bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of Alcohol Drinking on Gene Expression of Hepatic O6‐Methylguanine DNA Methyltransferase in Chronic Liver Diseases
Authors: Miyakawa Happei , Liu Jian , Noguchi Osamu , Marumo Fumiaki , Sato Chifumi
Published: April 2006

O6‐methylguanine DNA methyltransferase (MGMT) is a repair protein that transfers methyl groups from O6‐methylguanine to a cysteine acceptor in its own molecule, and restores DNA to its undamaged state. If left unrepaired, O6‐methylguanine can pair with either a thymine or a cytosine, causing a C‐G to T‐A transition, which is considered to be one of the molecular mechanisms of both mutagenesis and carcinogenesis. The expression of MGMT mRNA in liver tissue was quantitatively assessed by the competitive reverse transcrip‐tion‐polymerase chain reaction method in patients with chronic liver diseases with or without alcohol drinking. MGMT mRNA expression was 1.4 ± 0.9 pg/μg RNA in control livers. Its expression in chronic hepatitis was 3.8 ± 0.7 in alcoholics and 2.7 ± 0.8 in nonalcoholics, which were not statistically different. MGMT mRNA expression in liver cirrhosis was significantly low, compared with that in chronic hepatitis, and 0.8 ± 0.3 in alcoholics and 0.5 ± 0.1 in nonalcoholics, which also were not significantly different. The present study shows that MGMT mRNA was not decreased in patients with chronic liver diseases with alcohol drinking, compared with those without alcohol drinking.
Alteration of Glutamyltranspeptidase Binding Proteins in Postmortem Brains of Heroin Addicts
Authors: Hashimoto Eri , Frölich Lutz , Ozawa Hiroki , Saito Toshikazu , Shichinohe Shin , Takahata Naohiko , Riederer Peter
Published: April 2006

Glutamyltranspeptidase binding (G) proteins play an important role in intracellular signal transduction downstream from many receptors, including opioid receptors. Moreover, it was recently reported that the β‐subunits of G proteins, in addition to the α‐subunits, regulate effector pathways. In this study, membrane G protein immunoreactivity was estimated by Western blotting with polyclonal antibodies (RM/1, AS/7, GC/2, QL, and SW/1) against specific G proteins (Gαs, Gαi‐1,2, Gαo, Gαq, and Gβ, respectively) in postmortem temporal cortex obtained from 6 heroin addicts and 6 control subjects without a history of drug abuse. Immunoreactivities of the Gβ‐subunit increased significantly (p < 0.05) in heroin addicts, compared with controls, and that of Gαi‐1,2 tended to increase in heroin addicts. Present findings suggest that the alterations in G protein‐mediated signal transduction may be involved in the mechanism of opiate addiction.
Role of Kupffer Cell‐Derived Reactive Oxygen Intermediates in Alcoholic Liver Disease in Rats In Vivo
Authors: Takeyama Yasuaki , Kamimura Seiichiro , Kuroiwa Ataru , Sohda Tetsuro , Irie Makoto , Shijo Hiroshi , Okumura Makoto
Published: April 2006

The pathophysiology of alcoholic liver disease (ALD) remains largely unknown. In this work, we have developed an experimental rat model to elucidate the mechanism of liver injury, including ALD, in which Kupffer cell‐derived reactive oxygen intermediates (ROIs) might be involved. Groups of male Wistar rats were pair‐fed on a liquid high‐fat diet containing ethanol (36% of total calories) or isocaloric carbohydrate with or without dietary carbonyl iron (0.5% w/v) for 3 weeks. In this rat model, we investigated Kupffer cell‐derived ROI generation, which affected hepatocellular injury and hepatic fibrosis in ALD. The production of ROIs in Kupffer cells isolated from the iron‐fed, the ethanol‐fed, and the ethanol plus iron‐fed rats were significantly increased, compared with that in Kupffer cells isolated from control rats (iron > ethanol + iron > ethanol ≫ control). However, hepatic vitamin E content in the ethanol plus iron‐fed rats was decreased rather than that in the iron‐fed rats. Then, lipid peroxidation of isolated microsomes was assessed as malondialdehyde equivalents determined by thiobarbituric acid assay. Compared with controls, the malondialdehyde equivalents were elevated in experimental groups (ethanol + iron > ethanol > iron > control). Serum ALT levels were greatly elevated in rats fed a diet containing both ethanol and iron (ethanol + iron > iron > ethanol > control). Hepatic content of hydroxyproline was significantly increased in ethanol plus iron‐fed rats, compared with rats other than the ethanol plus iron‐fed group (ethanol + iron > iron > ethanol > control). These results suggested that the enhanced Kupffer cell‐derived ROI generation could itself contribute to the increased susceptibility to lipid peroxidation, which might cause hepatocellular injury and lead to hepatic fibrosis in ALD.
Chronic Ethanol Consumption Enhances Endotoxin Induced Hepatic Sinusoidal Leukocyte Adhesion
Authors: Ohki E. , Kato S. , Horie Y. , Mizukami T. , Tamai H. , Yokoyama H. , Ito D. , Fukuda M. , Suzuki H. , Kurose I. , Ishii H.
Published: April 2006

