bluuebunny/crossref_metadata_2025 huggingface dataset:
Glucocorticoid Fast Feedback Is Not Altered in Rats Prenatally Exposed to Ethanol
Authors: Hofmann Candace , Glavas Maria , Yu Wayne , Weinberg Joanne
Published: May 2006

Animals exposed in utero to ethanol exhibit hormonal hyperresponsiveness to stressors in adulthood. One possible mechanism for this hyperresponsiveness is a deficit in negative feedback regulation of the hypothalamic‐pituitary‐adrenal axis. The present study tested the hypothesis that a deficit in the fast feedback time domain may play a role in the hormonal hyperresponsiveness in ethanol‐exposed rats. Sprague‐Dawley offspring from prenatal ethanol (E), pair‐fed (PF), and ad lib‐fed control (C) groups were tested in two experiments. Experiment 1 used a swim stress paradigm and tested animals at the trough of the corticosterone (CORT) circadian rhythm. Experiment 2 used ether stress and tested animals at the peak of the circadian rhythm. Animals were injected subcutaneously with CORT or saline and were immediately subjected to either a 5‐min swim stress or a I‐min ether stress. Half the animals were terminated immediately after stress (5‐min postinjection), and the rest were terminated 25 min later. Plasma levels of CORT and ACTH were assayed to determine whether E animals differed from control animals in showing a CORT‐induced blunting of the ACTH response to the stressor, indicating alterations in fast feedback regulation. Injection of CORT significantly bluntcd the ACTH response to swim stress (expcriment 1) in E, PF, and C females and males, compared with their saline‐injected counterparts. There were no significant differences among groups. Similarly, CORT‐injected males in E, PF, and C groups all exhibited a significantly blunted ACTH response to ether stress (experiment 2). CORT‐injected C females also exhibited a significantly blunted ACTH response to ether stress, whereas E females showed an obvious CORT decrease that approached significance. However, PF females showed a clear deficit in fast feedback regulation. Together, these data suggest that: (1) CORT injection can serve as a fast feedback signal that can blunt the ACTH response 10 a stressor; and (2) prenatal ethanol exposure does not produce a deficit in hypothalamic‐pituitary‐adrenal feedback regulation in the fast feedback time domain.
A Novel Polymorphism (‐357 G/A) of the ALDH2 Gene: Linkage Disequilibrium and an Association With Alcoholism
Authors: Harada Shoji , Okubo Takehito , Nakamura Takako , Fujii Chieko , Nomura Fumio , Higuchi Susumu , Tsutsumi Mikihiro
Published: May 2006

Background: Human mitochondrial aldehyde dehydrogenase (ALDH2) is a major enzyme responsible for the oxidation of acetaldehyde derived from ethanol metabolism. The human ALDH2 gene shows genetic polymorphism at position 1510 with a G to A transition in exon 12. This mutation leads to ALDH2 enzyme deficiency and protection against alcoholism. As yet, no polymorphism for the promoter region of the ALDH2 gene has been reported.

Method: We analyzed 600 nucleotides of the promoter region in addition to exon 12 from 571 Japanese, 68 Chinese, 80 Myanmar, 60 Mongolians, and 82 North‐American Caucasians using single‐strand conformational change polymorphism (SSCP) analysis and the polymerase chain reaction (PCR). PCR products that showed an aberrant banding pattern detected by the SSCP analysis were subjected to PCR direct sequencing.

Result: A novel polymorphism at‐357 with a G to A substitution was found in all the population groups, including North‐American Caucasians. In addition, the polymorphic status in the promoter and exon 12 suggested linkage disequilibrium between the two loci, which indicated that among Japanese, the ALDH2* 2 allele is linked to the G promoter allele, and theALDH2*1 allele is linked to the A allele. A total of 206 healthy male controls and 185 alcoholic male patients with the homozygous ALDH2* 1 genotype were analyzed for the polymorphism in the promoter. Genotypic frequencies of GG, GA, and AA for alcoholics were 54.1%, 44.3%, and 1.6%, and those for controls were 52.9%, 40.3%, and 6.8%, respectively. The A allele frequencies for alcoholics and controls were 0.24 and 0.27, respectively. A χ2 test for the entire 3 × 2 table indicated significant variations in the three genotypes (χ2=6.40, p < 0.05). However, no significant difference in allelic frequencies between the two groups was observed.

Conclusion: This new polymorphism in the ALDH2 promoter is present in all populations studied. Further analysis in other ethnic groups is necessary to establish this as an additional risk factor for alcoholism.
Comparing the Diagnostic Accuracy of Carbohydrate‐Deficient Transferrin, γ‐Glutamyltransferase, and Mean Cell Volume in a General Practice Population
Authors: Meerkerk G.‐J. , Njoo K. H. , Bongers I. M. B. , Trienekens P. , van Oers J. A. M.
Published: May 2006

