bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification and Confirmation of Quantitative Trait Loci Regulating Alcohol Consumption in Congenic Strains of Mice
Authors: Whatley Valerie J. , Johnson Thomas E. , Erwin V. Gene
Published: May 2006

Background:C57BL/6 inbred mice prefer alcohol whereas DBA/2 mice avoid it. We describe the construction of congenic strains of mice in which DBA/2 alleles for alcohol avoidance were placed on a C57BL/6 background using phenotypic selection.

Methods:Mice were primed to drink 10% v/v ethanol in water for 2 days before a two‐bottle choice paradigm. N2 males who demonstrated an alcohol‐avoidance phenotype were backcrossed to B6 females to construct 15 independent lines.

Results:Eight of these lines were lost due to failure to breed or absence of males with an alcohol‐avoidance phenotype. The remaining sublines were split to form a total of 21 sublines. In the N7 and N9 generations, a genome scan located provisional quantitative trait loci (QTLs) on chromosomes 1,2,3,6, and 9. Progeny testing confirmed QTLs on chromosomes 1 and 2.

Conclusions:The QTL on chromosome 2 overlaps the 95% confidence interval ofAlcpl whereas that on chromosome 1 is new and has been called Alcp5. Marker‐assisted selection was used in the N9 and subsequent generations to maintain the congenic lines and produce congenic strains.
Differences in the Opioid System in Selected Brain Regions of Alcohol‐Preferring and Alcohol‐Nonpreferring Rats
Authors: Fadda P. , Tronci S. , Colombo G. , Fratta W.
Published: May 2006

Background: Previous studies have suggested that alcohol‐reinforcing effects are mediated by the endogenous opioid system, which, in turn, stimulates mesolimbic dopaminergic neurotransmission. In addition, evidence obtained in both humans and rats indicates that genetic factors may influence alcohol‐drinking behavior. In the present study, we examined several components of the opioid system in selected brain regions of rats bred selectively for their innate alcohol preference (Sardinian preferring = sP) or alcohol aversion (Sardinian nonpreferring = sNP).

Methods: To evaluate whether differences observed were consequent to alcohol intake, sP rats were divided into two subgroups, ethanol‐naive sP (sP) and ethanol‐experienced sP (sPexp). Opioid receptors were labeled, using [3H]naloxone (μ, δ, and K receptors), [D‐Ala2,N‐Me‐Phe4,Gly,ol5]enkephalin ([3H]DAMGO; μ receptors), and [D‐Ala2,D‐Leu5]enkephalin ([3H]DADLE; δ receptors), by means of quantitative autoradiography. Enkephalin and dynorphin mRNA contents were measured by in situ hybridization by using 25‐ and 47‐base oligonucleotide probes with sequences complementary to mRNA encoding rat enkephalin or dynorphin.

Results: Our results revealed a significant reduction of opioid receptors in caudate‐putamen nucleus and in the shell portion of the nucleus accumbens in sP compared with sNP rats. Alcohol intake partially reversed this reduction in the caudate‐putamen nucleus. In addition, enkephalin mRNA expression was found to be decreased in the ventral part of caudate‐putamen nucleus and increased in the cerebral cortex of sP rats compared with sNP rats; no significant differences were found in dynorphin mRNA expression in any of the brain areas examined.

Conclusions and Significance: Differences observed between the two lines of rats may implicate that genetic modifications in the opioid system are possibly responsible for the innate preference of sP rats toward alcohol intake. At the same time, it cannot be excluded that other functions might also be affected to some degree.
Association of Low‐Voltage Alpha EEG With a Subtype of Alcohol Use Disorders
Authors: Enoch Mary‐Anne , White Kenneth V. , Harris Claudia R. , Robin Robert W. , Ross Jerilyn , Rohrbaugh John W. , Goldman David
Published: May 2006

Background: Neurophysiological traits may identify more homogeneous subgroups of alcoholics. Such discoveries could yield information regarding pathophysiological development, leading to more specific preventive measures and treatments. In an earlier study of 127 individuals, 59 of whom were unrelated, we found that a heritable resting Electroencephalographic (EEG) phenotype, i.e., the low‐voltage alpha (LVA) trait, was associated with alcohol use disorders and anxiety disorders.