In alcoholic liver disease, endotoxin has been postulated to play an important role in its pathogenesis. Endotoxin is known to lead to impediment of hepatic microcirculation, including the adhesion of leukocytes to sinusoidal endothelial cells. In this study, the effect of chronic ethanol consumption on the leukocyte adhesion elicited by endotoxin was examined. Male Wistar rats were pair‐fed with a liquid diet containing ethanol or an isocaloric control diet for 6 weeks. The liver of anesthetized rats were placed on the nonfluorescent cover‐glass for observation by an intravital inverted microscope equipped with a silicon intensified target camera. The red blood cell (RBC) velocity in hepatic sinusoids was measured by an off‐line temporal correlation velocimeter (Capiflow, Sweden) after intravenous injection of fluorescein isothiocyanate‐labeled rat RBC. RBC velocity in sinusoids was more severely disturbed in ethanol fed rats than in controls. Leukocytes were stained by the intravenous injection of carboxyfluorescein succinimidyl ester for a fluorographic observation of leukocyte adhesion. After lipopolysaccharide injection, the number of adherent leukocytes was significantly greater in ethanol‐fed rats than in controls. Plasma tumor necrosis factor‐α levels were also higher in ethanol‐fed rats than in controls. These results suggest that chronic ethanol consumption aggravates endotoxin induced leukocytes adhesion that may result in hepatic microcirculatory disturbances. Leukocyte adhesion to the sinusoidal wall may be associated with increased in tumor necrosis factor‐α levels.
Protective Mechanism of High‐Density Lipoprotein against Endotoxemia in Chronic Alcohol Ingestion
Authors: Kitano Hiroyuki , Fukui Hiroshi , Okamoto Yasuyuki , Kikuchi Eiryou , Matsumoto Masami , Kikukawa Masaji , Morimura Masafumi , Tsujita Sigenobu , Nagamoto Issei , Hoppo Kazushige , Nakatani Yoshihiro , Nakatani Toshiya , Tsuji Tadasu
Published: April 2006

In the present study, we evaluated the role of high‐density lipoprotein (HDL) as an endotoxin‐binding protein in chronically alcohol‐fed rats. Although the blood endotoxin level was significantly elevated in chronic ethanol‐loaded rats, compared with control rats, serum tumor necrosis factor (TNF), ALT, and lactate dehydrogenase were not elevated. Serum HDL and its endotoxin‐binding capacity were significantly increased in chronic ethanol‐loaded rats. When Kupffer cells isolated from control and chronic ethanol‐loaded rats were cultured in the medium containing 3 to 30 mg/dl HDL and endotoxin (500 ng/ml), endotoxin uptake and TNF production of Kupffer cells were decreased in proportion to the concentration of HDL in the medium. These results suggest that the increase in endetoxin‐binding capacity of HDL may serve as a protective mechanism against endotoxin in chronic ethanol‐loaded rats.
Effect of Chronic Alcohol Intake on Energy Metabolism in Human Muscle
Authors: Yazaki Koji , Haida Munetaka , Kurita Daisaku , Shinohara Yukito
Published: April 2006

We investigated the effect of alcohol on muscle energy metabolism by using 31P magnetic resonance spectroscopy in 12 chronic alcoholics [6 with neurological signs and symptoms (such as cerebellar ataxia or diplopia) and 6 without neurological signs or symptoms], compared with five healthy subjects who also received acute alcohol loading. Intracellular pH and phosphocreatine (PCr) index [PCr/ (PCr + Pi)] were measured during rest, exercise, and recovery in the left flexor digitorum superficialis muscle. In healthy subjects, acute alcohol loading did not influence the changes of muscle pH and PCr index. Alcoholics with neurological signs showed marked decreases in muscle intracellular pH and PCr index during exercise and a marked delay of pH recovery after exercise. There was no delay of PCr index recovery. Alcoholics without neurological signs showed slight decreases in intracellular pH and PCr index, but rapid recovery of both intracellular pH and PCr index was observed. Marked decrease and delayed recovery in pH, but rapid recovery of PCr index, indicate that the muscle of patients with neurological signs produced lactate during and after exercise to maintain the ATP level, which implies that anaerobic metabolism is favored over aerobic metabolism in these patients.
Influence of Nicotine on Myocardial Stiffness and Fibrosis During Chronic Ethanol Use
Authors: Rajiyah G. , Agarwal R. , Avendano G. , Lyons M. , Soni B. , Regan T. J.
Published: April 2006

Cardiomyopathy related to ethanol abuse is often accompanied by cigarette use. To examine if the major cardioactive component may intensify the abnormal function and composition induced by chronic ethanol, nicotine was administered orally, 2.5 mg bid, to a canine model receiving 36% of calories as ethanol for 6 months (group III). These animals were compared with group II receiving ethanol alone, group IV on nicotine alone, and controls (group I). In the intact, ventilated, anesthetized dog, left ventricular pressures and volumes were measured before and after dextran infusion and related to left ventricular collagen alterations. Basal heart rate, aortic pressure, and ejection fraction were comparable with controls. End‐diastolic pressure and diastolic chamber stiffness (KPV) were significantly higher in the basal state and during dextran infusion in the three experimental groups, compared with group I. The increment was largest in the ethanol‐nicotine group. Analysis of left ventricular myocardium revealed a rise of collagen concentrations in all three experimental groups, with an interstitial distribution on histochemical examination. Moreover, determination of advanced glycosylation endproducts, as a measure of alterations in collagen cross‐links, revealed higher concentrations versus controls. The greater increase of diastolic stiffness in the nicotine‐ethanol group occurred despite a similar concentration of fluorescent products as group II. Because the former had a larger increase of collagen concentration, total cross‐linked collagen content was presumably greater after the combined use of nicotine‐ethanol. Thus, nicotine in relatively high dose when combined with ethanol, elicited a modest further increase in the left ventricular chamber stiffness and collagen concentration.
Thyrotropin‐Releasing Hormone Analog TA‐0910 Reduces Voluntary Alcohol Intake of P Rats Subchronically in a Limited Scheduled Access Paradigm
Authors: Mason George A. , Rezvani Amir H. , Overstreet David H. , Garbutt James C.
Published: April 2006

