bluuebunny/crossref_metadata_2025 huggingface dataset:
fMRI Measurement of Brain Dysfunction in Alcohol‐Dependent Young Women
Authors: Tapert Susan F. , Brown Gregory G. , Kindermann Sandra S. , Cheung Erick H. , Frank Lawrence R. , Brown Sandra A.
Published: April 2006

Background: Studies of brain functioning in alcohol‐dependent adults have produced varied results but generally suggest that alcohol affects brain functioning and that relatively short durations of heavy drinking may adversely affect women. It remains unclear when in the course of alcohol dependency and at which developmental stage these brain changes emerge. Our neuropsychological studies have indicated that drinking‐related neurocognitive effects occur as early as adolescence (Brown et al., 2000; Tapert & Brown, 1999). This study seeks to characterize brain regions that subserve the affected neurocognitive functions.

Methods: Alcohol‐dependent young women (n= 10) were recruited from a longitudinal study of alcohol‐ and drug‐abusing youth, all of whom met criteria for alcohol dependence. Control participants (n= 10) had no history of alcohol or drug problems and were comparable with alcohol‐dependent participants on age (18–25 years), family history of alcohol use disorders, and education. After a minimum of 72 hr of abstinence, functional magnetic resonance imaging, neuropsychological, alcohol/drug involvement, and mood data were collected. Participants performed spatial working memory and vigilance tasks during functional magnetic resonance imaging acquisition to probe brain response.

Results: Alcohol‐dependent women demonstrated significantly less blood oxygen level‐dependent response than controls during the spatial working memory task in the right superior and inferior parietal, right middle frontal, right postcentral, and left superior frontal cortex, after controlling for the baseline vigilance response.

Conclusions: Working memory produces a larger neuronal response in some cortical regions than vigilance. Alcohol‐dependent women showed less differential response to working memory than controls in frontal and parietal regions, especially in the right hemisphere. Heavy, chronic drinking appears to produce adverse neural effects that are detectable by functional magnetic resonance imaging.
Azide Inhibits Human Cytochrome P‐4502E1, 1A2, and 3A4
Authors: Salmela Katja S. , Tsyrlov Ilya B. , Lieber Charles S.
Published: April 2006

Background: Recently, we showed that, in addition to cytochrome P‐4502E1 (CYP2E1), CYP1A2 and CYP3A4 also contribute to the microsomal ethanol o‐idizing system (MEOS). When MEOS activity is measured, sodium azide commonly is used to block the contaminating catalase. However, although CYP2E1 is considered insensitive to azide, its effect on the other P‐450s is unknown. Therefore, the aim of the present study was to determine the effect of azide on human recombinant and hepatic CYP2E1, CYP1A2, and CYP3A4.

Methods and Results : Concentrations of sodium azide as low as 0.1 mM markedly inhibited the specific ethanol o‐idation (mean ± SEM) by recombinant CYP1A2 and CYP3A4 e‐pressed in HepG2 cells (to 16 ± 1% and 22 ± 2% of control without azide, respectively;p < 0.01). By contrast, the specific activity of CYP2E1 was only slightly (and not significantly) inhibited at this azide concentration (to 79 ± 12% of control). Similarly, in human liver microsomes (n= 6), 0.1 mM azide strongly inhibited CYP1A2‐dependent (to 25 ± 2%) and CYP3A4‐dependent (to 15 ± 2%) ethanol oxidation, whereas CYP2E1 was inhibited only at 10 mM azide (to 60 ± 10%). Azide also strongly affected the apparent kinetic values of all three isoenzymes. Furthermore, azide inhibited the specific monooxygenase activities, both by recombinant and microsomal P‐450s. CYP2E1‐specific p‐nitrophenol hydroxylation was the most sensitive to azide, whereas CYP1A2‐dependent 7‐methoxyresorufin O‐ dealkylation was only slightly inhibited. Judging from its effect on p‐nitrophenol hydroxylation by human liver microsomes, the inhibition of azide was competitive (K i 0.09 mM).

Conclusions: Sodium azide at a concentration as low as 0.1 mM inhibited ethanol o‐idation by CYP1A2 and CYP3A4. With CYP2E1, although o‐idation of 50 mM ethanol was not inhibited by 0.1 mM azide, higher azide concentrations were inhibitory and 0.1 mM azide seemed to affect the kinetics of ethanol o‐idation by CYP2E1. Therefore, azide should be avoided when measuring the MEOS activity because it may lead to underestimation, especially of CYP1A2‐ and CYP3A4‐dependent ethanol o‐idation.
Endotoxin, Endotoxin‐Neutralizing‐Capacity, sCD14, sICAM‐1, and Cytokines in Patients With Various Degrees of Alcoholic Liver Disease
Authors: Urbaschek Renate , McCuskey Robert S. , Rudi Volker , Becker Klaus‐Peter , Stickel Felix , Urbaschek Bernhard , Seitz Helmut K.
Published: April 2006

Background: Chronic alcohol ingestion leads to endoto‐emia which is believed to play an important role in the pathogenesis of alcoholic liver disease (ALD). The purpose of this study was to determine if chronic ethanol consumption, in addition to affecting plasma endoto‐in and cytokines, also affects the endoto‐in‐neutralizing capacity (ENC), sCD14, and sICAM‐1, in patients with ALD. A second aim was to identify correlations between these latter parameters, endoto‐in, and cytokines, especially IL‐10.