In certain populations, the biological alcohol marker carbohydrate‐deficient transferrin (CDT) is known to have a high diagnostic accuracy. The aim of this study was to compare the diagnostic accuracy of CDT, γ‐glutamyltransferase (γ‐GT), and mean cell volume (MCV) in a general practice population; more specifically, to ascertain whether CDT is a better tool than γ‐GT and MCV for (early) recognition of excessive alcohol use. To represent the general practice situation as realistically as possible, three different drinking patterns are defined: irregular excessive, regular excessive, and very excessive. From a sample of 524 men from seven general practices, sensitivity, specificity, and predictive values of the three markers for the three drinking patterns were compared, and receiver‐operating characteristic analysis was used to compare differences between the markers. The results indicate that drinking patterns do influence the (difference in) diagnostic accuracy. CDT has a higher diagnostic accuracy for all three drinking patterns than y‐GT and higher predictive values for hazardous [(ir)regular excessive] drinking patterns than MCV. However, receiver‐operating characteristic analyses failed to demonstrate a significant difference between these patterns. It is concluded that the performance of all tests is too low to be useful for screening procedures in a general population; however, some tests may be useful for case finding. CDT seems to be the best alcohol marker available, although the difference between CDT and MCV is small.
Self‐Reported Alcohol‐Associated Symptoms and Drinking Behavior in Three ALDH2 Genotypes Among Japanese University Students
Authors: Takeshita Tatsuya , Morimoto Kanehisa
Published: May 2006

Background: Alcohol abuse is one of the most serious health problems among young adults. Nearly half of the Japanese population is sensitive to alcohol due to a genetic polymorphism in low Km aldehyde dehydrogenase (ALDH2). In the present study, we investigated the effects of the ALDH2 genotype on both self‐reported alcohol‐associated symptoms and alcohol drinking behavior among Japanese university students.

Method: The study subjects were 423 (389 males and 34 females) university students in a medical university. The subjects completed a questionnaire regarding self‐reported alcohol‐associated symptoms and alcohol drinking behavior. The ALDH2 genotype was determined through digestion of polymerase chain reaction (PCR) products by a restriction enzyme Ksp632I.

The frequency of alcohol‐associated symptoms generally increased in the order ALDH2*1/*1, ALDH2*1/*2, ALDH2*2/*2 among males. The frequency of those who drink <5 days/week was less than 10% in all genotype groups. However, the frequency of those who drink 1‐4 days/week was significantly higher inALDH2*1/*1 than that mALDH2*1/*2 and mALDH2*2/*2. A similar tendency also was observed in females. Mean amounts of alcohol consumption per occasion in the three ALDH2 genotypes stratified by drinking frequency generally increased significantly in the order ALDH2*2/*2, ALDH2*1/*2, ALDH2*1/*1 in both sexes. The proportion of binge drinkers defined by those who drink ethanol of > 75 ml per occasion on average also increased in the order ALDH2*2/*2 (0.0%), ALDH2*1/*2 (9.8%), ALDH2*1/*1 (22.1%) among male drinkers (> 1 day/month).

Conclusions:

We for the first time demonstrated clear associations between the ALDH2 genotype, self‐reported alcohol‐associated symptoms, and alcohol drinking behavior among Japanese university students.
Effect of Ethanol on Platelet Function
Authors: Rubin Raphael
Published: May 2006

Epidemiological studies have linked an inhibition of platelet function by ethanol, among other factors, to the cardioprotective effects of moderate ethanol consumption. Platelet defects have been noted in alcoholics and in human experimental studies. Importantly, in in vivo experimental settings, ethanol diminishes thrombus formation on damaged arterial walls. Ethanol inhibits platelet activation in vitro in response to diverse agonists. Phospholipase A2 is a major site for ethanol inhibition, corresponding to a reduction in the formation of stimulatory arachidonate metabolites. Additional signal transduction pathways are likely targets for ethanol including phosphoinositide‐specific phospholipase C and cyclic AMP. The role of additional cofactors in the inhibition of platelet responses by ethanol is discussed.
What Is Inherited in the Predisposition Toward Alcoholism? A Proposed Model
Authors: Begleiter Henri , Porjesz B.
Published: May 2006

Background:The etiological factors associated with the predisposition to develop alcohol dependence remain largely unknown. In recent years, neurophysiological anomalies have been identified in young and adult offspring of alcoholic probands. These neuroelectric features have been replicated in several laboratories across many different countries and are observed in male and female alcoholics and some of their relatives and offspring. Moreover, these electrophysiological abnormalities are heritable and predictive of future alcohol abuse or dependence.

Methods:A model is presented which hypothesizes that the genetic predisposition to develop alcoholism involves an initial state of central nervous system (CNS) disinhibition/hyperexcitability. We propose that the event‐related brain potential (ERP) anomalies reflect CNS disinhibition. This homeostatic imbalance results in excess levels of CNS excitability which are temporarily alleviated by the ingestion of alcohol. It is hypothesized that this hyperexcitability is heritable, and is critically involved in the predisposition toward alcoholism and the development of dependence. A brief review of the relevant literature is presented.

Results:Neurophysiological, neurochemical, and genetic evidence support the proposed model. In addition, strikingly similar observations between animal research and the human condition are identified. Finally, it is asserted that the proposed model is primarily biological in nature, and therefore does not account for the entire clinical variance.

Conclusion:A putative CNS homeostatic imbalance is noted as a critical state of hyperexcitability. This hyperexcitability represents a parsimonious model of what is inherited in the predisposition to develop alcoholism. It is our hope that this model will have heuristic value, resulting in the elucidation of etiological factors involved in alcohol dependence.
Chlordiazepoxide‐Induced Expression of c‐Fos in the Central Extended Amygdala and Other Brain Regions of the C57BL/6J and DBA/2J Inbred Mouse Strains: Relationships to Mechanisms of Ethanol Action
Authors: Hitzemann Barbara , Hitzemann Robert
Published: May 2006

Background: Previous studies have established an association between the ethanol‐induced locomotor response and activation of the central nucleus of the amygdala (CeA) as determined by changes in the number of Fos‐like immunoreactive (Fos‐li) neurons. The purpose of the current study was to determine if the benzodiazepine chlordiazepoxide (CDP) would produce similar effects to ethanol on behavior and the CeA.