We previously reported that single intraperitoneal injections of the thyrotropin‐releasing hormone analog TA‐0910 dose‐dependently reduce alcohol intake in alcohol‐preferring (P) rats in a free‐choice continuous access protocol. We later showed, using the same protocol, that a transient tolerance develops to this effect after several consecutive, once‐daily injections. In the present study, P rats that had been accustomed to continuous access to alcohol were acclimated to a limited scheduled access protocol in which alcohol was available only between 10 and 11 AM. This resulted in an elevated rate of alcohol intake. Rats were then injected once daily with TA‐0910 (0.75 mg/kg) or an equal volume of a saline vehicle at 9:45 AM for 12 consecutive days. After 11 days of scheduled access, rats were allowed continuous access to alcohol. Intake of alcohol and water was measured each day at 11:00 AM. Compared with vehicle, TA‐0910 reduced alcohol intake on the 11 days of scheduled access and during the first hour of day 12 when continuous access was restored, but did not reduce total (24 hr) alcohol intake on day 12. Data from this experiment show that TA‐0910 reduces alcohol intake over a long period of time in a limited scheduled access protocol.
c‐Fos Induction in Rat Brainstem in Response to Ethanol‐ and Lithium Chloride‐Induced Conditioned Taste Aversions
Authors: Thiele Todd E. , Roitman Mitchell F. , Bernstein Llene L.
Published: April 2006

When consumption of a novel taste (conditioned stimulus; CS) is followed by exposure to a toxin, organisms will avoid consumption of that taste in the future. This learned response, known as a conditioned taste aversion (CTA), can be demonstrated using a variety of drugs, including lithium chloride (LiCl) and ethanol. c‐Fos immunohistochemistry was used to examine neural activation in the rat brainstem associated with drug administration and with a CS taste previously paired with these drugs. Relative to saline controls, animals injected with either LiCl (76 mg/kg) or ethanol (3.5 g/kg) displayed greater c‐Fos expression in area postrema, nucleus of the solitary tract (NTS), and lateral parabrachial nucleus. At these doses, LiCl‐ and ethanol‐injected groups did not differ from each other. For establishing a CTA, intraoral infusion of a 0.15% saccharin solution was followed by injection of either LiCl or ethanol. Both LiCl and ethanol produced quantitatively similar CTAs. Relative to unpaired control groups, saccharin paired with either drug induced significant c‐Fos expression in NTS. Thus, like LiCl, ethanol and tastes that have become aversive by virtue of their association with ethanol activate brainstem regions hypothesized to play a role in CTA learning.
Cytochromes P4502E1 and P4501A1 Genotypes and Susceptibility to Cirrhosis or Upper Aerodigestive Tract Cancer in Alcoholic Caucasians
Authors: Lucas D. , Ménez C. , Floch F. , Gourlaouen Y. , Sparfel O. , Joannet I. , Bodénez P. , Jezequel J. , Gouérou H. , Berthou F. , Bardou L.‐G. , Ménez J.‐F.
Published: April 2006

Genetic polymorphisms of various cytochromes P450 have recently been described and could be implicated in the individual susceptibility of alcoholics to ethanol‐related diseases. Rsal and Dral polymorphisms of CYP2E1 and Mspl polymorphism of CYP1A1 were studied in 260 controls and 511 alcoholic patients, without any clinical symptoms (n= 202) or with various ethanol‐related diseases (n= 309), such as liver cirrhosis (n= 110), esophageal cancer (n= 62), upper aerodigestive tract cancer (n= 96), and other miscellaneous diseases (n= 41). Frequencies of the mutated alleles were found to be 2.5% (Rsal), 7.9% (Dral), and 8.7% (Mspl) in controls; 4%, 14.1%, and 12% in alcoholics without clinical symptoms; and 3.1%, 12.5%, and 11.2% in alcoholics with ethanol‐related diseases. The only significant difference was found in the Dral polymorphism, whose frequency was enhanced in alcoholics with (p < 0.05) or without ethanol‐related diseases (p < 0.01) when compared with controls. No differences were found between alcoholics without clinical symptoms and alcoholics with cirrhosis, esophageal cancer, or upper aerodigestive tract cancer. However, in liver cirrhosis and in ethanol‐related cancers, the rare Dral‐C allele was three times less frequent in patients under the age of 45 than in older patients, suggesting a protective role for this allele. In conclusion, our data indicate that the aforementioned mutations do not play a critical role in the development of cirrhosis, esophageal cancer, or upper aerodigestive tract cancers in Caucasians.
Sex Differences in Alcohol Preference and Drinking Patterns Emerge during the Early Postpubertal Period in Sprague‐Dawley Rats
Authors: Lancaster Francine E. , Brown Tamara D. , Coker Kimberly L. , Elliott Judi A. , Wren Samuel B.
Published: April 2006

