bluuebunny/crossref_metadata_2025_split huggingface dataset:
Binge Ethanol Exposure in Adult Rats Causes Necrotic Cell Death
Authors: Obernier J. A. , Bouldin T. W. , Crews F. T. 
Published: April 2006

Background: Although alcoholics show neurodegeneration after decades of drinking, recent studies with an animal model of binge drinking have found corticolimbic damage after as few as four days. Neurodegeneration can occur through apoptotic or necrotic mechanisms. The goal of this research is to characterize the time course of binge ethanol‐induced neurodegeneration and to identify apoptotic or necrotic characteristics of this neurodegeneration.Methods: Histologic methods (e.g., amino cupric silver staining, Fluoro‐Jade B, hematoxylin and eosin, transmission electron microscopy) were used to quantify the time course of degeneration and to characterize the ultrastructural changes that occur with binge ethanol‐induced neurodegeneration.Results: After 2 days of binge ethanol, significant damage was evident in the olfactory bulb. After 4 days of binge ethanol, there was significant damage in the agranular insular cortex, anterior piriform cortex, perirhinal cortex, lateral entorhinal cortex, and the temporal dentate gyrus. Ultrastructural examination revealed shrunken soma, vacuolated cytoplasm, pyknotic nucleus, and irregularly clumped chromatin consistent with dark cell degeneration, a form of necrotic neuronal death.Conclusions: Binge drinking causes necrotic neurodegeneration after 2 days of exposure and increased damage after 4 days but does not increase during withdrawal. These studies indicate that binge drinking induced neurodegeneration is necrotic and occurs during ethanol intoxication and not as a result of ethanol withdrawal.
Forward, Relaxed, and Reverse Selection for Reduced and Enhanced Sensitivity to Ethanol's Locomotor Stimulant Effects in Mice
Authors: Phillips Tamara J. , Shen Elaine H. , McKinnon Carrie S. , Burkhart‐Kasch Sue , Lessov Christina N. , Palmer Abraham A. 
Published: April 2006

Background: Rarely have trait markers for alcoholism risk been identified. However, relative sensitivity to the arousing effects of ethanol and sensitivity to ethanol's sedative effects have been distinguished as potentially valuable behavioral risk factors. Both traits are genetically influenced and have been modeled in mice by measuring sensitivity to ethanol‐induced locomotor stimulation and hypnosis. Reverse selection was performed to examine the hypothesis that forward selection for differential sensitivity to ethanol's locomotor stimulant effects resulted in homozygous fixation of selection trait‐relevant alleles and to test the hypothesis that common genes influence ethanol's stimulant and sedative effects.Methods: Bidirectional selective breeding was completed for enhanced (FAST mice) and reduced (SLOW mice) sensitivity to ethanol's locomotor stimulant effects. Selection was terminated (relaxed), and the lines were tested to detect genetic drift. Reverse selection for enhanced sensitivity to ethanol‐induced stimulation in SLOW mice and reduced sensitivity in FAST mice was performed for 16 generations. Forward and reverse selected lines were tested for sensitivity to ethanol's sedative effects by measuring duration of ethanol‐induced loss of righting reflex.Results: Differential sensitivity to the sedative effects of ethanol emerged with selection for differential ethanol stimulation, indicating a common genetic influence on these traits. SLOW mice developed greater sensitivity to ethanol's sedative effects relative to FAST mice. Reverse selection, never before reported for a pharmacogenetic trait, was effective in eliminating most of the difference in stimulant sensitivity between the FAST and SLOW lines and also eliminated the difference in loss of righting reflex duration.Conclusions: Residual heterozygosity persisted at trait‐relevant loci even at the selection plateau, possibly due to heterosis, natural selection favoring heterozygosity, or epistatic phenomena involving differences in the sets of genes regulating the high‐ versus low‐sensitivity traits. They also suggest that some common genes influence sensitivity to ethanol's locomotor stimulant and sedative effects.
Acamprosate Has No Effect on NMDA‐Induced Toxicity But Reduces Toxicity Induced by Spermidine or by Changing the Medium in Organotypic Hippocampal Slice Cultures From Rat
Authors: Mayer Sveta , Harris Barton , Gibson D. Alex , Blanchard John , Prendergast Mark A. , Holley Robert C. , Littleton John 
Published: April 2006

