bluuebunny/crossref_metadata_2025 huggingface dataset:
Choline Deficiency Augments and Antibody to Tumor Necrosis Factor‐α Attenuates endotoxin‐Induced Hepatic Injury
Authors: Eastin Charles E. , McClain Craig J. , Lee Eun Y. , Bagby Gregory J. , Chawla Rajender K.
Published: May 2006

Alcoholic liver disease can be associated with hepatic choline deficiency and hepatic steatosis, abnormalities also observed in rats administered choline‐deficient (CD) diets. Bacterial lipopolysaccharides (LPS) have been postulated to play a key role in this choline deficiency model of liver injury, and LPS hepatotoxicity is mediated to a major extent by the inflammatory cytokine tumor necrosis factor‐α (TNF‐α). This study addressed the following questions: Does LPS administration exacerbate an in vivo liver injury induced by choline deficiency? If so, do CD rats have increased serum TNF‐α concentrations and does pretreatment anti‐TNF‐α IgG attenuate this injury? Rats administered choline‐sufficient (CS) or CD diets for 16 days were intravenously administered either saline or LPS. One group of CD rats also received a single dose of anti‐TNF‐α IgG before LPS administration. Changes in histology and serum transaminase levels were determined. Both liver histology and serum transaminases were unchanged in the CS group treated with LPS, compared with the CS group treated with saline (control group). However, compared with this control group, transaminases were 5‐ to 7‐fold higher in saline‐treated CD rats and 30‐ to 50‐fold higher in LPS‐treated CD rats. Livers of saline‐treated CD rats had massive fatty infiltration, and no necrosis but livers of LPS‐treated CD rats showed both extensive fatty infiltration and large areas of necrosis. Serum TNF‐α concentrations in CD rats (saline or LPS treated) were significantly elevated, compared with levels in corresponding CS rats. Pretreatment with the anti‐TNF‐α IgG prevented hepatonecrosis in LPS‐treated CD rats and lowered their serum transaminases by one‐third. Thus, LPS administration exacerbated liver injury induced by choline deficiency, and this injury was probably partially mediated by TNF‐α and attenuated by anti‐TNF‐α IgG.
6‐OHDA‐Lesions of the Nucleus Accumbens Disrupt the Acquisition but not the Maintenance of Ethanol Consumption in the Alcohol‐Preferring P Line of Rats
Authors: Ikemoto Satoshi , McBride William J. , Murphy James M. , Lumeng Larry , Li Ting‐Kai
Published: May 2006

The aim of the present study was to determine whether reduction of dopamine (DA) innervation to the nucleus accumbens (ACB) alters the maintenance and/or acquisition of ethanol drinking in female alcohol‐preferring P rats. Compared with sham‐lesioned animals, bilateral microinjections of 6‐OHDA (12 μg/2.4 μl/site) into the ACB did not alter the consumption of 10% ethanol in rats that had prior experience of ethanol drinking, with both sham‐ and 6‐OHDA‐lesioned groups recovering to presurgical consumption levels at similar rates. On the other hand, the identical lesion procedure disrupted the acquisition of ethanol intake in rats with no ethanol‐drinking experience prior to the lesions. A sham‐lesioned group attained an ethanol intake of approximately 7 g/kg/day in 1 week, which was maintained over the following 2‐week period, while the ethanol intake of the 6‐OHDA‐lesioned group was approximately 60% lower after 1 week and 30% lower at the end of 3 weeks. DA content of the ACB was 60% lower in both groups of the 6‐OHDA‐treated rats compared with the controls. The results suggest that different neural mechanisms may underlie the acquisition and maintenance of ethanol drinking behavior; the ACB DA system appears to play an important role in the acquisition of ethanol drinking.
Effects of Chronic Ethanol Exposure on GABA Receptors and GABAB Receptor Modulation of 3H‐GABA Release in the Hippocampus
Authors: Peris Joanna , Eppler Bärbel , Hu Ming , Walker Don W. , Hunter Bruce E. , Mason Karla , Anderson Kevin J.
Published: May 2006

Chronic ethanol treatment (CET), sufficient for decreasing long‐term potentiation (LTP) in rats, also enhances 3H‐GABA release from hippocampal slices in these same animals. The mechanism for an increase in GABA release may involve changes in presynaptic receptors. Therefore, we characterized presynaptic autoreceptor modulation of 3H‐GABA release in hippocampal slices from control and CET rats. The effects of a GABAB receptor agonist (baclofen) and antagonist [2‐hydroxy (OH)‐saclofen] were tested for their ability to modulate electrically stimulated 3H‐GABA release from superfused hippocampal slices. Baclofen decreased stimulated release in a dose‐dependent manner and 2‐OH‐saclofen increased release consistent with the existence of presynaptic GABAB autoreceptors in hippocampus. The GABAA antagonist bicuculline did not significantly modulate basal or stimulated release. When the effects of baclofen and 2‐OH‐saclofen were measured in animals 48 hr after withdrawal from CET, presynaptic modulation of release by baclofen and 2‐OH‐saclofen was decreased. In addition, we examined the density of 3H‐baclofen and 3H‐bicuculline binding in the hippocampal formation using quantitative autoradiographic techniques. We found that the density of 3H‐baclofen binding sites was not affected by CET, whereas the density of 3H‐bicuculline binding sites was increased by 28% in ethanol‐treated rats. These data may explain how CET increases presynaptic regulation of GABA release from hippocampus that may contribute to the decrease in LTP seen in rats after CET.
Modulation of Two Cloned Potassium Channels by 1‐Alkanols Demonstrates Different Cutoffs
Authors: Chu Benson , Treistman Steven N.
Published: May 2006

