bluuebunny/crossref_metadata_2025 huggingface dataset:
Upregulated Expression of VLA Proteins and CD29 in Peripheral Blood Lymphocytes of Chronic Alcoholics Without Ethanol‐Related Diseases
Authors: Sacanella E. , Estruch R. , Gaya A. , Ferrer K. , Fernández‐Sola J. , Alonso J. R. , Nicolás J.M. , Urbano‐Márquez A.
Published: May 2006

To analyze adhesion molecule expression on peripheral blood mononuclear cells (PBMCs) and on different lymphocyte subpopulations (CD2+, CD8+, CD19+, and CD56+ subsets) in chronic alcoholism, 30 well‐nourished chronic alcoholics without ethanol‐related diseases and 30 matched controls were included in the study. Adhesion molecules that mediate adhesion to other cells and to extracellular matrix proteins, and whose cellular expression is modified during lymphocyte activation, were selected for study. A detailed clinical evaluation, laboratory analysis, nutritional assessment, and study of adhesion molecule expression was performed. A significant higher expression of CD29 (β1‐integrin) (p= 0.001), VIA‐3 (p= 0.002), VLA‐4 (p= 0.03), and VLA‐5 (p= 0.001) were observed on PBMCs of chronic alcoholics, compared with control subjects, whereas no changes were observed in CD18 (β2‐integrin) and CD50 (ICAM‐3) expression. The upregulation of CD29 and VLA proteins only affected T lymphocytes (CD2+/CD8+/CD4+ cells). These data confirm that T cells of chronic alcoholics are basally activated and that changes in adhesion molecule expression on PBMCs may be responsible of disturbances of adhesion processes in chronic alcoholics without ethanol‐related diseases.
Increased Expression of Mitochondrial Genes in Human Alcoholic Brain Revealed by Differential Display
Authors: Fan Li , van der Brug Marcel , Chen Wenbin , Dodd Peter R. , Matsumoto Izuru , Niwa S. , Wilce Peter A.
Published: May 2006

Polymerase chain reaction (PCR)‐based differential display was used to screen for alterations in gene expression in the mesolimbic system of the human alcoholic brain. Total RNA was extracted from the nucleus accumbens of five alcoholic and five control brains. A selected subpopulation of mRNA was reverse‐transcribed to cDNA and amplified by PCR. A differentially expressed cDNA fragment was recovered, cloned, and sequenced. Full sequence analysis of this 467 bp fragment revealed 98.2% homology with the human mitochondrial 125 rRNA gene. Dot‐blot analysis showed increased expression of this gene in nucleus accumbens and hippocampus, but not in the superior frontal cortex, primary motor cortex, caudate, and pallidus/putamen in a total of eight human alcoholic brains, compared with seven control brains. A similar increased expression was observed by dot‐blot analysis, using RNA from the cerebral cortex of rats chronically treated with alcohol vapor. Hybridization of a 16S rRNA oligonucleotide probe indicated that the expression of both rRNAs genes was significantly increased in nucleus accumbens. These results indicate that chronic alcohol consumption induces alteration in expression of mitochondrial genes in selected brain regions. The altered gene expression may reflect mitochondrial dysfunction in the alcohol‐affected brain.
Effects of Dexmedetomidine on Rat Locus Coeruleus and Ethanol Withdrawal Symptoms During Intermittent Ethanol Exposure
Authors: Riihioja Päivi , Jaatinen Pia , Haapalinna Antti , Kiianmaa Kalervo , Hervonen Antti
Published: May 2006

In the present study, the neuroprotective effects of dexmedetomidine on rat locus coeruleus were studied during a 5‐week intermittent ethanol exposure. Male Wistar rats (3 to 4 months old) were given ethanol or isocaloric sucrose by intragastric intubations three times a day for 4 days, which was followed by a 3‐day withdrawal period. This 7‐day cycle of ethanol exposure and withdrawal was repeated five times. Dexmedetomidine (at a dose decreasing from 30 μg/kg to 10 μg/kg, sc) was given to the treatment group during the withdrawal phase. The results showed that, during the 5‐week experiment, dexmedetomidine significantly relieved the ethanol withdrawal syndrome, measured as the sum of the three most specific symptoms (rigidity, tremor, and irritability). The total neuron number of locus coeruleus (LC) decreased in the ethanol‐treated group by 24%, compared with the nontreated control group and by 11%, compared with the sucrose‐treated control group. Interestingly, the LC neuron numbers were found to decrease in the sucrose‐intubated rats as well, compared with the nontreated control group. Dexmedetomidine was found to relieve ethanol‐induced neuronal loss in the LC. Dexmedetomidine might be a new interesting alternative in the treatment of ethanol withdrawal syndrome, particularly due to its possible neuroprotective effects in the central nervous system.
Naltrexone Effects on Ethanol Reward and Discrimination in C57BL/6 Mice
Authors: Middaugh Lawrence D. , Kelley Brian M. , Cuison Eduardo R. , Groseclose Chad H.
Published: May 2006