Young male and female Sprague‐Dawley rats (30 days old) were assigned randomly to three treatment groups: (1) alcohol treatment—received beer with 5% ethanol added, food, and water ad libitum; (2) pair‐fed treatment—received nonalcoholic beer plus sucrose and food to match intake by the alcohol‐treated animals; and (3) control treatment—received food and water ad libitum. Animals were tested for alcohol preference for 24 hr and then received their assigned treatments for a period of 30 days, followed by a period of abstinence before alcohol preference testing again at 74 days of age. Males given free access to beer and water did not drink large quantities of beer. Females given free access to beer and water drank a lot of beer on the first day, but decreased intake until ˜52 days of age. A developmental change in young female rats at ˜52 days of age resulted in increased voluntary ethanol intake, possibly caused by hormonal changes associated with the establishment of estrous cycles. When the animals were tested for alcohol preference at 74 days of age after a period of abstinence, males and females in the pair‐fed group had greater alcohol preference than animals in the other groups. Females in the pair‐fed group had greater alcohol intake based on body weight than males in the pair‐fed group and males and females in all other groups. These results provide insight into sex differences in the development of voluntary drinking behavior and responses of drinking behavior to the early stress of pair‐feeding.
Nitric Oxide and Liver Injury in Alcohol‐Fed Rats after Lipopolysaccharide Administration
Authors: Chamulitrat Walee , Spitzer John J.
Published: April 2006

Earlier studies showed that alcohol‐fed animals were more susceptible than controls to injurious effects of endotoxin. Increased super‐oxide radical production by hepatocyte organelles, Kupffer cells, and neutrophils from alcohol‐fed animals has been well documented. In this study, electron paramagnetic resonance spectroscopy was used to detect nitrosyl protein complexes indicating nitric oxide (˙NO) production. We showed that the concentrations of nitrosyl complexes in whole blood and in liver tissues of alcohol‐fed rats treated with lipopolysaccharide (alc+LPS), increased 3‐fold, compared with those from rats on control diet treated with LPS (con+LPS). Electron paramagnetic resonance spectra of whole blood and liver tissues from the alc+LPS‐treated group exhibited features characteristic of hemoglobin nitrosyl complexes. Plasma levels of the hepatic ASTs and ALTs from the alc+LPS‐treated group were increased 2‐ to 3‐fold, compared with those from the con+LPS‐treated group. Inhibition of ˙NO production by aminoguanidine treatment attenuated plasma hepatic enzyme levels in the alc+LPS‐treated group. Thus, under the conditions of elevated inflammatory oxidative states caused by chronic alcohol feeding, endotoxin treatment enhanced liver injury as a result of the actions of ˙NO, and/or the cytotoxic species derived from ˙NO.
Free Radicals and Ethanol‐Induced Cytotoxicity in Neural Crest Cells
Authors: Chen Shao‐yu , Sulik Kathleen K.
Published: April 2006

Associations between ethanol‐induced cranial neural crest cell (NCC) damage in mammalian embryos and subsequent malformations as observed in human fetal alcohol syndrome have previously been illustrated. The vulnerability of NCCs to this teratogen may result, at least in part, from their sensitivity to free radical damage. To examine relationships between free radical generation and NCC cytotoxicity, primary culture of mouse NCCs was used. NCC viability was determined in both dose‐ and time‐response studies involving ethanol exposure. After 48 hr of culture, cell viability was significantly diminished at all doses tested (i.e., 50,100,150, and 200 mM ethanol). At 100 mM ethanol (a dosage that is teratogenic in vivo and in whole embryo culture), cell viability decreased to ˜50% of control values over the first 12 hr of culture, and decreased further, to ˜20% by 48 hr. Using nitroblue tetrazolium as a probe, it was observed that exposure of NCCs to ethanol stimulated the production of superoxide anion radicals. Co‐treatment of the ethanol‐exposed NCCs with free radical scavengers including 300 units/ml of superoxide dismutase, catalase (500 units/ml), or œ‐tocopherol (300 μM) significantly improved NCC viability. These results suggest that the ethanol‐induced NCC injury is mediated, at least in part, through the generation of free radicals. To test this hypothesis further, NCCs were exposed in culture to xanthine/xanthine oxidase. Exogenous free radicals generated by the xanthine/xanthine oxidase system resulted in reduced NCC viability, the severity of which Increased in a time and enzyme concentration‐related manner. Superoxide dismutase (300 units/ml) and catalase (500 units/ml) significantly reduced the effects of the xanthine/xanthine oxidase‐generated free radicals on NCC viability. The similarity between the susceptibility of NCCs to ethanol and their susceptibility to exogenous free radicals in concert with the free radical scavenger‐mediated amelioration of ethanol and exogenous free radical‐induced NCC death strongly suggest that free radicals play a significant role in ethanol‐induced NCC death.
Polydrug Use in Adolescent Drinkers with and without DSM‐IV Alcohol Abuse and Dependence
Authors: Martin Christopher S. , Kaczynski Nancy A. , Maisto Stephen A. , Tarter Ralph E.
Published: April 2006

Alcohol and other substance use disorders are highly comorbid, but little is known about patterns of polydrug use in adolescents with different levels of alcohol involvement. This research examined patterns and correlates of polydrug use in 176 adolescent drinkers with DSM‐IV alcohol dependence (n= 61), alcohol abuse (n= 57), and no alcohol diagnosis (n= 58). Alcohol and other Substance Use Disorders were assessed using a modified version of the Structured Clinical Interview for the DSM. Lifetime histories of alcohol use and other drug use were assessed using a structured interview. Subjects also completed a questionnaire measure of the frequency of use of specific alcohol‐drug combinations. The total number of illicit drugs ever used was greater in the alcohol dependence (mean = 3.8, SD = 2.1) and abuse groups (mean = 3.0, SD = 2.1), compared with the no‐alcohol diagnosis group (mean = 1.9, SD = 1.3). Consistent with previous findings, there was a consistent pattern in the age of onset of psychoactive substance use: alcohol, followed by marijuana, followed by other drugs. The recent use of alcohol and other drugs in combination was reported by a greater percentage of subjects in the alcohol dependence (69%) and abuse groups (72%), compared with drinkers without an alcohol diagnosis (45%). The most common alcohol‐drug combination was alcohol with marijuana (58% of the total sample), followed by alcohol‐hallucinogens (16%). The frequency and extent of polydrug use was associated with being older and having higher levels of behavioral undercontrol and negative emotionality. Adolescent polydrug use, particularly the use of alcohol and other drugs in combination, is an important area for research, treatment, and prevention.
Evaluating Three Reading Tests for Use with Alcohol and Other Drug‐Abusing Populations
Authors: Johnson Mark E. , Fisher Dennis G.
Published: April 2006

