bluuebunny/crossref_metadata_2025 huggingface dataset:
In Vitro Exposure to Malondialdehyde‐Acetaldehyde Adducted Protein Inhibits Cell Proliferation and Viability
Authors: Willis Monte S. , Klassen Lynell W. , Tuma Dean J. , Sorrell Michael F. , Thiele Geoffrey M.
Published: April 2006

Background: Circulating antibodies against malondialdehyde‐acetaldehyde (MAA) haptenated proteins are increased significantly in patients with alcohol‐induced cirrhosis and hepatitis and are associated with severity of liver damage. Additionally, MAA haptenated proteins are highly immunogenic without the use of adjuvant and have been suggested to induce autoreactive responses. The mechanism of this immunogenicity is currently unknown but may be mediated by cell death in a similar manner as other autoimmune diseases such as systemic lupus erythematosus, mixed connective tissue disease, myositis, and Sjögren's disease.

Methods: Antigen‐presenting cells, lymphocytes, and hepatocytes were exposed to different levels of MAA haptenated hen egg lysozyme and assessed by [3H]thymidine incorporation and (3‐(4,5‐Dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide) conversion for viability.

Results: The cells investigated in this study were those that potentially may be involved in the development of autoimmune liver damage; they include antigen‐presenting cells, lymphocytes, and cells of the liver itself. Each cell type was found to be sensitive to MAA haptenated protein‐induced cell death at levels between 690 μM (10 μg/ml) and 6.9 mM (100 μg/ml), which may be found locally after chronic ethanol consumption. Antigen‐presenting cells (macrophage and B cells) were found to be activated at concentrations just under those levels associated with cell death.

Conclusions: A dose response to MAA haptenated protein‐induced cell death is seen in antigen‐presenting cells, lymphocytes, and hepatocytes in vitro. Recent reports have associated both apoptotic and necrotic cell death with the development of autoimmune disease; thus, it is possible that this may be one mechanism by which in vivo immunogenicity is mediated by aldehyde haptenated proteins.
Bidirectional Modulation of Spatial Working Memory by Ethanol
Authors: Rossetti Zvani L. , Carboni Sonia , Stancampiano Roberto , Sori Pierpaolo , Pepeu Giancarlo , Fadda Fabio
Published: April 2006

Background: It is common knowledge that ethanol causes cognitive and memory impairments. Although these deficits are attributed to its central depressant properties, ethanol has biphasic effects and at low doses can produce excitatory actions.

Methods: Here we examined whether ethanol could have biphasic effects on performance in a delayed alternation task in a T‐maze, a behavioral test of working memory.

Results: A dose‐response study showed that intermediate doses of ethanol (1 g/kg) were associated with impairments of working memory in rats, as assessed at short intertrial intervals (10 sec). In contrast, at longer delays (120 sec), when the delayed alternation performance was reduced markedly in controls, a lower dose of ethanol (0.5 g/kg) significantly improved working memory.

Conclusions: These results demonstrate a dose‐dependent, bidirectional effect of ethanol on working memory and implicate the prefrontal cortex, the site of working memory function, as a target of ethanol action. The cognitive improvements caused by low, excitatory doses of ethanol may be perceived as rewarding and could have relevance for chronic ethanol consumption in humans.
Injury Among Detoxification Patients: Alcohol Users’ Greater Risk
Authors: Rees Vaughan W. , Horton Nicholas J. , Hingson Ralph W. , Saitz Richard , Samet Jeffrey H.
Published: April 2006

Background: Little information exists about serious injury in alcohol or drug abusers who seek detoxification. This study examined injury prevalence, and the impact of alcohol use on injury, among alcohol‐ and drug‐dependent persons.

Method: We enrolled patients at a detoxification unit into a prospective cohort study and performed follow‐up interviews to determine the prevalence of injury. Baseline and follow‐up (6, 12, 18, and 24 month) data were examined separately by using multivariate logistic regression to determine factors associated with self‐reported episodes of serious injury. The main independent variable was self‐reported first and second substances of choice at admission: alcohol only, drug only, or both.

Results: Overall, 24% of the 470 subjects reported at least one instance of serious injury over the 6‐month period before detoxification. Similarly, approximately 20% of subjects had serious injury during each 6‐month follow‐up period. Injury in the past 6 months was highest among the 63% of subjects who reported alcohol as a drug of choice (28–29% vs. 16% for drug only), even after we controlled for potential confounders. Analysis of 2‐year follow‐up data revealed a similar association, after we controlled for baseline injury and alcohol consumption.

Conclusions: Injury is a serious problem for a substantial proportion of patients who undergo detoxification, particularly those with alcohol dependence. This marked risk for serious injury persisted for 24 months after detoxification. Patients at detoxification, particularly those with alcohol problems, represent a high‐risk population for injury that may benefit from interventions to reduce these preventable complications.
Beverage Choice Among Native American and African American Urban Women
Authors: Graves Karen , Kaskutas Lee Ann
Published: April 2006

Background: Little is known about beverage preference, especially among understudied urban minority populations. Also, most studies do not differentiate between beer and malt liquor or among wine, wine coolers, and fortified wine. This article examines whether ethnicity or drinking frequency are associated with beverage choice, considering six types of alcoholic beverages: beer, wine, spirits, malt liquor, fortified wine, and wine coolers.

Methods: Data were analyzed from Native American (n= 70) and African American (n= 129) urban pregnant women who reported drinking in the 12 months before an index pregnancy. A small comparison group of white women (n= 22) was included. Women were queried about their consumption of each of six beverage types during the 12 months before pregnancy.