Background: It has been suggested that the antirelapse drug acamprosate can inhibit or potentiate glutamate/NMDA receptor‐mediated responses via a polyamine site. Additionally, subchronic exposure to acamprosate increases expression of some NMDA receptor subunits. These effects on NMDA receptors imply that the drug may have neurotoxic or neuroprotective actions under different conditions, and these studies were undertaken to evaluate this possibility in hippocampal neuronal cultures.Methods: Organotypic hippocampal cultures from 8‐day‐old neonatal rats were maintained in medium for 28 days. The effects of acamprosate (100 μM) alone or on neurotoxic challenges induced by either 50 μM NMDA or 100 μM spermidine were studied. Neurotoxicity was assessed by uptake of propidium iodide 24 hr after challenge. Calcium entry was measured by uptake of 45Ca2+ into the culture during the challenge.Results: Acamprosate produced no neurotoxicity in these cultures after acute or subchronic exposure. In contrast, the presence of acamprosate significantly reduced “basal” propidium iodide uptake caused by the medium change procedure; similar effects were obtained with dizocilpine (MK‐801; 30 μM) and, to a lesser extent, with ifenprodil (50 μM). Acamprosate did not significantly potentiate or inhibit NMDA‐induced neurotoxicity, but the presence of acamprosate significantly reduced spermidine‐induced neurotoxicity.Conclusion: No evidence was obtained that the putative agonist or coagonist effects of acamprosate on the NMDA receptor are able to cause neurotoxicity. Similarly, no evidence for inhibitory effects of acamprosate on NMDA‐induced toxicity was observed under any of these conditions. However, acamprosate significantly inhibited the toxicity associated with changing medium and the toxicity induced by spermidine in these hippocampal cultures. The mechanism is unknown but is compatible with previously reported inhibition of polyamine‐mediated effects.
Effects of Ethanol and Basic Fibroblast Growth Factor on the Transforming Growth Factor β1 Regulated Proliferation of Cortical Astrocytes and C6 Astrocytoma Cells
Authors: Miller Michael W. , Luo Jia 
Published: April 2006

Background: The effects of ethanol on transforming growth factor β1 (TGFβ1)‐regulated proliferation of primary cultured cortical astrocytes and C6 astrocytoma cells were determined.Methods: Cultured cells were treated with TGFβ1 (0 or 10 ng/ml) and ethanol (0 or 400 mg/dl) for as many as 4 days. The effects of these treatments on cell growth (the change in cell number) and cell proliferation (incorporation of [3H]thymidine) were determined. In addition, the effects of serum and basic fibroblast growth factor (bFGF) on TGFβ1‐affected cell proliferation were examined.Results: Both TGFβ1 and ethanol inhibited cell growth and proliferation among the two types of cells; this effect was only evident when the cells were grown in the presence of a mitogen, serum, or bFGF. When added together (either in a serum‐supplemented or serum‐free medium), however, TGFβ1 and the mitogen effectively nullified each other. TGFβ1 blocked the mitogenic effect of bFGF on astrocytes and C6 cells. Ethanol did not affect (i.e., neither added nor nullified) this antagonistic effect.Conclusions: TGFβ1, like ethanol, is a potent anti‐proliferative agent; either can nullify the mitogenic activity of serum or bFGF. Astrocytes and astrocyte‐like cells react to combined TGFβ1 and ethanol treatment differently than do neurons for which the inhibitory effects of TGFβ1 and ethanol are additive.
Speed and Efficiency but Not Accuracy or Timing Deficits of Limb Movements in Alcoholic Men and Women
Authors: Sullivan Edith V. , Desmond John E. , Lim Kelvin O. , Pfefferbaum Adolf 
Published: April 2006