Methods: Hospitalized patients with various degrees of ALD (n= 59), and 20 healthy volunteers were studied. Plasma endotoxin and ENC were determined using our kinetic Limulus amebocyte lysate test. Cytokines, sCD14, and sICAM‐1 were measured by enzyme‐linked immunosorbent assay.

Results: Patients with ALD e‐hibited a mild endoto‐emia (p < 0.01) and a marked decrease in ENC (p < 0.0002). TNF‐α (p < 0.05), IL‐6 (p < 0.0001), sICAM (p < 0.005), and sCD14 (p < 0.0005) were significantly elevated in all patients with ALD, and IL‐10 (p < 0.05) in patients with cirrhotic ALD. With the exception of IL‐10, the cytokines correlated with each other and with sICAM‐1. No correlations occurred between endotoxin, ENC, and sCD14, and between these and the cytokines and sICAM‐1. Elevated levels of endotoxin correlate with acute excessive alcohol ingestion. No gender differences were observed.

Conclusions: Acute alcohol into‐ication rather than severe ALD results in significant endoto‐emia. The limited capacity of plasma to neutralize endoto‐in in liver injury seems to be an important factor in ALD which may be responsible for the release of endoto‐in‐induced mediators, such as cytokines, as well as s‐ICAM‐1, that are relevant in the pathogenesis of ALD.
Effects of SR141716A on Ethanol and Sucrose Self‐Administration
Authors: Freedland C.S. , Sharpe A.L. , Samson H.H. , Porrino L.J.
Published: April 2006

Background: Previous studies have demonstrated that administration of central cannabinoid receptor (CB1) ligands can produce marked effects on ingestive behaviors. However, the possible relationship to ethanol self‐administration has not been fully examined. The present series of experiments was designed to characterize further the role of CB1 receptors in appetitive and consummatory behaviors related to sucrose and ethanol.

Methods: To determine the relative contribution of CB1 receptors to ethanol seeking and consumption, a series of experiments was designed using the sipper‐tube model. In this paradigm, the appetitive and consummatory phases of ethanol and sucrose self‐administration are separated. In the appetitive phase, animals are required to complete a response requirement (16 lever presses) within 20 min. If the requirement is successfully completed, access to a sipper tube containing either sucrose or ethanol (consummatory phase) is made available for 20 min.

Results: In the ethanol condition, the CB1 receptor antagonist SR141716A (0.3–3.0 mg/kg, ip) produced dose‐related decreases in the probability of response requirement completion without significantly affecting latency to first lever press or overall lever press rate. In the sucrose condition, SR141716A (0.3–3.0 mg/kg, ip) increased first lever press latency without affecting lever press rate. In the consummatory phase, SR141716A (0.3–3.0 mg/kg, ip) administration markedly decreased total intake and the total number of licks for both ethanol and sucrose.

Conclusions: These data indicate that CB1 receptors are involved in mediating both appetitive and consummatory aspects of ingestive behaviors related to sucrose and ethanol.
Innovative Technologies for the Diagnosis of Alcohol Abuse and Monitoring Abstinence
Authors: Bean Pamela , Harasymiw James , Peterson Charles M. , Javors Marty
Published: April 2006

This article summarizes the proceedings of a workshop presented at the 2000 RSA Meeting in Denver, Colorado. The aim of this workshop was to discuss the basic methodologies, diagnostic performance, and clinical utility of three technologies: carbohydrate‐deficient transferrin, the “Early Detection of Alcohol Consumption” score, and whole blood associated acetaldehyde. Each method adopts a different strategy to identify heavy alcohol consumption and offers a unique approach to determine alcohol abstinence and relapses. Appropriate application of these technologies can lead to early intervention for alcohol problems before significant tissue damage occurs. To date these methodologies have yet to be formally contrasted and compared. Sensitivity, specificity, predictive value, availability, ease of use, and interpretation of tests results are important aspects to consider when selecting the most appropriate and cost‐effective system. Critical evaluation of these methodologies can enable research and clinical laboratories to choose the system that best meets their particular needs in terms of assay feasibility, budget, and goals.
Acute Effects of Ethanol on Behavior of Adolescent Rats: Role of Social Context
Authors: Varlinskaya Elena I. , Spear Linda P. , Spear Norman E.
Published: April 2006

Background: First experiences with alcohol in humans occur predominantly in adolescence, and to a large extent the attractiveness of alcohol at this age is based on its ability to facilitate certain forms of social behavior (social facilitation). Adolescence is strongly marked by a focus on peer relationships, and the social nature of the situation plays an important role in responsiveness to alcohol. Peer‐directed social activity of adolescent rats may be a valuable experimental model for the study of ethanol‐induced changes in social behavior and assessment of the role of the social context in responsiveness to ethanol.

Method: In the present study we used a modified dyad social interaction test to characterize acute effects of ethanol on different forms of social behavior (social investigation, contact behavior, and play) and social motivation (preference/avoidance of a peer) in adolescent rats. Ethanol effects on behavior directed toward a peer were compared with those induced by exposure to an inanimate novel object.

Results: In the social context, the effects of ethanol were dose‐dependent and biphasic. Low doses of ethanol (0.25–0.75 g/kg) produced apparent social facilitation (increased social activity and enhanced social preference), whereas higher doses (3 and 4 g/kg) caused social inhibition (decreased social activity and avoidance of a peer). This pattern was not observed for a nonsocial stimulus: Although overall activity in the nonsocial context was suppressed by 2 and 3 g/kg of ethanol, 0.5 g/kg of ethanol did not activate overall activity directed to the inanimate object.

