bluuebunny/crossref_metadata_2025_split huggingface dataset:
Binge Pattern Ethanol Exposure in Adolescent and Adult Rats: Differential Impact on Subsequent Responsiveness to Ethanol
Authors: White Aaron M. , Ghia Amol J. , Levin Edward D. , Swartzwelder H. Scott 
Published: April 2006

Background: Recent evidence indicates that adolescent animals are more sensitive than adults to the disruptive effects of acute ethanol exposure on spatial learning. It is not yet known whether adolescent animals are also more sensitive than adults to the enduring neurobehavioral effects of repeated ethanol exposure. In this study, animals were exposed to ethanol in a binge‐pattern during either adolescence or adulthood. At a time when all subjects were adults, spatial working memory was examined in the absence and presence of an acute ethanol challenge.Methods: Rats were exposed to ethanol (5.0 g/kg intraperitoneally) or isovolumetric saline at 48 hr intervals over 20 days. Exposure began on either postnatal day 30 (adolescent group) or 70 (adult group). Twenty days after the final injection, a time at which all animals were adults, the subjects were tested on an elevated plus maze and then were trained to perform a spatial working memory task on an eight‐arm radial maze. At the beginning of each session of training on the working memory task, subjects retrieved food rewards on four of the eight arms. After a delay, subjects were placed on the maze and allowed to retrieve food from the remaining four arms.Results: Prior exposure to ethanol did not influence behavior on the plus maze. Performance of the groups did not differ during acquisition of the spatial working memory task with a 5 min delay or during subsequent testing with a 1 hr delay. However, animals treated with ethanol during adolescence exhibited larger working memory impairments during an ethanol challenge (1.5 g/kg intraperitoneally) than subjects in the other three groups.Conclusions: The findings indicate that binge pattern exposure to ethanol during adolescence enhances responsiveness to the memory‐impairing effects of ethanol in adulthood.
Alcohol and Eating Disorders: Implications for Alcohol Treatment and Health Services Research
Authors: Sinha Rajita , O'Malley Stephanie S. 
Published: April 2006

Background: This paper focuses on the co‐occurrence of alcoholism and eating disorders and the clinical implications for treating this comorbidity in women with alcohol use disorders. There is substantial literature that supports higher than expected rates of co‐occurrence of these two disorders. In addition, there is evidence that the co‐occurrence of alcoholism and eating disorders is more likely to occur in the presence of other psychiatric disorders. A critical analysis of the studies on the comorbidity of these disorders is conducted along with a review of the possible etiologic association between the two disorders. Crucial questions related to pharmacological and behavioral treatments for this subgroup of alcoholic women with eating disorders are raised from a health services research perspective.Conclusions: There is substantial evidence that alcoholism and eating disorders co‐occur at high rates. However, as this review points out, several important research questions remain regarding both the clinical manifestations of each problem in women who are comorbid for both disorders and the treatment implications.
Role of Phosphorylation in Ethanol‐Induced Aggregation of Keratin Intermediate Filaments
Authors: Negron Gerardo , Eckert Barry S. 
Published: April 2006

Background: Keratins are members of a diverse group of tissue‐specific cytoskeletal components known as intermediate filaments. Regulation of the structure and intracellular distribution of intermediate filaments is known to be related to the phosphorylation state of their structural subunits. It also is known that disruption of the keratin filaments of hepatocytes in response to chronic ethanol ingestion is characteristic of alcoholic liver disease.Methods: To characterize the mechanism of ethanol‐induced keratin filament reorganization and dephosphorylation, cells were grown in culture with and without ethanol, and then were treated at the end of the incubation period for 1 hr with either 8‐bromo‐adenosine 3′:5′‐cyclic monophosphate (8Br), water‐soluble forskolin (ws‐forskolin), H‐89 diHCL, or okadaic acid. Morphology of the cells was examined by immunofluorescence microscopy, and keratin phosphorylation levels were determined by analysis of 32P labeling.Results: We found that treatment of hepatoma cells with 300 mM ethanol results in disruption and aggregation of the keratin network in the vicinity of the nucleus as well as a hypophosphorylation of keratin subunits from ethanol‐treated cells compared with non‐ethanol‐treated controls. 8Br and ws‐forskolin treatment of ethanol groups restored keratin phosphorylation to control levels and reversed the ethanol‐induced aggregation of keratin filaments. When H‐89, an inhibitor of A‐kinase, was added to control cells, keratin filament disorganization and dephosphorylation was observed. H‐89 produced only a slight additional decrease in keratin phosphorylation in ethanol‐treated cells, with no change in keratin distribution. Okadaic acid treatment of control cells produced hyperphosphorylation and filament network disruption, whereas in ethanol groups a reversal of the ethanol‐mediated hypophosphorylation was observed but without reversal of the keratin filament aggregation.Conclusions: These results suggest that site‐specific phosphorylation of keratin filaments is important in maintaining their integrity and that activation of the A‐kinase system can antagonize the effects of ethanol, whereas its inhibition results in filament dephosphorylation and reorganization, mimicking effects of ethanol treatment.
Ethanol Pharmacokinetics in White Women: Nonlinear Model Fitting Versus Zero‐Order Elimination Analyses
Authors: Mumenthaler Martin S. , Taylor Joy L. , Yesavage Jerome A. 
Published: April 2006