Methods: In experiment 1, C57BL/6J (B6) and DBA/2J (D2) mice were administered CDP over a dose range of 3 to 30 mg/kg and the effects on locomotor behavior and the number of Fos‐li neurons in the extended CeA determined. For experiment 2, B6D2 F2 intercross animals were phenotyped for their locomotor response to ethanol using a test‐retest design. The activity responsive and nonresponsive extreme phenotypes were then tested in the same fashion as the inbred strains.

Results: Similar to ethanol, CDP increased locomotor activity in the D2 strain but not the B6 strain; furthermore, the D2 strain was 3 to 10 times more sensitive than the B6 strain in terms of CDP activating the CeA and the associated lateral posterior aspect of the bed nucleus of the stria terminalis (BSTLP). In the shell of the nucleus accumbens (NAc), CDP inhibited the number of Fos‐positive neurons in both strains. CDP also discriminated between the responsive and nonresponsive extremes both in terms of behavior and activation of the CeA.

Conclusions: Overall, these data point to the importance of GABAA mediated mechanisms in the ethanol‐induced locomotor response. It is suggested that both drugs block the feed‐forward inhibition in the CeA, resulting in activation of the GABAergic projection neurons. The overall net effect of CDP or ethanol administration on the output from the CeA will be inhibitory, from which it follows that the locomotor activation response must be associated with the selective inhibition of some behavior or ensembles of behaviors that are known to be mediated by the CeA and reduce locomotor activity (i.e., the “freezing” response).
A Preliminary Study of Acute Responses to Clamped Alcohol Concentration and Family History of Alcoholism
Authors: Ramchandani Vijay A. , O'Connor Sean , Blekher Tanya , Kareken David , Morzorati Sandra , Nurnberger John , Li Ting‐Kai
Published: May 2006

Background: The clamping method of alcohol administration was combined with a battery of dependent measures of frontal lobe brain function, and a novel index of acute adaptation, in a preliminary study in order to explore the paradigm's sensitivity to a familial history of alcoholism (FHA).

Methods: Ten family history‐positive (FHP) and 10 family history‐negative (FHN) adult social drinkers of both genders underwent alcohol clamping. Twenty minutes after the start of an intravenous infusion of alcohol, the breath alcohol concentration was clamped at a target of 60 ± 5 mg/dl for 150 min. Initial and adaptive responses to alcohol were assessed using scalar indices of change. One index assessed initial improvements or impairments in brain function after alcohol. The other index assessed acute adaptation (tolerance or sensitization) to alcohol while the brain's exposure to alcohol was held constant. The battery of dependent measures included subjective perceptions, neuropsychological tests, saccadic eye‐movement tasks, and event‐related potential (ERP) tasks. Effect sizes for FHA were estimated for 10 dependent variables that showed adequate baseline test‐retest reliability (r>0.6).

Results: FHP subjects showed less intense initial responses to alcohol in subjective perceptions, but greater changes in the latency of volitional saccades and ERP P3 components than did the FHN controls. FHP subjects generally showed greater acute tolerance to alcohol than did controls, who showed more instances of acute sensitization at this moderate breath alcohol concentration. Effect sizes for FHA exceeded 0.4 in more than half of the indices.

Conclusions: The BrAC clamping paradigm assesses initial and adaptive responses of a battery of behavioral and electrophysiological measures of frontal lobe function to ethanol that appear both reliable and sensitive to FHA.
A New Model of Ethanol Self‐Administration in Newborn Rats: Gender Effects on Ethanol Ingestion Through a Surrogate Nipple
Authors: Varlinskaya Elena I. , Petrov Evgeniy S. , Cheslock Sarah J. , Spear Norman E.
Published: May 2006

Background: Ethanol intake in the context of suckling may have distinct and potentially long‐lasting consequences for further responsiveness to and acceptance of ethanol, compared to other, more indirect and less natural ways of ethanol exposure early in ontogeny.

Method: Our findings presented in this paper show that a surrogate nipple technique can be used for the study of early ethanol intake in cesarean‐derived rat pups tested before any suckling experience.

Results: Neonatal rats attached to and voluntary ingested ethanol through the surrogate nipple as early as 4 hr after birth. Moderate concentrations of ethanol (2% and 5%, v/v) promoted substantial initial suckling behavior, including sustained attachment to the nipple. Higher concentrations (10% and 15%) were not effective in sustaining suckling. Females responded less positively to 10% ethanol than did males. High concentrations of ethanol were less effective in eliciting suckling behavior, probably due to the aversiveness of ethanol odor. However, when ethanol was presented in solution with milk, newborn pups attached to the nipple and ingested even 15% ethanol. Contamination of milk with 15% ethanol was more aversive for females than for males. Newborn rat pups demonstrated similar patterns of nipple attachment and ingestive behavior for 5% ethanol and milk. Initial experience with milk in the context of suckling did not prevent further voluntary ethanol ingestion from the same nipple; furthermore, initial exposure to 5% ethanol did not impair subsequent responsiveness to milk.