Methods: We evaluated these findings using an independent, similarly established, dataset of 120 subjects. Wc also extended the study to a larger set of 149 unrelated individuals from a total sample of 247 subjects for whom psychiatric diagnoses and resting EEG phenotypes were available. Blind‐rated psychiatric diagnoses were formulated according to DSM‐III‐R criteria.

Results: In the replication sample, the LVA trait was again more common among subjects with anxiety disorders than among those without. In the total group of unrelated individuals, alcoholics were significantly (3 times) more likely to show the LVA trait than were nonalcoholics. Again, individuals with anxiety disorders were significantly (3 times) more likely to exhibit the LVA trait than were those without anxiety disorders. Of 11 unrelated alcoholics with anxiety disorders, seven showed the LVA trait. It was specifically the LVA trait and not low‐amplitude alpha activity that was associated with alcohol use disorders.

Conclusions: The results of this replication study and the analysis of the total sample of unrelated individuals support an association between LVA EEG and the subtype of alcohol use disorders associated with anxiety disorders. The LVA phenotype may be a vulnerability factor for alcohol use disorders and anxiety disorders.
Blood Ethanol Concentrations in Rats Drinking Sucrose/Ethanol Solutions
Authors: Czachowski Cristine L. , Samson Herman H. , Denning Charles E.
Published: May 2006

Background: The addition of sucrose to ethanol solutions results in a substantial increase in ethanol self‐administration by rats that are deprived of neither food nor water. However, if sucrose alters ethanol absorption or metabolism, resulting in blood ethanol concentrations (BECs) not different from those resulting from lower intakes of ethanol/water solutions, then the usefulness of sucrose/ethanol mixtures in increasing ethanol consumption is questionable. The present study was conducted to determine whether the addition of sucrose to ethanol solutions altered BECs in an operant self‐administration paradigm.

Methods: Tail blood (from male Long‐Evans rats) was collected 30 min after the intake of four different solutions, i.e., 5% sucrose/20% ethanol, 5% sucrose/10% ethanol, 2% sucrose/10% ethanol, and 10% ethanol.

Results: Ethanol intakes (mean, 1.57 ± 0.21 g/kg) and BECs (mean, 78.4 ± 9.3 mg/100 ml) were highest when 5% sucrose was added to the ethanol solution. Moreover, the ratios between ethanol intakes and resulting BECs were approximately the same for all solutions.

Conclusions: These findings indicate that, under the conditions of this procedure, the BEC reached is dependent on the amount of ethanol consumed and is not influenced by the addition of sucrose to the solution.
Oral Ethanol Self‐Administration in Rhesus Monkeys: Behavioral and Neurochemical Correlates
Authors: Vivian J. A. , Higley J. D. , Linnoila M. , Woods J. H.
Published: May 2006

Background: Previous research has revealed that orally administered ethanol serves as a reinforcer in nonhuman primates. The purposes of the present study were to examine the relationship between ethanol preferences and intakes in two distinct self‐administration contexts and to reveal some of the behavioral and neurochemical correlates of oral ethanol self‐administration in monkeys.

Methods: Three cohorts of 13 to 29 rhesus monkeys (Macaca mulatto) were socially housed and given daily, 1‐hr, one‐spout access to an ethanol solution (8.4%, w/v) sweetened with aspartame. Twelve of these monkeys were subsequently selected, individually housed, and given daily, 2‐hr, two‐spout access to a range of ethanol concentrations (0.25‐16%, w/v) concurrently with water.

Results: These monkeys (National Institute on Alcohol Abuse and Alcoholism group) showed a marked preference for ethanol (0.5‐4%, w/v) over water, and ethanol preferences were 3‐fold greater than those of a second group of 12 monkeys (University of Michigan group) purchased from a commercial vendor. Ethanol consumption was consistent across the self‐administration paradigms. Monkeys that consumed large quantities of ethanol under the one‐spout, social‐housing conditions continued to drink large quantities of ethanol under the two‐spout, individual‐housing conditions (r= 0.86). An association between ethanol preferences and intakes was also demonstrated. Monkeys with the greatest preferences for ethanol over water under the two‐spout choice conditions consumed the largest quantities of ethanol (r= 0.82). Finally, cerebrospinal fluid 5‐hydroxyindoleacetic acid concentrations were inversely related to ethanol preference but not to ethanol intake.