Conclusions: These findings demonstrate that the social nature of the testing situation plays an important role in responsiveness to alcohol in adolescence, especially to its activating effects. The results suggest also that the study of ethanol effects on social behavior of adolescent rats may be an effective tool for the study of adolescent alcohol use and abuse.
Effect of Neuropeptide Y (NPY) on Oral Ethanol Intake in Wistar, Alcohol‐Preferring (P), and ‐Nonpreferring (NP) Rats
Authors: Badia‐Elder N.E. , Stewart R.B. , Powrozek T.A. , Roy K.F. , Murphy J.M. , Li T.‐K.
Published: April 2006

Background: Neuropeptide Y (NPY) deficient mice consume more ethanol than controls, whereas NPY over‐expressing mice consume less ethanol than controls. Thus, ethanol drinking may be inversely associated with NPY activity. To determine whether exogenously administered NPY would alter ethanol intake, two experiments were conducted.

Methods: A within‐subject design was used with intracerebroventricular (ICV) administration of NPY or artificial cerebral spinal fluid (aCSF) into the lateral ventricles. Infusions were separated by 2 to 7 days. In experiment 1, male Wistar rats (n= 10) were tested for the effects of NPY on an intake of 5% sucrose or 8% (w/v) ethanol during daily 2‐hr testing periods with food and water available at all other times. In experiment 2, male alcohol‐preferring (P) and alcohol‐nonpreferring (NP) rats (n= 8/line) were tested for the effects of NPY on 8% (w/v) ethanol intake.

Results: In experiment 1, NPY (5, 10, 20 μg) significantly increased sucrose intake relative to aCSF baseline in Wistar rats, a finding consistent with previous observations of the orexigenic effects of the peptide. However, NPY (10 μg) did not alter ethanol intake in Wistar rats. In experiment 2, NPY (5 and 10 μg) significantly decreased ethanol intake in P rats, but not in NP rats.

Conclusion: The reduction in ethanol intake seen with the P rats is consistent with the postulated negative relationship between NPY activity and ethanol intake. The lack of effect of NPY on ethanol intake in Wistar and NP rats may be related to the lower baseline levels of ethanol intake in these rats or to differential central nervous system basal NPY activity or sensitivity to the peptide.
Ethanol as a Reinforcer in the Newborn's First Suckling Experience
Authors: Cheslock Sarah J. , Varlinskaya Elena I. , Petrov Evgeniy S. , Silveri Marisa M. , Spear Linda P. , Spear Norman E.
Published: April 2006

Background: Recent evidence suggests that human infants prefer alcohol‐flavored milk when fed through a bottle. Animal models also indicate a surprising predisposition for neonatal and infant rats to voluntarily and willingly ingest ethanol. These findings suggest high susceptibility to the reinforcing properties of ethanol early in ontogeny.

Methods: A surrogate nipple technique—a highly effective tool for investigation of the reinforcing properties of different fluids—was applied in the present study. Tests of ethanol reinforcement were accomplished in terms of two basic paradigms of Pavlovian conditioning. In one paradigm, the conditioned stimulus (CS) was the surrogate nipple, and in the other, the CS was a novel odor.

Results: Newborn rats showed sustained attachment to the nipple providing 5% ethanol, and later reproduced this behavioral pattern toward the empty nipple (CS alone). Ingestion of ethanol yielding appetitive reinforcement was accompanied by detectable blood alcohol concentrations, with most in the range of 20–30 mg/dl. The reinforcing efficacy of ethanol was also confirmed in the classical olfactory conditioning paradigm: following pairing with intraoral ethanol infusions, the odor (CS) alone elicited sustained attachment to an empty nipple. Females showed better olfactory conditioning with low concentrations of ethanol, whereas males were effectively more conditioned to high concentrations. Although there were no reinforcing consequences of intraperitoneally injected ethanol [as an unconditioned stimulus (US)] when a neutral odor was the CS, when paired with ingestion of water from a nipple, the injection of ethanol had a reinforcing effect.

Conclusions: The present series of experiments revealed ethanol reinforcement in the newborn rat. Two varieties of Pavlovian conditioning established that ethanol can serve as an effective US, and hence reinforcer, in such a way as to increase the approach and responsiveness toward stimuli paired with that US, indicating appetitive reinforcement.
Reduced Folate Carrier: Tissue Distribution and Effects of Chronic Ethanol Intake in the Micropig
Authors: Villanueva Jesus A. , Devlin Angela M. , Halsted Charles H.
Published: April 2006

Background: Folate deficiency is common in alcoholic patients, in part due to abnormal transport across membranes relevant to folate homeostasis. The reduced folate carrier (RFC) transports monoglutamyl folates across tissue membranes and could be affected by chronic exposure to ethanol. The micropig model is suitable to study the effect of alcoholism on RFC and folate transport across membranes.

Methods: The membrane transport of [3H]‐folic acid was measured by a vacuum filtration method in jejunal brush border (JBB), liver plasma membrane (LPM), and kidney brush border (KBB) membranes vesicles from micropigs fed control or 40% ethanol diets for 12 months. RFC transcripts were analyzed by reverse transcription polymerase chain reaction in jejunal mucosa, liver, and kidney from the same animals.