It is not known whether alcohols modulate ion channels by directly binding to the channel protein or by perturbing the surrounding membrane lipid. Cutoff describes the phenomenon where the potency of 1‐alkanols monotonically increases with alkyl chain length until a loss of efficacy occurs. Determination of the cutoff for a variety of channels can be important, because similar and/or dissimilar cutoffs might yield information regarding the nature of ethanol's site of action. In this study, the two‐electrode voltage clamp technique was used to determine the cutoffs for the 1‐alkanol potentiation of cloned Ca2+‐activated‐K+ (BK) channels and for the inhibition of cloned Shaw2 K+ channels, expressed in Xenopus oocytes. Ethanol, butanol, hexanol, and heptanol reversibly enhanced BK currents, whereas octanol and nonanol had no effect. In contrast, Shaw2 currents were potently inhibited by both octanol and decanol, but not by undecanol. Taken together, data demonstrate that the modulation of K+ channels by long chain alcohols is channel‐specific. Interestingly, ethanol was a less potent activator of BK currents in the intact oocyte in comparison with its effect on this channel in excised membrane patches. The decrease in potency could not be attributed to an ethanol‐dependent change in Ca2+ influx through endogenous voltage‐gated channels, an effect that would alter the concentration of Ca2+ available to activate BK channels.
Moderate Alcohol Consumption Does Not Augment Bone Density in Ovariectomized Rats
Authors: Sampson H. Wayne , Shipley Debra
Published: May 2006

Moderate levels of alcohol consumption have been reported to have a beneficial effect on bone mineral density in postmenopausal women. The objective of this study was to examine the effect of a moderate level of alcohol consumption on bone density in a rigorously controlled animal model of osteoporosis. Ovariectomized and nonovariectomized rats were placed on standard lab pellets with free access to deionized water ad libitum. Alcohol‐treated animals were given 0.38 g/kg of alcohol daily by intubation in the mid‐afternoon and free access to standard lab pellets for 6 weeks. The amount of the alcohol solution was calculated daily to give the human equivalent of 2 glasses of wine/day. Pair‐fed control animals were given, on the following day, an equal volume of the diet consumed by individual ethanol‐fed rats. They received daily intubation solutions, with the ethanol replaced by isocaloric and isovolumetric amounts of maltose‐dextrin. Chow‐fed control animals received no intubations and were given access to standard lab pellets ad libitum. Ovariectomized animals had increased weight and decreased femur density and bone volume per total volume. They also had decreased total trabecular area, trabecular area, and number, as well as increased trabecular separation. Significant differences were found between the ovariectomized and nonovariectomized animals in the parameters under discussion, but there were no differences between diet groups. No beneficial effects were found after daily alcohol treatments.
Transglutaminase Activity in Rat Brain after Ethanol Exposure
Authors: Sessa Angela , Tunici Patrizia , Rabellotti Elisa , Perin Antonio
Published: May 2006

The effect of acute and chronic ethanol treatment on the activity of tissue transglutaminase (a calcium‐dependent enzyme that catalyzes the covalent association between proteins, as well as proteins and polyamines) was studied in homogenate and in the cytosolic fraction of rat brain (telencephalon and diencephalon). A single dose of ethanol (5 g/kg of body weight, by gastric intubation) caused a 2‐fold increase in enzyme activity at 6 hr after the ethanol dose, with a return toward the basal values at 24 hr. In vitro experiments with ethanol or acetaldehyde showed that the increase in transglutaminase activity was due to ethanol per se and not to its metabolism. The enzyme stimulation was correlated with a decrease in the levels of the polyamine spermine, a physiological substrate for the enzyme. Similar results were also found in the brain from rats fed on an ethanol diet for 4 months. The enhancement in tissue transglutaminase activity may thus lead to a decline in spermine, a polyamine known to have important protective functions in the cell.
Regional Brain Metabolic Response to Lorazepam in Alcoholics during Early and Late Alcohol Detoxification
Authors: Volkow Nora D. , Wang Gene‐Jack , Overall John E. , Hitzemann Robert , Fowler Joanna S. , Pappas Naomi , Frecska Ede , Piscani Kathleen
Published: May 2006

Changes in GABA function have been postulated to be involved in alcohol tolerance, withdrawal and addiction. In this study we measured regional brain metabolic responses to lorazepam, to indirectly assess GABA function (benzodiazepines facilitate GABAergic neurotransmission), in alcoholics during early and late withdrawal. Brain metabolism was measured using PET and 2‐deoxy‐2[18F]fluoro‐D‐glucose after placebo (baseline) and after lorazepam (30 μg/kg intravenously) in 10 alcoholics and 16 controls. In the alcoholics evaluations were performed 2 to 3 weeks after detoxification and were repeated 6 to 8 weeks later. Controls were also evaluated twice at a 6 to 8 weeks interval. While during the initial evaluation metabolism was significantly lower for most brain regions in the alcoholics than in controls in the repeated evaluation the only significant differences were in cingulate and orbitofrontal cortex. Lorazepam‐induced decrements in metabolism did not change with protracted alcohol withdrawal and the magnitude of these changes were similar in controls and alcoholics except for a trend towards a blunted response to lorazepam in orbitofrontal cortex in alcoholics during the second evaluation. Abnormalities in orbitofrontal cortex and cingulate gyms in alcoholics are unlikely to be due to withdrawal since they persist 8 to 11 weeks after detoxification. The fact that there was only a trend of significance for an abnormal response to lorazepam in orbitofrontal cortex indicates that mechanisms other than GABA are involved in the brain metabolic abnormalities observed in alcoholic subjects.
Is Carbohydrate‐Deficient Transferrin a Specific Marker for Alcohol Abuse? A Study in Patients with Chronic Viral Hepatitis
Authors: Perret Renaud , Froehlich Florian , Lavanchy Daniel , Henry Hugues , Bachman Claude , Pécoud Alain , Bianchi Leonardo , Gonvers Jean‐Jacques
Published: May 2006