Results: The alcoholic beverage most often used, adjusted for other beverages consumed, was beer, followed in order by spirits, wine coolers, malt liquor, wine, and fortified wine. The Native American women preferred beer, which accounted for one third of total intake. In contrast, malt liquor and spirits each accounted for approximately a quarter of intake among African Americans. Compared with other drinkers, women who drank daily were significantly more likely to choose the beer and wine products with a higher alcohol content. In general, these bivariate results were borne out by multivariate analyses that controlled for age, marital status, and education.

Conclusions: These findings suggest that when accuracy is desired, alcohol studies focusing on urban African American samples (and, to a lessor degree, Native American respondents) should consider not just beer, wine, and spirits consumption, but also stronger beer products, such as malt liquor; stronger wine products, such as fortified wine; and sweeter products, such as wine coolers.
Alcohol Use Disorders Identification Test: Factor Structure in an Adolescent Emergency Department Sample
Authors: Chung Tammy , Colby Suzanne M. , Barnett Nancy P. , Monti Peter M.
Published: April 2006

Background: This study examined whether the factor structure of a modified version of the Alcohol Use Disorders Identification Test (AUDIT) represented the three intended conceptual domains of consumption, dependence symptoms, and alcohol‐related consequences in an adolescent sample. Additionally, the utility of factor‐specific cut scores in identifying patients with DSM‐IV alcohol diagnoses was investigated.

Methods: Adolescents treated for an injury in an emergency department and who reported alcohol use in the last year (n= 173; 57% male, 72% white) constituted the study sample. A modified version of the AUDIT and the alcohol section of the Diagnostic Interview Schedule for Children were administered. The AUDIT's factor structure was determined by confirmatory factor analysis and exploratory principal components analysis. Factor‐specific cut scores that identified adolescents with a DSM‐IV alcohol diagnosis were determined by using receiver operating characteristic analysis.

Results: A two‐factor model representing consumption and dependence/consequences provided the best fit to the data. A cut score of 3 on the consumption factor and a cut score of 1 on the dependence/consequences factor demonstrated optimal performance in identifying patients with alcohol diagnoses. The consumption factor had better overall performance compared with the dependence/consequences factor, and it had similar overall performance compared with the AUDIT total score.

Conclusions: The AUDIT comprised two correlated factors: consumption and dependence/consequences. The better performance of the consumption factor in detecting adolescents with DSM‐IV alcohol diagnoses suggests the utility of including consumption items in brief alcohol screens used with adolescents. Results also indicate the need to identify developmentally appropriate alcohol‐related problems to enhance screening performance among adolescents.
Altered EEG Responses to Ethanol in Adult Rats Exposed to Ethanol During Adolescence
Authors: Slawecki Craig J.
Published: April 2006

Background: Adolescent ethanol (EtOH) exposure is a significant health concern due to the potential long‐term effects of EtOH on the developing brain. However, few studies have assessed how exposure to EtOH during adolescence influences the response of adults to EtOH after a long period of withdrawal. This study was designed to assess long‐term changes in EEG activity after EtOH challenge in adult rats exposed to EtOH during adolescence.

Methods: Male Sprague Dawley® rats (n= 24) were exposed to EtOH vapor for 5 days (12 hr/day) between postnatal days 35 and 40. After maturing to adulthood, rats were implanted with cortical, amygdalar, and hippocampal electrodes. Then EEG activity after EtOH challenge (0.0–1.5 g/kg) was assessed.

Results: There were no EEG differences between groups under baseline or vehicle conditions, but EtOH did have differential behavioral and electrophysiological effects when adolescent ethanol‐exposed rats were compared with controls. After 1.5 g/kg EtOH, ethanol‐exposed rats displayed decreased behavioral indexes of intoxication. In addition, EtOH significantly increased 4 to 6 Hz power in the hippocampus and parietal cortex of the control group but had no effect on 4 to 6 Hz power in the ethanol‐exposed group in either of these brain regions. EtOH produced maximal increases in cortical EEG variability in control rats after 1.5 g/kg EtOH but produced maximal increases in cortical EEG variability in ethanol‐exposed rats after 1.0 g/kg EtOH. As a result, ethanol‐induced increases in EEG variability after 1.5 g/kg ethanol were blunted in the ethanol‐exposed group compared with the control group.

Conclusions: These data demonstrate persistent and brain‐region‐specific changes in the neurobehavioral effects of acute EtOH challenge in adult rats exposed to EtOH during adolescence in the absence of baseline neurophysiological differences. Decreased EEG responses to high doses of EtOH combined with decreased behavioral measures of intoxication suggest that adolescent ethanol exposure produces long‐lasting tolerance to the sedative effects of ethanol.
Auditory and Visual Sustained Attention in Adolescents Prenatally Exposed to Alcohol
Authors: Coles Claire D. , Platzman Kathleen A. , Lynch Mary Ellen , Freides David
Published: April 2006

Background: Sustained attention problems and impulsivity are reported in association with prenatal alcohol exposure and fetal alcohol syndrome, but research in this area is limited and contradictory.

Methods: Auditory and visual sustained attention were investigated in 265 low‐income, predominantly African‐American, adolescents (mean age, 15.12 years; SD, 0.92). Included were 53 unexposed controls and 128 exposed to alcohol and other drugs prenatally, with 46 of these exhibiting dysmorphic features and growth retardation, as well as a special‐education contrast group (n= 84). Sustained attention was measured with “AK” subtests from a commercially available Continuous Performance Task program. Outcomes included total correct, total errors, omissions, commissions, preservations, hit rate, false alarms, reaction time, and response sensitivity (d′). A repeated‐measures multivariate analysis of variance procedure was used with the exposure group (four groups) as the independent variable and presentation mode (visual or auditory) and trial block (four blocks) as within‐subject repeated measures.