Conclusions: Gender differences in responsiveness or sensitivity to ethanol can be detected in rat pups as early as a few hours after birth. The results suggest a leftward shift in the dose‐response curve for females compared with males, indicating that female neonates are more sensitive or more responsive than males to ethanol. The similarity of suckling behaviors produced by moderate concentrations of ethanol and milk suggests a certain unity in their reinforcing mechanisms in the context of the first suckling episode.
Dissociation of Ethanol and Saccharin Preference in sP and sNP rats
Authors: Agablo Roberta , Caral Mauro A.M. , Lobina Carla , Pani Marialaura , Reali Roberta , Bourov Iouri , Gessa Gian Luigi , Colombo Giancarlo
Published: May 2006

Background:

It has been proposed that ethanol intake and consumption of sweet tasting solutions are positively correlated in rodents. Experiment 1 of the present study investigated whether selectively bred ethanol‐preferring (sP) and ‐nonpreferring (sNP) rats differed, consistently with the above hypothesis, as to saccharin intake and preference. Experiment 2 evaluated whether saccharin addition to the ethanol solution, likely resulting in a highly palatable fluid, would result in an increase in voluntary ethanol intake in sP rats.

Methods:

The saccharin solution was offered, in free choice with water, at a fixed concentration of 1 giliter for 6 consecutive days in Experiment 1A or at ascending concentrations (0.002 to 16.4 g/liter, doubling the concentration every day) in Experiment 1B. In Experiment 2, 1 g/liter, doubling the concentration every day) in Experiment 1B. In Experiment 2, 1 g/liter saccharin was added to the standard 10% ethanol solution and offered to sP rats in free choice with water for 7 consecutive days.

Results:

In both Experiments 1A and 1B, sP and sNP rats showed avidity for the saccharin solution with marginal line difference in saccharin intake and preference. In Experiment 2, daily ethanol intake remained stable at baseline levels (6–7 g/kg), irrespective of the saccharin addition to the ethanol solution.

Conclusions:

The results of Experiments 1A and 1B suggest that saccharin drinking behavior in sNP rats deviates from the hypothesis that saccharin and ethanol intakes may co‐vary; thus, at least in sNP rats, saccharin and ethanol intakes do not appear to be influenced by the same genetic factors. The results of Experiment 2 provide further support to the existence of a central set‐point mechanism that regulates daily ethanol intake in sP rats, likely based on the pharmacological effects of ethanol.
Alcohol Consumption, Alcohol Dependence, and All‐Cause Mortality
Authors: Dawson Deborah A.
Published: May 2006

Background:

This study examined the effects of alcohol consumption and DSM‐IV alcohol dependence on the risk of mortality.

Methods:

Data from the 1988 National Health Interview Survey Alcohol Supplement were matched to the National Death Index for the years 1988 to 1995 (baseline n= 37,682 U.S. adults age ≥25 linked to 3,586 deaths). All mortality analyses were based on proportional hazards models that adjusted for age, sex, race/ethnicity, marital status, education, income, labor force status, body mass index, smoking status, and poor health indicators at baseline.

Results:

When dependence was not considered and all past‐year abstainers were used as the reference group, both light and moderate drinkers exhibited a reduced risk of mortality, with hazards ratios of 0.76 (0.68–0.84) and 0.84 (0.74–0.96). Heavy drinkers had about the same risk of dying as did past‐year abstainers, and very heavy drinkers had an increased risk that was not significant (OR = 1.17, CI = 0.93–1.47). When lifetime abstainers were used as the reference category, the protective effect of moderate drinking fell short of significance, and there were nearly significant increased risks among former drinkers and very heavy drinkers. When dependence was considered, light and moderate drinkers without dependence had a reduced mortality risk regardless of reference group, and there was no significant effect among heavy or very heavy drinkers without dependence. Among dependent drinkers, there was no protective effect of light or moderate drinking, and very heavy drinkers had a significantly increased risk (OR = 1.56 relative to past‐year abstainers and 1.65 relative to lifetime abstainers).

Conclusions:

Because alcohol dependence nullifies the protective effect of light and moderate drinking, it is important to understand its role as an independent risk factor for mortality. Differences between dependent and nondependent drinkers who drank comparable amounts suggest that this risk may result from longer and heavier drinking histories before baseline, more severe health problems at baseline, more heavy episodic drinking, and, possibly, differences in beverage preference.
Ethanol Increases the Neurotoxic Effect of Tumor Necrosis Factor‐α in Cultured Rat Astrocytes
Authors: DeVito William J. , Stone Scott , Shamgochian Maureen
Published: May 2006

Background:

The central nervous system is particularly sensitive to the cytotoxic effect of ethanol. In vivo and in vitro studies indicate that ethanol decreases cell proliferation in a number of cells types, including neurons and glial cells in the central nervous system. The cellular mechanisms involved in ethanol‐induced cell toxicity, however, are unclear. In this study, we examined the effect of ethanol on tumor necrosis factor‐α (TNFα)‐induced cell death in a homogeneous population of cultured rat astrocytes.

Methods:

Flow cytometric and 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenytetrazolium bromide (MTT) dye reduction analyses were performed on cultured rat astrocytes to determine the effect of alcohol on TNFα‐induced cell death.

Results:

Flow cytometric analysis revealed that, in quiescent astrocytes, high concentrations of ethanol were required to increase DNA fragmentation and decrease cell viability. Preexposure of astrocytes to low concentrations of ethanol (10 to 50 mM), however, increased the sensitivity of astrocytes to TNFα with low TNFα concentrations (25 to 50 ng/ml) resulting in increased DNA fragmentation. Furthermore, MTT dye reduction analysis revealed that exposure of astrocytes to 5 mM ethanol was sufficient to increase the susceptibility of astrocytes to the cytotoxic effect of ethanol. In a number of cell types, TNFα receptor binding results in the activation of specific signal transduction cascades, including the hydrolysis of sphingomyclin to ceramide. We show that preexposure of astrocytes to a low concentration of ethanol increased the sensitivity of astrocytes to sphingomyelinase, and C2‐ceramide resulting in increased DNA fragmentation and decreased cell viability. More importantly, astrocytes prepared from rats exposed to ethanol prenatally showed increased susceptibility to TNFα‐induced cell death.