Results: When we compared results from three relevant membranes in control animals, the transport of [3H]‐folic acid was highest in LPM, 3‐fold lower in KBB (p < 0.001), and 6‐fold lower in JBB (p < 0.001). The concentration of RFC transcripts per total RNA was greatest in liver, followed by kidney and jejunum. The transport of [3H]‐folic acid by JBB vesicles from chronic ethanol‐fed animals exhibited 2‐fold lower Km and Vmax (p < 0.05), whereas there was no ethanol effect on the Vmax of [3H]‐folic acid transport by LPM or KBB. RFC transcript levels were 10‐fold lower in jejunal mucosa from ethanol‐fed animals than in control‐fed animals (p < 0.005).

Conclusions: Although our findings demonstrate different RFC transcript amounts and transport efficiencies among tissues, the present studies suggest that chronic ethanol exposure decreases the intestinal absorption of folic acid by altering the expression of RFC and consequently its transport kinetics in JBB. These findings provide a mechanism for the clinical finding of reduced folic acid absorption in chronic alcoholics.
Mice That Lack Corticotropin‐Releasing Factor (CRF) Receptors Type 1 Show a Blunted ACTH Response to Acute Alcohol Despite Up‐Regulated Constitutive Hypothalamic CRF Gene Expression
Authors: Lee S. , Smith G. W. , Vale W. , Lee K.‐F. , Rivier C.
Published: April 2006

Background: The purpose of this work was to determine the influence of acute alcohol treatment, injected intraperitoneally, on the hypothalamic‐pituitary‐adrenal axis of mice that lack type 1 receptor for corticotropin‐releasing factor (CRFR1).

Methods: CRFR1‐deficient (CRFR1−/−), heterozygous (CRFR1±), and wild‐type (CRFR1+/+) mice were generated and maintained under standard conditions. Homozygous, heterozygous, and wild‐type offspring were identified by polymerase chain reaction analysis of tail DNA. Experiments were performed on 9‐ to 16‐week‐old male and female mice. All blood samples were obtained by rapid decapitation of conscious mice conducted between 10 AM‐12 PM. Blood sample collection was completed within 20 to 30 sec of disturbing the animals, and all samples were terminal. Preliminary experiments were conducted to determine the time‐course of the ACTH and hypothalamic responses to alcohol in all three groups of mice, and a single time point (30 min and 2 hr, respectively), corresponding to peak responses, was chosen to measure the corresponding parameters in all subsequent studies.

Results: In vehicle‐injected animals, basal ACTH and corticosterone levels were statistically comparable in heterozygotes and mice with a null allele for the CRFR1 gene, although values of this latter hormone were slightly lower in the mutants. Alcohol (4.0 g/kg) elicited the expected significant (p < 0.01) increase in plasma ACTH and corticosterone levels in heterozygous mice. These responses were virtually abolished or markedly decreased, respectively, in CRFR1‐deficient animals. As previously reported, constitutive CRF mRNA levels were elevated in the paraventricular nucleus (PVN) of the hypothalamus in mice that lacked CRFR1, compared to wild‐type control mice. Interestingly, this was not the case for transcripts of the immediate early gene NGFI‐B. When measured 2 hr after alcohol, PVN NGFI‐B gene expression was significantly (p < 0.01) increased in both control and mutant mice, as were CRF mRNA levels in mutant mice, but the hypothalamic responses of the mutants were larger (p < 0.01) than those of the control mice. This difference may be due, at least in part, to the lack of steroid feedback in the mutants.

Conclusion: These results indicate that although the intraperitoneal injection of alcohol remains capable of eliciting PVN CRF neuronal activation in mice that lack CRFR1, the ACTH and corticosterone responses are significantly blunted, a phenomenon believed to be due to the lack of CRFR1 in the pituitary of these animals.
Enhanced Antioxidant Activity After Chlorination of Quercetin by Hypochlorous Acid
Authors: Binsack Ralf , Boersma Brenda J. , Patel Rakesh P. , Kirk Marion , White C. Roger , Darley‐Usmar Victor , Barnes Stephen , Zhou Fen , Parks Dale A.
Published: April 2006

Background: Several epidemiological studies indicate that moderate consumption of red wine decreases both the incidence and mortality associated with cardiovascular disease. Quercetin and rutin (quercetin‐3‐rutinoside) are polyphenols present in relatively large concentrations in red wine and may play a role in this cardioprotective phenomenon. The precise mechanisms of cardioprotection remain unclear but may involve the action of these polyphenols as antioxidants, which attenuate the tissue injury that results from the production of proinflammatory oxidants such as hypochlorous acid (HOCl).

Methods: To study the interaction of these polyphenols with proinflammatory oxidants, we mixed quercetin or rutin with HOCl (0–150 μM) and analyzed the reaction products by high‐performance liquid chromatography, mass spectrometry, and nuclear magnetic resonance.

Results: Stable mono‐ and dichlorinated derivates were detected for both quercetin and the glycoside derivative, rutin, which suggests that both the conjugated and unconjugated forms of quercetin reacted with HOCl similarly. Chlorination of quercetin occurred only at two sites, and the derivates (6‐chloroquercetin, 6,8‐dichloroquercetin) were more potent antioxidants toward oxidative modification of low‐density lipoproteins and ABTS radical formation than the unmodified form.

