimbic dopamine systems are known to be involved in the reinforcing effects of ETOH, the role of nicotinic receptors within the nucleus accumbens (NAc) in ETOH reinforcement has not been studied. To address this issue, adult male Long‐Evans rats were initiated to self‐administer ETOH (l0% v/v, n= 14) using the sucrose‐substitution procedure or sucrose (5% w/v, n= 8) in a 30‐min operant session. They were then surgically implanted with bilateral stainless‐steel guide cannulae to allow for microinjection into the core of the NAc. After recovery from surgery, presession micro‐injections of NIC (0.3, 3.3, 10, 30, and 60 μg/1 μ1/brain) or the antagonist mecamylamine (MEC) (1, 3, 10, 30, and 60 μg/1 μl/brain) were performed prior to an ETOH or sucrose self‐administration session. NIC (3.3 and 60 μg/μl) and MEC (30 μg/μl) both reduced ETOH self‐administration behavior, without affecting sucrose‐reinforced behavior. A reduction in the total duration of ETOH responding (termination) was also observed after either 60 μg/μl of NIC and 30 μg/μl of MEC. The lack of a clear dose‐response relationship for the agonist and the antagonist indicates that the interaction between the NAc nicotinic system and ETOH self‐administration is complex.
A Characterization of Approach and Avoidance Learning in Alcohol‐Preferring and Alcohol‐Nonpreferring Rats
Authors: Blankenship Matthew R. , Finn Peter R. , Steinmetz Joseph E.
Published: May 2006

Although numerous biochemical and physiological differences have been shown to be correlated with alcohol preference, less is known about behavioral factors that may correlate with alcohol preference. Using a signaled barpressing task, alcohol‐preferring (P;n= 18) and alcohol‐nonpreferring (NP;n= 19) rats were compared for their ability to learn an appetitive and an aversive task. Results showed that P rats had difficulty learning the tasks in comparison with NP and non‐selected, control rats when appetitive training was given first. However, if aversive training came first, the NP rats performed poorly in comparison with the P and nonselected rats. These results suggest that these lines of rats may differ in behavioral inhibition and sensitivity to conditioned fear. Furthermore, these behavioral differences may offer a richer analysis of the traits that were co‐selected with the alcohol‐seeking and alcohol‐avoiding phenotypes.