Conclusions:

These studies suggest that ethanol increases the susceptibility of astrocytes to TNFα‐induced cell death by shifting the balance of sphingolipid metabolism in favor of a pathway that increases the susceptibility of astrocytes to the cytotoxic effect of TNFα.
Polymorphism in the Interleukin‐1 Receptor Antagonist Gene Is Associated With Alcoholism in Spanish Men
Authors: Pastor Isabel J. , Laso F. Javier , Àvila José J. , Rodriguez Raquel E. , González‐Sarrniento Rogelio
Published: May 2006

Background:

A polymorphism located in intron 2 of the interleukin‐1 receptor antagonist (IL1RN) gene recently has been associated with the development of hepatic fibrosis in Japanese alcoholics. In the present study, we analyzed whether there is an association between this polymorphism, alcoholism, and alcoholic liver disease in a Spanish male population of alcoholics.

Methods:

The IL1RN genotype was assessed by polymerase chain reaction by using oligonucleotides that flank a variable nucleotide tandem repeat polymorphism located in intron 2 of this gene in 90 male alcoholic patients from Spain; 30 alcohol‐dependent men, 30 alcohol abusers, and 30 alcoholics with liver cirrhosis. We also studied 40 healthy subjects.

Results:

The distribution of the IL1RN allelic frequencies in Spanish healthy subjects is similar to that previously reported in White subjects. However, the A1 allele is overrepresented in Spanish alcoholics when compared with healthy subjects. No significant differences in allelic frequencies were observed between alcoholics with liver cirrhosis and alcoholics without liver disease or between alcohol‐dependent subjects and alcohol abusers.

Conclusion:

The presence of the A1 allele of the IL1RN gene is associated with a higher risk of alcoholism in Spanish men.
Predictors of Substance Abuse Treatment Retention Among Women and Men in an HMO
Authors: Mertens Jennifer R. , Weisner Constance M.
Published: May 2006

Background:

Although prior research has examined predictors of treatment retention in public alcohol and drug treatment programs, little is known about factors that influence treatment retention in an insured outpatient population. Because there is growing evidence that the factors which influence treatment retention may differ by gender, we identify sex‐specific predictors.

Methods:

We recruited all eligible intakes to a health maintenance organization's outpatient alcohol and drug treatment program during a 2‐year period and obtained a sample of 317 women and 599 men. The programs, day hospital and traditional outpatient modalities, were abstinence based. We separated our sample by sex and used least squares and logistic regression to identify independent predictors of length of stay and program completion, respectively.

Results:

One general pattern of predictors of increased retention was shared by women and men in this alcohol and drug treatment program—fewer and less severe drug problems. However, most predictors were sex‐specific. Among women, retention was predicted by having higher incomes, belonging to ethnic categories other than African American, being unemployed, being married, and having lower levels of psychiatric severity. Among men, predictors of higher retention included being older, receiving employer suggestions to enter treatment, and having abstinence goals.

Conclusions:

These findings highlight the importance of examining aspects of the course of treatment separately by sex. They also suggest treatment factors that may enhance retention among insured populations, including employer referrals, psychiatric services, and drug‐related services.
6‐β‐Naltrexol Reduces Alcohol Consumption in Rats
Authors: Rukstalis Margaret R. , Stromberg Michael F. , O'Brien Charles P. , Volpicelli Joseph R.
Published: May 2006

Background:

In humans, 6‐β‐naltrexol is the major metabolite of naltrexone, and its effectiveness at suppressing alcohol consumption in any species has not been previously investigated. Naltrexone is an opiate antagonist that reduces excessive drinking in many species, including humans with alcohol dependence. Whether 6‐β‐naltrexol is an active metabolite that contributes to the efficacy of naltrexone remains unknown.

Methods:

Placebo and four doses of 6‐β‐naltrexol were given by intraperitoneal injection to outbred Wistar rats and alcohol consumption was measured using a limited access model.

Results:

6‐β‐Naltrexol reduced alcohol consumption in a dose‐dependent manner. At doses 7.5, 12.5, and 25 mg/kg, 6‐β‐naltrexol significantly decreased consumption of a 6% ethanol solution compared with saline control groups.

Conclusions:

These data suggest that there may be a potential clinical use for 6‐β‐naltrexol in recovering alcoholics.
Association Between the Functional Polymorphism of Catechol‐O‐Methyltransferase Gene and Alcohol Consumption Among Social Drinkers
Authors: Kauhanen Jussi , Hallikainen Tero , Tuomainen Tomi‐Pekka , Koulu Markku , Karvonen Matti K. , Salonen Jukka T , Tiihonen Jari
Published: May 2006

Background:

A common functional genetic polymorphism in the catechol‐O‐methyltransferase (COMT) gene (Val158 Met) results in 3‐ to 4‐fold differences in COMT enzyme activity and dopamine inactivation rate. Previous studies have shown that type I alcoholism is more common among subjects with low activity COMT genotype (LL), compared with high activity (HH) or heterozygotic (LH) genotypes.

Methods:

We studied alcohol consumption and the COMT genotype in middle‐aged Finnish men (n= 896), who represented an unselected ethnically homogenous population sample and reported using alcohol during the past year. Average alcohol use in pure ethanol (grams per week) was compared between subjects with LL genotype and subjects with LH or HH genotypes.