Conclusions: These results indicate that ethanol consumption is stable across contexts and is positively correlated with the preference for ethanol over water.
Individual Differences in Auditory and Visual Attention Among Fetal Alcohol‐Affected Adults
Authors: Connor Paul D. , Streissguth Ann P. , Sampson Paul D. , Bookstein Fred L. , Barr Helen M.
Published: May 2006

Background:Deficits in attention are commonly identified among patients who have been prenatally exposed to alcohol, and they often affect the ability of the patients to function appropriately in society.

Methods:Eleven adult patients with fetal alcohol syndrome (FAS) or fetal alcohol effects (FAE) were compared with nine adult subjects with no history of prenatal alcohol exposure, using four tests of visually and auditorially mediated attention.

Results:In relation to the comparison group, patients with FAS/FAE exhibited substantial deficits in both auditory and visual attention; the auditory deficits were greater. We observed two predominant patterns of deficits among patients with FAS/FAE, one involving both auditory and visual attention problems and the other involving less severe auditory problems and even fewer visual problems. Most subjects with FAS or FAE had some manifestations of attention problems in at least one of the tests of attention used in this study. We present a new graphical representation of individual auditory Continuous Performance Test data across a 6‐min period, which, compared with conventional scores, more clearly reveals the markedly disrupted and variable attention patterns displayed by some individuals with FAS or FAE.

Conclusions:These findings suggest that detailed analysis of the pattern of individual performance for each subject is an important aspect of Continuous Performance Test assessment. Our findings further suggest that intellectual performance (intelligence quotient score) alone is not sufficient to account for the patterns of disrupted attention for individuals with FAS/FAE. Assessment of individuals with FAS or FAE should include measurement of attentional functioning in both the visual and auditory modalities.
Prognostic Factors in Severe Alcoholic Liver Injury
Authors: Fujimoto Masao , Uemura Masahito , Kojima Hideyuki , Ishii Yoshinobu , Ann Tatsuichi , Sakurai Shinya , Okuda Kouji , Noguchi Ryuichi , Adachi Satoshi , Kitano Hiroyuki , Hoppo Kazushige , Higashino Tadashi , Takaya Akira , Fukui Hiroshi ,   the Nara Liver Study Group
Published: May 2006

Severe alcoholic liver injury has been relatively rare, but is gradually increasing in Japan. The clinical features and prognostic factors in severe alcoholic liver injury were retrospectively investigated in 105 patients, consisting of 3 with severe alcoholic hepatitis (SAH), 43 with cirrhosis with superimposed alcoholic hepatitis [liver cirrhosis (LC) +alcoholic hepatitis (AH)], 38 with AH, and 21 with alcoholic cirrhosis. Seven of the 105 patients (6.7%, 2 with SAH and 5 with LC+AH) died of hepatic failure. Patients with SAH showed severe hyperbilirubinemia, reduced hepatic biosynthetic capacity, and marked acute inflammatory reactions, and developed multiple organ failure, such as disseminated intravascular coagulation (DIC), renal failure, acute pancreatitis, or pneumonia. Two SAH patients died within 1 month, whereas five with LC+AH died within 77 days during the second episode of AH. In these nonsurvivors, the serum total bilirubin (T.Bil) level was not normalized, and the hepaplastin test (HPT), serum albumin, cholesterol, and platelet count were not markedly improved after the first episode of AH. In the survivors, elevation of AST lasted longer, and the improvement of T.Bil, hepatic biosynthetic capacity, and the platelet count were much less in patients with LC+AH than in those with AH. Multivariate analysis using the Cox proportional hazards model showed serum C‐reactive protein (CRP) and DIC as significant independent prognostic factors among SAH, LC+AH, and AH groups. When factors related to multiple organ failure, such as DIC and renal failure, were excluded, T.Bil and CRP were selected as independent prognostic factors. In patients with LC+AH and AH, CRP, and HPT were shown to be significant independent prognostic factors. These results suggest that SAH with multiple organ failure, and another episode of AH in advanced LC with hyperbilirubinemia and reduced hepatic biosynthetic capacity, are indicative of an extremely poor prognosis in chronic alcoholics.
Mechanisms of Hepatic Microcirculatory Disturbances Induced by Acute Ethanol Administration in Rats, With Special Reference to Alterations of Sinusoidal Endothelial Fenestrae
Authors: Takashimizu Shinji , Watanabe Norihito , Nishizaki Yasuhiro , Kawazoe Kazuya , Matsuzaki Shohei
Published: May 2006

