bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sex Differences in Rats in the Development of and Recovery From Ethanol Dependence Assessed by Changes in Seizure Susceptibility
Authors: Devaud Leslie L. , Chadda Ritu 
Published: April 2006

Background: Previous investigations have found sex differences in rats in response to chronic ethanol exposure. The most dramatic differences were observed with anticonvulsant treatment during ethanol withdrawal, when seizure susceptibility is significantly increased. Sex differences in this response were found for both GABAergic and glutamatergic compounds. This study was aimed at exploring whether sex also influences the timing for the development of and recovery from ethanol dependence.Methods: Ethanol was administered in a liquid diet, with pair‐fed animals receiving dextrose, substituted isocalorically for the ethanol. Ethanol dependence and withdrawal were assessed by measurement of seizure thresholds after abrupt removal of the ethanol diet. Seizure thresholds were determined by slow, tail vein infusion of the γ‐aminobutyric acidA–receptor antagonist bicuculline.Results: Male and female rats displayed differences in timing for both onset and recovery from ethanol dependence, as determined by changes in ethanol withdrawal seizure susceptibility. Female rats were slower to develop dependence and quicker to recover compared with male rats. Furthermore, acute ethanol administration did not alter seizure susceptibility in pair‐fed control animals, but it was anticonvulsant in ethanol‐withdrawn rats. Ethanol‐withdrawn female rats showed a greater response to acute ethanol administration than did male rats.Conclusions: This set of experiments uncovered additional sex differences in one measure of ethanol dependence and withdrawal. Proposed mechanisms for the development of ethanol dependence involve alterations in subunit assembly of γ‐aminobutyric acidA and NMDA receptors or various posttranslational modifications. In consideration of these findings, whatever mechanisms underlie the development of ethanol dependence, there is a different sequence of events in male compared with female rats. Studies are ongoing to determine associations between behavioral measures of ethanol dependence/withdrawal and selective neuronal adaptations.
GABAA‐Receptor δ Subunit Knockout Mice Have Multiple Defects in Behavioral Responses to Ethanol
Authors: Mihalek Robert M. , Bowers Barbara J. , Wehner Jeanne M. , Kralic Jason E. , VanDoren Margaret J. , Morrow A. Leslie , Homanics Gregg E. 
Published: April 2006

Background: The γ‐aminobutyric acid type A receptors (GABARs) are involved in mediating some of the behavioral effects of beverage alcohol (ethanol). However, the unique pharmacological and behavioral responses conferred by each of the various receptor subunits are not well understood.Methods: To address the role of the GABAR δ subunit in mediating ethanol responses, gene knockout mice that lack this subunit were tested for a variety of ethanol‐induced behavioral responses.Results: Our results indicate that, compared with controls, δ‐deficient mice (δ−/−) have (1) reduced ethanol consumption, (2) attenuated withdrawal from chronic ethanol exposure, and (3) reduced anticonvulsant (seizure‐protective) effects of ethanol. These mice demonstrate a normal anxiolytic response to ethanol and a normal hypothermic response to ethanol, and they develop both chronic and acute tolerance.Conclusions: These results further establish the link between GABARs and specific behavioral responses to ethanol and begin to reveal the role of the δ subunit in these responses.
Dose‐Related Impact of Alcohol Consumption on Cognitive Function in Advanced Age: Results of a Multicenter Survey
Authors: Zuccalà Giuseppe , Onder Graziano , Pedone Claudio , Cesari Matteo , Landi Francesco , Bernabei Roberto , Cocchi Alberto 
Published: April 2006