Carbohydrate‐deficient transferrin, a transferrin isoform, is hailed as a new marker of chronic alcohol abuse, but its specificity is, however, not unequivocally accepted. The aim of the present study was therefore to determine carbohydrate‐deficient transferrin levels in patients with chronic hepatitis B and C with or without documented chronic alcohol intake. Carbohydrate‐deficient transferrin was measured using a double‐antibody radioimmunoassay (CDTectTM, Pharmacia®) in serum samples from 66 patients (45 males and 21 females; mean age: 39 years) with chronic viral hepatitis B (n= 20) or C (n= 46). Diagnosis of the underlying liver disease was established by liver biopsy. Carbohydrate‐deficient transferrin levels were raised in 15 patients [23%; hepatitis B (n= 2) and hepatitis C (n= 13)]. In patients with chronic hepatitis B, the carbohydrate‐deficient transferrin level was raised in two abstainers. In the 46 patients with chronic hepatitis C, 10 (22%) patients with an alcohol consumption of > 60 g/day for the men and 30 g/day for the women had raised carbohydrate‐deficient transferrin levels. The overall specificity of carbohydrate‐deficient transferrin for chronic alcohol abuse was thus 78%, suggesting an association between elevated carbohydrate‐deficient transferrin levels and the presence of chronic viral hepatitis. Carbohydrate‐deficient transferrin levels were not correlated with the histological grading or staging of chronic hepatitis B and C, or with biological markers of hepatic synthesis and cellular damage. Thus, an increased carbohydrate‐deficient transferrin level may occur in patients with chronic viral hepatitis in the absence of chronic alcohol abuse. This fact should be kept in mind by physicians when using this marker to detect alcohol abuse.
Association Analysis of a Regulatory Variation of the Serotonin Transporter Gene with Severe Alcohol Dependence
Authors: Sander Thomas , Harms Helmut , Lesch Klaus‐Peter , Dufeu Peter , Kuhn Silke , Hoehe Margret , Rommelspacher Hans , Schmidt Lutz G.
Published: May 2006

The present study tested the hypothesis that the short, low activity variant of a biallelic polymorphism in the 5’regulatory region of the human serotonin transporter (5‐HTT) gene confers susceptibility to severe alcohol dependence marked by severe withdrawal symptoms. Applying a phenotype‐genotype strategy, our population‐based association analysis included 216 German controls and an extreme sample of 103 severely affected alcoholics who were selected from 315 German alcohol‐dependent subjects by a history of alcohol withdrawal seizure or delirium. The frequency of the short allele (S) was significantly increased in the severely affected alcoholics, compared with that in the controls (X2= 3.87, df= 1, nominal p= 0.049). The post‐hoc exploration indicated that this allelic association resulted exclusively from a significant excess of the S/S genotype in the severely affected alcoholics (p= 0.035), suggesting a recessively acting effect. Consistently, we found a weak but significant correlation (p= 0.013) between the frequency of the S/S genotype and severity of withdrawal symptoms (WDS): no WOS [18.3%, odds ratio (OR) = 1.16], vegetative WDS only (21.8%, OR = 1.44), and severe WDS with either withdrawal seizure only or delirium only (25.0%, OR = 1.69), and both withdrawal seizure and delirium (30.8%, OR = 2.30). Further studies are required to test whether the tentative genotype‐phenotype relationship occurred by chance or reflects a real genotypic association between a recessively modifying effect of the short variant of the functional 5‐HTT promoter polymorphism and alcohol withdrawal vulnerability.
Gastric Ethanol Metabolism and Gastritis: Interactions with Other Drugs, Helicobacter pylori, and Antibiotic Therapy (1957‐1997)—a Review
Authors: Lieber Charles S.
Published: May 2006

The stomach provides some protection against the penetration of ethanol into the body by contributing to the metabolism of ethanol. The latter is attenuated by various drugs and, although the magnitude of this effect is still the subject of debate, patients should be warned of the corresponding possible increase in blood alcohol levels. Furthermore, oxidation of ethanol generates acetaldehyde, a toxic metabolite. In addition, chronic alcohol abuse seems to favor colonization by Helicobacter pylori, which produces ammonia that also contributes to the commonly associated chronic gastritis. Because antibiotics were shown over the last 4 decades to effectively eliminate gastric ammonia, they should be considered for the routine treatment of such chronic gastritis in the way they are now being used for ulcer therapy.
Neurophysiological Correlates of Response Production and Inhibition in Alcoholics
Authors: Cohen H. L. , Porjesz B. , Begleiter H. , Wang W.
Published: May 2006