This study compared three reading tests commonly used in research for screening, descriptive, and educational purposes with alcohol and other drug‐abusing individuals. To that end, 82 male and 41 female substance abusers were administered the Slosson Oral Reading Test‐Revised, Woodcock Reading Mastery Test‐Revised, and the Wide Range Achievement Test‐Revised in random order. Results revealed that the tests have high concurrent validity, provide approximately the same grade‐equivalent level scores, and yield raw scores that, when standardized, do not differ significantly from one another. However, if used for screening purposes, the three tests result in different proportions of subjects meeting specified criteria, particularly at lower grade levels. Specific test selection depends on the purpose of testing. For example, when the entire range of possible scores is of interest, the Woodcock Reading Mastery Test‐Revised has a distinct advantage, because it has the widest range of grade‐equivalent levels. Other considerations for test selection are discussed.
Drinking Patterns and Problems and Drinking in the Event: An Analysis of Injury by Cause Among Casualty Patients
Authors: Cherpitel Cheryl J.
Published: April 2006

The association of alcohol and injury might be expected to vary by the specific cause of injury, but few studies have examined such associations across all causes of injury coming from the same population, largely because of the lack of a sufficient number of cases. This study examines the association of drinking patterns and problems and drinking‐in‐the‐injury‐event for six mutually exclusive causes of injury (falls, penetrating trauma, motor vehicle accidents, fires, violence, and other causes) in a merged sample of 3109 patients from four emergency room/trauma center studies that used identical study methodology. The predictive value of drinking and demographic variables are examined separately for each cause of injury, and variables predictive of reporting drinking before the event, feeling drunk at the time of injury, and attributing a causal association of drinking and the injury. Injuries sustained from violence and falls had the greatest association with drinking variables, with those with positive breathalyzer readings, and those who reported drinking before injury, frequent heavy drinking, and frequent drunkenness overrepresented in these two causes. Those who reported a larger number of drinks consumed before injury and those who reported feeling drunk at the time were also overrepresented among those with injuries related to violence and falls. A larger proportion than expected of those who attributed a causal association of drinking with the event sustained injuries related to violence, whereas a smaller proportion sustained injuries from falls. Demographic characteristics were more predictive than drinking characteristics of each cause of injury, whereas drinking characteristics, particularly positive breathalyzer readings, were more predictive of drinking before specific causes of injury. These data provide information that may be useful in developing brief interventions for the prevention of alcohol‐related injuries in the emergency room or trauma center setting.
Thiamine Status in Liver and Brain of Rats Genetically Selected for Different Sensitivity to Hypnotic Effect of Alcohol
Authors: Zimatkina Tamara I. , Chernikevich Ivan P. , Zimatkin Sergey M. , Deitrich Richard A.
Published: April 2006

Background: The mechanisms of the different sensitivity or resistance of animals and humans to alcohol are still not completely understood. For further biochemical characterization of animals genetically selected for high‐alcohol sensitivity (HAS) and low‐alcohol sensitivity (LAS) with the hypnotic effect of alcohol, the thiamine status and thiamine metabolizing enzymes in these animals have been studied.

Methods: We investigated thiamine diphosphate and thiamine triphosphate levels as well as the activity of thiamine‐dependent enzyme, transketolase, and thiamine‐metabolizing enzymes, thiamine kinase, and thiamine triphosphatase in the liver and brain of HAS, LAS, and CAS (control) rats by standard biochemical techniques.

Results: It was found that the activity of transketolase, and the level of the coenzyme form of thiamine, thiamine diphosphate (TDP), were significantly lower in HAS versus LAS rats. The activation of transketolase by the exogenous TDP (TDP‐effect) was significantly higher in the liver and brain regions of HAS rats compared with LAS rats. The level of TDP in the liver and cerebellum of HAS rats was significantly lower compared with LAS rats. These results indicate a severe deficiency of TDP in HAS rats. HAS rats have a significantly lower activity of thiamine triphosphatase, the additional source of TDP. Accordingly, HAS rats have much higher thiamine triphosphate levels in the liver and brain, compared with LAS rats. There were no significant differences between groups with respect to the thiamine diphosphatase and thiamine kinase activity. Most of the above parameters had the intermediate values in CAS rats, compared with LAS and HAS rats. These data indicate the possible role of the thiamine phosphate esters and related enzymes in the mechanisms that bring about the differential sensitivity to the hypnotic effect of alcohol.

Conclusions: HAS rats have the genetically mediated thiamine diphosphate deficiency and increased thiamine triphosphate levels, probably due to reduced activity of thiamine triphosphatase in the liver and brain, compared with LAS rats. It can be related with the higher initial sensitivity of HAS rats to hypnotic effect of ethanol.
Do Risk Factors for Re‐Arrest Differ for Female and Male Drunk‐Driving Offenders?
Authors: Lapham Sandra C. , Skipper Betty J. , Hunt William C. , Chang Iyiin
Published: April 2006

Background: The present study investigated gender differences in factors affecting recidivism among 628 female and 659 male drunk‐driving offenders. The study population included residents from New Mexico who completed a screening program for offenders and who were still residents when contacted 5 years later.