The effects of the opioid antagonist, naltrexone, on operant responding for oral ethanol reward delivered on a fixed‐ratio schedule, and on the discriminative stimulus properties of intraperitoneally injected ethanol, was examined in two separate experiments. The ages, food/water motivational conditions, and naltrexone doses for the two experiments were similar to allow a direct comparison of naltrexone effects on the two measures. Male food‐deprived C57BL/6 mice responded for ethanol during either preprandial (low thirst, high hunger motivation) or postprandial (high thirst, low hunger motivation tests). The reinforcing value of ethanol relative to water was greater during the preprandial tests; however, the amounts of ethanol consumed was greater during the postprandial tests, with some mice becoming unconscious during the 15‐min test session. Naltrexone produced dose‐responsive reductions in responding for ethanol under either testing condition. During postprandial tests, naltrexone reduced responding for ethanol reward at a dose (1.25 mg/kg) that had little effect on responding for water reward, suggesting some selectivity for ethanol reward. In addition, doses of naltrexone that reduced responding for ethanol rewards did not alter the discrimination of ethanol (g/kg) in an operant discrimination task, but did reduce the total number of responses made during these tests. Thus, under similar motivational and dosing conditions, the opiate antagonist attenuated the reinforcing, but not the discriminative properties of ethanol, suggesting that the latter is mediated by either different or additional neural mechanisms in C57BL/6 mice.
Glucose Metabolism, Insulin‐like Growth Factor‐I, and Insulin‐like Growth Factor‐Binding Protein‐1 After Alcohol Withdrawal
Authors: Paassilta Marita , Kervinen Kari , Kesäniemi Y. Antero
Published: May 2006

Alcohol abusers often present with deteriorated glucose metabolism and insulin resistance. Changes in other glucoregulators, such as insulin‐like growth factor‐I (IGF‐I) and IGF‐binding protein‐1 (IGFBP‐1) may also be related to alcohol abuse. We studied the effects of alcohol withdrawal on blood glucose, serum insulin and C‐peptide, and plasma IGF‐I and IGFBP‐1 levels in 27 noncirrhotic male alcoholics aged 43 ± 9.0 (mean ± SD) years on four consecutive days immediately after withdrawal. A 4‐day monitoring period was conducted in four healthy nonalcoholic control men. The groups were similar in age and body mass index. Glucose, insulin, IGF‐I, and IGFBP‐1 did not differ significantly between the groups at the baseline, but C‐peptide was higher in alcoholics (p < 0.01). After alcohol withdrawal, serum insulin and C‐peptide levels increased in close correlation with each other (r = 0.82, p < 0.001). During the 4‐day observation period in alcoholics, IGFBP‐1 levels declined by 59%, whereas IGF‐I increased by 41 % (p < 0.001 for both comparisons). The change in insulin correlated inversely with the change in IGFBP‐1 levels (r= ‐0.39, p < 0.05). In the control group, glucose, insulin, IGF‐I, and IGFBP‐1 remained unchanged during the 4‐day monitoring period, whereas some reduction was observed in C‐peptide. In conclusion, alcohol withdrawal enhances insulin production, as seen in increased C‐peptide levels. An inverse correlation between the changes in insulin and that in IGFBP‐1 might suggest that inhibition of IGFBP‐1 by insulin remains largely unchanged during the acute phase of alcohol withdrawal.
The Tridimensional Personality Questionnaire as a Predictor of Relapse in Detoxified Alcohol Dependents
Authors: Meszaros Kurt , Lenzinger Elisabeth , Hornik Kurt , Füreder Thomas , Willinger Ulrike , Fischer Gabriele , Schönbeck Georg , Aschauer Harald N. ,   on behalf of The European Fluvoxamine in Alcoholism Study Group
Published: May 2006

Personality traits have been found as strong predictors for treatment response in different psychiatric disorders. We administered the Tridimensional Personality Questionnaire, which measures the three personality dimensions: novelty seeking, harm avoidance (HA), and reward dependence, as introduced by Cloninger in a multicenter study (11 centers in the United Kingdom, Eire, Switzerland, and Austria) with detoxified alcohol‐dependent patients (n= 521). The objective of this study was to evaluate a possible predictive value of these three dimensions on relapse over 1‐year follow up. A logistic regression analysis showed that novelty seeking is a strong predictor for relapse in detoxified male alcoholics (p= 0.0007; p values adjusted for treatment), but not in females. In both sexes, HA and reward dependence were of no predictive value. However, we found a trend for significance of HA for predicting “early” relapse (4 weeks) in females (p= 0.074). Our results show that Tridimensional Personality Questionnaire personality traits have direct clinical applications for prediction of relapse in detoxified alcohol dependents and indicate the necessity of additional therapeutic treatment in risk groups.
Ethyl Linoleate in Meconium: A Biomarker for Prenatal Ethanol Exposure
Authors: Bearer Cynthia F. , Lee Siemay , Salvator Ann E. , Minnes Sonia , Swick Alan , Yamashita Toyoko , Singer Lynn T.
Published: May 2006

Background: Fetal alcohol syndrome, fetal alcohol effects, alcohol‐related neurodevelopmental disorder, and alcohol‐related birth defects, all terms referring to the spectrum of consequences of in utero exposure to ethanol, are a major public health burden. There is currently no laboratory test to identify newborns exposed to ethanol in utero. Meconium was analyzed for ethyl linoleate, a metabolite of ethanol, as a biological marker for fetal ethanol exposure. Methods: Samples of meconium were obtained from 248 infants and analyzed for fatty acid ethyl esters. Detailed maternal alcohol, tobacco, and drug use histories were obtained within 1 month of giving birth. Results: The detection of ethyl linoleate in meconium was called a positive test. The mean number of drinks reported per week in the month before pregnancy, the first trimester, and overall were significantly higher in the positive group (unadjusted: 9.2 ± 1.9 vs. 4.3 ± 1.4, p= 0.004; 7.3 ± 1.7 vs. 3.8 ± 1.2, p= 0.03; and 6.1 ± 1.3 vs. 3.0 ± 1.0, p= 0.006). A positive test was not associated with marijuana, cocaine, or tobacco use. Sensitivity and specificity of the test were 72% and 51% to distinguish women who reported 1 or more drinks/week in the third trimester from women who denied use, and 68% and 48% to distinguish women who used 1 drink/week from women who used <1 drink/week in the month before pregnancy. Conclusions: The presence of ethyl linoleate in meconium is the first reported biological marker for maternal ethanol use during pregnancy. Because of the inherent inaccuracy associated with the use of self‐reporting, the establishment of true values of sensitivity and specificity will require validation where the presence, quantity, and timing of exposure to alcohol is known. Further validation of this marker will permit identification and intervention of at‐risk infants.
Alcoholic Pancreatitis and Polymorphisms of the Variable Length Polythymidine Tract in the Cystic Fibrosis Gene
Authors: Haber Paul S. , Norris Murray D. , Apte Minoti V. , Rodgers Sally C. , Norton Ian D. , Pirola Romano C. , Roberts‐Thomson Ian C. , Wilson Jeremy S.
Published: May 2006