Results: There was an interaction of group with presentation mode for total correct, errors, error type, hit rate, and d′. Most groups processed visual information more effectively than auditory information. In contrast, dysmorphic adolescents performed as effectively when presented with auditory stimuli but were less efficient in processing visual information. Significantly higher error rates, particularly omission errors [F (3,261) = 7.16;p < 0.000], as well as lower d′ [F (3,261) = 5.77;p < 0.001], were noted in this group.

Conclusions: These results suggest that there may be specific patterns to the effect of prenatal alcohol exposure on cognitive performance that can be identified during adolescence. In this study of sustained attention, processing in the visual modality was more affected than that in the auditory modality. Deficits in visual processing seemed to result from insensitivity to target stimuli.
Central Nervous System Mechanisms in Alcohol Relapse
Authors: McBride W. J. , Le A.‐D. , Noronha A.
Published: April 2006

Background: Alcohol relapse is a major problem in the treatment of alcohol abuse and alcoholism. Understanding the long‐term neuronal alterations that promote relapse of alcohol drinking is critical for the development of pharmacotherapies to treat alcoholism and alcohol abuse. The major objectives of this workshop were to present recent findings, by using rodent models, on behavioral and neurobiological factors that may underlie alcohol relapse and the results of clinical and pharmacological treatment strategies for preventing relapse.

Methods: Prolonged ethanol drinking and repeated periods of alcohol deprivation were studied in nonselected rats and in rats selectively bred for high alcohol preference (P rat). The expression of a robust alcohol deprivation effect (ADE) was used as a model for alcohol relapse in rodents. Operant techniques were used to examine responding for ethanol after deprivation in both rats and C57BL/6J mice. Environmental cues and stress were used to assess their effects on reinstatement of alcohol responding. Microdialysis and [14C]‐2‐deoxyglucose techniques were used to examine neuronal alterations associated with alcohol relapse.

Results: Prolonged free‐choice ethanol drinking followed by deprivation produced an ADE in both stock and P rats. These rats demonstrated loss of control on reinstatement after chronic drinking and after prolonged deprivation. Acamprosate and naltrexone effectively reduced the ADE in stock rats. Stress reinstated operant responding for alcohol, and rats trained to associate a cue with ethanol presentation increased responding on the ethanol‐associated lever in the absence of ethanol. After repeated deprivations, P rats shifted their preference toward drinking higher concentrations of ethanol, which increased the magnitude and duration of the ADE. Stock rats also shifted their preference toward solutions with higher ethanol concentrations and demonstrated a loss of control after prolonged ethanol drinking and deprivation. Long‐lasting alterations in neuronal activity, serotonin‐3 receptor function, and dopamine neurotransmission within the mesolimbic system were evident after chronic drinking that followed a prolonged deprivation period.

Conclusions: The ADE is a useful model for studying alcohol relapse in both rats and mice. The potential validity of this model is supported by the findings that acamprosate and naltrexone are effective in preventing the ADE in rodents, and both compounds have gained recognition for their therapeutic effects in clinical populations. Genetics, stress, and environmental cues are all important factors that influence alcohol relapse. Long‐term alterations in neuronal activity within the mesolimbic system, which possibly involve dopamine and serotonin, may underlie alcohol relapse.
Ethanol and Membrane Protein Trafficking: Diverse Mechanisms of Ethanol Action
Authors: Nagy Laura E. , Lakshman M. Raj , Casey Carol A. , Bearer Cynthia F.
Published: April 2006

This article represents the proceedings of a symposium at the 2001 RSA Meeting in Montreal, Quebec. The cochairs were Laura E. Nagy and M. Raj Lakshman. The presentations were (1) Ethanol and protein trafficking in liver: modifications of small GTP binding proteins (Rabs), by M. Raj Lakshman; (2) Impaired receptor‐mediated endocytosis: its role in alcoholic liver injury, by Carol A. Casey; (3) Ethanol and L1 mediated neurite outgrowth: receptor recycling and L1 signal transduction, by Cynthia F. Bearer; and (4) Ethanol and glucose transport, GLUT4 vesicle trafficking, by Laura E. Nagy.
Alcohol‐Related ERP Changes Recorded From Different Modalities: A Topographic Analysis
Authors: Cohen Howard L. , Ji Jun , Chorlian David B. , Begleiter Henri , Porjesz Bernice
Published: April 2006

Background:There is controversy in the literature regarding the relationship between event‐related‐potential (ERP) abnormalities in abstinent alcoholics and stimulus‐processing modality (i.e., visual versus auditory). The first purpose of this study was to address questions about whether ERP abnormalities observed in alcoholics are modality specific. The second purpose was to employ current source density (CSD) analyses to investigate topographic differences between alcoholics and controls within each modality.

Methods:Data were collected from 30 sober male alcoholics and 39 normal males in a typical auditory oddball task and in a visual oddball paradigm with novel stimuli, with an extensive set of 61 scalp electrodes. Visual and quantitative assessment of CSD maps as well as analyses of variances on both raw and normalized ERP data were performed.