Background: Moderate alcohol consumption has been associated in several studies with decreased risk of cardiovascular and cerebrovascular events; however, available data on the effects of alcohol intake on cognitive functioning are conflicting. We assessed the association between alcohol consumption and cognitive impairment in a series of older subjects enrolled in a multicenter pharmacoepidemiology survey.Methods: The association between average alcoholic intake and cognitive performance was assessed in 15,807 patients admitted to participating centers during the survey periods. Demographic variables, comorbid conditions, medications, and objective tests that were associated with cognitive impairment (as indicated by a Hodkinson Abbreviated Mental Test score <7) in separate logistical regression models were examined as potential confounders in a summary model.Results: Cognitive impairment was detected in 1693 (19%) of 8755 drinkers and 2008 (29%) of 7052 nondrinkers (Fisher's exact test, p < 0.0001). After adjusting for potential confounders, alcohol consumption was associated with decreased probability of cognitive impairment (odds ratio, 0.75; 95% confidence interval, 0.66–0.85). The relationship between drinking level and cognitive dysfunction was nonlinear, because the probability of cognitive impairment was decreased for moderate alcohol use as compared with abstinence, but it was increased for daily consumption exceeding one wine‐equivalent liter among men and 0.5 liter among women. This nonlinear association persisted when cerebrovascular and Alzheimer's disease were considered separately.Conclusions: Alcohol abuse is associated with increased prevalence of cognitive dysfunction among older subjects; however, a daily alcohol consumption of less than 40 g for women and 80 g or less for men might be associated with a decreased probability of cognitive impairment. This possible protective effect of alcohol consumption should be further assessed by prospective studies.
Expression and Cytoskeletal Association of Integrin Subunits Is Selectively Increased in Rat Perivenous Hepatocytes After Chronic Ethanol Administration
Authors: Schaffert Courtney S. , Sorrell Michael F. , Tuma Dean J. 
Published: April 2006

Background: For normal function and survival, hepatocytes require proper cell–extracellular matrix (ECM) contacts mediated by integrin receptors and focal adhesions. Previous studies have shown that chronic ethanol consumption selectively impairs perivenous (PV) hepatocyte attachment and spreading on various ECM substrates but increases expression of the β1 integrin subunit, the common β subunit for two major hepatocyte‐ECM receptors, α1β1 and α5β1 integrins. This study examined the effects of ethanol treatment on the expression and cytoskeletal distribution of α1, α5, and β1 integrin subunits, the epidermal growth factor receptor (EGF‐R), and the cytoskeletal proteins focal adhesion kinase, paxillin, vinculin, and actin in periportal and PV hepatocytes.Methods: Periportal and PV hepatocytes were isolated from control and ethanol‐fed rats. For expression analysis, lysates were examined by SDS‐PAGE and immunoblotting procedures. For cytoskeletal distribution studies, Triton‐soluble and ‐insoluble (cytoskeletal) fractions from hepatocytes cultured on collagen IV were analyzed by SDS‐PAGE and immunoblotting.Results: Chronic ethanol administration caused PV‐specific increases in expression and cytoskeletal association of the integrin subunits. Although ethanol treatment did not affect expression of the EGF‐R in either cell type, it did increase the association of the EGF‐R with the cytoskeleton selectively in PV hepatocytes. Ethanol treatment had no significant effect on either the expression or the cytoskeletal distribution of focal adhesion kinase, paxillin, vinculin, or actin in either cell type.Conclusions: The increases in integrin expression and cytoskeletal association observed after chronic ethanol administration suggest that a process downstream of integrin‐ECM interactions is impaired selectively in PV hepatocytes, possibly involving altered focal adhesion assembly or turnover, processes essential for efficient cell‐ECM adhesion. Alterations in these processes could contribute to the impaired hepatocyte function and structure observed after chronic ethanol administration.
Ethanol Consumption Alters Electroretinograms and Depletes Neural Tissues of Docosahexaenoic Acid in Rhesus Monkeys: Nutritional Consequences of a Low n‐3 Fatty Acid Diet
Authors: Pawlosky Robert J. , Bacher John , Salem Norman 
Published: April 2006