Scalp recordings of the P300 component of the event‐related potential were made from a group of medication‐free, chronic male alcoholics and a control group, participating in a visual Go/No Go reaction time paradigm. Subjects were presented with large and small forms of the letters T and V. The large forms (Go stimuli) required a button press with either the left or right hand, whereas the small forms (No Go stimuli) required response inhibition. Recordings were made from 31 electrodes that, for statistical analyses, were grouped into five regions: frontal, central, parietal, occipital, and temporal. The results indicated that, in each of the five regions, both Go and No Go response amplitudes were larger in the controls than in the alcoholics. No group differences in latency were observed in any region. Surface energy (Wang et al., Brain Topogr. 6:193‐202, 1994) magnitudes paralleled P300 amplitudes and in the controls, compared with the alcoholics, were larger during both Go and No Go trials. Our findings suggest that abstinent, chronic alcoholics differ electro‐physiologically from control individuals. These differences are manifested as widespread reductions in P300 amplitudes during the performance of a simple information processing paradigm. The reduced amplitudes may reflect a deficiency in an inhibitory mechanism proposed to underlie P300 generation.
The Density of Monoamine Oxidase B Sites Is Not Altered in the Postmortem Brain of Alcoholics
Authors: Maeztu Ana I. , Ballesteros Javier , Callado Luis F. , Gutiérrez Miguel , Meana J. Javier
Published: May 2006

The status of the enzyme monoamine oxidase B (MAO‐B) was directly evaluated in the postmortem brain from 20 alcoholics and 23 matched controls. The density of MAO‐B sites was quantified by the specific binding of the selective inhibitor [3H]Ro 19‐6327 (lazabemide) (8 nM) to cortical membranes. A positive correlation between age at death and MAO‐B density was observed in the total sample (r= 0.37, p= 0.015). The density of MAO‐B in alcoholics (Bmax= 1,263 ± 131 fmol/mg of protein) was not different form that in control (Bmax= 1,131 ± 96 fmol/mg of protein). Ethanol in vitro inhibited [3H]Ro 19‐6327 binding, with similar potency in membranes form alcoholics (Ki= 280 ± 13 mM) and controls (Ki= 338 ± 84 mM). The present results in brain tissue contrast with previous reports of decreased MAO‐B enzymatic activity in platelets of alcoholics, but strongly agree with recent genetic studies on MAO‐B status in alcoholism.
II. Functional Consequences of Intragastrically Administered Ethanol in Rats as Measured by the 2‐[14C]Deoxyglucose Method: The Contribution of Dopamine
Authors: Williams‐Hemby Lisa , Porrino Linda J.
Published: May 2006

As outlined in the companion paper, many of the changes in functional activity produced by acute intragastric ethanol administration as determined by the quantitative autoradiographic 2‐[14C]deoxyglucose method occur in structures of the mesocorticolimbic and nigrostriatal dopamine circuits. In this study, a dopaminergic antagonist, flupenthixol, was used to determine the contribution of dopamine to the ethanol‐induced increases in functional activity. To assess the ability of flupenthixol to block dopaminergic‐induced increases in glucose utilization, it was first examined in conjunction with the indirect dopaminergic agonist methylphenidate. Pretreatment with flupenthixol significantly reduced methylphenidate‐induced increases in glucose utilization in structures of the mesocorticolimbic and nigrostriatal dopamine circuits. These findings indicate that this is an effective strategy for the determination of the neurochemical contributions to the changes in CNS functional activity. Flupenthixol pretreatment blocked many of the ethanol‐induced increases in glucose utilization at the 0.25 g/kg dose, particularly in mesocorticolimbic and nigrostriatal structures. At the 1.0 and 2.0 g/kg ethanol doses, however, pretreatment with flupenthixol did not reverse the increases in glucose utilization in several brain regions, suggesting that dopaminergic activity is not responsible for the observed increases in glucose utilization and further, that these increases involve other neurotransmitter systems. In some regions, however, flupenthixol pretreatment resulted in augmented levels of glucose utilization above those rates produced by the administration of higher doses of ethanol alone. These findings suggest that the contribution of dopamine to the increases in functional activity are more complex at higher doses of ethanol.
Effect of Pretreatment with Alcohol on Subsequent Endocrine and Immune Responses in the Adult Male Rat
Authors: Rivier Catherine
Published: May 2006

We have previously shown that daily injection of alcohol for 3 days induced a significant and long‐lasting blunting of the hypothalamicpituitary‐adrenal (HPA) axis response to a subsequent treatment with this drug. The fact that, in contrast, the HPA axis response to footshocks was not altered by prior alcohol administration, suggested the presence of a phenomenon of selective neuroendocrine tolerance. To further test this hypothesis, we determined whether an initial alcohol challenge would alter the ACTH response to immune signals, such as interleukin‐1 β (IL‐1β) and/or endotoxin (lipopolysaccharide; LPS). Because of the functional connection between the HPA axis and immune responses, we also determined whether the LPS‐induced release of tumor necrosis factor‐a and interleukin‐6, as well as IgG and IgM responses to an antigenic challenge, would be influenced by previous exposure to alcohol. We show here that the intragastric injection of 3 g of alcohol/kg daily for 3 days did not significantly alter the ability of IL‐1β (400 ng/kg) or LPS (1 μg/kg), both injected intravenously 7 days later, to release ACTH. Drug pretreatment did not significantly alter the tumor necrosis factor‐α response to the low dose of endotoxin used, whereas there was a tendency toward increased circulating interleukin‐6 levels in alcohol‐pretreated animals. Finally the IgG, but not IgM, response to the antigen phosphocholine‐keyhole limpet hemocyanin was significantly (p < 0.05) augmented in rats administered alcohol 7 days before the antigenic challenge. Collectively, these results indicate that an initial exposure to alcohol does not induce long‐term changes in the ability of an immune signal (1L‐1β or endotoxin) to activate the HPA axis. In contrast, a small but detectable enhancement of cytokine responses to LPS, and of the IgG response to phosphocholine‐keyhole limpet hemocyanin, was observed.
Measurement of Alcohol‐Involved Injury in Community Prevention: The Search for a Surrogate III
Authors: Treno Andrew J. , Holder Harold D.
Published: May 2006