Elucidation of the hepatic hemodynamics in acute ethanol administration is an issue of clinical importance for better understanding of alcoholic liver diseases. The purpose of this study is to clarify the mechanism of hepatic microcirculatory disturbances after acute ethanol administration, especially regarding the effects of ethanol on alterations of sinusoidal endothelial fenestrae (SEF) and the involvement of endothelin‐l (ET‐1) in the mechanism of portal hypertension induced by ethanol. Ethanol was administrated into the portal vein via the mesenteric vein branch of rats as a continuous infusion (4 and 8 mg/min of ethanol) for 60 min. Hepatic tissue blood flow measured with a laser Doppler blood flowmeter was found to be remarkably decreased with time, whereas portal pressure began to increase at 10 min and showed a significant increase by ˜1.5 cm H2O at 60 min. Ethanol concentrations in blood at 60 min after 4 and 8 mg/min of ethanol infusion were 0.75 mg/ml and 1.77 mg/ml, respectively. At this point, scanning electron microscopy revealed significant decreases in number and diameter of SEF both in zone 1 and zone 3, with the increase in ethanol level. These findings suggested that decreases in number and diameter of SEF, whether primary or secondary, may lead to the impairment of the transport of plasma substances from sinusoids to hepatocytes in acute ethanol administration. Furthermore, the pretreatment of BQ‐123 inhibited a decrease in hepatic tissue blood flow and an increase in portal pressure caused by ethanol, indicating that ET‐1 may be involved in the mechanism of hepatic circulatory disturbances in acute ethanol administration.
Effect of Long‐Term Ethanol Consumption on Ability to Produce Cytokine‐Induced Neutrophil Chemoattractant‐1 in the Rat Liver and Its Gender Difference
Authors: Yamada Shinwa , Matsuoka Hirofumi , Harada Yuji , Momosaka Yasuhiro , Izumi Hiroto , Kohno Kimitoshi , Yamaguchi Yasuo , Eto Sumiya
Published: May 2006

Gut‐derived lipopolysaccharide (LPS) may contribute to hepatocellular necrosis in alcoholic hepatitis through neutrophil sequestration in hepatic sinusoids. It is well known that the female has a greater susceptibility to alcoholic liver injury than the male. The aim of the present study was to investigate the effect of long‐term ethanol consumption on ability of the liver to produce cytokine‐induced neutrophil chemoattractant‐1 (CINC‐1), the most potent neutrophil‐chemokine in rats, after LPS administration. Furthermore, we aimed to evaluate the gender difference in this ability. Male and female rats were pair‐fed a liquid diet containing 36% of the total calories as ethanol or dextrose for 6 to 8 weeks. They were given LPS intravenously, and chemokine mRNA expression in the liver was evaluated after 2 and 6 hr. To study the organ or chemokine specificity, CINC‐1 mRNA expression in the spleen and monocyte chemoattractant protein (MCP)‐l mRNA level were also determined. Serum ALT activity started to increase between 2 and 6 hr. Female rats fed an ethanol diet showed significantly higher ALT activity 6 hr after LPS injection than the male rats. CINC‐1 mRNA expressions in the liver after 2 and 6 hr were significantly higher in the ethanol‐fed group, compared with the pair‐fed control. Female rats fed an ethanol diet showed a significantly higher level of CINC‐1 mRNA in the liver than the male rats 2 hr after LPS injection. CINC‐1 levels in the liver homogenates paralleled closely its mRNA expression, whereas its concentrations in sera did not correlate with those in the liver. Neither CINC‐1 mRNA expression in the spleen nor MCP‐1 mRNA expression in the liver was affected by ethanol feeding or gender. An additional experiment using the gonadectomized rats fed an ethanol diet showed that gonadectomy totally abolished the gender difference in CINC‐1 mRNA of the liver. We conclude that CINC‐1 induction in the liver may be responsible for LPS‐induced hepatitis in the ethanol‐fed rats, and that the difference in ability to produce CINC‐1 between males and females is one important factor that may partly account for the gender difference of alcoholic liver disease.
Genotypes of Alcohol‐Metabolizing Enzymes in Relation to Alcoholic Chronic Pancreatitis in Japan
Authors: Maruyama Katsuya , Takahashi Hisao , Matsushita Sachio , Nakano Masayuki , Harada Hideo , Otsuki Makoto , Ogaw Michio , Suda Kouichi , Baba Tadao , Honma Tatsuji , Moroboshi Toshio , Matsuno Masaki
Published: May 2006