Method: Risk factors for re‐arrest in the 5‐year period after screening referral were examined using multiple logistic regression models. Predictor variables included gender, age, ethnicity, education, marital status, blood alcohol concentration at arrest, parental alcohol problems, spousal alcohol problems, lifetime use of cannabis, cocaine, or amphetamines, abusive behavior toward spouse, and scores on two standardized assessments.

Results: Risk factors for re‐arrest were similar for males and females except that young age predicted higher recidivism among males but not females. The overall 5‐year re‐arrest rate was 26%–20% for women, 38% for males age 30 and under, and 24% for males age 31 and older.

Conclusions: Young age predicts re‐arrest for males but not for females. Neither the type of risk factors nor the number of risk factors fully explained female offenders’ disproportionately lower recidivism rates, compared with young males.
Alcohol Use in the Year Before Marriage: Alcohol Expectancies and Peer Drinking as Proximal Influences on Husband and Wife Alcohol Involvement
Authors: Leonard Kenneth E. , Mudar Pamela J.
Published: April 2006

Background: Models of adolescent alcohol involvement that include individual difference, family, and peer risk factors indicate a significant association between the drinking of adolescents and that of their peers. Peer drinking influences, however, have not been investigated extensively in integrative models of adult drinking. The purpose of this study was to test a model of adult drinking that incorporated the potentially important risk factor of partner drinking and in which proximal risk factors (peer drinking, alcohol expectancies) were hypothesized to be strongly associated with adult alcohol use and to mediate relationships between more distal risk factors and drinking.

Methods: Couples (n= 389) were assessed at the time of their first marriage. Separate, self‐administered questionnaires were completed at home by both husbands and wives. Distal risk factors included family history of alcoholism, antisocial behavior, and depressive symptomatology. Substantive relationships were tested in a model that included spousal associations with respect to distal risk factors, proximal risk factors, and drinking.

Results: Findings demonstrate the unique association of alcohol expectancies and peer drinking with adult alcohol use. Of particular relevance is the significance of the social network as a correlate of adult drinking. A peer network characterized by a higher level of alcohol involvement was strongly associated with heavier drinking among both men and women. This relationship was independent of sociodemographic and individual difference factors, alcohol expectancies, and partner's drinking. Results also demonstrate the similarity between husband and wife drinking, an association that cannot be attributed to assorting with respect to the other risk factors.

Conclusions: The social network continues to significantly impact drinking behavior in adulthood. The relevancy of peer and partner drinking influences to adult alcohol involvement suggests that the immediate social environment may have a prominent role in the continuity/discontinuity of heavy or problem drinking during the transition to marriage.
Skeletal Response to Alcohol
Authors: Turner Russell T.
Published: April 2006

Abstract: This review briefly assesses the well‐established effects of alcohol consumption on bone and mineral metabolism and addresses areas of controversy that need additional research. Alcohol consumption is a risk factor for osteoporosis based on the frequent finding of a low bone mass, decreased bone formation rate, and increased fracture incidence in alcoholics. Alcohol also has been shown to reduce bone formation in healthy humans and animals and to decrease proliferation of cultured osteoblastic cells. On the other hand, it has been difficult to demonstrate alcohol‐induced bone loss and increased fracture rate in population‐based studies. Indeed, most population‐based studies have shown a positive association between alcohol and bone mass and no change or a decrease in fracture risk. Overall, the evidence generally supports a detrimental effect of chronic alcohol abuse on the skeleton of men and a neutral or generally beneficial effect of light to moderate alcohol consumption, especially in older women. This latter putative beneficial effect may be due to a reduction in the age‐related increase in bone remodeling associated with postmenopausal bone loss. Specific areas of research are recommended to clarify the dose and sex effects of alcohol consumption and to determine cellular and molecular mechanisms of action. The goals of this proposed research emphasis are to determine the degree of risk for the range of alcohol consumption, to set guidelines of consumption compatible with maintaining bone health, and to develop appropriate countermeasures to prevent or reverse the detrimental skeletal effects of alcohol abuse.
Anxiety and Sensitivity to Ethanol and Pentobarbital in Alcohol Withdrawal Seizure‐Prone and Withdrawal Seizure‐Resistant Mice
Authors: Atkins Alison L. , Rustay Nathan R. , Crabbe John C.
Published: April 2006

Background: Withdrawal Seizure‐Prone (WSP) and Withdrawal Seizure‐Resistant (WSR) mice were selectively bred for high and low handling‐induced convulsions, respectively, after chronic ethanol treatment. Withdrawal severity is one factor that may contribute to the development of alcoholism and/or substance abuse, and anxiety is another. We sought to explore whether these factors are genetically related.

Methods: WSP and WSR mice of two replicate pairs of selected lines were tested for anxiety‐related behaviors on the canopy stretched‐attend‐posture apparatus 20 min after intraperitoneal injection of ethanol (2 g/kg, 20% v/v), pentobarbital (20 mg/kg), or an equivalent volume of saline. Dependent measures of anxiety included number of stretched attend postures (SAP) and time spent in the exposed area of the apparatus. Number of line crossings, which measures overall activity, was also scored.

Results: WSP mice given saline exhibited more SAP than WSR mice given saline, which indicated greater baseline anxiety. Ethanol and pentobarbital both reduced SAP and increased time spent in the exposed area of the apparatus, which indicated that both drugs exerted an anxiolytic effect. Despite baseline differences in SAP between selected lines, both anxiolytic drugs reduced SAP to similar levels in WSP and WSR mice.