Results:Positive findings were limited to the N1 and P3 components. The visual N1 amplitude was significantly smaller in alcoholics than in controls at the parietal region; no significant group differences in N1 were found in the auditory modality. Alcoholics had widespread reductions in P3 amplitudes in both modalities compared with controls, although in the frontal region this effect was partially due to the influence of age. These P3 reductions in alcoholics were statistically more pronounced in the posterior compared with the anterior regions regardless of modality. Topographically, sources in CSD maps were weaker in alcoholics than in controls; in the frontal and central regions, the weakness was more pronounced in the auditory modality but, in parietal and occipital regions, it was more pronounced in the visual modality.

Conclusions:The results suggest that, in abstinent alcoholics, abnormalities in auditory ERPs may be localized to more anterior sources, while abnormalities in visual ERPs may be localized to more posterior sources. ERP topographic features are more sensitive than amplitude measurements in assessing alcoholic‐related modality effects.
Mecamylamine Modifies the Pharmacokinetics and Reinforcing Effects of Alcohol
Authors: Blomqvist Ola , Hernandez‐Avila Carlos A. , Van Kirk Jeffrey , Rose Jed E. , Kranzler Henry R.
Published: April 2006

Background: Central nicotinic cholinergic receptors modify alcohol‐induced mesolimbic dopamine activation, which seems to be important in the reinforcing properties of alcohol. Consistent with this model, acute administration to rats of the tertiary nicotinic receptor antagonist mecamylamine blocks both alcohol consumption and alcohol‐induced dopamine release in the nucleus accumbens. This study was conducted to test the hypothesis that, during the ascending limb of the blood alcohol concentration curve, mecamylamine would reduce the stimulating and pleasurable effects of an intoxicating dose of alcohol in humans.

Methods: Ten female and 10 male volunteers with no history of alcohol or substance use disorders, including nicotine dependence, completed the study. During two laboratory sessions, subjects consumed three aliquots of an alcohol‐containing drink, with a total ethanol content of 0.7 g/kg (in women) or 0.8 g/kg (in men), over a 30‐min period. Two hours before the first drink, subjects were pretreated with mecamylamine or placebo, with the order of sessions counterbalanced. Primary outcome measures included the Drug Effect Questionnaire, the central stimulation subscale of the Alcohol Sensation Scale, and the stimulant subscale of the Biphasic Alcohol Effects Scale. Breath alcohol level (BAL) was examined to identify the ascending and descending limbs of the blood alcohol curve and to assess pharmacokinetic interactions between alcohol and mecamylamine.

Results: Significant effects of time, study drug, and their interaction were observed. Compared with placebo, mecamylamine reduced BAL. After controlling for BAL at each time point, mecamylamine also reduced the Drug Effect Questionnaire and Alcohol Sensation Scale stimulant subscale scores, with a trend for a similar effect on the Biphasic Alcohol Effects Scale score.

Conclusions: Mecamylamine seems to modify both the pharmacokinetic profile of alcohol and the rewarding effects of alcohol in healthy volunteers.
Paternal Alcohol Exposure Affects Sperm Cytosine Methyltransferase Messenger RNA Levels
Authors: Bielawski Dawn M. , Zaher Fadi M. , Svinarich David M. , Abel Ernest L.
Published: April 2006

Background: Although paternal alcohol exposure has been shown to affect the growth and behavior of offspring, the mechanisms underlying these effects still remain to be elucidated. This study examines one possible mechanism, namely, altered genomic imprinting as reflected by changes in sperm cytosine methyltransferase messenger RNA (mRNA) levels.

Methods: Male rats were treated with alcohol for 9 weeks before breeding. Resulting fetuses were counted and weighed, and paternal sperm was examined for changes in cytosine methyltransferase mRNA levels.

Results: Alcohol did not affect mating, fecundity, or litter size, but it did result in significantly decreased mean fetal weight, increased fetal runt incidence in offspring, and decreased cytosine methyltransferase mRNA levels in paternal sperm, compared with pair‐fed and ad libitum controls.

Conclusions: Alcohol‐induced reductions in cytosine methyltransferase mRNA levels may reflect altered genomic imprinting caused by reduced DNA methylation, which, in turn, may lead to the expression of normally silent paternal alleles and may be a mechanism for paternal alcohol effects.
Grape Polyphenols Inhibit Chronic Ethanol‐Induced COX‐2 mRNA Expression in Rat Brain
Authors: Simonyi Agnes , Woods Danielle , Sun Albert Y. , Sun Grace Y.
Published: April 2006

Background: Chronic ethanol has been shown to increase oxidative stress leading to neurodegenerative changes in the brain. Oxidative stress may up‐regulate extracellular signal regulated kinases (ERK1/2) and, subsequently, the arachidonic acid cascade mediated by phospholipase A2 (PLA2) and cyclooxygenase (COX‐2). Our earlier study showed that grape polyphenols (GP) could ameliorate oxidative damage to synaptic membrane proteins due to chronic ethanol treatment. This study was aimed at examining the effects of GP on mRNA expression of ERK1/2, cytosolic PLA2 (cPLA2), and COX‐2 in different brain regions after chronic ethanol treatment.

Methods: Male Sprague‐Dawley rats were fed a Lieber‐DeCarli liquid diet with ethanol or isocaloric amount of maltose, with or without GP for 2 months. In situ hybridization was carried out using coronal brain sections through the hippocampus.

Results: Quantitative in situ hybridization showed no changes in ERK1 and cPLA2 mRNA levels in cortical areas and hippocampus after ethanol and/or GP administration. However, a decrease in ERK2 and an increase in COX‐2 mRNA level was found in the hippocampus of ethanol‐treated animals. GP completely inhibited the increase in COX‐2 due to ethanol treatment.