Long‐term consumption of large amounts of alcohol is the main cause of chronic pancreatitis. All heavy drinkers, however, do not contract chronic pancreatitis. Although genetic predisposition to alcoholism and alcoholic liver disease has been reported, genetic susceptibility to alcoholic pancreatitis is still a matter of debate. To determine the relation between genotypes of alcohol‐metabolizing enzymes and chronic alcoholic pancreatitis, we examined genotype patterns of aldehyde dehydrogenase 2 (ALDH 2), alcohol dehydrogenase 2 (ADH 2) and cytochrome P‐4502E1 (CYP2E1) in 54 patients with chronic alcoholic pancreatitis who were diagnosed in general hospitals in all over Japan and compared with those in 30 patients with chronic nonalcoholic pancreatitis or in 46 alcoholics with normal pancreatic function. There were no significant differences in the distribution of genotypes of ALDH 2 and CYP2E1 among those three groups. As for the ADH 2 genotype, distribution of 21/21,21/22, and 22/22 was 35%, 30%, and 35% in alcoholics with normal pancreatic function; 4%, 39%, and 57% in the chronic alcoholic pancreatitis group; and 0%, 50%, and 50% in the chronic nonalcoholic pancreatitis group, respectively. The frequency of ADH 22 allele was significantly higher in the chronic alcoholic pancreatitis group, compared with alcoholics with normal pancreatic function; but, it was not significantly different from that in the chronic nonalcoholic pancreatitis group. We also examined the relation between pancreatic fibrosis or pancreatitis histologically diagnosed and genotypes of alcohol‐metabolizing enzymes in alcoholic autopsy cases. Twenty of 31 cases showed moderate or severe pancreatic fibrosis and showed intralobular + interlobular fibrosis, which is characteristic in alcoholic pancreatitis or intralobular fibrosis. ADH 22 allele tended to show a high frequency in the intralobular + interlobular fibrosis group, compared with that in the intralobular fibrosis group (75.0% vs. 41.7%, p < 0.1). The chronic pancreatitis group had a significantly higher frequency of the ADH 22 allele than that in cases without such findings (87.5% vs. 58.7%, p < 0.05). However, the ALDH 2 and CYP2E1 genotypes showed no significant relation to the findings of pancreatic fibrosis or histological pancreatitis. These data suggest that the risk of chronic alcoholic pancreatitis diagnosed clinically and pathologically seems to be associated with the ADH 22 allele in the genotypes of alcohol‐metabolizing enzymes.
Evidence for Ethanol Oxidation by Kupffer Cells
Authors: Nakamura Yuji , Yokoyama Hirokazu , Okamura Yukishige , Ohgo Hideki , Fukuda Masahiko , Horie Yoshinori , Kato Shinzo , Ishii Hiromasa
Published: May 2006