Background: Lesions of the cerebellum, a concomitant of alcoholism, can disrupt quality and regularity of movement. Whether evidence for such dysfunction lingers in patients with uncomplicated alcoholism, which is known to affect cerebellar structural integrity, is controversial.Methods: We used quantitative measures to examine component processes of five classes of movement associated with regional cerebellar function: limb ataxia (alternated finger tapping and variants of the finger‐to‐nose and heel‐to‐shin tests), paced tapping, eye‐hand coordinated tracing, timed response reflecting preparation and execution time, and postural stability. The subjects examined were 39 abstinent alcoholics (13 men and 26 women) and 21 age‐matched controls (9 men and 12 women). For limb ataxia, the dependent measures were the trajectory deviation from the subject's own average movement path and the speed of travel from beginning points to endpoints.Results: Repeated‐measures analysis of variance comparing movement speed of finger to nose and heel to shin yielded significant interactions in all conditions (p < 0.007); this indicated that the alcoholics were relatively slower in the upper‐ than lower‐limb tasks. Movements by the alcoholic men were significantly slower but less deviant from an ideal trajectory in all upper‐limb conditions than those of the control men (p < 0.002). Although measures of lower‐limb movement trajectory did not distinguish the groups, tests of ataxia of stance and gait did. The groups did not differ, however, on tests of timed tapping or sinusoid tracing.Conclusions: Alcohol‐related postural instability in abstinent alcoholics is functional evidence supporting the postulated damage to the anterior superior vermis. Altered speed or accuracy trade‐offs, with alcoholics moving slower to attain equivalent or even smaller trajectory deviations, are symptomatic of cerebellar hemisphere dysfunction that is characterized by deliberation of otherwise automatic movements.
Discriminative Stimulus Effects of Ethanol in C57BL/6J and DBA/2J Inbred Mice
Authors: Shelton Keith L. , Grant Kathleen A. 
Published: April 2006

Background: Two of the most widely used mouse strains for studying the behavioral effects of ethanol are C57BL/6J (B6) and DBA/2J (D2) mice. These strains exhibit marked differences in behavioral and physiological responses to ethanol. The subjective discriminative stimulus effects of ethanol may play a role in ethanol abuse, but the discriminative stimulus profile of ethanol has not been compared in B6 and D2 mice. Examination of the discriminative stimulus effects of ethanol in B6 and D2 mouse strains may enhance our understanding of the relationship between the subjective effects of ethanol and other ethanol‐induced behavioral effects.Methods: Twelve adult male C57BL/6J mice and 12 male DBA/2J mice were trained to discriminate 1.5 g/kg ethanol from saline in daily 15 min, milk‐reinforced operant sessions. After training, ethanol substitution and response‐rate suppression dose response curves were determined for ethanol, midazolam, diazepam, pentobarbital, pregnanolone, 4,5,6,7‐Tetrahydroisoxazolo[5,4‐c]pyridin‐3‐ol (THIP), dizocilpine, and morphine.Results: D2 mice learned the ethanol discrimination significantly more quickly than did B6 mice. Ethanol, midazolam, pregnanolone, and dizocilpine fully substituted for ethanol in both strains. Pentobarbital was more potent in producing ethanol‐like discriminative stimulus effects in D2 than B6 mice. Midazolam and diazepam were significantly more potent in suppressing response rates in D2 than B6 mice. Morphine failed to substitute for ethanol in either strain, but the ED50 for morphine suppression of responding was significantly lower in B6 than D2 mice.Conclusions: The initial stimulus effects of 1.5 g/kg ethanol may be more salient in D2 than B6 mice. This does not appear to result from differences in the neurotransmitter systems that mediate ethanol's discriminative stimulus effects. In both strains, γ‐aminobutyric acid‐positive modulators and a noncompetitive NMDA antagonist substituted for ethanol. However, strain differences did exist in the potency of γ‐aminobutyric acid‐positive modulators and morphine for suppressing operant responding.
Detection and Localization of Protein‐Acetaldehyde Adducts in Rat Brain After Chronic Ethanol Treatment
Authors: Upadhya Sudarshan C. , Ravindranath Vijayalakshmi 
Published: April 2006