Alcohol is involved in a substantial percentage of injuries, with estimates in the United States ranging from 3% of drownings up to 50% of fatal traffic crashes. Thus, alcohol‐involved injury is a natural target for prevention efforts, particularly at the community level. Although a potentially valuable target, the measurement of alcohol‐involved injuries for purposes of outcome evaluation of such prevention is problematic. The consistent measurement of alcohol in the blood of injured persons is not a regular aspect of acute medical treatment Thus, alternatives are needed both for epidemiological, as well as prevention, research. This study will review three alternative measurements of alcohol‐involved injury [i.e., (a) emergency room interviews and breath testing for blood alcohol concentration, (b) telephone surveys of self‐reported injuries after drinking, and (c) injury surrogate derived archival data from hospital inpatient treatment]. After comparing the strengths and weaknesses of all three and investigating the sensitivity of the injury surrogate to detect changes in alcohol‐involved injuries, this study concludes that the injury surrogate is a reliable, low‐cost, and valid outcome measure for prevention evaluation.
Relationship Between the Flushing Response and Drinking Behavior Among Japanese High School Students
Authors: Suzuki Kenji , Matsushita Sachio , Ishii Toshio
Published: May 2006

In a study of the relationship between the flushing response and drinking behavior, the Adolescent Alcohol Involvement Scale was used to survey 932 male and female Japanese high school students identified by the ethanol patch test as flushers (338; 36.3%) and nonflushers (594; 63.7%). The goal was to clarify whether the flushing response inhibits adolescent drinking. Students with the flushing response reported drinking significantly less than nonflushers with respect to both frequency and amount. Although the flushing response was associated with less drinking, the flushers and nonflushers had similar drinking partners and reasons for drinking, and their total Adolescent Alcohol Involvement Scale scores did not differ significantly. The survey showed that many flushers were seeking the pleasures of alcohol despite the discomforts it caused, suggesting that Japanese adolescents need more education on the risks of adolescent drinking.
Smoking and Intoxication after Alcohol Challenge in Women and Men: Genetic Influences
Authors: Madden P. A. F. , Heath A. C. , Martin N. G.
Published: May 2006

In an earlier analysis, men and women who were current or former smokers were found to report feeling less intoxicated on average than nonsmokers after ingestion of a challenge dose of alcohol. Here, we examine whether differences in subjective response to alcohol and a tendency to smoke cigarettes are transmitted together in families; and, if so, whether this association might be entirely explained by the same heritable factors that influence alcohol intake (as we might expect if both smoking and subjective intoxication are influenced by some general susceptibility for substance use). Alcohol challenge data on 388 Australian male and female twins (194 complete pairs) were reanalyzed using multivariate genetic analysis to evaluate the association between cigarette smoking and self‐report intoxication after a standard dose of alcohol. In women, we could not reject the hypothesis of complete genetic overlap between effects on intoxication rating and history of smoking, and a significant residual genetic correlation between smoking and postalcohol intoxication persisted even when genetic influences on alcohol consumption were controlled for. In men, the familial association seemed to be largely environmentally mediated and associated with differences in drinking history. These findings prompt the question of whether, in some individuals, cigarette smoking may contribute to the development of tolerance to the effects of alcohol.
Research on Tolerance: What Can We Learn From History?
Authors: Kalant Harold
Published: May 2006

The concept of tolerance to ethanol has evolved gradually over the past two centuries, and all of the basic clinical features, as they are now understood, have been clearly recognized for nearly 100 years. The basic mechanisms involved in central nervous system tolerance, however, have been elucidated only in the past 20 to 30 years. Little progress was made as long as tolerance was viewed as a purely cellular or physiological adaptation to alcohol, and researchers used overly simple paradigms based on mere exposure to the drug. With the recognition that learning, both operant and associative, can play a major role in the development of tolerance to alcohol and cross‐tolerance to other drugs, a radical change in research approaches became possible. Most of the neural mechanisms related to learning and memory are now known to be involved in the development and retention of tolerance, and the simplistic models used in earlier research must now be abandoned. Nevertheless, a review of the history of past research points to a number of important lessons for future work, including the following: (1) many of the present concepts were enunciated by astute observers many decades ago, and research was hindered because this older literature was forgotten; (2) for many decades progress was slow because of a narrow focus on specific techniques, questions, and hypotheses that overlooked important research in related disciplines; (3) the course of research is often irregular, and past questions may have to be revisited with new approaches– but these are more likely to be fruitful if based on knowledge of past history; and (4) excellent researchers often obtain apparently contradictory findings, but the disagreements may hold the key to deeper understanding of the phenomena, and should not be brushed over by ignoring the minority findings and interpretations. As in all scientific research, the most important requirement for major progress is the formulation of good questions or hypotheses: the results yielded by the best available techniques can be only as good as the questions they are meant to answer.
Visual and Auditory Event‐Related Potentials in Young Children of Alcoholics from High‐ and Low‐Density Families
Authors: Holguín Socorro Rodríguez , Corral Montserrat , Cadaveira Fernando
Published: May 2006