Background: Alcohol amblyopia is a rare neuropathy characterized by the development of blurred vision and a reduction in visual acuity. Further diagnostic details of this condition have shown abnormalities in the electroretinogram (ERG) that include an increase in implicit times in the a‐ and b‐waves and a depression of b‐wave amplitude.Methods: Periodically, the ERGs and the fatty acyl composition of nervous tissue were analyzed from alcohol‐consuming rhesus monkeys (Macaca mulatta) (mean consumption 2.6 g kg/day over a 5‐year period) and controls that were maintained on a nutritionally sufficient diet that had low, yet adequate, amounts of linoleic acid but very low α‐linolenic acid.Results: Animals consuming alcohol had increased a‐ and b‐wave implicit times and decreased b‐wave amplitudes in their electroretinograms compared with those of the dietary control group at 2.5 and 5 years. The fatty acyl composition of brain specimens obtained by surgical biopsy at baseline, 2.5 years, and 5 years demonstrated that docosahexaenoic acid (DHA) had decreased in both groups of animals compared with baseline values. In the brains of the alcohol‐treated animals, DHA was even further decreased (2.5 years: −20%; 5 years: −33%) compared with the diet controls. In the retinas of the alcohol‐consuming animals at 5 years, there was a similar decrease in DHA (‐35%) compared with controls. Generally, the n‐6 fatty acid, docosapentaenoic acid (DPAn‐6) increased in these tissues, apparently compensating for the loss of DHA.Conclusions: A reciprocal change in the DHA/DPAn‐6 ratio is known to be associated with abnormal electroretinograms in a number of species. Thus, a marginal intake of n‐3 fatty acids in some alcohol abusers may, in part, be responsible for the biochemical changes that underlie the diminished retinal function associated with the visual abnormalities observed in alcohol‐amblyopic patients.
Ethanol‐Induced Up‐Regulation of the Urokinase Receptor In Cultured Human Endothelial Cells
Authors: Tabengwa Edlue M. , Grenett Hernan E. , Benza Raymond L. , Abou‐Agag Laila H. , Tresnak Jennifer K. , Wheeler Crystal G. , Booyse Francois M. 
Published: April 2006

Background: Moderate alcohol consumption has been correlated to reduced coronary artery disease (CAD) risk and mortality. This alcohol effect may be mediated in part by an increased endothelial cell (EC) fibrinolysis. ECs synthesize fibrinolytic proteins, tissue plasminogen activator (t‐PA), urokinase type plasminogen activator (u‐PA), and plasminogen activator inhibitor type‐1(PAI‐1). In addition, they synthesize and regulate receptors for fibrinolytic proteins, namely (t‐PA and plasminogen receptor) Annexin II and u‐PA receptor (u‐PAR). These receptors play an important role in the regulated expression of receptor‐bound plasminogen activator conversion of receptor‐bound plasminogen to receptor‐bound plasmin on the EC surface (surface‐localized fibrinolytic activity). Therefore, systemic factors, such as ethanol, that affect the level, or activity or interaction of one or more of these components, resulting in the increased expression of surface‐localized EC fibrinolytic activity, will be expected to reduce the risk for thrombosis, CAD, and myocardial infarction (MI). We have previously shown that low ethanol up‐regulates t‐PA and u‐PA gene transcription, while it down‐regulates PAI‐1, hence resulting in increased (sustained, 24 hr) surface‐localized EC fibrinolytic activity. The current studies were carried out to determine whether low ethanol increased u‐PAR expression in cultured human umbilical cord vein ECs (HUVECs).Methods: Cultured HUVECs were preincubated (1 hr) in the absence/presence of ethanol (0.025–0.2%, v/v); u‐PAR mRNA (RT‐PCR), antigen (western blot), and activity (125I‐u‐PA ligand binding/Scatchard analysis) levels were then measured after 0–24 hr. To determine whether the ethanol‐induced changes in the u‐PAR expression were transcriptional, transient transfection studies were carried out using a u‐PAR/luciferase promoter construct (pu‐PAR120/luc [1.2‐kb u‐PAR promoter fragment ligated to a promoterless luciferase vector]).Results: uPAR mRNA levels increased 2‐ to 3‐fold and antigen levels (western blot) increased 2‐ to 4‐fold while u‐PA binding activity increased 36% (1.25 vs. 1.7 − 105 sites/cell, Bmax) without significantly affecting the Kd (1–2 nM). Transient transfection of cultured HUVECs with a pu‐PAR120/luc construct resulted in a 2‐ to 3‐fold increase in promoter activity in ethanol‐induced cultures, compared with controls.Conclusion: These combined results demonstrate that low ethanol (≤0.1%, v/v) induces the up‐regulation of u‐PAR gene transcription, resulting in increased u‐PAR ligand binding activity. These results also further identify/define the contribution and role of another fibrinolytic protein in the overall ethanol‐induced increase in surface‐localized EC fibrinolysis that may underlie and contribute, in part, to the cardioprotection attributed to moderate alcohol consumption.
No Effect of Albinism on Sedative‐Hypnotic Sensitivity to Ethanol and Anesthetics
Authors: Rikke Brad A. , Simpson Victoria J. , Montoliu Lluis , Johnson Thomas E. 
Published: April 2006