Conclusions: These results support the hypothesis that WSP mice are more sensitive than WSR mice to the anxiety‐reducing effects of ethanol and pentobarbital. Some genes that influence this difference are likely to be the same as those that influence ethanol withdrawal severity. Thus, higher basal anxiety and greater genetic sensitivity to anxiolytic drug effects may relate to a greater genetic predisposition to the development of severe alcohol withdrawal signs.
N‐methyl‐d‐aspartate Receptor Responses Are Differentially Modulated by Noncompetitive Receptor Antagonists and Ethanol in Inbred Long‐Sleep and Short‐Sleep Mice: Behavior and Electrophysiology
Authors: Hanania Taleen , Negri Cori A. , Dunwiddie Thomas V. , Zahniser Nancy R.
Published: April 2006

Background: Short‐sleep (SS) mice exhibit higher locomotor activity than do long‐sleep (LS) mice when injected with low doses of ethanol or the noncompetitive N‐methyl‐D‐aspartate receptor (NMDAR) antagonist MK‐801 (dizocilpine). SS mice also have higher densities of brain NMDARs. However, two strains of LS X SS recombinant inbred (RI) mice also show differential activation to ethanol and MK‐801, but have similar numbers of NMDARs. Here we used inbred LS (ILS) and SS (ISS) mice to investigate further the relationship between NMDARs and sensitivity to the stimulant effects of low doses of ethanol.

Methods: Open field activity and spontaneous alternations were measured after saline or drug injection. [3H]MK‐801 binding parameters were determined in hippocampus, cortex, striatum, and nucleus accumbens. Extracellular field excitatory postsynaptic potentials (fEPSPs) were recorded in the CA1 region of hippocampal slices.

Results: Systemic injection of either ethanol or MK‐801 increased locomotor activity to a greater extent in ISS mice than in ILS mice. The competitive NMDAR antagonist 2‐carboxypiperazin‐4‐yl‐propyl‐1–1phosphonic acid (±CPP) depressed activity of ILS, but not ISS, mice. No strain differences were observed in spontaneous alternations or in the number or affinity of NMDARs in the brain regions examined. Likewise, the magnitudes of hippocampal NMDAR‐mediated fEPSPs were similar in ILS and ISS mice and were inhibited to the same extent by a competitive NMDAR antagonist. However, both ethanol and the NMDAR NR2B receptor antagonist ifenprodil inhibited the late component of hippocampal NMDAR fEPSPs to a greater extent in ISS, than in ILS, mice.

Conclusions: Differential ethanol‐ and MK‐801‐induced behavioral activation in ILS and ISS mice was not associated with differences in NMDAR number. Nonetheless, pharmacological differences in hippocampal NMDAR responsiveness suggest that ISS mice express NMDARs that have a greater sensitivity to noncompetitive, but not competitive, NMDAR antagonists. These differences, which may reflect differences in NMDAR subunit composition, could underlie the differential responsiveness to low doses of ethanol in ILS and ISS mice.
Effects of Vitamin A Deficiency on Rat Liver Alcohol Dehydrogenase Expression and Alcohol Elimination Rate in Rats
Authors: Pinaire Jane , Smith Jennifer R. , Cho Won Kyoo , Crabb David W.
Published: April 2006

Background: Vitamin A has been suggested to regulate the expression of liver alcohol dehydrogenase (ADH) in humans. There are few studies on the ability of retinoic acid to affect ADH expression in vivo and none on its effects on alcohol metabolic rate.

Methods: Male Sprague Dawley® rats were used for isolation of hepatocytes or were rendered vitamin A deficient by feeding a deficient diet for 7 weeks. ADH, retinoic acid receptor β, and retinoid X receptor α protein levels were analyzed by Western blotting. Alcohol elimination rate was determined by following blood alcohol levels after administering a 1.5 g/kg dose of ethanol intraperitoneally.

Results: Retinoic acid had no effect on ADH protein in cultured hepatocytes. In the vitamin A deficient rats, retinol was not detectable in serum or liver at the time animals were killed. ADH and retinoid X receptor α protein levels were unchanged in the deficient group compared with a vitamin A sufficient control group, whereas retinoic acid receptor β levels increased 40%. The deficient rats had a reduced volume of distribution of alcohol, but this largely was accounted for by their smaller body size. The alcohol elimination rates were lower in the deficient animals, but this was accounted for by reduced body and liver weights.

Conclusions: Severe vitamin A deficiency did not alter liver ADH protein expression or rates of alcohol elimination when expressed per gram of body or liver weight.
Altered Amygdalar CRF Release and Increased Anxiety‐Like Behavior in Sardinian Alcohol‐Preferring Rats: A Microdialysis and Behavioral Study
Authors: Richter Regina M. , Zorrilla Eric P. , Basso Ana Maria , Koob George F. , Weiss Friedbert
Published: April 2006

Background: Dysregulation of the stress‐regulatory corticotropin‐releasing factor (CRF) system in the central nucleus of the amygdala (CeA) may be a factor in genetically determined alcohol preference.

Methods: To test this hypothesis, basal and restraint stress‐induced CRF efflux in the CeA was determined by microdialysis in Sardinian alcohol‐preferring (sP) and nonpreferring (sNP) rats. In addition, differences in anxiety‐like behavior between sP and sNP rats were evaluated by using the elevated plus maze and conditioned defensive burying tests.