Background: Studies have shown repeatedly that ethanol pharmacokinetics are not linear, yet most researchers still determine ethanol elimination by linear, zero‐order kinetics. The goals of the present work were to: (1) fit four nonlinear pharmacokinetic models to mean breath alcohol concentration (BrAC)‐time data of 27 women and determine the best‐fit model; (2) fit the determined best‐fit model to individual BrAC data and estimate the pharmacokinetic parameters; and (3) compare the method of nonlinear model fitting with the classical zero‐order elimination method and determine in which cases the classical approach is justified.Methods: Twenty‐seven healthy white women ingested four drinks (total of 0.67 g·kg−1) of ethanol on two test days. Approximately 24 breath ethanol samples (for pharmacokinetic analyses) and one blood sample (for hormonal markers) were taken per day. Pharmacokinetic model evaluation was based on the coefficient of variation, the weighted residual sum of squares, and the sequence of the weighted residuals. Because hormonal changes across the menstrual cycle did not significantly influence ethanol pharmacokinetics, data from the two test days were pooled.Results: The best‐fit model was a one‐compartment open model with first‐order absorption and sequential first‐order elimination, followed by Michaelis‐Menten elimination kinetics. Fitting this model to the individual BrAC data yielded mean ka= 0.062 hr−1, Vd= 0.457 L·kg−1, ke= 0.011 hr−1, Vmax= 0.136 g·L−1·hr−1, and Km= 0.096 g·L−1. For the classical analyses, mean time to peak BrAC = 1.83 hr, disappearance rate = 0.179 g·L−1·hr−1, and area under the blood ethanol‐time curve (AUC) = 2.884 g·L−1·hr. Correlational analyses showed that more frequent drinkers eliminated ethanol significantly faster and reached significantly lower AUC than less frequent drinkers.Conclusions: After multiple dose ingestion in white women, classical zero‐order elimination analyses can be applied only to a limited portion of the descending BrAC‐time curve. They seem justified and practical from 0.5 hr after peak BrAC until BrAC reaches 0.2 g·L−1. To describe ethanol pharmacokinetics across the entire BrAC‐time curve, however, sophisticated nonlinear model fitting is required.
Nicotinic Receptor Pore Mutations Create a Sensitive Inhibitory Site for Ethanol
Authors: Forman Stuart A. , Zhou Qing 
Published: April 2006