Background: The observation that only a minority of alcoholics develops clinical pancreatic disease has led to a search for a predisposing factor to the disease. One possible predisposing factor is mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) gene as cystic fibrosis leads to pancreatic injury. We have recently demonstrated that 15 common CFTR mutations are not found in patients with alcoholic pancreatitis. Another common polymorphism of the CFTR gene has recently been implicated in the pathogenesis of idiopathic chronic pancreatitis, the 5T variant of the variable length polythymidine tract in intron 8 (the normal genotypes are 7T and 9T). The 5T variant inhibits transcription of exon 9 resulting in a CFTR protein lacking chloride channel activity. The aim of this study was to determine whether the 5T variant is associated with alcoholic pancreatitis. Methods: Fifty‐two patients with alcoholic pancreatitis were identified using standardized diagnostic criteria. Fifty alcoholics without pancreatitis were also studied as controls. Genomic DNA was extracted from peripheral blood leukocytes and the polythymidine tract of intron 8 was amplified by nested polymerase chain reaction using established primers. The polymerase chain reaction products were digested with Msel, separated by electrophoresis on 15% polyacrylamide gels and genotypes assigned by comparison with known positive controls. Results: The 5T allele was found in only two patients with alcoholic pancreatitis (3.9% of the index group; 95% confidence intervals 0‐10%) and in seven alcoholic controls. Allele frequencies for 5T, 7T, and 9T in patients with alcoholic pancreatitis were 1.9%, 85.6%, and 12.5%, respectively. These did not differ from the allele frequencies in alcoholic controls (7%, 79%, and 14% for 5T, 7T, and 9T, respectively). Conclusion: The 5T allele was not associated with alcoholic pancreatitis. Individual susceptibility to this disease remains unexplained.
Parallels to Early Onset Alcohol Use in the Relationship of Early Onset Smoking with Drug Use and DSM‐IV Drug and Depressive Disorders: Findings From the National Longitudinal Epidemiologic Survey
Authors: Hanna Eleanor Z. , Grant Bridget F.
Published: May 2006

This paper endeavored to determine (1) if early onset of regular tobacco use is as predictive of drug use and depressive disorders as it is of alcohol use disorders; and (2) if a biological commonality, as measured by a family history of alcoholism and both early onset and severity of disease, among all three disorders can be evidenced in a large nationally representative sample. Prevalences of lifetime drug use, drug abuse and dependence, and major depressive disorders, as well as indices of their severity, were compared among smoking groups defined by age at onset of regular tobacco use and among nonsmokers. Linear logistic regression analyses, controlling for important covariates, including a family history positive for alcoholism, were conducted to assess the relationship between age at smoking onset and drug use, abuse and dependence, as well as depressive disorders. Both objectives were met. Moreover, results suggest that smoking may play an equally, if not even more, insidious role than drinking in the use and development of dependence on illicit substances and depression.
Drinking Patterns and Problems: A Comparison of Two Black Primary Care Samples in Two Regions
Authors: Cherpitel Cheryl J.
Published: May 2006

This paper explores the effect of regional (“wet” vs. “dry”) variation in drinking patterns and problems on the prevalence of alcohol‐related problems among those seeking care in primary care settings. A sample of black primary care patients interviewed in Hinds County, MS (n= 740) and in Contra Costa County, CA (n= 93) are compared on quantity and frequency of usual drinking, drunkenness, consequences of drinking, and alcohol dependence. Controlling for demographic differences in logistic regression analysis, drinkers in Contra Costa, while no more likely to report heavy drinking, were four times more likely to report alcohol‐related consequences, more than five times more likely to report alcohol dependence experiences, and more than nine and a half times more likely to report ever having had treatment for an alcohol problem than those in Hinds County. Data suggest that regional variations in drinking patterns may be reflected in alcohol involvement in primary care caseloads, and that the large variation in the prevalence of alcohol‐related problems found in primary care settings may, in part, be attributable to this. All primary care settings do not appear to hold equal promise for screening for and intervening with problem drinking, and further research is needed in determining those settings that provide the greatest potential for targeting prevention efforts.
Cerebrospinal Fluid Tau Protein Levels in Demented and Nondemented Alcoholics
Authors: Morikawa Yu‐ichi , Arai Hiroyuki , Matsushita Sachio , Kato Motoichiro , Higuchi Susumu , Miura Masakazu , Kawakami Hisako , Higuchi Makoto , Okamura Nobuyuki , Tashiro Manabu , Matsui Toshifumi , Sasaki Hidetada
Published: May 2006