Conclusions: These data suggest that under certain pathological conditions in vivo (e.g., inflammation), flavonols may be converted to chlorinated derivates, which exhibit an enhanced antioxidant potential and thereby play a role in cardioprotection.
The Problem of College Drinking: Insights From a Developmental Perspective
Authors: Schulenberg John , Maggs Jennifer L. , Long Stephen W. , Sher Kenneth J. , Gotham Heather J. , Baer John S. , Kivlahan Daniel R. , Alan Marlatt G. , Zucker Robert A.
Published: April 2006

This article represents the proceedings of a symposium at the 2000 RSA Meeting in Denver, Colorado. John Schulenberg and Jennifer L. Maggs were Organizers. Stephen W. Long was Chair and provided opening remarks. The presentations were: (1) I'm not a drunk, just a college student: Binge drinking during college as a developmental disturbance, by John Schulenberg; (2) Course of alcohol use disorders during college, by Kenneth J. Sher; (3) How do students experience alcohol and its effects? Positive versus negative expectancies and consequences, by Jennifer L. Maggs; and (4) Brief intervention in the context of developmental trends in college drinking, by G. Alan Marlatt. Critique and commentary were provided by Robert A. Zucker.
Ethanol Enhances GABAA Receptor Function in Short Sleep and Long Sleep Mouse Brain Membranes
Authors: Davies Daryl L. , Alkana Ronald L.
Published: April 2006

Background: SS and LS mice have been used to explore the genetic and neurochemical bases for differences in sensitivity to ethanol. The present study investigated the effects of ethanol on GABAA receptor function in microsacs from these genotypes. The purpose was to test a key element of the hypothesis that differences between these lines in sensitivity to ethanol‐induced enhancement of GABAA receptor function underlie their selected differences in sensitivity to ethanol‐induced loss of righting reflex (LORR).

Methods: The effects of ethanol on GABA‐activated 36Cl− uptake in brain membranes (microsacs) isolated from male SS and LS mice were tested using a chloride flux filtration assay.

Results: Ethanol significantly enhanced GABA‐activated 36Cl− uptake in SS microsacs at concentrations of 100–300 mM. Ethanol did not significantly affect GABA‐activated chloride uptake in this preparation at concentrations of 25 and 50 mM. Ethanol significantly enhanced GABA‐activated 36Cl− uptake in LS microsacs at concentrations of 25–100 mM, but not at 200 mM.

Conclusion: The present studies are the first to show a statistically significant effect of ethanol on GABA‐activated chloride uptake in both SS and LS mice with a clear difference between the genotypes in threshold. The relative threshold differences between SS and LS microsacs in sensitivity to ethanol indicate that selection for resistance to ethanol‐induced LORR in SS mice has shifted the ethanol‐GABAA receptor concentration‐response curve to the right. The findings add key evidence that supports a cause‐effect relationship between sensitivity to ethanol‐induced potentiation of GABAA receptor function and genetically determined sensitivity to ethanol's behavioral effects.
Influence of Age, Sex, and Helicobacter pylori Infection Before and After Eradication on Gastric Alcohol Dehydrogenase Activity
Authors: Kechagias Stergios , Jönsson Kjell‐Åke , Borch Kurt , Jones Alan Wayne
Published: April 2006

Background: Gastric alcohol dehydrogenase may contribute to the metabolism of orally ingested ethanol and decrease the bioavailability of the drug. The aims of this study were to assess the impact of Helicobacter pylori infection and its eradication on gastric alcohol dehydrogenase activity and to relate the findings to gastric histology. Furthermore, the role of age‐ and sex‐related differences in gastric alcohol dehydrogenase activity were studied.

Methods: A total of 76 subjects (39 women and 37 men) underwent upper gastrointestinal endoscopy, and biopsies were obtained from the corpus and antrum. The specimens were used for determining gastric alcohol dehydrogenase activity, histological examination, and urease testing. Subjects with H. pylori infection (n= 36) received medication to eradicate the infection, and repeat biopsies were taken 2 and 12 months later.

Results: No significant difference in gastric alcohol dehydrogenase activity was found between men and women (p > 0.05). Gastric alcohol dehydrogenase activity did not differ significantly between the subjects older than 50 years (n= 39) and those 50 years or younger (n= 37). In subjects with H. pylori infection, gastric alcohol dehydrogenase activity was significantly reduced in the antrum (p < 0.05). After eradication of H. pylori, alcohol dehydrogenase activity in the antrum increased significantly within 2 months (p < 0.01). Antral biopsies with the most pronounced inflammation and histological changes had significantly decreased alcohol dehydrogenase activity (p < 0.05). In contrast, no significant differences were found in corpus.

Conclusions: H. pylori infection is associated with decreased antral alcohol dehydrogenase activity, which seems to be related to the severity of the inflammatory changes in the mucosa. Eradication of H. pylori normalizes antral alcohol dehydrogenase activity within 2 months.
Visual P3 in Female Alcoholics
Authors: Prabhu V. Radha , Porjesz Bernice , Chorlian David B. , Wang Kongming , Stimus Arthur , Begleiter Henri
Published: April 2006

Background: The P300 (P3) component of the event related potential has been established as a sensitive risk marker of vulnerability to alcoholism. Most alcoholism studies have focused on men; recent studies indicate that women are equally vulnerable to developing alcoholism.

Methods: Visual P3 recorded from 31 electrode positions was evaluated in 44 alcoholic and 60 control women, 24–50 years of age. P3 amplitudes and latencies of the two groups were statistically compared using Analysis of Variance; source localization of surface amplitude values from each group were plotted using a low‐resolution brain electromagnetic tomography.

Results: The results indicated that alcoholic women had significantly smaller P3 amplitudes in the frontal and central regions compared with controls. Source localization showed lowered activation in alcoholic women in right dorso‐lateral prefrontal cortex and the ventro‐medial fronto‐central regions.