Results:

Men with LL genotype (30% of all subjects) reported 27% higher weekly alcohol consumption compared with the two other genotype groups (p< 0.05). The difference remained statistically significant after a multivariate adjustment for sociodemographic factors and prior or existing diseases (p= 0.031).

Conclusions:

The results indicate that COMT polymorphism may contribute significantly to alcohol intake not only in alcoholics but also in a general male population.
Differential Effects of Ethanol on Insulin‐Like Growth Factor‐I Receptor Signaling
Authors: Seiler Andrea E.M. , Ross Brian N. , Green Jaime S. , Rubin Raphael
Published: May 2006

Background:

Activation of the insulin‐like growth factor I receptor (IGF‐IR) by its ligands IGF‐I and IGF‐II induces cell proliferation and protects against apoptosis. Ethanol inhibits IGF‐IR tyrosine autophosphorylation, which subsequently interferes with the activation of key downstream signaling mediators including insulin‐receptor substrate‐1, phosphatidylinositol 3‐kinase, and mitogen‐activated protein (MAP) kinase. The ethanol‐induced inhibition of IGF‐IR signaling reduces mitogenesis and enhances apoptosis. In the current study, we demonstrate that the antiproliferative action of ethanol can be modulated by differential sensitivity of the autophosphorylation of the IGF‐IR to ethanol.

Methods:

A series of subclones was generated from 3T3 cells that express the human IGF‐IR.

Results:

There was considerable variability in the ability of ethanol to inhibit IGF‐I‐dependent IGF‐IR tyrosine autophosphorylation and MAP kinase activation, despite equivalent IGF‐IR expression. The IGF‐IR was completely resistant to a high concentration of ethanol (150 mM) in several subclones. The sensitivity of IGF‐IR autophosphorylation to ethanol correlated directly with the inhibition of IGF‐I‐mediated MAP kinase activation and cell proliferation. Resistant subclones exhibited features of the transformed phenotype including high MAP kinase activity, partial loss of contact inhibition, and the development of foci at confluency. The IGF‐IR isolated from ethanol‐resistant cells was similarly resistant to ethanol in autophosphorylation reactions in vitro, whereas ethanol inhibited the autophosphorylation of IGF‐IR obtained from sensitive cells.

Conclusions:

Our findings are the first to demonstrate the modulation of ethanol sensitivity of a tyrosine kinase receptor, and they provide a molecular basis for differential effects of ethanol on cell proliferation.
Attenuation of Alcohol‐Induced Apoptosis of Hepatocytes in Rat Livers by Polyenylphosphatidylcholine (PPC)
Authors: Mi Li‐Jun , Mak Ki M. , Lieber Charles S.
Published: May 2006

Background:

Alcohol consumption increases apoptosis of hepatocytes. This effect appears to be mediated by the induction of hepatic cytochrome P‐4502E1(CYP2E1) and its generation of free radicals, which results in an enhanced lipid peroxidation that initiates apoptosis. Because polyenylphosphatidylcholine (PPC), a soybean extract rich in polyunsaturated phosphatidylcholines, decreases the induction of ethanol‐specific CYP2E1 and opposes oxidative stress, we hypothesized that PPC supplementation may attenuate hepatocyte apoptosis caused by ethanol ingestion.

Methods:

Twenty‐eight male Sprague Dawley® rats were pair‐fed Lieber‐DeCarli liquid diets containing 36% of energy as alcohol or an isocaloric amount of carbohydrate for 28 days. Half of the rats were given PPC (3 g/liter), whereas the other half received the same amount of linoleate (as safflower oil) and of choline as the bitartrate. An additional dose of alcohol (3 g/kg) was given intragastrically 90 min before the livers were removed. We assessed apoptosis in formalin‐fixed, paraffin‐embedded liver sections by using the TUNEL (terminal transferase dUTP nick end labeling) assay. Apoptotic hepatocytes were identified by positive TUNEL staining in conjunction with condensation of nucleoplasm or margination of chromatin. In each rat, 20,000 to 60,000 hepatocytes were counted by light microscopy by using Image‐Pro Plus computer software, and the incidence of apoptosis was expressed as the percentage of total hepatocytes.

Results:

Alcohol feeding resulted in a 4.5‐fold increase in apoptosis of hepatocytes compared to pair‐fed control rats; PPC supplementation decreased the alcohol‐induced apoptosis to less than half. No difference in the incidence of apoptosis between the control and PPC‐supplemented rats was found in the absence of alcohol. Apoptosis was distributed randomly in the liver lobules of the rats fed the control diet, whereas the alcohol‐induced apoptosis was significantly increased in the perivenular area. PPC supplementation strikingly reduced this effect.

Conclusions:

PPC attenuates alcohol‐induced apoptosis of hepatocytes; this effect may provide a mechanism for PPC's protection against liver injury, possibly in association with its antioxidative action via the down‐regulation of ethanol‐mediated CYP2E1 induction.
Acute Effects of Ethanol on Kainate Receptors in Cultured Hippocampal Neurons
Authors: Costa Edmar T. , Soto Eli E. , Cardoso Rita A. , Olivera Dorian S. , Valenzuela C. Fernando
Published: May 2006

Background:

Kainate receptors are a subclass of ionotropic glutamate receptors that regulate excitability and mediate synaptic transmission and plasticity in the hippocampus. The acute effects of ethanol on these receptors are not completely understood.