Event‐related potentials (ERPs), particularly the P3 wave, have been proposed as biological markers of genetic risk for alcoholism. The present study assesses the ERPs from 102 boys and girls (7 to 15 years old) divided into three groups: two groups of sons and daughters of alcoholic fathers, with and without other first‐ or second‐degree relatives affected, and a control group of children of nonal‐coholics. Both visual and auditory discrimination tasks with three stimuli (standard, target, and infrequent nontarget) were used. P3 amplitudes did not reach significant reduction for the high‐risk males and were complex for females. There were significant differences among females in P3 visual latency elicited by targets; delays in this variable were associated with multigenerational familial alcoholism. Results are discussed in light of the tasks used for eliciting the ERPs and the characteristics of the selected sample.
Acute Ethanol Intoxication Inhibits Neutrophil β2‐Integrin Expression in Rats During Endotoxemia
Authors: Zhang Ping , Bagby Gregory J. , Xie Ming , Stoltz David A. , Summer Warren R. , Nelson Steve
Published: May 2006

The effects of acute ethanol intoxication on neutrophil [polymorphonuclear leukocyte (PMN)] adhesion molecule expression and certain other functional properties during endotoxemia were studied in rats to elucidate the mechanisms underlying the immunosuppressive effects of ethanol. Acute ethanol intoxication was induced by an intraperitoneal injection of 20% ethanol at a dose of 5.5 g of ethanol/kg. Control animals received an intraperitoneal injection of saline. Thirty minutes after intraperitoneal injection, animals were given a 90‐min intravenous infusion of Escherichia coli endotoxin (total dose of 112.5 μg/rat in 2.5 ml of saline) or saline. Certain rats received granulocyte colony‐stimulating factor (G‐CSF; 50 μg/kg in 5% dextrose, subcutaneous injection twice daily) or vehicle pretreatment for 2 days before intravenous endotoxin infusion. Endotoxemia significantly upregulated CD11b/c and CD18 expression on PMNs when compared with those of saline‐infused rats. Acute ethanol intoxication inhibited this endotoxin‐induced upregulation of CD11b/c and CD18 expression on PMNs. Ethanol intoxication also suppressed the phagocytic activities of PMNs in saline‐infused rats, but this suppression failed to reach statistical significance in endotoxin‐infused rats. Hydrogen peroxide generation by PMNs in saline‐ or endotoxin‐infused rats was not affected by ethanol intoxication. Histological examination showed extensive PMN sequestration in the liver after endotoxin infusion, and ethanol intoxication significantly attenuated this hepatic sequestration of PMNs. G‐CSF pretreatment enhanced neutrophil phagocytosis, CD11b/c and CD18 expression in endotoxin‐infused rats, and prevented the ethanol‐induced inhibition of neutrophil CD18 expression and phagocytosis. The impairment of β2‐integrin expression on PMNs may be one mechanism underlying ethanol‐induced defects of neutrophil delivery into tissue sites of infection. G‐CSF may be of benefit to the infected alcoholic host by enhancing leukocyte defense functions.
Acamprosate Enhances N‐Methyl‐D‐Apartate Receptor‐Mediated Neurotransmission But Inhibits Presynaptic GABAB Receptors in Nucleus Accumbens Neurons
Authors: Berton Fulvia , Francesconi Walter G. , Madamba Samuel G. , Zieglgänsberger Walter , Siggins George Robert
Published: May 2006

Acamprosate (calcium acetylhomotaurine) is used therapeutically in Europe to reduce relapse in weaned alcoholics. However, the mechanisms of acamprosate action in the central nervous system are still obscure, although early studies suggested an action on GABA receptors. The nucleus accumbens (NAcc) is a brain region thought to underlie ethanol reinforcement. Recent studies from our laboratory have demonstrated that ethanol inhibits both N‐methyl‐D‐aspartate (NMDA) and non‐NMDA types of glutamatergic synaptic transmission in the NAcc.1,2 In the present study, we used voltage‐ and current‐clamp intracellular recording of NAcc core neurons in a slice preparation to examine acamprosate actions on resting membrane properties and pharmacologically isolated synaptic responses. We isolated NMDA and non‐NMDA receptor‐mediated excitatory postsynaptic potentials or currents (EPSP/Cs) with 6‐cyano‐7‐nitro‐quinoxaline‐2,3‐dione (CNQX) and DL‐2‐amino‐5‐phosphonovaler‐ate (d‐APV), respectively. Bicuculline was also included to block GABAA receptors. Superfusion of acamprosate (5, 50, and 300 μM) did not alter the resting membrane properties of NAcc neurons. However, 300 μM acamprosate significantly increased the NMDA receptor‐mediated components of EPSP/Cs (NMDA‐EPSP/Cs) with recovery on washout. In contrast, 300 μM acamprosate had no significant effect on the non‐NMDA receptor component of the EPSP/Cs (non‐NMDA‐EPSP/Cs). To test acamprosate actions on the GABA system, we superfused 60 μM d‐APV and 20 μM CNQX to block glutamatergic transmission and evoked monosynaptic GABAA receptor‐mediated synaptic responses within the NAcc. Acamprosate (300 μM) did not change these monosynaptic GABAA‐IPSCs. We also used a paired‐pulse paradigm to test whether acamprosate could act on presynaptic GABAB, autoreceptors, in the presence of d‐APV and CNQX to block glutamatergic transmission. Like 0.5 μM CGP 34358 (a GABAB receptor blocker), acamprosate significantly decreased the paired‐pulse inhibition (PPI) of GABAA‐IPSCs at short interstimulus intervals (ISIs). Thus, acamprosate may concomitantly enhance NMDA‐EPSP/Cs while blocking presynaptic GABAB receptor‐mediated inhibition of GABA release. These results suggest that acamprosate's clinical efficacy in preventing relapse in weaned alcoholics could derive from its interactions with both the glutamatergic and GABAergic systems in the NAcc.