The tau protein levels in cerebrospinal fluid (CSF‐tau) were examined in 27 patients with alcohol dependence (20 demented and 7 nondemented), 36 age and dementia severity‐matched patients with Alzheimer's disease (AD), and 23 age‐matched normal control subjects. The CSF‐tau levels in the demented alcoholic group (alcohol‐induced organic brain disorders, 25.4 ± 10.2 pg/ml) was significantly lower (p < 0.0001) than that in the AD group (96.1 ± 53.3 pg/ml), but not significantly different from that in the nondemented alcoholics (18.1 ± 10.2 pg/ml) or the controls (19.2 ± 12.9 pg/ml). Using a 44.9 pg/ml as a cut‐off value (mean + 2 SD of the normal control group), only one patient with alcohol‐induced organic brain disorders exceeded the value, whereas 3 of 36 of the AD group showed CSF‐tau levels less than this level. These findings suggest that alcohol‐induced organic brain disorders are a group of dementias that are characterized by normal CSF‐tau levels, and that the CSF examination for tau in combination with other clinical findings may help in differentiating alcohol‐induced organic brain disorders from AD.
Visual P3a in Male Alcoholics and Controls
Authors: Holguin Socorro Rodriguez , Porjesz Bernice , Chorlian David B. , Polich John , Begleiter Henri
Published: May 2006

The goal of this study was to assess the P3a component of event‐related potentials in a population of abstinent, chronic alcoholics. A three‐stimulus visual oddball paradigm was used to elicit robust P3a components in a large group of well‐characterized male alcoholics (n= 44) and controls (n= 28). The task required subjects to make a difficult perceptual discrimination between randomly presented, frequently occurring vertical lines (.80) and infrequent target lines that were tilted 2° to the right of vertical (.10) by only responding with a button press to the target stimuli. A nontarget infrequent horizontal line occurred (.10) randomly to which no response was made. The target stimulus elicited robust late P3b components with a parietal maximum amplitude, and the nontarget stimulus elicited reliable P3a components with a fronto‐central maximum amplitude distribution. Group differences in P3a were assessed using repeated measures ANCOVA analyses in five scalp regions. Alcoholic subjects produced smaller P3a amplitudes over the central, parietal, temporal, and occipital areas compared with controls. Current source density analyses supported these findings with extension of the differences between the groups to the frontal region. The results suggest that the P3a may be important in the evaluation of alcoholism and its heritability. Theoretical implications are discussed.
No Association BetweenDRD2Locus and Alcoholism After Controlling theADHandALDHGenotypes in Chinese Han Population
Authors: Lee Jia‐Fu , Lu Ru‐Band , Ko Huei‐Chen , Chang Fong‐Ming , Yin Shih‐Jiun , Pakstis Andrew J. , Kidd Kenneth K.
Published: May 2006

Background:Recent studies on the genetics of alcoholism have examined the association between alcoholism and the dopamine D2 receptor locus(DRD2); our study of Chinese Han gave negative results (Lu et al., 1996). The different genotypes at the genes encoding the enzymes involved in alcohol metabolism, class one alcohol dehydrogenase (ADH2 and ADH3) and mitochondrial aldehyde dehydrogenase (ALDH2), have previously been shown to confer different predispositions to the development of alcoholism in Chinese Han males (Thomasson et al., 1991; Chen WJ et al., 1996; Chen CC et al., unpublished data). Therefore, association studies of alcoholism in Chinese Han might be more sensitive if controlled for the genotypes ofADH2, ADH3, and ALDH2, when other loci, such asDRD2, are examined. This study employs such controls to evaluate the evidence for an association between alcoholism andTaqI‐AandTaqI‐Bgenotypes and haplotypes atDRD2in the Chinese Han population.

Methods:We studied 213 Chinese Han subjects (128 alcoholics and 85 nonalcoholics) with alcohol dependence defined according to DSM‐III‐R criteria.

Results:Significant linkage disequilibrium was observed between theTaqI‐AandTaqI‐Bsites at theDRD2locus, as previously seen in smaller samples, but no significant association was observed between these genetic variants at theDRD2locus and alcoholism in Chinese Han. Several different stratifications byADHandALDH2genotypes were examined; no genotypes or haplotypes atDRD2differ between alcoholics and nonalcoholics except for a small number of nominally significant p‐values which do not constitute significant results given the many tests done, some of which are not independent of one another due to linkage disequilibrium. These tests included considering the high risk (ADH2*1/*1; *l/*2;ADH3*l/*2; *2/*2; and ALDH2*l/*l)and the low risk(ADH2*2/*2;ADH3*1/*1;andALDH2*1/*2; *2/*2)groups of alcoholics, as well as nonalcoholic controls.

Conclusions:After stratification by the relevant genotypes ofADH2, ADH3, andALDH2no significant association exists between the genetic variants at theDRD2locus and alcoholism in the Chinese Han population.
Estrogen‐Dependent Hypotensive Effects of Ethanol in Conscious Female Rats
Authors: El‐Mas Mahmoud M. , Abdel‐Rahman Abdel A.
Published: May 2006

This study investigated the role of estrogen in the acute hemodynamic responses to intragastric (ig) ethanol in conscious female rats. Changes evoked by ethanol or equal volume of water in mean arterial pressure, heart rate, cardiac index, stroke volume (SV), and total peripheral resistance were followed in sham‐operated, ovariectomy (OVX) vehicle‐treated (OVX‐veh), and OVX 17/3‐estradiol (E2)‐treatcd (OVX‐E2) Sprague‐Dawley rats. Plasma norepinephrine (NE) was measured as an index of sympathetic activity. In sham‐operated rats, ethanol caused significant decreases in mean arterial pressure that were associated with significant reductions in cardiac index and SV, whereas total peripheral resistance was not changed. Measured plasma NE levels were not affected by ethanol except for a significant reduction observed one time. OVX abolished the hypotensive effect of ethanol and the associated decreases in cardiac output, SV, and plasma NE. Treatment of OVX rats with E2 restored the hypotensive and sym‐pathoinhibitory (decreases in plasma NE) responses to ethanol. Blood ethanol concentrations were not affected by OVX or subsequent E2 administration. These findings suggest that intragastric ethanol elicits estrogen‐dependent decreases in blood pressure in female rats, which results mainly from a reduction in cardiac output. The mechanism by which ethanol elicits E2‐dependent hypotension remains to be determined.
Conversion of Acetaldehyde‐Protein Adduct Epitopes From a Nonreduced to a Reduced Phenotype by Antigen Processing Cells
Authors: Klassen Lynell W. , Jones Bonnie L , Sorrell Michael F. , Tuma Dean J. , Thiele Geoffrey M.
Published: May 2006