Conclusion: Increase in COX‐2 expression may be an underlying mechanism for the increase in oxidative stress induced by chronic ethanol administration. Dietary supplementation of GP may have a beneficial role in inhibiting certain alcohol effects.
Ethanol‐Enhanced Cytotoxicity of Alkylating Agents
Authors: Couch David B. , Baker Rodney C.
Published: April 2006

Background: Although ethanol itself is not genotoxic, chronic alcohol consumption increases the risk of neoplastic disease. The mechanism by which ethanol exerts a cocarcinogenic effect is not well established, and the aim of this study was to determine whether exposure to ethanol increased the cytotoxicity of known carcinogens.

Methods: To assess cell survival, the ability of Chinese hamster A10 cells, which express alcohol dehydrogenase, to form colonies was determined after exposure to ethanol and other substances, including both genotoxicants and non–DNA‐reactive cytotoxic agents.

Results: 1‐Methyl‐3‐nitro‐1‐nitrosoguanidine (MNNG) is an alkylating agent that forms covalent bonds with DNA. The cytotoxicity of MNNG at concentrations of 0.17 to 0.68 μM was markedly enhanced when cells were also treated with 50 mM ethanol. When combined with 0.34 μM MNNG, concentrations of ethanol as low as 2 mM exacerbated the toxicity of this alkylating agent. When these experiments were repeated in the presence of 4‐methylpyrazole, an inhibitor of alcohol dehydrogenase, pretreatment with ethanol did not affect the toxicity of MNNG. When ethanol treatment was combined with exposure to other carcinogens, as well as agents that do not directly damage DNA, the cytotoxicity of the DNA‐reactive agents 4‐nitroquinoline‐N‐oxide, mitomycin C, and 6‐chloro‐9‐(3‐[2‐chloroethyl]aminopropylamino)‐2‐methoxyacridine was modestly enhanced, and that of a second alkylating agent, ethyl methanesulfonate, was markedly increased.

Conclusions: The results are consistent with impairment of DNA repair processes, particularly base excision repair, by acetaldehyde, as a mechanism by which ethanol increases the genotoxicity of certain genotoxic agents.
Chronic Ethanol Treatment and Withdrawal Alter ACPD‐Evoked Calcium Signals in Developing Purkinje Neurons
Authors: Netzeband Jeffrey G. , Schneeloch Jaimes R. , Trotter Carol , Caguioa‐Aquino Jodilyn N. , Gruol Donna L.
Published: April 2006

Background: Alcohol exposure during human fetal development can result in fetal alcohol syndrome, a condition characterized by central nervous system dysfunction. Detailed studies in animal models of fetal alcohol syndrome show that the cerebellar region is particularly sensitive to alcohol exposure during early development; however, the cellular mechanisms underlying the alcohol sensitivity of the immature cerebellum are poorly understood.

Methods: Primary neuronal cultures of cerebellar cells were prepared from embryonic day 20 rat pups. Cultures were exposed to ethanol (33 mM; 150 mg/100 ml) during the main period of morphological development of the Purkinje neurons, from 6 to 17 days in vitro. After the ethanol treatment, the response of Purkinje neurons to the selective metabotropic glutamate receptor (mGluR) agonist (1S,3R)‐1‐aminocyclopentane‐1,3‐dicarboxylic acid (ACPD; 300 μM) was examined in parallel fura‐2 Ca2+ imaging and current‐clamp experiments. In an additional set of experiments, ethanol‐treated cultures were allowed to withdraw from ethanol overnight before recordings were performed.

Results: In Ca2+ imaging studies, the mean peak amplitude of ACPD‐evoked Ca2+ signals was depressed in the dendritic region of chronic ethanol–treated Purkinje neurons compared with control neurons (p < 0.05, unpaired t test), whereas there was no apparent difference in the somatic region. In contrast, peak ACPD‐evoked Ca2+ signals were enhanced in both the somatic and dendritic regions of withdrawn Purkinje neurons compared with control neurons. Parallel current‐clamp studies showed no consistent effect of chronic ethanol treatment or ethanol withdrawal on the membrane response to ACPD.

Conclusions: These results show that prolonged ethanol exposure and early withdrawal lead to alterations in mGluR‐evoked Ca2+ signaling in cerebellar Purkinje neurons. Metabotropic GluRs in the Purkinje neuron play important roles in cerebellar development and function, suggesting that alterations of mGluR signaling pathways by ethanol may play a key role in the actions of ethanol on the developing cerebellum.
Effects of Combined Systemic Alcohol and Central Nicotine Administration into Ventral Tegmental Area on Dopamine Release in the Nucleus Accumbens
Authors: Tizabi Yousef , Copeland Robert L. , Louis Vely A. , Taylor Robert E.
Published: April 2006

Background: Alcoholism is associated with a higher incidence of smoking. The mesolimbic dopaminergic pathway is believed to play an important role in the reinforcing effects of both ethanol and nicotine. This study was undertaken to determine whether simultaneous administration of systemic ethanol and microinjection of nicotine into the ventral tegmental area (VTA) would result in exaggerated release of dopamine (DA) in the shell region of nucleus accumbens.

Methods: Microdialysis was applied in awake, freely moving adult male Wistar rats, and DA concentration in the dialysate was measured by HPLC‐electrochemical detectors.

Results: Systemic administration of ethanol or microinjection of nicotine into VTA resulted in a dose‐dependent increase in DA release (extracellular DA concentration). Simultaneous administration of lower doses of nicotine and ethanol resulted in an additive effect on the released DA. This additive effect was not observed with higher doses of nicotine and ethanol. Administration of the nicotinic antagonist mecamylamine into VTA completely blocked ethanol‐induced DA release.