Methods:

The acute effects of ethanol on pharmacologically isolated kainate receptor‐mediated currents were studied in cultured hippocampal neurons obtained from neonatal rats. Whole‐cell patch‐clamp electrophysiological techniques were used for these studies. LY303070 (GYKI‐53784), a potent AMPA (α‐amino‐3‐hydroxy‐5‐methylisoxazole‐4‐propionic acid) receptor‐selective noncompetitive antagonist, was used to isolate kainate currents.

Results:

Kainate receptor‐mediated currents corresponded to 7% of the total non‐N‐methyl‐d‐aspartate (non‐NMDA) currents in these neurons and were reduced to 24% of control values in the presence of 15 μM lanthanum. These kainate receptor‐mediated currents were significantly inhibited by ethanol concentrations of 50 mM or more. Under our recording conditions, ethanol inhibited non‐NMDA receptor‐ and NMDA receptor‐mediated currents to a similar extent as kainate receptor‐mediated currents. Western blot analysis indicated that glutamate receptor‐5 and ‐6/7 subunits, and kainic acid‐2 subunits are expressed in these cultured hippocampal neurons.

Conclusions:

The present results suggest that kainate receptors are important targets for the actions of ethanol in the central nervous system.
Pronounced Hepatic Free Radical Formation Precedes Pathological Liver Injury in Ethanol‐Fed Rats
Authors: Reinke Lester A. , Moore Danny R. , Nanji Amin A.
Published: May 2006

Background: The role of free radicals in alcoholic liver injury remains uncertain. These experiments were conducted to measure radical formation in rats that were fed alcohol along with either fish oil or saturated fats, which cause different types of liver pathology.

Methods: Liquid diets containing alcohol or isocaloric dextrose were administered to rats by intragastric infusion for 2 weeks. Radical intermediates detected by spin trapping were measured in bile.

Results: In rats that were fed alcohol plus fish oil, biliary concentrations of trapped radicals, which most likely originated from lipids, were 6‐fold higher than in controls that were fed fish oil plus dextrose. High rates of radical formation persisted 24 hr after alcohol withdrawal, when all alcohol had been metabolized. In contrast, diets containing alcohol and medium chain triglycerides did not stimulate lipid radical formation.

Conclusions: High rates of lipid radical formation were observed only in rats that were fed alcohol in combination with a fish oil diet, and a persistent flux of radical formation continued after alcohol with‐ drawal. These radical phenomena precede serious liver pathology, which develops after longer periods of fish oil plus alcohol diets.
Association Study Between Genetic Polymorphisms in the 14–3‐3 η Chain and Dopamine D4 Receptor Genes and Alcoholism
Authors: Ishiguro H. , Saito T. , Shibuya H. , Arinami T.
Published: May 2006

Background:The dopaminergic system may be involved in the development of alcoholism. As part of our ongoing studies on the association between alcoholism and dopaminergic genes, we report herein a mutation analysis of the 14–3‐3 η chain gene (YWHAH) and an association study between alcoholism and theYWHAHand dopamine D4 receptor gene (DRD4) polymorphisms.

Methods:Nucleotide mutations were investigated using single‐strand conformation polymorphism methods. Associations were analyzed using a case‐control design involving 185 Japanese alcoholics and 286 Japanese controls.

Results:Five polymorphisms, ‐147G>A, ‐134(GCCTGCA)2–4, IVS1+31(G)7–8. IVS1+73–74ins(G), and 753A>G, were detected on theYWHAH, and three of them were novel. No significant associations were found between alcoholism and these polymorphisms or two additional polymorphisms onDRD4exon III andDRD4‐521C/T.

Conclusions:YWHAHandDRD4do not appear to play a major role in the development of alcoholism.
Ethanol Improves Decreased Filterability of Human Red Blood Cells Through Modulation of Intracellular Signaling Pathways
Authors: Oonishi Tadahiro , Sakashita Kanako
Published: May 2006

Background: Deformability of red blood cells (RBCs) is one of the most important factors in maintaining the microcirculation system. In vitro studies have revealed that ethanol seriously impairs the deformability of RBCs at concentrations far higher than those easily achievable in the blood after alcohol consumption. We examined the effect of ethanol on deformability at the physiologically achievable concentrations.

Methods: To impair deformability quantitatively, washed RBCs from healthy young male volunteers were mechanically stressed by being injected rapidly through a fine needle. The deformability of RBCs was evaluated by measuring the filterability through a nickel mesh filter. The activities of protein kinase A and protein kinase C in RBCs were measured by the ELISA method using an antibody for the phosphorylated substrate of the kinases.

Results: Ethanol exhibited a biphasic effect on the mechanically impaired filterability of human RBCs, that is, an improvement at concentrations from 0.02% to 0.2% (v/v) and a marked deterioration at 0.5% and higher. Without mechanical stress, ethanol decreased filterability at concentrations of 0.5% and higher. Ethanol increased the protein kinase A and protein kinase C activities of the mechanically stressed RBCs at concentrations of 0.02% and higher and those of the RBCs without mechanical stress at concentrations of 0.05% and higher.

Conclusions: The present results suggest a beneficial effect of ethanol on blood rheology at concentrations that are physiologically achievable in the blood and indicate the importance of intracellular signaling pathways in regulating the deformability of RBCs.
Prospective Study on Alcohol Intake and Risk of Subarachnoid Hemorrhage Among Japanese Men and Women
Authors: Sankai Tomoko , Iso Hiroyasu , Shimamoto Takashi , Kitamura Akihiko , Naito Yoshihiko , Sato Shinichi , Okamura Tomonori , Imano Hironori , Lida Minoru , Komachi Yoshio
Published: May 2006

Background: Few prospective data are available to evaluate potential risk factors of subarachnoid hemorrhage among the Japanese, although several prospective studies conducted in the United States and in Europe have shown a positive relationship between alcohol intake and the risk of subarachnoid hemorrhage.