Many investigators have suggested that an immune reaction to acctaldchydc‐protein adducts may be involved in the development and/or progression of alcohol liver disease. The most often reported acetaldehyde adduct is the reduced adduct prepared in vitro in the presence of strong reducing agents. However, the production of this adduct in vivo has been difficult to prove. Nevertheless, the detection of scrum antibodies to this reduced adduct following alcohol exposure in animals and humans has been used to support the formation of this adduct in vivo. We have recently observed that when acetaldehyde‐protein adducts prepared under nonrcducing conditions are used to immunize animals, antibody to the reduced protein adduct is detected. Therefore, it was the purpose of this study to demonstrate that nonreduced (NR) adduct epitopes can be modified by intact cells to express reduced (R) adduct epitopes. This was accomplished using the monoclonal antibody RT1.1 that has been previously characterized by this laboratory and has been shown to recognize only R and not NR acetaldchyde adducts. In these studies, Balb/c mice were injected intraperitoneally (500 μg/animal) with either keyhole limpet hemocyanin (KLH)‐NR or KLH‐R adductcd proteins. Immunization with KLH‐NR produced significant amounts of antibodies that recognized both NR and R epitopes. In contrast, immunization with KLH‐R produced antibodies to only R and not NR epitopes. Isolated peritoneal macrophages from nonimmunized mice were incubated in vitro with either KLH‐NR, KLH‐R, or unmodified KLH proteins, and the cell surface expression of the reduced epitope (RT1.1) and the activated macrophage marker (MAC‐3) determined by double immunofluores‐cent staining. Activated macrophages incubated with KLH‐NR expressed the R adduct on 11.5% of the cells, compared with 3.8% following incubation with unmodified KLH, and 19.4% following incubation with KLH‐R. These data suggest that the NR adduct and/or the carrier protein are modified by peritoneal macrophages in vivo and present an epitope that is detected as a reduced adduct (RT1.1 positive). These observations may explain the presence of circulating antibodies to the reduced adduct that has been reported in human and animal studies.
Motivational Effects of Alcohol on Memory Consolidation and Heart Rate in Social Drinkers
Authors: Bruce Kenneth R. , Shestowsky John S. , Mayerovitch Jamie I. , Pihl R. O.
Published: May 2006

Several studies have documented the retrograde facilitation of memory by alcohol, but the mechanisms responsible for this curious effect are unknown. In an experiment designed to complement previous studies on incidental learning, social drinkers (men aged 18 to 30; n= 44) took part in an experiment examining the effects of alcohol on intentional learning of emotionally salient verbal stimuli. Learning occurred when participants were sober. Alcohol or placebo (1.0 vs. 0.1 ml/kg) was consumed after learning, and memory was tested, sober, 24 hr later. Compared with placebo, alcohol modestly enhanced recall of positive but not negative stimuli. Furthermore, results suggest that the reinforcing effects on memory for positive (relative to negative) stimuli occurred in association with acute psychomotor stimulant effects during the ascending limb of the blood alcohol curve. The present finding that alcohol appeared to enhance intentional learning in association with its incentive effects contrasts results from previous studies, demonstrating that alcohol appears to enhance incidental learning by memory mechanisms independent of its incentive effects. These findings support a theory of alcoholism that is based on motivational systems.
Effects of Alcohol Intake and Low Km Aldehyde Dehydrogenase on Hepatic Function in a High Hepatitis C Virus‐Prevalent Japanese Island Population
Authors: Yang Xing , Takeshita Tatsuya , Hirata Mari , Sato Shigeaki , Morimoto Kanehisa
Published: May 2006

In Asians from the Pacific rim countries, alcohol sensitivity has been attributed mainly to a highly prevalent polymorphism in low Km aldehyde dehydrogenase (ALDH2). Chronic alcohol abuse may accelerate or aggravate the liver injury in chronic hepatitis C virus (HCV)‐infected subjects. In this study, we examined the relationships among alcohol intake, ALDH2 genotypes, and liver injury in a high HCV‐prevalent Japanese native island population. The ALDH2 genotypes are significantly associated with drinking habits. In HCV RNA positive subjects, serum alanine aminotransferase (ALT), as well as aspartate transaminase (AST) and γ‐glutamyl transpeptidase (GGT), were significantly higher in habitual drinkers than in nonhabitual drinkers. In male habitual drinkers, the ALDH2*1/*1 subjects had higher liver necroinflammatory scores than the ALDH2*1/*2 subjects in all groups classified as: I, anti‐HCV‐seronegative; II, anti‐HCV‐seropositive with negative HCV RNA; and III, HCV RNA positive, although scores for the latter two groups were not statistically significant because of limited sample size. It was suggested that the liver function might be affected by the interaction between the ALDH2 genotypes and alcohol intake. These findings indicate that HCV‐infected ALDH2*1/*1 habitual drinkers are the major target for the prevention of alcoholic liver diseases.
The Heritability of Alcoholism Symptoms: “Indicators of Genetic and Environmental Influence in Alcohol‐Dependent Individuals” Revisited
Authors: Slutske Wendy S. , True William R. , Scherrer Jeffrey F. , Heath Andrew C. , Bucholz Kathleen K. , Eisen Seth A. , Goldberg Jack , Lyons Michael J. , Tsuang Ming T.
Published: May 2006