Conclusions: These data support the hypothesis that the reinforcing effects of ethanol are at least partially mediated through the nicotinic receptors in the VTA. Furthermore, administration of selective nicotinic antagonists may be of therapeutic potential in reducing the rewarding effects of ethanol. The data also suggest that the combined effects of ethanol and nicotine on the “reward pathway” may be a contributing factor to the high incidence of smoking in alcoholics.
Using Acquired Knowledge and New Technologies in Alcoholism Treatment Trials
Authors: Flannery Barbara A. , Allen John P. , Pettinati Helen M. , Rohsenow Damaris J. , Cisler Ron A. , Litten Raye Z.
Published: April 2006

This article represents the proceedings of a symposium held at the 2001 RSA meeting in Montreal, Canada. The organizer and chair was Barbara A. Flannery and the discussant was Raye Z. Litten. The presentations were (1) The use of biomarkers in alcohol‐dependence treatment trials, by John P. Allen; (2) Strategies for enhancing patient compliance in clinical treatment trials, by Helen M. Pettinati; (3) The predictive utility of an alcohol‐craving measure, by Barbara A. Flannery; (4) What should be the primary outcome measures in a clinical trial, by Damaris J. Rohsenow; (5) Innovative strategies for assessing functional outcomes in alcoholism treatment clinical trials, by Ron A. Cisler.
Locomotor Activity Induced by Noncompetitive NMDA Receptor Antagonists Versus Dopamine Transporter Inhibitors: Opposite Strain Differences in Inbred Long‐Sleep and Short‐Sleep Mice
Authors: Hanania Taleen , Zahniser Nancy R.
Published: April 2006

Background: The actions of ethanol in the brain involve multiple neuroreceptor systems, including glutamatergic N‐methyl‐D‐aspartate receptor (NMDAR) channels. In a novel environment, both ethanol and the noncompetitive NMDAR antagonist MK‐801 stimulate locomotor activity to a lesser extent in inbred long‐sleep (ILS) mice compared with inbred short‐sleep (ISS) mice. The behaviorally activating effects of noncompetitive NMDAR antagonists are thought to involve increased monoamine neurotransmission. Thus, in this study, we sought to determine whether: (1) habituation to the behavioral environment alters the differential locomotor‐stimulant effects of noncompetitive NMDAR antagonists in ILS and ISS mice and (2) the differential behavioral sensitivity of ILS and ISS mice to noncompetitive NMDAR antagonists is mediated through direct inhibition of the dopamine transporter (DAT).

Methods: Open field locomotor activity was measured following acute systemic injection of saline or drug. [3H]DA uptake parameters were determined in striatal synaptosomes prepared from drug‐naïve mice.

Results: Habituation to the testing environment abolished the strain differences in saline‐induced locomotor activity. However, ethanol‐ as well as MK‐801‐treated ILS mice still exhibited reduced locomotor activity compared with ISS mice, suggesting that a drug‐environment interaction is not the primary explanation for the strain differences. The noncompetitive NMDAR antagonists phencyclidine and ketamine also induced significantly lower locomotor activity in ILS than in ISS mice. In contrast, the DAT inhibitors cocaine and GBR 12909 and the DA releaser amphetamine induced greater locomotor activity in ILS than in ISS mice, a strain difference opposite that of the noncompetitive NMDAR antagonists. Furthermore, the differential behavioral effect found with DAT inhibitors was not mediated by differences in the affinity nor number of striatal DATs between ILS and ISS mice.

Conclusions: Our results support the conclusion that the differential locomotor‐stimulant effects of ethanol and noncompetitive NMDAR antagonists in ILS and ISS mice are not mediated through direct inhibition of DAT.
Prevention of Alcohol‐Related Deaths in Middle‐Aged Heavy Drinkers
Authors: Kristenson Hans , Österling Agneta , Nilsson Jan‐Åke , Lindgärde Folke
Published: April 2006

Background: Alcohol as a cause of death in middle‐aged patients is well‐known from clinical studies. A similarly important correlation in the general population of urban middle‐aged men is highly underestimated. Health screening investigations have shown that mortality related to alcohol is five times more common in nonparticipants than in participants. From the mid‐70s, the Malmoe Screening and Intervention Study (MSIS) commenced screening investigations including a large number of residents of Malmoe. One goal was to find intervention programs for individuals in an early development of problem drinking, thereby preventing development of serious complications of endstage alcoholism. Herein, we report on the mortality of heavy drinkers (drinking more than 40 g alcohol/day) who were randomized to an intervention or control procedure and whose median survival was 13 years postentry into the MSIS.

Methods: Health‐screened men, aged 45–49 years at the initial screening examination and displaying serum gamma‐glutamyltransferase (GT) in the top decentile of the GT distribution, were included. A total of 978 out of 11,257 participants met this criteria. A randomized intervention and control study was performed for four years and consisted of men (n= 667) who were born between 1927–1937 and who had two consecutive high GT values within 3 weeks along with heavy alcohol consumption. Half the individuals were informed of the test results and invited for further assessment by a senior physician (n= 365). The principles for brief intervention (DiClemente et al.,1991; Miller and Sanchez, 1993; National Institute of Alcohol Abuse and Alcoholism, 1999) were applied. The other half of the men (n= 302) were left with the information that they had a high GT value and were followed up with laboratory checkups every 2nd year. Mortality was followed up until 1991 and information on deaths was obtained from hospital and police records, necropsy reports, and death certificates.