Synaptic Transmission, Alcohol, Ethanol, EPSPs, NMDA Receptors.
Brain Neuronal Degeneration Caused by Episodic Alcohol Intoxication in Rats: Effects of Nimodipine, 6,7‐Dinitro‐quinoxaline‐2,3‐dione, and MK‐801
Authors: Corso Thomas D. , Mostafa Hisham Mohamed , Collins Michael A. , Neafsey E. J.
Published: May 2006

Rats repeatedly intoxicated with alcohol (ethanol, three times daily) over a 4‐day period display neuronal degeneration in the dentate gyrus; entorhinal, piriform, insular, orbital, and perirhinal cortices; and in the olfactory nerve fibers and terminals in the olfactory bulb. Postulating a role for excitotoxicity, we have attempted to prevent the degeneration using antagonists that are neuroprotective in this type of brain damage. In an initial study, continuous subcutaneous infusion of a high dose of the glutamate/NMDA receptor antagonist MK‐801 (2 mg/kg/day) by itself caused extensive neuronal degeneration in several brain regions and severe behavioral intoxication that precluded survival if combined with high blood alcohol levels (∼300 mg/dl). Moreover, the lower, nonneurotoxic blood alcohol levels (∼150 mg/dl) that were compatible with survival worsened the MK‐801‐induced brain damage. In a subsequent experiment, daily intraperitoneal injections of a lower dose of MK‐801 (1 mg/kg/day) resulted in no MK‐801 toxicity and, when combined with neurotoxic levels of alcohol, no reduction in alcohol‐induced neurotoxicity. Nimodipine, a voltage‐gated Ca2+ channel blocker, reduced the neuronal damage in the dentate gyrus, but greatly increased it in the piriform cortex when administered intragastrically at 600 mg/kg/day; it provided no protection from alcohol‐dependent degeneration when given intragastrically at 100 mg/kg/day. Continuous intracere‐broventricular delivery of 0.24 to 0.29 mg/day of 6,7‐dinitro‐quinoxa‐line‐2,3‐dione, a glutamate/α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole receptor antagonist, failed to diminish alcohol‐dependent neuronal damage in any brain region. We conclude that brain damage from episodic “binge” alcohol intoxication is not primarily mediated by excitotoxic mechanisms, implying that other, nonexcrtotoxic pathophysiological mechanisms, are involved. Furthermore, MK‐801, far from protecting from the alcohol‐induced damage, at high doses causes widespread neuropathology that is significantly potentiated by alcohol.
Prenatal Exposure to Alcohol Affects the Ability to Maintain Postural Balance
Authors: Roebuck Tresa M. , Simmons Roger W. , Mattson Sarah N. , Riley Edward P.
Published: May 2006

Prenatal exposure to alcohol is known to affect gross motor functioning. Animal studies have shown that balance is particularly affected, and there is some evidence that similar deficits exist in alcohol‐exposed children. In the current study, postural balance, or the ability to maintain equilibrium, was assessed in a group of alcohol‐exposed children (ALC group; n=11) and controls (NC group; n= 11) individually matched for age and sex. Balance was measured across six conditions designed to systematically manipulate or eliminate visual or somatosensory information. Equilibrium and strategy scores for each condition and a derived composite balance score were analyzed. Although the ALC group had a lower mean composite balance score, their performance was similar to that of the NC group on all conditions where somatosensory input was reliable. However, when somatosensory input was manipulated, and when both somatosensory and visual input were inaccurate, the ALC group performed more poorly than controls. Interestingly, there were no differences between the ALC group and NC group in the type of control strategy used to maintain balance. These results suggest that alcohol‐exposed children are overly reliant on somatosensory input. When this input is atypical, alcohol‐exposed children display significantly greater anterior‐posterior body sway and are unable to compensate using available visual or vestibular information. These deficits may be related to cerebellar anomalies previously reported in fetal alcohol syndrome children.
Additive Reduction of Alcohol Drinking by 5‐HT1A Antagonist WAY 100635 and Serotonin Uptake Blocker Fluoxetine in Alcohol‐Preferring P Rats
Authors: Zhou Feng C. , McKinzie David L , Patel Tushar D. , Lumeng Lawrence , Li Ting‐Kai
Published: May 2006