Background: Ethanol is metabolized to acetaldehyde in the cell, which is potentially deleterious because it can react with cellular proteins and form protein‐acetaldehyde adducts, which can interfere with normal cellular function. Because the primary site of ethanol action is the brain, the present study was carried out to determine whether protein‐acetaldehyde adducts are formed in rat brain after chronic ethanol administration.Methods: Rats were treated with ethanol for 1 year, and the formation of protein‐acetaldehyde adducts was examined by immunoblot analysis and localized in brain by immunohistochemical analysis by using affinity purified antibody to acetaldehyde‐hemocyanin adduct.Results: In the brain of rats administered ethanol for up to 1 year, protein‐acetaldehyde adducts were detectable by immunoblot analysis. In brain, mitochondria was the primary site of adduct formation, unlike the liver, where the major protein‐acetaldehyde adduct has been detected in the cytosol. Immunohistochemical localization of protein‐acetaldehyde adducts in chronic ethanol‐treated rat brain demonstrated the selective presence of adducts in cortical neurons, granule cell layer of dentate gyrus, neurons in the midbrain, and granular cell layers of cerebellum.Conclusions: These results demonstrate the significant formation of protein‐acetaldehyde adducts in rat brain after ethanol ingestion. The modification of mitochondrial proteins in brain by protein‐acetaldehyde adduct formation is significant because mitochondrial dysfunction has been implicated in neurodegeneration.
Epidermal Growth Factor Protects the Liver Against Alcohol‐Induced Injury and Sensitization to Bacterial Lipopolysaccharide
Authors: Deaciuc Ion V. , D'Souza Nympha B. , Burikhanov Ravshan , Lee Eun Y. , Tarba Corneliu N. , McClain Craig J. , de Villiers Willem J. S. 
Published: April 2006

Background: Whereas the role of proinflammatory cytokines in the pathogenesis of alcoholic liver disease has been at the forefront of investigation, a possible role for anti‐inflammatory cytokines in this disease has received little attention. This study investigated (1) the hepatic protective effect of an anti‐inflammatory cytokine, epidermal growth factor (EGF), against deleterious effects of alcohol and sensitization to bacterial lipopolysaccharide (LPS), and (2) the possible mechanisms that underlie such protection.Methods: Male C57BL/6 mice were fed a Lieber‐DeCarli liquid diet that contained alcohol or an isocaloric replacement for 6 weeks. The animals then were treated daily with human EGF for 7 days (5 μg/mouse), after which they were injected with either LPS (1 mg/kg of body weight) or vehicle and killed 8 hr later. Blood and liver were analyzed for plasma aminotransferase activity, liver histology, liver apoptotic nuclei, mRNA of several cytokines (tumor necrosis factor [TNF]‐α, interleukin [IL]‐1β, IL‐6, and IL‐10), apoptotic ligands (TRAIL), cytokine receptors (TNFRp55), pro‐ and antiapoptotic regulators/adaptors (Fas receptor, FasL, FADD, TRADD, RIP, Bak, Bax, Bcl‐X, Bcl‐2 and Bcl‐w), and caspase‐8.Results: Alcohol increased plasma aminotransferase activity and sensitized the liver to the effects of LPS, such as polymorphonuclear infiltration, occurrence of necrotic foci and microabscesses, and increased apoptosis. These changes were associated with elevated mRNA expression of proapoptotic regulators/adaptors. EGF either counteracted or markedly blunted most of these effects. EGF did not affect liver mRNA expression of TNF‐α, IL‐1β, IL‐6, and IL‐10, which suggested that these cytokines were not involved in EGF protective effect. EGF protection was mediated by down‐regulation of apoptosis through suppression of proapoptotic gene expression.Conclusions: EGF protects the liver against both alcohol‐induced liver damage and liver sensitization to bacterial LPS through down‐regulation of apoptosis.
Acquisition and Retention of Verbal and Nonverbal Information in Children With Heavy Prenatal Alcohol Exposure
Authors: Mattson Sarah N. , Roebuck Tresa M. 
Published: April 2006

Background: Memory deficits are reported commonly in children with fetal alcohol syndrome. However, little is known about nonverbal memory performance in this population.Methods: The current study examined learning and memory abilities in alcohol‐exposed children and nonexposed controls. Multiple verbal and nonverbal measures were used that incorporated repeated learning trials and delayed recall trials. The alcohol‐exposed group included children with heavy prenatal alcohol exposure with and without fetal alcohol syndrome. Children ranged in age from 8 to 16 years, and groups were matched on age, sex, ethnicity, and socioeconomic status.Results: Children with heavy prenatal alcohol exposure displayed deficits in learning and recall of verbal and nonverbal information across all measures. On learning trials, they recalled fewer words and displayed a lower rate of acquisition. However, when we analyzed delayed verbal recall data after controlling for initial verbal learning, group differences were not apparent. The same pattern did not occur for nonverbal information; children with prenatal alcohol exposure recalled less on delayed recall even when we accounted for initial learning.Conclusions: These data are consistent with previous studies that indicate immediate memory deficits but suggest that, at least for verbal information, delayed recall deficits in this population are better accounted for by deficits in initial learning. Importantly, a different pattern of results was demonstrated for verbal versus nonverbal information, which suggests the need for additional research in this area.
Ethanol Consumption Increases Nitric Oxide Production in Rats, and Its Peroxynitrite‐Mediated Toxicity Is Attenuated by Polyenylphosphatidylcholine
Authors: Baraona Enrique , Zeballos Guillermo A. , Shoichet Lilia , Mak Ki M. , Lieber Charles S. 
Published: April 2006