Results: Long‐term follow‐up of mortality for 10–16 years (median, 13 years) showed that 124 of the 978 men had died (12.7%). Autopsy was performed in 96.5% of the cases. In 59 men (48%), death was alcohol‐related. In the intervention group (n= 365), 38 (10.4%) men were dead and in the control group (n= 302), 42 (13.9%) men had died. There was a statistically significant difference (p= 0.026), with advantage for treatment. Less alcohol‐related deaths and deaths occurring later during follow‐up were found in the intervention group compared with the control group. The difference between the groups in total mortality, coronary heart disease, and cancer death was not statistically significant.

Conclusions: These findings support previous results from the MSIS study indicating that long‐term intervention in urban males with alcohol‐induced GT increases may be beneficial in terms of survival.
Changes in Serum Apolipoprotein and Lipoprotein Profile After Alcohol Withdrawal: Effect of Apolipoprotein E Polymorphism
Authors: Gueguen Sonia , Herbeth Bernard , Pirollet Pascal , Paille François , Siest Gérard , Visvikis Sophie
Published: April 2006

Background: Apolipoprotein (Apo) E genotype and alcohol consumption or withdrawal strongly affect lipoprotein (Lp) metabolism and, as with any genetic and environmental factors, they might interact. The aim of this study was to investigate this gene/environment interaction by analyzing the effect of the apoE genotype on the alcohol withdrawal–induced alterations in the serum Apo and Lp profile.

Methods: ApoE genotypes and concentrations of serum cholesterol, triglyceride, and Lps containing apoA‐I, A‐II, B, E, and C‐III were determined in 84 male alcohol abusers before and after 3 weeks of abstinence.

Results: After withdrawal, concentrations of serum apoA‐I, LpA‐I, LpA‐I/A‐II, apoC‐III, LpC‐III‐non‐B, apoE, and LpE‐non‐B significantly decreased, whereas those of triglycerides and apoB increased; levels of cholesterol, LpC‐III:B, and LpB:E were not affected. ANOVA shows that apoE polymorphism effects were quite similar before and after alcohol withdrawal on all serum Apos and Lps (the interaction term between withdrawal and apoE genotype was not significant). The only interaction term that was borderline significant (p≤ 0.10) concerned the apoB concentration. Before withdrawal, no association between apoB level and apoE polymorphism was observed, whereas after abstinence, a borderline significant (p≤ 0.10) gradient of concentration across the three groups of subjects (ε2 carriers < ε3/ε3 < ε4 carriers) was noticed.

Conclusions: Alcohol abstinence causes major changes in the antiatherogenic Apos and Lps and may increase those known to be atherogenic. Heavy alcohol consumption seems to alter the effect of apoE polymorphism on apoB levels, and further investigations are needed to clarify the mechanisms involved in this phenomenon: a defect in sialylation of apoE, formation of acetaldehyde adducts on apoB, or both.
Fracture Healing and Bone Mass in Rats Fed on Liquid Diet Containing Ethanol
Authors: Elmali Nurzat , Ertem Kadir , Ozen Süleyman , Inan Muharrem , Baysal Tamer , Güner Güntekin , Bora Arslan
Published: April 2006

Background: Studies in animal models for alcohol abuse have suggested that ethanol inhibits bone growth, decreases bone formation, and increases fracture risk.

Methods: Experimental tibia fracture healing in rats fed a liquid diet containing 7.2% ethanol for 8 weeks was investigated with histological and osteodensitometric studies with respect to the control group. After 4 weeks of vitamin A– and sucrose‐enriched milk containing 7.2% ethanol feeding, we created closed tibia fractures, which were then fixed with intramedullary nails, in 10 rats. After a follow‐up time of 4 weeks, the rats were killed for examination. The same procedure was performed in another 10 rats, which were fed on the same diet (isocaloric modified liquid diet) but without ethanol and used as the control group. A histological scoring system was developed for fracture healing.

Results: Histological evaluation of fracture region revealed an average fracture healing score of 1.9 in the ethanol‐fed group versus 2.6 in the control group (p= 0.014). In the test group, dual‐energy x‐ray absorptiometry measurements in the fracture region showed a mean bone mineral density of 0.11 ± 0.03 g/cm2, whereas it was 0.130 ± 0.051 g/cm2 in the control group (p= 0.000). The mean bone mineral content in the fracture region was 0.103 ± 0.08 g/cm3 in the test group versus 0.128 ± 0.06 g/cm3 in the control group (p= 0.000). A significant correlation was found among histological scores, bone mineral density (r= 0.64, p= 0.04), and bone mineral content (r= 0.63, p= 0.04).

Conclusions: This study showed that rats fed on a diet mixed with ethanol have a histologically delayed fracture healing associated with decreased bone density and mineral content. Besides the negative effects of ethanol on bone metabolism, it also interferes with the fracture‐healing process.
Effects of In Vitro Ethanol on Tumor Necrosis Factor‐α Production by Blood Obtained From Simian Immunodeficiency Virus–Infected Rhesus Macaques
Authors: Stoltz David A. , Nelson Steve , Kolls Jay K. , Zhang Ping , Bohm Rudolf P. , Murphey‐Corb Michael , Bagby Gregory J.
Published: April 2006

Background: Tumor necrosis factor‐α (TNF‐α), a product of monocytes and macrophages, functions as an important proinflammatory cytokine in the host's response to invading pathogens.