Results: Basal dialysate CRF levels in the CeA were elevated in the alcohol‐preferring line (sP, 281.2 ± 83.96 pg/ml; sNP, 70.2 ± 16.76 pg/ml;p < 0.05). In contrast, no differences in whole‐tissue CRF content in the CeA were observed (sP, 1143 ± 142 ng/mg protein; sNP, 1181 ± 139 ng/mg protein). Restraint stress elevated CRF dialysate concentrations in both sP and sNP rats. Rats of the sP line exhibited more anxiety‐like behavior than sNP rats in the elevated plus maze but not in the conditioned defensive burying test.

Conclusions: The results suggest that ethanol‐preferring sP rats show a dysregulation in basal CRF release within the CeA that may, in turn, heighten ethanol intake and increase susceptibility to anxiogenic stimuli in these animals.
Maintenance Factors of Recovery From Alcohol Dependence in Treated and Untreated Individuals
Authors: Bischof Gallus , Rumpf Hans‐Jürgen , Hapke Ulfert , Meyer Christian , John Ulrich
Published: April 2006

Background: Research on natural recovery from alcohol dependence has focused mainly on triggering mechanisms of the remission process. Only a few studies have considered maintenance factors of natural recovery.

Methods: In the present study, 93 natural remitters and 42 self‐help group participants were compared. Both groups remitted from alcohol dependence according to DSM‐IV criteria. Several alcohol‐related variables and maintenance factors of the remission process were assessed in a personal interview by using standardized questionnaires.

Results: Logistic regression analysis that focused on maintenance factors showed that, independent from direct self‐help group context, self‐help group attendees informed more individuals about their former alcohol problems and sought social support more often as a coping strategy to deal with craving. No further group differences could be identified.

Conclusions: Self‐help group participants revealed a higher social engagement to maintain their recovery. Besides this major difference, data support the assumption that more commonalities than differences exist within successful recoveries from alcohol dependence, independent of help‐seeking status.
Environmental Transmission of DSM‐IV Substance Use Disorders in Adoptive and Step Families
Authors: Newlin David B. , Miles Donna R. , van den Bree Marianne B. M. , Gupman Anne E. , Pickens Roy W.
Published: April 2006

Background: One factor contributing to the 3‐ to 5‐fold increase in risk for substance use disorders (SUDs) among children of alcoholics may be the rearing environment. These influences may include availability of substances, modeling of SUDs, inadequate parenting, or other factors. The contribution of parental environmental influences on offspring with SUDs may be estimated independently of genetic influences through assessment of adoptees raised by nonbiological parents.

Methods: Relative risk of SUDs was assessed in adult adoptees (N = 442) of alcoholic and nonalcoholic adoptive parents as well as in stepchildren (N = 1859) with alcoholic or nonalcoholic stepfathers who participated in the community‐based National Longitudinal Alcohol Epidemiologic Survey (NLAES).

Results: Rearing by an alcoholic adoptive mother was associated with increased DSM‐IV alcohol abuse. Rearing by an alcoholic adoptive father was predictive of adoptees’ illicit drug use, as well as DSM‐IV drug dependence. Rearing by an alcoholic stepfather was predictive of stepchild DSM‐IV alcohol abuse, illicit drug use, and drug dependence, whereas an alcoholic stepmother was associated with increased illicit drug use in the stepchild. Alcoholism in adoptive parents or step parents did not increase risk for offspring DSM‐IV alcohol dependence. In both adoptive and biological families, there was a subadditive interaction of mother by father alcoholism such that the rate of substance abuse when both parents were alcoholic was less than that expected based on the additive effects of each alcoholic parent.

Conclusions: Rearing by an alcoholic parent had a greater influence on alcohol abuse by offspring than on alcohol dependence. The increased risk of proband illicit drug use and drug dependence associated with paternal alcoholism suggested nonspecificity of environmental transmission. Both maternal and paternal cultural transmission effects influenced offspring SUDs.
US Low‐Risk Drinking Guidelines: An Examination of Four Alternatives
Authors: Dawson Deborah A.
Published: April 2006

Background: This study compared four sets of US low‐risk drinking guidelines (two interpretations of the US Dietary Guidelines and two variations of the NIAAA physicians’ guidelines) in terms of adherence and how well they predicted five different alcohol‐related outcomes.

Methods: Using data from a nationally representative sample of 17,542 US adults 21 years of age and over who drank 12 or more drinks in the past year, this study assessed the sensitivity, specificity, overall accuracy, positive and negative predictive values, and odds ratios of the various drinking guidelines (specifically, of having exceeded them with different degrees of frequency) as predictors of alcohol dependence, impaired driving, liver disease, peptic ulcer, and hypertension.

Results: The proportions of past‐year regular drinkers exceeding the four sets of guidelines varied from 20.9%, whose average intake exceeded the weekly limits, to between 21.0% and 42.7% who exceeded the daily guidelines at least once a week, and to between 69.2% and 94.2% who ever exceeded the daily limits in the year preceding the interview. Sensitivity and odds ratios were highest for the ever exceeding the Dietary Guidelines daily limits, intermediate for ever exceeding the two variations based on the NIAAA physicians’ guidelines, and lowest for exceeding the Dietary Guidelines interpreted as weekly limits. The opposite pattern was observed for specificity and overall predictive accuracy. When frequently exceeding the daily limits was considered, their sensitivity declined but their specificity and positive predictive value increased.

Conclusions: If sensitivity and specificity are deemed equally important, the NIAAA physicians’ guidelines incorporating both daily and weekly limits seem to do the best job of balancing these dimensions in the prediction of a variety of alcohol‐related outcomes.