Conclusions: The results suggest that P3 is an equally sensitive endophenotypic marker of vulnerability to alcoholism in women. The findings are discussed in terms of functional and physiologic significance of the P3 amplitude in alcoholic women and its relationship to drinking behaviors.
Individual Differences in Responses to Ethanol and d‐Amphetamine: A Within‐Subject Study
Authors: Holdstock Louis , de Wit Harriet
Published: April 2006

Background: In some individuals, ethanol (EtOH) produces marked stimulant‐like subjective effects resembling those of stimulant drugs, like d‐amphetamine (AMP). In this study, we examined the neurochemical basis of these individual differences by examining the same subjects’ responses to both EtOH and AMP. A positive correlation between subjects’ responses to the two drugs may suggest that AMP and EtOH produce their stimulant‐like subjective effects by a shared mechanism.

Methods: Twenty‐seven volunteers (17 male, 10 female), aged 21–35, received beverages or capsules containing EtOH 0.8 g/kg, AMP 10 or 20 mg, or placebo on four separate sessions in random order and under double‐blind conditions. Various self‐reported and objective drug effects were measured, including measures sensitive to subjective and cognitive stimulant‐like effects.

Results: EtOH and AMP produced their prototypical subjective and behavioral effects, including increased ratings of stimulant‐like subjective effects, increased heart rate and blood pressure, and improved vigilance performance after AMP and increased ratings of sedative‐like subjective effects, increased heart rate and blood pressure, and impaired vigilance performance after EtOH. Consistent with previous reports, there was substantial intersubject variability in subjective responses to EtOH: some subjects reported primarily stimulant‐like effects, whereas others reported primarily sedative‐like effects. To examine the relationship between these responses to EtOH and subjects’ responses to AMP, correlations were examined between effects of EtOH and AMP. For all subjects together, there was a significant positive correlation between responses to EtOH and 20 mg AMP on the ARCI A scale (a measure of stimulant‐like subjective effects;r= 0.41, p < 0.05). Among only those subjects who reported primarily stimulant‐like effects from EtOH, the correlation between EtOH and AMP was 0.64 (p < 0.05).

Conclusions: Subjects who experience pronounced stimulant‐like effects from EtOH also report greater stimulant effects from AMP, suggesting that these effects may be mediated through similar mechanisms. These correlations between the drugs’ effects were not observed on other measures, such as DSST or vigilance task performance or heart rate. This may indicate that these other effects are mediated by separate mechanisms. The study illustrates a novel approach to studying the neurochemical basis of drug effects.
Sex and Strain Differences in Ethanol Drinking: Effects of Gonadectomy
Authors: Cailhol Stéphanie , Mormède Pierre
Published: April 2006

Background: Alcohol drinking behavior in rats is known to be sexually dimorphic and strain‐dependent.

Methods: To test whether the gonadal steroid milieu exerts activational effects on ethanol intake and can modulate individual sensitivity toward alcohol use and misuse, we examined the effects of gonadectomy on oral self‐administration (OSA) of ethanol in male and female rats from different strains. After castration, animals were given continuous free choice between water and ethanol solutions. The ethanol concentration was progressively increased from 2% to 10% and maintained at 6% (the preferred concentration) for 24 days. Ethanol solutions were then withdrawn for 9 days. During the second phase of free‐choice drinking, the ethanol concentration was gradually increased every 4 days by the following amounts, in order as listed: 6%, 12%, and 24%.

Results: Our results confirm both gender and strain differences in ethanol drinking: females exhibited higher ethanol intake than males, and the WKHA strain drank more than the WKY and SHR strains. However, except for a small decrease in ethanol drinking during the acquisition of ethanol OSA in males after castration, no clear‐cut difference was found between gonadectomized and sham‐operated animals during the maintenance of ethanol OSA behavior.

Conclusions: These data suggest that gender and strain differences observed are insensitive to gonadal steroids during adulthood, and that different sensitivities to the effect of gonadal steroids do not explain the sex × strain interaction observed in ethanol drinking.
Zinc Supplementation Does Not Attenuate Alcohol‐Induced Cerebellar Purkinje Cell Loss During the Brain Growth Spurt Period
Authors: Chen Wei‐Jung A. , Berryhill Eve C. , West James R.
Published: April 2006

Background: Alcohol‐induced zinc deficiency is one of the mechanisms proposed as a cause of developmental brain damage associated with fetal alcohol syndrome. It is known that alcohol exposure during the brain growth spurt period leads to cerebellar Purkinje cell loss. Therefore, this study examined whether zinc supplementation was capable of preventing alcohol‐induced Purkinje cell loss in the cerebellar vermis in a neonatal rat model system.

Methods: Sprague‐Dawley rat pups were given alcohol (EtOH; 4.5 g/kg/day), zinc (Zn; 0.54 mg/ml diet; [10 times the regular diet Zn concentration]), or both from postnatal days (PD) 4 through 9 using the artificial‐rearing paradigm. A gastrostomy control (GC) and a suckle control group (SC) also were included. All pups were killed on PD 10. Following perfusion, the cerebellar vermis was dissected and processed for stereological cell counting. The total number of Purkinje cells and the volume of the cerebellar vermis were determined.

Results: Alcohol produced a significant loss of Purkinje cells compared with that in the GC group (no EtOH and no Zn supplement). The zinc supplementation had no effect in attenuating alcohol‐induced Purkinje cell loss in the cerebellar vermis. In fact, the serum zinc concentration data indicated higher zinc concentrations following either EtOH or Zn treatment. Interestingly, the GC group showed a significantly lower zinc concentration compared with the SC group, even though no significant difference in Purkinje cell numbers was observed between these two control groups.