Background: Ethanol (EtOH) inhibition and enhancement of ligand‐gated ion channel functions may be due to direct interactions with sites on these membrane proteins. Peripheral nicotinic receptors have pore sites that long‐chain alcohols inhibit but EtOH does not, either because of weak binding (low affinity) or inability to impair ion translocation (low efficacy). We tested whether nicotinic pore mutations that increase hydrophobicity and/or size can create a site where EtOH inhibits at physiological concentrations.Methods: We studied recombinant expressed mouse muscle receptors with patch‐clamp electrophysiology to measure EtOH effects both on single‐channel conductance and on multichannel currents elicited with rapid agonist superfusion. We studied pairs of mutants with similar residue sizes but different hydrophobicities at position α252 to determine if size or hydrophobicity determines EtOH sensitivity.Results: Inhibition of wild‐type currents is seen at EtOH concentrations >300 mM. Receptors that contain the αS252I (serine to isoleucine) mutation are significantly inhibited by 100 mM EtOH. Adding a second homologous mutation on the β subunit (βT263I) further enhances sensitivity and creates receptors that are inhibited significantly by 50 mM EtOH. The open‐state conductance of single nicotinic channels is reduced in the presence of EtOH, which closely parallels EtOH inhibition of multichannel currents. In two isosteric mutant pairs at position α252, only hydrophobic side‐chains significantly increase receptor sensitivity to EtOH.Conclusions: Wild‐type nicotinic receptors have a very low affinity for EtOH, but only one or two mutations in the pore site create receptors inhibited by physiological EtOH concentrations. Ethanol inhibition is due primarily to channel interactions in the open state. At amino acid α252, side‐chain hydrophobicity, not size, determines receptor sensitivity to EtOH inhibition. We propose that similar sites may exist within the pores of other EtOH‐sensitive ion channels, such as NMDA receptors and neuronal nicotinic receptors.
Anti‐Interleukin‐6 Antibody Treatment Restores Cell‐Mediated Immune Function in Mice With Acute Ethanol Exposure Before Burn Trauma
Authors: Fontanilla Christine V. , Faunce Douglas E. , Gregory Meredith S. , Messingham Kelly A. N. , Durbin Elizabeth A. , Duffner Lisa A. , Kovacs Elizabeth J. 
Published: April 2006

Background: Previous studies from this laboratory reported that suppression of cell‐mediated immune function was coincident with elevated interleukin (IL)‐6 production after acute ethanol exposure before burn trauma, compared with either insult alone. The goal of this study was to investigate whether treatment with an anti‐IL‐6 antibody could restore immunocompetence in mice subjected to burn trauma with previous exposure to alcohol, as assessed by delayed‐type hypersensitivity (DTH) and mitogen‐induced splenocyte proliferative responses.Methods: Mice given an ethanol treatment designed to reach a blood alcohol level of 100 mg/dl before a 15% total body surface area burn injury were treated with an anti‐IL‐6 antibody at 30 min and 24 hr postinjury.Results: Burn/ethanol mice exhibited a 91% suppression of the DTH response (p < 0.01) and a 76% suppression of mitogen‐induced splenocyte proliferation (p < 0.01) at 48 hr postinjury, along with increased levels of circulating and splenic macrophage‐derived IL‐6, compared with all other treatment groups. After anti‐IL‐6 antibody administration to burn/ethanol mice, there was a 25% (p < 0.05) and 63% (p < 0.01) recovery of the DTH and splenocyte proliferative responses, respectively. Addition of exogenous IL‐6 to splenocyte cultures isolated from anti‐IL‐6 antibody‐treated burn/ethanol mice resulted in a 70% inhibition of mitogen‐induced proliferative responses (p < 0.03).Conclusions: These data confirm previous findings that burn in combination with acute ethanol exposure suppresses cell‐mediated immune function compared with either insult alone. Furthermore, the ability of the anti‐IL‐6 antibody treatment to improve cellular immune responses in the burn/ethanol group suggests that blocking this cytokine may be beneficial for the ethanol‐exposed, thermally injured individual.
Enzymic Catalysis of the Accumulation of Acetaldehyde From Ethanol in Human Prenatal Cephalic Tissues: Evaluation of the Relative Contributions of CYP2E1, Alcohol Dehydrogenase, and Catalase/Peroxidases
Authors: Person Richard E. , Chen Hao , Fantel Alan G. , Juchau Mont R. 
Published: April 2006