Methods: Because both alcohol abuse and human immunodeficiency virus infection affect TNF‐α production and are known to frequently coexist, this study examined the effects of simian immunodeficiency virus (SIV) infection and in vitro alcohol exposure on the lipopolysaccharide (LPS)‐induced TNF‐α response in blood obtained from SIV‐negative and ‐positive animals at the asymptomatic and terminal stages of infection.

Results: Spontaneous TNF‐α production was undetectable or low in all groups examined. LPS‐induced TNF‐α production was increased in blood obtained at the asymptomatic (746 ± 226 pg/ml) and terminal (1945 ± 1013 pg/ml) stages, compared with that from SIV‐negative animals (210 ± 28 pg/ml), whereas TNF‐α messenger RNA content did not differ in LPS‐stimulated blood obtained from SIV‐negative, asymptomatic SIV‐positive, or terminal SIV‐positive animals. Ethanol treatment suppressed TNF‐α protein production in all groups, whereas TNF‐α messenger RNA levels remained unchanged in blood obtained from animals not infected with SIV.

Conclusions: Blood cellular elements remain responsive to LPS stimulation with respect to TNF production even into the acquired immunodeficiency syndrome stage of SIV disease. However, intoxicating doses of alcohol suppress this response, and this may contribute to the immunocompromised state of the host.
Chronic Daily Ethanol and Withdrawal: 3. Forebrain Pro‐Opiomelanocortin Gene Expression and Implications for Dependence, Relapse, and Deprivation Effect
Authors: Rasmussen Dennis D. , Boldt Brian M. , Wilkinson Charles W. , Mitton Dennis R.
Published: April 2006

Background: Although forebrain pro‐opiomelanocortin (POMC)–producing neurons seem to mediate or modulate many responses to ethanol consumption, changes in activity of this opiomelanocortinergic system in response to chronic ethanol consumption, withdrawal, and subsequent abstinence remain unresolved.

Methods: We investigated the effects of chronic daily ethanol consumption, withdrawal, and subsequent abstinence on adult male Sprague‐Dawley rat forebrain opiomelanocortinergic activity as reflected by changes in hypothalamic POMC messenger RNA (mRNA) content by using a well characterized liquid diet model that we have previously demonstrated to accurately simulate not only daily oral ethanol consumption quantity and pattern, but also both neuroendocrine and behavioral changes characteristic of actively drinking and subsequently abstinent alcoholics.

Results: After 7 weeks of daily ethanol consumption at night and withdrawal during the day, evening mediobasal hypothalamus POMC mRNA concentrations were suppressed versus both ad libitum–fed and pair‐fed controls. Morning POMC mRNA concentrations were also suppressed versus ad libitum–fed controls and tended to be decreased versus pair‐fed controls. Three weeks after gradual removal of ethanol from the diet, mediobasal hypothalamus POMC mRNA concentrations were increased relative to ad libitum–fed and pair‐fed controls. Plasma concentrations of corticosterone, testosterone, and leptin were also altered by the daily ethanol/withdrawal treatment and by subsequent abstinence.

Conclusions: Because each of these hormones has been demonstrated to modify forebrain POMC gene expression under some conditions, the overall changes in forebrain opiomelanocortinergic regulation in response to chronic daily ethanol/withdrawal and subsequent abstinence probably reflect, at least in part, regulation by multiple endocrine mechanisms, together with responses to stress, development of tolerance during chronic daily ethanol consumption, and rebound of function after termination of this consumption. Overall, the demonstrated changes in forebrain POMC gene expression are consistent with significant roles for forebrain opiomelanocortinergic regulation in mediating alcohol dependence, propensity to relapse, and the alcohol deprivation effect.
Cortical Gray Matter Loss in Treatment‐Naïve Alcohol Dependent Individuals
Authors: Fein G. , Di Sclafani V. , Cardenas V. A. , Goldmann H. , Tolou‐Shams M. , Meyerhoff D. J.
Published: April 2006

Background: Most studies of the impact of alcohol dependence on the brain have examined individuals in treatment. Such samples represent a small proportion of alcoholics in the general population. Such samples may embody a bias (Berkson's fallacy) if the association between variables (for example, alcoholism and cortical gray matter loss) differs between the population of alcoholics in treatment and alcoholics in the general population. Our objective was to determine if treatment‐naïve alcoholics show structural brain changes versus controls and to compare our findings with reports evaluating alcoholic samples drawn from treatment populations.

Methods: Structural MRI was used to assess whole brain and regional volumes of cortical gray matter and white matter in 24 young to middle‐aged treatment‐naïve alcohol‐dependent males versus 17 controls.

Results: Cortical gray matter volumes in alcohol‐dependent individuals were negatively associated with age and lifetime duration of alcohol use (which were highly confounded). These subjects showed reduced whole brain (p < 0.05), prefrontal (p < 0.01), and parietal (p < 0.05) cortical gray matter compared with controls. White matter and temporal cortex, tissues that usually show volume reductions in samples drawn from treatment, did not differ between treatment‐naïve alcoholics and controls (all p > 0.40).

Conclusions: Our findings are consistent with the hypothesis that structural brain changes in treatment‐naïve alcoholics are less severe than those reported in clinical samples of alcoholics, perhaps due to less concomitant psychopathology and a reduced severity of alcoholism in treatment‐naïve alcoholics. However, caution must be taken when comparing our findings with results from clinical samples, as we did not directly compare treatment‐naïve alcoholics with treated alcoholics and our treatment‐naïve sample tended to be younger than the (clinical) samples reported in the literature. Nevertheless, we suggest that most of the reports of the central nervous system consequences of alcoholism may not accurately describe the majority of alcoholic‐dependent individuals.