Conclusion: These findings indicate that alcohol exposure during the third trimester equivalent did not result in zinc deficiency in this neonatal rat model system, nor did zinc supplementation rescue the alcohol‐induced Purkinje cell loss in the cerebellar vermis. These findings showed clearly that the serum zinc concentration was not correlated with Purkinje cell loss, suggesting that alcohol‐induced loss of cerebellar Purkinje cells in this neonatal rat model system is independent of the availability of serum zinc.
Removal of Glutathione Produces Apoptosis and Necrosis in HepG2 Cells Overexpressing CYP2E1
Authors: Wu Defeng , Cederbaum Arthur I.
Published: April 2006

Background: Previous studies have shown that addition of ethanol, iron, or arachidonic acid to HepG2 cells expressing CYP2E1 produced a loss in cell viability and caused apoptosis. These effects were enhanced when cellular reduced glutathione (GSH) levels were lowered by treatment with buthionine sulfoximine (BSO). Overexpression of CYP2E1 in HepG2 cells could produce toxicity even in the absence of added toxin after BSO treatment. Studies were carried out to characterize this CYP2E1‐and BSO‐dependent toxicity.

Methods: HepG2 cells expressing CYP2E1 were treated with BSO for 1 to 4 days, and various parameters associated with apoptosis and cell viability were assayed.

Results: Treatment of cells expressing CYP2E1 (E47 cells) with BSO resulted in apoptosis as well as necrosis. The apoptosis and necrosis were independent of each other. No toxicity was found with control HepG2 cells or HepG2 cells expressing CYP3A4 instead of CYP2E1 under these conditions. The antioxidant trolox partially prevented the apoptosis and necrosis, whereas diallylsulfide, a CYP2E1 inhibitor, was fully protective. The activity of caspase 3, but not caspases 1, 8, or 9, was increased in the BSO‐treated E47 cells, and an inhibitor of caspase 3 prevented apoptosis. Damage to mitochondria appears to play a role in the CYP2E1‐ and BSO‐dependent toxicity, because mitochondrial membrane potential was decreased and cyclosporin A, an inhibitor of the mitochondrial membrane permeability transition, prevented the apoptosis and the necrosis. The fall in membrane potential was prevented by trolox and diallylsulfide, suggesting damage to the mitochondria by CYP2E1‐derived reactive oxygen species.

Conclusions: These results indicate the critical role of GSH in protecting against CYP2E1‐mediated oxidative stress and that mitochondria may be a target for CYP2E1‐derived reactive oxygen species, and suggest that interactions between CYP2E1, mitochondria, and altered GSH homeostasis may play a role in alcohol‐induced liver injury.
Gene‐Environment Interaction in Patterns of Adolescent Drinking: Regional Residency Moderates Longitudinal Influences on Alcohol Use
Authors: Rose Richard J. , Dick Danielle M. , Viken Richard J. , Kaprio Jaakko
Published: April 2006

Background: Drinking frequency escalates rapidly during adolescence. Abstinence declines markedly, and drinking monthly or more often becomes normative. Individual differences in adolescent drinking patterns are large, and some patterns are predictive of subsequent drinking problems; little, however, is known of the gene–environment interactions that create them.

Methods: Five consecutive and complete birth cohorts of Finnish twins, born 1975–1979, were enrolled sequentially into a longitudinal study and assessed, with postal questionnaires, at ages 16, 17, and 18.5 years. The sample included 1786 same‐sex twin pairs, of whom 1240 pairs were concordantly drinking at age 16. Maximum likelihood models were fit in longitudinal analyses of the three waves of drinking data to assess changes in genetic and environmental influences on alcohol use across adolescence. Secondary analyses contrasted twin pairs residing in rural versus those in urban environments to investigate gene–environment interactions.

Results: Longitudinal analyses revealed that genetic factors influencing drinking patterns increased in importance across the 30‐month period, and effects arising from common environmental influences declined. Distributions of drinking frequencies in twins residing in urban and rural environments were highly similar, but influences on drinking varied between the two environments. Genetic factors assumed a larger role among adolescents residing in urban areas, while common environmental influences were more important in rural settings. Formal modeling of the data established a significant gene–environment interaction.

Conclusions: The results document the changing impact of genetic and environmental influences on alcohol use across adolescence. Importantly, the results also reveal a significant gene–environment interaction in patterns of adolescent drinking and invite more detailed analyses of the pathways and mechanisms by which environments modulate genetic effects.
Expression of c‐Fos in Alko Alcohol Rats Responding for Ethanol in an Operant Paradigm
Authors: Weitemier Adam Z. , Woerner August , Bäckström Pia , Hyytiä Petri , Ryabinin Andrey E.
Published: April 2006

Background: Identification of the brain regions involved in ethanol administration is important for understanding the neurobiology of ethanol addiction. Animal studies with different brain mapping techniques found that voluntary ethanol self‐administration leads to changes in activity of specific brain regions in patterns that only partially overlap with patterns of brain regions affected by involuntary (i.e., experimenter‐administered) ethanol administration. As an extension of studies mapping changes in neural activity after voluntary ethanol drinking, this study analyzed expression of the inducible transcription factor c‐Fos after ethanol consumption in an operant procedure.