We found previously that alcohol‐preferring (P) rats have fewer serotonin (5‐HT) neurons and fibers in key brain regions than alcoholnonpreferring (NP) rats. Because 5‐HT uptake blockers increase synaptic 5‐HT content and 5‐HT1A receptor antagonists increase 5‐HT release by disinhibiting 5‐HT autoinnervation, in the present study, our intent was to determine whether increased synaptic 5‐HT content and/or 5‐HT release in P rats would effectively reduce alcohol consumption. In experiment 1, the 5‐HT antagonist WAY 100635 (WAY) was tested on adult female P rats maintained on 24‐hr free‐choice access to ethanol (10% v/v) and water. Twice daily doses of WAY (0.05, 0.1, 0.5, and 1.0 mg/kg, subcutaneously) were administered to each rat in a counterbalanced order. Baseline ethanol intake, derived from the mean ethanol intakes of the three previous non‐drug days, was approximately 8 g/kg/day. Results indicated that 0.05,0.1, and 0.5 mg/kg doses of WAY reduced 24‐hr ethanol drinking by 25‐30% (p < 0.01) without affecting 24‐hr water intake or body weight In the second experiment, the effects of WAY (0.5 mg/kg), fluoxetine (1.0 mg/kg), or a combination of both were tested in another group of female P rats. WAY and fluoxetine, each alone, reduced ethanol drinking by around 20% and, when combined, decreased ethanol intake by 50%, whereas the body weight and the total fluid intake were not significantly affected. Taken together, these results indicate that both fluoxetine and WAY preferentially reduce ethanol drinking in the P line of rats and, when administered together, reduce ethanol intake in an additive manner. It is proposed that coadministration of these two compounds with distinct mechanisms of action may be a new strategy for reducing alcohol intake.
A Review of the Neuroanatomical Findings in Children with Fetal Alcohol Syndrome or Prenatal Exposure to Alcohol
Authors: Roebuck Tresa M. , Mattson Sarah N. , Riley Edward P.
Published: May 2006

Human and animal studies have clearly demonstrated that alcohol is both a physical and behavioral teratogen and that heavy prenatal alcohol exposure can lead to a distinct pattern of birth defects termed the fetal alcohol syndrome. Underlying the behavioral and cognitive anomalies seen in fetal alcohol syndrome are alterations in brain structure and/or function. This paper reviews the literature examining brain anomalies attributable to prenatal alcohol exposure, beginning with a survey of autopsy studies and leading up to current findings using magnetic resonance imaging and positron emission tomography studies. Autopsy reports clearly illustrate the wide and devastating influence alcohol has on the developing brain, although for the most part no specific pattern of brain malformation has been identified. More recent magnetic resonance imaging studies, particularly when combined with quantitative analysis, have indicated that specific brain areas–such as the basal ganglia, the corpus callo‐sum, and parts of the cerebellum–might be especially susceptible to alcohol's teratogenic effects. Further studies using functional brain imaging techniques may provide even more information about the unique effects prenatal alcohol exposure has on the developing brain. Discovering specific areas of the brain that are affected by alcohol may allow clinicians and researchers to look for patterns of vulnerable regions in the brain, thereby helping in the future detection of children who are prenatally exposed to alcohol.
Chronic Alcohol Intoxication Attenuates Human Immunodeficiency Virus‐1 Glycoprotein 120‐Induced Superoxide Anion Release by Isolated Kupffer Cells
Authors: Bautista Abraham P.
Published: May 2006

This work tests the hypothesis that chronic alcohol intoxication suppresses the microbicidal activity of Kupffer cells by modulating the expression of cell surface receptors associated with respiratory burst and the release of potent microbicidal agents [i.e., reactive oxygen species (ROS)]. Because alcohol is also a potential risk factor in human immunodeficiency virus‐1 (HIV‐1) infection, this study examines the effect of HIV‐1 glycoprotein 120 (gp120)‐induced ROS release by isolated Kupffer cells. After 16 weeks of ethanol feeding, Kupffer cells from male Sprague‐Dawley rats were isolated and assayed for HIV‐1 gp120‐induced superoxide release. Fluorescein iso‐thiocyanate (FITC)‐HIV‐I gp120 binding, NADPH oxidase, and protein kinase C activity in Kupffer cells were measured. Results show that HIV‐1 gp120 induced the release of superoxide anion in a dose‐dependent manner in normal rats. Mannosylated‐bovine serum albumin inhibited FITC‐HIV‐1 gp120‐mediated superoxide release in normal Kupffer cells by 85%. Moreover, 83 ± 6% of Kupffer cells were FITC‐HIV 1 gp120‐positive, whereas <30% were CD4‐positive. In alcohol‐fed rats, HIV‐1 gp120‐induced ROS release was reduced by 70% and FITC‐HIV‐1 gp120 binding (in terms of fluorescence intensity per 106 Kupffer cells) by 44% in Kupffer cells, without any change in percent positive cells for this ligand. Concomitantly, HIV‐1 gp120‐induced translocation of NADPH oxidase to the plasma membranes of Kupffer cells in alcohol‐fed rats was suppressed by 60%. In contrast, alcohol consumption significantly increased total protein kinase C activity and phorbol ester‐induced superoxide release by Kupffer cells. These studies demonstrate that Kupffer cells are likely targets of HIV‐1 whose binding sites on macrophages could also include mannose‐specific receptors. These observations further suggest that suppression of HIV‐1 gp120‐mediated ROS production in chronic alcoholics is due to altered cell surface receptor expression for gp120, and defective postreceptor signaling mechanisms, which in turn could lead to attenuated microbicidal activity of hepatic macrophages.