Background: Studies using the long‐sleep (LS) X short‐sleep (SS) (LSXSS) recombinant inbred mice and inbred long‐sleep (ILS) by inbred short‐sleep (ISS) intercrosses have found genetic linkage between Tyr albinism (c/c) and differential sensitivity to sedative‐hypnotic doses of ethanol and general anesthetics. This linkage could be due to a gene or genes near Tyr or Tyr itself. With regard to the latter possibility, the absence of tyrosinase activity (encoded by Tyr) in albinos could alter tyrosine availability and thus the rate‐limiting step in catecholamine synthesis. In addition, albinism is associated with altered brain development that could have pleiotropic effects on behavior. Therefore, in this study, we asked whether albinism affects sedative‐hypnotic sensitivity.Methods: Loss of righting reflex (LORR) duration was measured using doses of ethanol (4.1 g/kg), pentobarbital (70 mg/kg), isoflurane (2 g/kg), and etomidate (20 mg/kg) that were previously associated with differential sensitivity of albino versus nonalbino mice. Tyr transgenics (c/c, TgTyr+) were backcrossed to ISS (c/c) to compare pigmented (c/c, TgTyr+) and albino (c/c) mice in the context of an ISS‐like background. ISS was also crossed with C57BL/6 (B6) mice heterozygous for a spontaneous albino mutation (c2j) to compare pigmented (c/+) and albino (c/c2j) mice. Pigmented B6 (c2j/+ and +/+) and albino B6 (c2j/c2j) mice were also compared (pentobarbital).Results: For each sedative hypnotic, albinism had no effect on LORR duration. Each expected difference was ruled out at the 95% or 99% confidence level. For each sedative hypnotic, males were more sensitive than females even though the effect size was usually smaller than the expected albino effect size, arguing empirically that the inability to detect an albino effect was not due to systematic error or an insufficient number of mice.Conclusion: We conclude that the differential sensitivity associated with albinism is most likely due to a gene or genes near Tyr rather than Tyr itself.
Working Memory Impairments in Alcohol‐Dependent Participants Without Clinical Amnesia
Authors: Ambrose Margaret L. , Bowden Stephen C. , Whelan Greg 
Published: April 2006

Background: The delayed alternation (DA) task is highly sensitive to the deficits of nonhuman animals with alcohol‐related brain damage. DA is thought to measure working memory which serves as a temporary store for processing of information. However, performance on this type of task has only been investigated in alcohol‐dependent humans with severe cognitive deficits. The aim of the current study was to e‐plore the validity of DA as a test sensitive to alcohol‐related brain damage by manipulating storage and processing components in three versions of the task. It was hypothesized that alcohol‐dependent people would perform worse than control participants and that their deficits would be more pronounced in DA versions with ma‐imal working memory demands.Methods: A sample of 12 alcohol‐dependent participants without Wernicke‐Korsakoff syndrome was compared with a sample of 12 nonalcohol‐dependent controls on three versions of DA. These versions, in order of increasing working memory demand, were single alternation (LR), double alternation (LLRR), and asymmetric alternation (LRRR). DA was administered on a personal computer and performance measured by the number of trials taken to reach criterion.Results: Alcohol‐dependent participants, compared with the control participants, took more trials to reach learning criterion on DA on all versions when analyzed together (p= 0.002). Performance on DA was also found to deteriorate with increased working memory demands in both groups of participants (p < 0.001). However, the deficits of alcohol‐dependent participants were most pronounced on the DA task with moderate (LLRR) as opposed to extreme (LRRR) working memory demands.Conclusions: The results indicate that both storage and processing demands are necessary for task performance and demonstrate sensitivity of DA to alcohol‐related brain injury.
Maintaining Intentional Control of Behavior Under Alcohol
Authors: Grattan Karen E. , Vogel‐Sprott M. 
Published: April 2006