Methods: A 9.4 year follow‐up study was conducted on 12,372 men and women age 40 to 69 years who had no history of stroke, in six communities in Japan. The incident cases of subarachnoid hemorrhage were confirmed with computed tomography findings and/or clinical findings. Alcohol intake and other cerebro‐vascular risk factors were measured at the baseline examination. A Cox proportional hazard analysis was used to estimate the relative risks and 95% confidence intervals of the incidence of subarachnoid hemorrhage.

Results: During the follow‐up assessment, 71 cases of subarachnoid hemorrhages occurred. For men, heavy drinking appeared to be an independent risk factor for subarachnoid hemorrhage; multivariate‐adjusted relative risk was 4.3 (95% confidence interval [CI]: 1.1–16.8; p= 0.04). Among women, no excess risk was found for heavy drinking, probably due to the small number of heavy drinkers (n= 15). The combination of heavy drinking with smoking or hypertension increased the risk of subarachnoid hemorrhage substantially for men; the multivariate‐adjusted relative risk was 6.0 (95% CI: 1.8–20.1; p= 0.004) for heavy drinking smokers and 13.0 (95% CI: 3.9–43.9; p < 0.001) for heavy drinking hypertensives.

Conclusions: A reduction in alcohol intake, smoking cessation, and control of hypertension are important in preventing subarachnoid hemorrhage among Japanese men.
Alcoholism Susceptibility Loci: Confirmation Studies in a Replicate Sample and Further Mapping
Authors: Foroud Tatiana , Edenberg Howard J. , Goate Alison , Rice John , Flury Leah , Koller Daniel L. , Bierut Laura J. , Conneally P. Michael , Nurnberger John I. , Bucholz Kathleen K. , Li Ting‐Kai , Hesselbrock Victor , Crowe Raymond , Schuckit Marc , Porjesz Bernice , Begleiter Henri , Reich Theodore
Published: May 2006

Background: There is substantial evidence for a significant genetic component to the risk for alcoholism. A previous study reported linkage to chromosomes 1, 2, and 7 in a large data set that consisted of 105 families, each with at least three alcoholic members.

Methods: Additional, genotyping in the 105 families has been completed in the chromosomal regions identified in the initial analyses, and a replication sample of 157 alcoholic families ascertained under identical criteria has been genotyped. Two hierarchical definitions of alcoholism were employed in the linkage analyses: (1) Individuals who met both Feighner and DSM‐III‐R criteria for alcohol dependence represented a broad definition of disease; and (2) individuals who met ICD‐10 criteria for alcoholism were considered affected under a more severe definition of disease.

Results: Genetic analyses of affected sibling pairs supported linkage to chromosome 1 (LOD = 1.6) in the replication data set as well as in a combined analysis of the two samples (LOD = 2.6). Evidence of linkage to chromosome 7 increased in the combined data (LOD = 2.9). The LOD score on chromosome 2 in the initial data set increased after genotyping of additional markers; however, combined analyses of the two data sets resulted in overall lower LOD scores (LOD = 1.8) on chromosome 2. A new finding of linkage to chromosome 3 was identified in the replication data set (LOD = 3.4).

Conclusions: Analyses of a second large sample of alcoholic families provided further evidence of genetic susceptibility loci on chromosomes 1 and 7. Genetic analyses also have identified susceptibility loci on chromosomes 2 and 3 that may act only in one of the two data sets.
Contribution of Gastric Oxidation to Ethanol First Pass Metabolism in Baboons
Authors: Baraona Enrique , Abittan Chaim S. , Lieber Charles S.
Published: May 2006

Background: A portion of ingested alcohol does not reach the systemic blood, undergoing a first‐pass metabolism (FPM) during gastric and hepatic circulation.

Methods: To determine whether the stomach can metabolize sufficient ethanol to account for the FPM, and to what extent gastric alcohol dehydrogenase (ADH) activity is responsible, the hepatic vein, the portal vein, and the aorta were cannulated nonocclusively in baboons to measure the conversion of ethanol to acetate in vivo. 14C‐ethanol (300 mg/kg as a 15% solution) was given intragastrically (IG) whereas 3Hacetate was continuously infused intravenously (IV).14C‐acetate was measured after exhaustive evaporation of ethanol. Simultaneous sampling of hepaticvenous, portal and arterial blood was carried out for 3 hr, at the end of which the same alcohol dose was given IV to calculate the Michaelis‐Menten parameters of elimination.

Results: Analysis of the IV and IG ethanol curves revealed a FPM of 94 ± 11 mg/kg (31% of dose). The portal‐arterial differences were negative for 3H‐acetate (indicating net extraction) and positive for 14Cethanol and 14C‐acetate (indicating net output). Portal acetate production (extraction plus net output multiplied by the portal plasma flow) increased with time and accounted, over the first 3 hr (82 ± 13 mg/kg), for 87% of the FPM. Alcohol oxidation by gastric ADH activity (28.7 ± 7.2 mg/kg) accounted for only 31% of the FPM.

Conclusions: The in vivo oxidation of ethanol to acetate in the upper digestive tract accounts for the FPM of ethanol and is mediated, at least in part, by ADH activity.