There is consistent evidence from twin and adoption studies implicating genetic factors in the etiology of alcoholism, yet few studies have examined the role of genetic influences on individual symptoms of alcoholism. In a previous study of 113 male twins, Johnson et al. (1996a) identified 7 alcoholism symptoms that were more “genetic” and 14 that were more “environmental” (that is, non‐genetic) in their etiology by examining symptom concordances among monozygotic and dizygotic twin pairs. The present study represents an attempt to replicate the results of this previous study and extend them by estimating the contribution of genetic factors to the variation in liability for different alcoholism symptoms. Subjects were 3356 male twin pairs from the Vietnam Era Twin Registry. Lifetime histories of alcoholism symptoms were assessed by a structured psychiatric telephone interview. The results of the previous study were not replicated. The correlations between symptom classifications as genetic and non‐genetic in the present and previous study were nonsignificant and ranged from ‐0.27 to 0.11. However, within the present study the correlation between symptom classifications as genetic and non‐genetic was statistically significant across random split‐half subsamples (r= 0.59); nine alcoholism symptoms were consistently classified as genetic and six symptoms as non‐genetic in their etiology. Model‐fitting analyses applied to different alcoholism symptoms yielded heritability estimates ranging from 0.03 to 0.53 with broad and overlapping confidence intervals around these estimates, ranging from 0.00 to 0.65. The results of this study highlight the difficulty of identifying more or less heritable phenotypes in twin research, and suggest that it may not be possible to identify specific alcoholism symptoms that are more genetic in their etiology than others. Nevertheless, there appears to be potentially important variation in the relative magnitude of genetic influences for individual alcoholism symptoms, and exploring these differences may lead to further insights into the nosology and etiology of alcohol‐related problems.
Differential Effects of Ethanol on Insulin‐Signaling Through the Insulin Receptor Substrate‐1
Authors: de la Monte S. M. , Ganju N. , Tanaka S. , Banerjee K. , Karl P. J. , Brown N. V. , Wands J. R.
Published: May 2006

Insulin stimulation increases cell proliferation and energy metabolism by activating the insulin receptor substrate I (IRS‐1)‐signaling pathways. This downstream signaling is mediated by interactions of specific tyrosyl phosphorylated (PY) IRS‐1 motifs with SH2‐containing molecules such as growth‐factor receptor‐bound protein 2 (Grb2) and Syp. Ethanol inhibits insulin‐stimulated tyrosyl phosphorylation of IRS‐1 and DNA synthesis. This study explores the roles of the Grb2‐ and Syp‐binding motifs of IRS‐1 in relation to the inhibitory effects of ethanol on insulin‐stimulated DNA synthesis, proliferating cell nuclear antigen (PENA) and glyceraldehyde 3‐phosphate dehydrogenase (GAPDH) expression, and activation of mitogen‐activated protein kinase (MAPK), which is known to be essential for cell proliferation. NIH3T3 cells were stably transfected with wild‐type IRS‐1, or IRS‐1 mutated at the Grb2 (IRS‐lΔGrb2), Syp (IRS‐lΔSyp), or Grb2 and Syp (IRS‐lΔGrb2ΔSyp)‐ binding sites. Cells transfected with IRS‐1 had increased levels of DNA synthesis, PCNA, GAPDH, and activated MAPK. The IRS‐lΔGrb2 transfectants were highly responsive to insulin stimulation, achieving levels of GAPDH, PCNA, and activated MAPK that were higher than control. In contrast, the IRS‐IΔSyp and IRS‐lΔGrb2ΔSyp transfectants had reduced levels of DNA synthesis, PCNA, and activated MAPK. Ethanol exposure decreased insulin‐stimulated DNA synthesis, PCNA, GAPDH, and activated MAPK levels in all clones, but the wild‐type IRS‐1 transfectants were relatively resistant, and the IRS‐IΔGrb2 transfectants were extraordinarily sensitive to these inhibitory effects of ethanol. The findings suggest that insulin‐stimulated DNA synthesis and PCNA expression are mediated through the Syp‐binding domain, whereas GAPDH expression and MAPK activation are modulated through both the Grb2 and Syp motifs of IRS‐1. In addition, ethanol exposure may preferentially inhibit downstream signaling that requires interaction between Syp and PY‐IRS‐1.
Potentiation of Calcium‐Mediated Stimulation of DNA Synthesis by Ethanol in Human and Mouse Fibroblasts
Authors: Crilly Karan S. , Li Jingxia , Anderson Wayne H. , Kiss Zoltan
Published: May 2006

Alcohol abuse is a risk factor for cancers of the gastrointestinal tract, and it also can precipitate psoriasis characterized by hyperproliferation of epidermal cells. Because these effects of alcohol may involve stimulation of cell growth, and ethanol (EtOH) was shown to enhance DNA synthesis in mouse fibroblasts and epidermal cells, we conducted a study to determine whether EtOH can also stimulate mitogenesis in human fibroblasts and keratinocytes. In keratinocytes, EtOH had no effects on mitogenesis after shorter (17‐hr) treatments, but it partially prevented inhibition of DNA synthesis elicited by longer treatments (3‐4 days) with 2 mM calcium (Ca2+), a differentiation‐inducing agent. In contrast, treatment of serum‐starved zinc‐treated (40 μM) human skin fibroblasts with 50‐60 mM EtOH for 17 hr resulted in increased DNA synthesis. EtOH‐induced DNA synthesis was blocked by 1 mM EGTA, a specific Ca2+ chelator. Despite the presence of 1.8 mM Ca2+ in the cell culture medium, the addition of 1 mM extra Ca2+ (final concentration, 2.8 mM) for 17 hr induced DNA synthesis, presumably mediated by Ca2+ receptors. In eight independent human skin fibroblast lines examined, treatment with EtOH for 46 hr, but not for 17 hr, invariably enhanced the effects of Ca2+ on DNA synthesis, consistent with synergistic stimulation of cell proliferation by EtOH and Ca2+. Neomycin, a Ca2+ receptor agonist, and EtOH also exerted synergistic effects on DNA synthesis after longer (46‐hr) treatments. In mouse NIH 3T3 fibroblasts, both EtOH‐ and Ca2+ ‐enhanced DNA synthesis after 17‐hr treatment, but they stimulated cell proliferation only in combination. The results indicate that in human fibroblasts, EtOH can potentiate the longer‐term effects of high concentrations of Ca2+ on DNA synthesis whereas, in keratinocytes, EtOH may inhibit Ca2+ ‐induced differentiation.
Chronic Ethanol Exposure Enhances Signaling Through Muscarinic Receptors Expressed by cRNA Injection in Xenopus Oocytes: Implications for Mechanism of Action
Authors: Hönemann Christian W. , Wong Andrea , Arledge John A. M. , Durieux Marcel E.
Published: May 2006