Methods: AA (Alko alcohol) rats were trained to operantly respond for water, 0.2% saccharin, 0.2% saccharin/10% (w/v) ethanol, or 10% ethanol in a 30‐min limited‐access procedure. Animals were allowed to self‐administer solutions for at least 40 ethanol response sessions and were killed 1.5 hr after beginning of the last session. Forty‐seven brain regions were immunohistochemically analyzed for c‐Fos expression.

Results: In this paradigm, ethanol dose‐dependently increased c‐Fos expression in the Edinger‐Westphal nucleus (EW) and decreased expression in the dorsal tenia tecta compared with no‐ethanol controls. No effects of saccharin on c‐Fos expression were found.

Conclusions: Our results extend previous findings of preferential sensitivity of EW to alcohol in voluntary self‐administration procedures to operant responding for ethanol and warrant further investigation of ethanol's effects on the EW. The finding that ethanol attenuated c‐Fos expression in the tenia tecta is novel. Taken together, these findings confirm that voluntary ethanol self‐administration leads to changes in activity of a limited number of brain regions with previously unexamined roles in ethanol sensitivity and addiction.
Can Encouraging Substance Abuse Patients to Participate in Self‐Help Groups Reduce Demand for Health Care? A Quasi‐Experimental Study
Authors: Humphreys Keith , Moos Rudolf
Published: April 2006

Background: Twelve‐step‐oriented inpatient treatment programs emphasize 12‐step treatment approaches and the importance of ongoing attendance at 12‐step self‐help groups more than do cognitive‐behavioral (CB) inpatient treatment programs. This study evaluated whether this difference in therapeutic approach leads patients who are treated in 12‐step programs to rely less on professionally provided services and more on self‐help groups after discharge, thereby reducing long‐term health care costs.

Methods: A prospective, quasi‐experimental comparison of 12‐step‐based (N = 5) and cognitive‐behavioral (n= 5) inpatient treatment programs was conducted. These treatments were compared on the degree to which their patients participated in self‐help groups, used outpatient and inpatient mental health services, and experienced positive outcomes (e.g., abstinence) in the year following discharge. Using a larger sample from an ongoing research project, 887 male substance‐dependent patients from each type of treatment program were matched on pre‐intake health care costs (N = 1774). At baseline and 1‐year follow‐up, patients’ involvement in self‐help groups (e.g., Alcoholics Anonymous), utilization and costs of mental health services, and clinical outcomes were assessed.

Results: Compared with patients treated in CB programs, patients treated in 12‐step programs had significantly greater involvement in self‐help groups at follow‐up. In contrast, patients treated in CB programs averaged almost twice as many outpatient continuing care visits after discharge (22.5 visits) as patients treated in 12‐step treatment programs (13.1 visits), and also received significantly more days of inpatient care (17.0 days in CB versus 10.5 in 12‐step), resulting in 64% higher annual costs in CB programs ($4729/patient, p < 0.001). Psychiatric and substance abuse outcomes were comparable across treatments, except that 12‐step patients had higher rates of abstinence at follow‐up (45.7% versus 36.2% for patients from CB programs, p < 0.001).

Conclusions: Professional treatment programs that emphasize self‐help approaches increase their patients’ reliance on cost‐free self‐help groups and thereby lower subsequent health care costs. Such programs therefore represent a cost‐effective approach to promoting recovery from substance abuse.
MK‐801 Can Exacerbate or Attenuate Behavioral Alterations Associated With Neonatal Alcohol Exposure in the Rat, Depending on the Timing of Administration
Authors: Thomas J.D. , Fleming S.L. , Riley E.P.
Published: April 2006

Background: We have reported that administration of MK‐801, an NMDA receptor antagonist, during ethanol withdrawal in the developing rat attenuates ethanol's adverse effects on behavioral development. In the present study, we altered the timing of MK‐801 delivery in relation to the last alcohol dose to determine if its protective effects were specific to the ethanol withdrawal phase.

Methods: Five groups of rats were artificially reared and exposed to alcohol in a binge‐like manner on postnatal day (PD) 6, producing peak blood alcohol levels of 335 mg/dl that cleared to 0 mg/dl by 33 hours. Four groups received MK‐801 at various times after alcohol treatment (0, 9, 21, or 33 hr post‐ethanol). The fifth alcohol‐treated group received saline. Two artificially reared control groups were included: one was injected with saline and the other injected with 0.5 mg/kg MK‐801. Finally, a normally reared suckle control group was also included. Activity level and performance on a spatial discrimination reversal‐learning task were evaluated at PD 18 and PD 40, respectively.

Results : Administration of MK‐801 at the same time as ethanol treatment (0 hr) produced a high rate of mortality. Ethanol exposure on PD6 increased activity level relative to controls. Administration of MK‐801 at 0 hr exacerbated this ethanol‐induced overactivity, whereas administration of MK‐801 at 21 and 33 hr reduced the severity of ethanol‐related overactivity. Similarly, ethanol exposure on PD 6 significantly increased the number of errors committed on a spatial discrimination reversal‐learning task. MK‐801 injections 9 hrs after ethanol exacerbated this effect, whereas MK‐801 treatment 33 hrs after ethanol attenuated this effect. Thus, MK‐801 administration at the time of ethanol treatment was highly toxic, whereas during the withdrawal period it was protective.

Conclusion : These data are consistent with the hypothesis that ethanol exposure in the neonatal rat inhibits the NMDA receptor, producing a subsequent rebound in NMDA receptor activation and possible excitotoxicity during withdrawal. Both the acute inhibitory effects of ethanol and the excitatory effects of withdrawal may contribute to fetal alcohol effects.