Background: This research used a process dissociation paradigm to measure the influence of controlled and automatic processes on a word‐stem completion task when correct performance under alcohol was positively reinforced, or had no particular consequence. It was predicted that the impairing effect of alcohol on controlled processes that govern intentional control of behavior would be resisted when drinkers were reinforced for performing well.Methods: Four groups of eight male drug‐free social drinkers initially studied a list of words. Two of the groups then received 0.56 g/kg alcohol (A) and two received a placebo (P) before the stem‐completion task was performed. During the task, the correct responses of one pair of A and P groups were reinforced (money and verbal approval) whereas no reinforcement was provided to the other pair.Results: As predicted, under alcohol, the influence of controlled processes that govern intentional responses was greater when reinforcement was provided than when it was absent (p= 0.005). Without reinforcement, controlled processes in the A group were lower than the P control group (p= 0.01). In contrast, the A and P groups that received reinforcement did not differ (p= 0.142). Controlled processes in the P groups were not affected by reinforcement (p= 0.65). In addition, the influence of automatic processes was not affected by alcohol or by reinforcement (p > 0.781).Conclusions: Positive reinforcement for behavior under alcohol increases the influence of controlled processes. These results suggest that the degree to which intentional control is retained under alcohol depends on the consequence of behavior in the situation. It seems that controlled processes enable drinkers to intentionally display the behavior that is rewarded.
Neurochemical Characteristics Associated With Ethanol Preference in Selected Alcohol‐Preferring and ‐Nonpreferring Rats: A Quantitative Microdialysis Study
Authors: Katner Simon N. , Weiss Friedbert 
Published: April 2006

Background: Rodent lines selected for alcohol preference and nonpreference have been used extensively to determine the neurobiological basis of alcohol‐seeking behavior. Evidence suggests that innate differences in the mesolimbic dopamine and serotonin systems may contribute to disparate alcohol‐seeking behaviors between these selected lines. Therefore, the purpose of this study was to identify neurochemical characteristics which may predict ethanol preference in selected alcohol‐preferring and ‐nonpreferring rats [high–alcohol‐preferring (HAD), low–alcohol‐preferring (LAD), Alko alcohol (AA), Alko nonalcohol (ANA), Wistar].Methods: Basal release of dopamine (DA) and serotonin (5‐HT) in the nucleus accumbens of ethanol‐naive rats was analyzed for its relationship with subsequent measures of ethanol preference. Initially, basal extracellular DA and 5‐HT levels were measured by “no‐net‐flux” quantitative microdialysis. Subsequently, the dopaminergic response to systemic ethanol administration (1.5 g/kg; intraperitoneal) was determined. After completion of the neurochemical tests, the rats received unlimited two‐bottle, free‐choice access to 10% (w/v) ethanol and water in the home cage for 28 days.Results: Analysis of the data across individual animals revealed that extracellular dopamine levels ([DA]e;r=+ 0.64;p < 0.006) and the percent of baseline increase in DA (%incrDA;r=+ 0.77;p < 0.001) due to ethanol were significant predictors of ethanol preference. Comparison of the data between genetic lines yielded a significant relationship between preference and %incrDA (r=+ 0.87;p < 0.05). Analysis of the data across animals within each line and their respective control line determined that in the AA/ANA line pair (r=+ 0.67;p < 0.03) and Wistar line (r=+ 0.66;p < 0.03) %incrDA was a significant predictor of preference. In the HAD/LAD line pair, %incrDA (r=+ 0.56;p < 0.005) and [DA]e (r=+ 0.86;p < 0.004) were significant predictors of ethanol preference.Conclusions: Overall, these findings suggest that elevated extracellular levels of dopamine within the nucleus accumbens and a greater responsivity to enhancements in DA release by ethanol may be factors which contribute to high‐alcohol preference. Furthermore, the data suggest that alcohol may be more reinforcing in animals that exhibit an enhanced dopaminergic response to the first ethanol exposure, and that this effect may subsequently be associated with high–alcohol‐seeking behavior.