The molecular mechanisms underlying the cerebral symptoms of ethanol withdrawal syndrome are poorly understood. In addition to ethanol's effect on GABA and NMDA receptors, ethanol affects muscarinic acetylcholine signaling. This interaction has attracted attention because of the importance of muscarinic signaling in consciousness. Chronic ethanol exposure increases muscarinic receptor binding. Increased transcription of receptor message has been suggested as the underlying mechanism, but this hypothesis has not been tested directly. Therefore, we studied the effects of ethanol on muscarinic signaling in a model that bypasses transcription of muscarinic receptor genes. We expressed rat m1 muscarinic receptors by cRNA microinjection in Xenopus oocytes. Cells were voltage‐clamped at ‐70 mV and effects of prolonged (24, 48, and 72 hr) exposure to ethanol (25, 50, and 100 mM) on methylcholine‐induced calcium‐activated Cl‐ currents were determined. Effects of prolonged ethanol exposure on currents induced by stimulation of lysophosphatidate receptors, direct G protein activation, or inositol trisphosphate receptor activation were studied as well. Prolonged ethanol exposure enhanced methylcholine (or lysophosphatidate‐)‐induced currents in a time‐ and concentration‐dependent manner. Thus, enhanced muscarinic gene transcription is not required for ethanol enhancement of muscarinic signaling. Lack of ethanol effect on inositol trisphosphate‐induced signaling suggests that intracellular signaling systems downstream of phospholipase C are not involved. In contrast, currents induced by direct G protein stimulation were enhanced significantly. Therefore, one potential site of ethanol's action on muscarinic signaling is upregulation of the associated G protein or enhancement of its functioning.
AcuteLead Acetate Administration Potentiates Ethanol‐Induced Locomotor Activity in Mice: The Role of Brain Catalase
Authors: Correa M. , Miquel M. , Sanchis‐Segura C. , Aragon C.M.G.
Published: May 2006

It has been proposed that brain catalase plays a role in the modulation of some psychopharmacological effects of ethanol. The acute administration of lead acetate has dcmonstrated a transient increase in several antioxidant cell mechanisms, including catalase. In the present study, we investigated the effects of acute lead acetate administration on ethanol‐induced behavior, brain catalase activity, and the relation between both effccts. Lead acetate (100 mgkg) or saline was injected intraperitoneally in mice. At different intervals of time (1.3, 5, 7, 9, or 11 days) after this treatment, ethanol (2.5 g/kg) was injected intraperitoneally and the mice were placed in open field chambers. Results indicated that the locomotor activity induced by ethanol was significantly increased. Maximum ethanol‐induced locomotion increase (70% more activity than control animals) was found in animals treated with lead acetate 7 days before ethanol administration. Total brain catalase activity in lead‐pretreated animals also showed a significant induction, which was maximum 7 days after lead administration. A significant correlation was found between both effects of locomotor and catalase activity. In a second study, the effect of lead administration on d‐amphetamine (2.0 mg/kg) and tert‐butanol‐ (0.5 g/kg) induced locomotor activity was investigated. Lead acetatc treatment did not affect the locomotion induced by these drugs. These data suggest that brain catalase is involved in cthanol's effects. They also provide furthcr support for the notion that acetaldehyde may be produced directly in the brain via catalase and that it may be a factor mediating some of ethanol's central effects.
Alcohol Effects on Mood, Equilibrium, and Simulated Driving
Authors: Liguori Anthony , D'Agostino Ralph B. , Dworkin Steven I. , Edwards Don , Robinson John H.
Published: May 2006

Background

: The effects of alcohol on simple versus complex psychomotor performance were compared in 18 adults.

Methods

: Subjects received ethanol doses of 0.0, 0.5, and 0.8 g/kg in a randomized, double‐blind, within‐subject design. Forty minutes after finishing their drinking, the subjects completed a 60‐min battery of tests that included: 1) a sensory organization posturography test (EquiTest); 2) latency to apply the brake after appearance of a barrier in a driving simulator (brake reaction time); 3) visual analog subjective‐effects scales (VAS); 4) the Profile of Mood States (POMS); 5) critical flicker fusion (CFF); and 6) choice reaction time (CRT).

Results

: Alcohol dose dependently reduced composite equilibrium scores and increased brake reaction time. On the CRT task, total reaction time was significantly increased after the high dose but not the low dose. Alcohol dose dependently increased VAS “dizzy,”“high,” and “drug effect” ratings. The POMS and CFF were not significantly affected by alcohol.