Background: The human prenatal brain is very sensitive to the toxic effects of ethanol, but very little information is available concerning the conversion of ethanol to the highly cytotoxic metabolite, acetaldehyde, in that organ. Thus, experiments were designed to investigate rates of accumulation of acetaldehyde from ethanol in the prenatal human brain.Methods: Prenatal human cephalic tissue homogenates were used as enzyme sources and were compared with analogous preparations of adult rat livers. Generated acetaldehyde was derivatized with cyclohexane‐1,3‐dione to yield fluorescent decahydroacrizine‐1,8‐dione, which was readily separated, detected, and quantitated with HPLC.Results: Detected rates of accumulation were unexpectedly high, even in the absence of added NADPH, NAD+, or H2O2, which are cofactors/cosubstrates for cytochrome P‐450‐, alcohol dehydrogenase‐ and catalase/peroxidase‐catalyzed reactions, respectively. Without added cofactors/cosubstrates or other components and under linear reaction conditions, rates in human prenatal cephalic preparations were approximately 20% of those observed with analogous preparations of adult rat livers. Cofactor/cosubstrate‐independent reactions were localized in the cytosolic (soluble) fraction and were strongly dependent on molecular oxygen (O2). They were not inhibited substantially by carbon monoxide (CO:O2= 80:20 vs N2:O2= 80:20) or by pyrazole in concentrations up to 10 mM and were only weakly inhibited by azide. Preincubations with excess catalase did not result in decreased activity. Reactions exhibited substrate saturation and heat inactivation indicating enzymic catalysis.Conclusions: Experiments indicated a relatively rapid accumulation of acetaldehyde from ethanol in human prenatal brain tissues and suggested that the observed cofactor/cosubstrate‐independent reactions were largely independent of P‐450 cytochromes, alcohol dehydrogenases, or catalase/peroxidases. Results were consistent with catalysis by an as yet unidentified cytosolic oxidase(s).
Levels of γ‐Aminobutyric Acid‐Benzodiazepine Receptors in Abstinent, Alcohol‐Dependent Women: Preliminary Findings From an 123I‐Iomazenil Single Photon Emission Tomography Study
Authors: Lingford‐Hughes A. R. , Acton P. D. , Gacinovic S. , Boddington S. J. A. , Costa D. C. , Pilowsky L. S. , Ell P. J. , Marshall E. J. , Kerwin R. W. 
Published: April 2006

Background: Although alcohol dependence in women is an increasing problem, little is known about the effects of alcohol on the female brain. Evidence from a few structural and functional neuroimaging studies suggests that the female brain may be more susceptible than the male brain to the harmful effects of alcohol. However, no in vivo studies of the neuropharmacology of alcohol dependence in women have been carried out. The aim of this preliminary study was to test the hypothesis that alcohol dependence in women is associated with greater reduction in γ‐aminobutyric acid (GABA)‐benzodiazepine receptor levels than in men with an equivalent drinking history.Methods: We used single photon emission tomography and 123I‐iomazenil to label the central GABA‐benzodiazepine receptor and to compare semiquantified levels in 9 abstinent alcohol‐dependent and 13 control women. These groups were further compared with equivalent male groups from a previous study.Results: There was a trend toward a reduction in GABA‐benzodiazepine receptor levels in alcohol‐dependent women, but this did not reach significance. These lower levels were seen primarily in the cerebellum, occipital lobes, and parietal cortex (left > right). This was in marked contrast with the pattern of reduction seen in the previous study of male dependence, where significant reductions were seen primarily in the frontal cortex.Conclusions: Due to the semiquantitative analysis performed and the relatively small number of subjects in this study, which resulted in a nonsignificant trend, we can only comment on the differences in the pattern of lower levels of GABA‐benzodiazepine receptors seen in alcohol dependence in men and women. Although we are not able to ascertain whether the female brain is more susceptible to the effects of alcohol, it appears that alcohol has a differential effect on the central GABA‐benzodiazepine receptors in men and women. Recent animal evidence supports this hypothesis. Future studies should explore whether other neuropharmacological differences exist between men and women in alcohol dependence that could have implications for pharmacotherapy.
Alcohol Inhibits the Progression as Well as the Initiation of Atherosclerotic Lesions in C57Bl/6 Hyperlipidemic Mice
Authors: Emeson Eugene E. , Manaves Vlasios , Emeson Brian S. , Chen Lu , Jovanovic Igor 
Published: April 2006

Background: Evidence that a moderate consumption of alcohol is associated with a reduced incidence of and mortality due to coronary artery disease continues to accumulate. Despite recent evidence that substances in red wine confer resistance to coronary artery disease, it is clear that at least a substantial proportion of the protective effect is due to the alcohol content of the beverage. We have previously shown that the chronic ingestion of alcohol incorporated into a total liquid diet during a 24‐week period inhibits the development of fatty streak lesions in hyperlipidemic C57Bl/6 mice. We have now repeated this study and demonstrated that alcohol continues to markedly inhibit atherogenesis during a 48‐week period.Methods: Mice were fed a high fat atherogenic liquid diet with 0% or 6% alcohol or a high fat atherogenic pelleted diet with 0% or 15% alcohol in their drinking water. After 24 and 48 weeks on these diets, subgroups of mice were euthanized and the aortas were studied for extent of atherosclerosis. Plasma lipid levels were also measured and flow cytometry studies performed to characterize their T and B lymphocyte populations. Additional groups of mice were given the high fat atherogenic diets for 24 weeks to allow lesions to develop and were then treated with alcohol diets to determine whether they inhibit the progression of the lesions.Results: The alcohol diets suppressed the development of atherosclerotic lesions at both 24 and 48 weeks in both the liquid and pelleted diet models. The addition of the alcohol diets after allowing lesions to form for 24 weeks halted the further progression of the lesions. The alcohol treatments also decreased the plasma levels of total cholesterol and high density lipoprotein (HDL) cholesterol at almost all time intervals.Conclusions: We conclude that alcohol not only inhibits the initial development of atherosclerotic lesions but also inhibits the progression of existing atherosclerotic lesions. The alcohol‐mediated decrease in HDL cholesterol in these experiments suggests that HDL plays little or no role in amelioration of atherogenesis in this model.
Suppression of Ethanol Responding by Centrally Administered CTOP and Naltrindole in AA and Wistar Rats
Authors: Hyytiä Petri , Kiianmaa Kalervo 
Published: April 2006