Background: Nitric oxide generally mediates beneficial responses but becomes deleterious when coexistence with enhanced superoxide formation leads to the synthesis of peroxynitrite, a potent oxidant and nitrating agent.Methods: To study the effects of ethanol and polyenylphosphatidylcholine on nitric oxide metabolism and toxicity, 36 rats were pair‐fed liquid diets with 36% of energy either as ethanol or as additional carbohydrate for 24 days and were killed 90 min after intragastric feeding. Half received polyenylphosphatidylcholine in the diet (3 g/liter), and the other half equivalent amounts of essential fatty acids and choline. Nitric oxide was measured by chemiluminescence in arterial blood and liver cytosol and as a product of the inducible nitric oxide synthase activity. Peroxynitrite formation was assessed by the increase in nitrotyrosine protein residues, measured immunochemically.Results: In blood, administration of ethanol with or without polyenylphosphatidylcholine doubled nitric oxide levels. In the liver, ethanol increased nitric oxide by 52% (p < 0.01), and polyenylphosphatidylcholine attenuated this effect. Ethanol consumption increased the cytosolic activity of the inducible nitric oxide synthase and induced microsomal cytochromes P‐450 capable of producing both nitric oxide and superoxide. This was associated with an 18% (p < 0.01) increase in nitrotyrosine protein residues, products of peroxynitrite toxicity, which occurred predominantly in steatotic hepatocytes. Polyenylphosphatidylcholine attenuated these changes by decreasing the ethanol effect on both the cytosolic and the microsomal activities, in addition to acting as a powerful antioxidant. Acute administration of the same ethanol dose increased nitric oxide levels, but did not affect nitrotyrosine protein residues.Conclusions: Chronic, but not acute, ethanol administration increases peroxynitrite hepatotoxicity by enhancing concomitant production of nitric oxide and superoxide, both of which are prevented by polyenylphosphatidylcholine.
Promoting Self‐Change With Alcohol Abusers: A Community‐Level Mail Intervention Based on Natural Recovery Studies
Authors: Sobell Linda Carter , Sobell Mark B. , Leo Gloria I. , Agrawal Sangeeta , Johnson‐Young Lisa , Cunningham John A. 
Published: April 2006

Background: By using a public health approach to the treatment of alcohol problems, this study analyzed the efficacy and cost analysis of two versions of a community‐level mail intervention to promote self‐change among alcohol abusers who had never sought help or treatment.Methods: A total of 825 participants who responded to media solicitations were randomly assigned to one of two interventions: (a) for bibliotherapy/drinking guidelines (n= 411), they were given two pamphlets with information about the effects of alcohol and guidelines for low‐risk drinking and self‐monitoring, and (b) for motivational enhancement/personalized feedback (n= 414), personalized advice/feedback was provided on the basis of the participants’ assessment of their drinking and related behaviors.Results: Although both groups exhibited significant reductions in drinking from 1 year before to 1 year after intervention, there were no significant differences between the two interventions for any variable. This suggests that the materials, irrespective of whether they were personalized, facilitated the reduction of drinking. Cost analysis revealed that a brief mail intervention could reduce drinking at a very low cost per participant (US$46 to US$97).Conclusions: A brief community‐level mail intervention for problem drinkers who had never sought treatment resulted in sizable reductions in alcohol use over the year after the intervention compared with the year before. Furthermore, many of those with poorer outcomes engaged in a natural stepped‐care process by seeking help. These results, coupled with the low cost to deliver the intervention, suggest that public health campaigns could have a substantial effect on reducing alcohol problems and associated costs as well as getting some individuals into treatment. Such an approach would represent a shift from the alcohol field's long‐standing clinical focus to a broader public health perspective.