Conclusions

: These data suggest that an ethanol dose that neither influences certain mood states nor impairs simple psychomotor task performance nonetheless may impair equilibrium and complex psychomotor tasks (e.g., driving).
Prospective Study of Alcohol Consumption Patterns in Relation to Symptomatic Gallstone Disease in Men
Authors: Leitzmann Michael F. , Giovannucci Edward L. , Stampfer Meir J. , Spiegelman Donna , Colditz Graham A. , Willett Walter C. , Rimm Eric B.
Published: May 2006

Although the association between alcohol intake and gallstone disease has been characterized previously, the relation between alcohol consumption patterns, specific types of alcoholic beverages, and risk for cholelithiasis has not been addressed systematically. These issues were examined prospectively in a cohort of men who were free from symptomatic gallstone disease in 1986 and were followed to 1996. During follow‐up, 2.4% of the men reported newly symptomatic gallstones that were diagnosed by ultrasonography or x‐ray, or a cholecystectomy.

After adjusting for other known or suspected risk factors, an increase in the amount of alcohol consumed was associated with a decreased risk of symptomatic gallstone disease. An increase in frequency of alcohol consumption also was related to decreased risk. Combining the reports of quantity and frequency of alcohol intake, a consumption pattern that reflected frequent intake (5‐7 days/week) of any given amount of alcohol was associated with a decreased risk, as compared with nondrinkers. In contrast, infrequent alcohol intake (1‐2 days/week) showed no significant association with risk. All alcoholic beverage types were inversely associated with risk of symptomatic gallstone disease, independent of patterns of consumption.

These results suggest that frequent, moderate intake of alcohol decreases the risk for symptomatic gallstone disease, in contrast to infrequent or episodic alcohol intake. Recommendations regarding the benefit of moderate quantities of alcohol for gallstone disease should be weighed against the potential health hazards of alcohol consumption.
Effect of Acute Ethanol Administration on Toloxatone Pharmacokinetics in Rabbits
Authors: Kaltenbach Matthieu L. , Vistelle Richard , Hoizey Guillaume , Larniable Denis , Zbierski Liliane
Published: May 2006

The pharmacokinetics of toloxatone and ethanol were determined in plasma and cerebrospinal fluid of conscious rabbits. According to a cross‐over design, rabbits (n= 5) randomly received on three separate occasions either toloxatone (5 mg/kg), ethanol (1 g/kg), or toloxatone and ethanol (5 mg/kg and 1 g/kg, respectively) by intravenous injection. Toloxatone and ethanol concentrations were measured by HPLC with UV detection and GC with flame ionization detection, respectively. Ethanol concentration profiles in plasma were characterized by a rapid decline occurring within the first 30 min after administration followed by a linear (zero‐order) phase that persisted for the length of the experiment. The maximum ethanol elimination rate was 0.31 ± 0.20 g/h.kg. Toloxatone concentrations in plasma and cerebrospinal fluid were characterized by a multiexponential decay with effective half‐lives of 0.39 ± 0.06 and 0.56 ± 0.07 hr, respectively. Toloxatone passage through the blood brain barrier was rapid and important. Our results also demonstrate that acute ethanol administration had no effect on toloxatone pharmacokinetics and that toloxatone administration had no effect on ethanol pharmacokinetics.
Intracellular Signaling Pathways in Stellate Cell Activation
Authors: Britton Robert S. , Bacon Bruce R.
Published: May 2006

Pathological fibrogenesis in the liver is mediated by activated stellate cells. These cells have a myofibroblastic phenotype with the ability to proliferate and synthesize large quantities of extracellular matrix coniponents. A number of factors have been proposed to initiate and perpetuate the fibrogenic process in stellate cells, including inflammatory cytokines, alterations in the extracellular matrix, growth factors, and oxidative stress. Some recent research has focused on the intracellular signaling pathways that are stimulated by these factors in stellate cells. including mitogen‐activated protein kinases, phosphatidylinositol 3‐kinase, focal adhesion kinase, and protein kinase C. This paper will summarize the experimental evidence that implicates these pathways in stellate cell activation, focusing on the effects of exposure to platelet‐derived growth factor, tumor necrosis factor‐α, and fibronectin. Implications for alcohol‐induced hepatic fibrosis and future directions for research will also be discussed.
Tissue Inhibitors of Metalloproteinases: Role in Liver Fibrosis and Alcoholic Liver Disease
Authors: Arthur Michael J. P. , Iredale John P. , Mann Derek A.
Published: May 2006

In liver fibrosis, activated hepatic stellate cells (HSC) play a major role in the deposition of excess extracellular matrix, including fibrillar collagens type I and type III. In addition to matrix protein synthesis, HSC regulate matrix degradation in the liver. This is mediated via a combination of synthesis of matrix (pro)metalloproteinases, which activate these zymogens via specific mechanisms and by inhibiting the active matrix‐degrading enzymes via expression of tissue inhibitors of metalloproteinases (TIMPs). There are currently four members of the TIMP family described and of these, both TIMP‐1 and TIMP‐2 are synthesised by HSC. These observations have led to the suggestion that inhibition of matrix degradation mediated by a change in HSC‐expression of TIMPs relative to metalloproteinases, such as interstitial collagenase, may contribute to progression of liver fibrosis. This hypothesis is supported by studies of human liver disease in which TIMP‐1 expression is upregulated 5‐fold in cirrhotic compared with normal liver. TIMP‐1 and TIMP‐2 expression is also upregulated in animal models of progressive fibrosis, whereas expression of collagenase is unchanged. In a model which is characterized by natural resolution of liver fibrosis, degradation of the deposited fibrillar liver matrix is accompanied by rapid down‐regulation of TIMP‐1 expression.

In alcoholic liver disease, the role of TIMPs has not been studied exhaustively, but the evidence currently available supports a role for inhibition of matrix degradation by TIMPs in this progressive fibrotic liver disease.