Background: Both μ‐ and δ‐opioid receptors have been implicated in the reinforcing actions of ethanol. However, selective opioid receptor antagonists have not altered ethanol intake in all rodent strains consistently, which suggests that genotype may modulate their suppressive effects. Therefore, we tested the effects of the selective μ‐antagonist D‐Pen‐Cys‐Tyr‐D‐Trp‐Orn‐Thr‐Pen‐Thr‐NH2(CTOP) and the selective δ‐antagonist naltrindole in both high‐drinking AA (Alko, Alcohol) and heterogeneous Wistar rats.Methods: AA and Wistar rats were trained to respond for ethanol (10% w/v) in a two‐lever operant condition by using a saccharin fading procedure. After stable baseline responding was established, rats were implanted stereotaxically either with a guide cannula above the lateral ventricle or with bilateral cannulas above the nucleus accumbens, basolateral amygdala, or ventral tegmental area. After postoperative recovery, AA and Wistar animals were tested after intracerebroventricular microinjections of either CTOP (0–3 μg) or naltrindole (0–30 μg) or subcutaneous injections of naloxone (0–1 g/kg), which was used as a reference antagonist. Effects of intracerebral microinjections of CTOP and naltrindole (both 0–500 ng) were tested only in Wistar rats.Results: Subcutaneous naloxone and intracerebroventricular CTOP and naltrindole suppressed ethanol self‐administration in a similar manner in AA and Wistar rats. Cumulative response patterns indicated that naloxone and naltrindole had no effect on the initiation of responding but suppressed it later during the session, whereas CTOP also affected initiation. In Wistar rats, naltrindole microinjections into both the nucleus accumbens and basolateral amygdala decreased ethanol responding, whereas CTOP was effective only in the amygdala. Injections of these antagonists into the ventral tegmental area had little effect on ethanol intake.Conclusions: The results confirm previous results which showed that both μ‐ and δ‐opioid receptors are involved in the regulation of ethanol self‐administration and indicate that genetic differences between AA and Wistar rats produced by selection do not modify the effects of opioid antagonists. The nucleus accumbens and the basolateral amygdala may be important central sites for the mediation of their suppressive effects.
Possible Reasons Why Heavy Drinking Increases Carbohydrate‐Deficient Transferrin
Authors: Sillanaukee Pekka , Strid Nuria , Allen John P. , Litten Raye Z. 
Published: April 2006

Background: Transferrin is a globular protein synthesized in the liver that is responsible for iron transport in plasma. The structure of the molecule consists of two carbohydrate residues to which six sialic acid moieties can be attached. After periods of chronic, heavy alcohol consumption, carbohydrate‐deficient transferrin (CDT) isoforms often increase, which makes CDT a useful marker in screening for alcohol abuse and monitoring progress of alcoholics in treatment. However, the precise mechanism behind CDT increase remains unknown.Methods: A review of the most relevant literature on CDT was conducted with a computer‐assisted literature search.Results: During the past several years, a number of studies have explored possible mechanisms that may account for the alcohol‐induced increase of CDT. An inhibition of protein synthesis and a general effect of alcohol on protein glycosylation have been reported. Although the exact mechanisms that underlie production of CDT are not yet fully understood, possible bases for the phenomenon are presented in this article.Conclusions: Experimental findings indicate that the ethanol‐induced effect on glycoprotein metabolism is a multistep process in which protein transport and changes of enzyme activity may play an important role.