Ethanol oxidation in Kupffer cells was investigated by measuring 14C‐acetate formation from 14C‐ethanol, and the role of aldehyde dehydrogenase 2 (ALDH2) in this process was also examined. Formation of 14C‐acetate from 20 mM of 14C‐ethanol was significantly increased in medium‐containing Kupffer cells (9,003 + 2,066 cpm/5 × 106 cells), compared with medium containing no cells (1,826 + 46 cpm,p < 0.01), or containing acid‐killed Kupffer cells (1,629 + 210 cpm,p < 0.01). Ethanol formation was significantly attenuated when 20 and 200 μM cyanamide or 2 μM disulfiram were given. Reverse transcriptase‐polymerase chain reaction demonstrated that Kupffer cells carry mRNA for ALDH2. These findings indicate that Kupffer cells can oxidize ethanol to acetate. ALDH2 may participate in this process, especially in the conversion of acetaldehyde to acetate.
Cholesterol Hydroperoxides in Erythrocyte Membranes of Alcoholic Patients
Authors: Adachi Junko , Asano Migiwa , Naito Takeaki , Ueno Yasuhiro , Imamichi Hiroyuki , Tatsuno Yoshitsugu
Published: May 2006

Evidence for the presence of 5α‐hydroperoxycholest‐6‐en‐3β‐ol (cholesterol 5α‐hydroperoxide, Ch 5α‐OOH) and 7α‐ and 7β‐hydroperoxycholest‐5‐en‐3β‐ols (cholesterol 7‐hydroperoxides: Ch 7α‐OOH and Ch 7β‐OOH, respectively) in human erythrocyte membrane was found. Blood samples were collected from alcoholic patients and healthy volunteers (controls), and their cholesterol hydroperoxides were analyzed by high‐performance liquid chromatography postcolumn chemiluminescence and roughly identified by liquid chromatography‐mass spectrometry. Ch 7α‐OOH and Ch 7β‐OOH were present in each sample, being significantly higher in alcoholic samples than in control samples. Ch 5α‐OOH was present in some alcoholic samples, but not in the control ones. The accumulation of cholesterol hydroperoxides suggests enhanced lipid peroxidation by active oxygen species and/or a reduced elimination system for lipid peroxide in alcoholic patients.
Premorbid Risk Factors for Alcohol Dependence in Antisocial Personality Disorder
Authors: Yoshino Aihide , Fukuhara Taihei , Kato Motoichiro
Published: May 2006

Background:

Many, but not all, types of antisocial personality disorders (ASP) are complicated by alcohol dependence. Therefore, some additional risk factors may exist for alcohol dependence co‐occurring with ASP. We studied whether severe childhood conduct disorder and a family history of alcohol dependence are possible risk factors for the development of alcohol dependence in ASP.

Methods:

The subjects were 81 male Japanese criminals diagnosed with DSM‐III‐R ASP. Relative risks of alcohol dependence for severe conduct disorder and for a positive family history were estimated by using a multiple logistic model.

Results:

Forty‐three subjects (53.0%) met criteria for DSM‐111‐R alcohol dependence. The relative risk of alcohol dependence for severe conduct disorder (n= 44), compared with mild conduct disorder, was 4.1; whereas the relative risk for a positive family history (n= 31), relative to a negative family history, was 1.9. Severe childhood conduct disorder was also associated with severe adulthood antisocial behavior and an earlier onset of alcohol dependence.

Conclusions:

The results suggest that severe childhood conduct disorder and a positive family history of alcohol dependence are independent premorbid risk factors for developing alcohol dependence among persons with ASP.
Genetic and Developmental Modulation of Cardiac Deficits in Prenatal Alcohol Exposure
Authors: Cavieres Maria Fernanda , Smith Susan M.
Published: May 2006

Background:

Increasing evidence demonstrates that genetic background is an important modulator of alcohol's effects on the developing fetus. Such effects are separable from maternal ethanol metabolism. Here, we study ethanol's effects on cardiogenesis in an avian model that shows strong cell death within neuronal and neural crest precursors following ethanol exposure.

Methods:

The study design tested the hypothesis that ethanol‐induced losses of cardiac neural crest populations would disrupt outflow tract development and thus contribute to the valvuloseptal deficits observed in prenatal alcohol exposure. Three chick strains were exposed to alcohol at gestational windows between gastrulation and early heart septation (day 3 incubation), and then hearts were examined at the completion of morphogenesis (day 10 incubation).

Results:

Ethanol's impact on cardiac development was influenced by fetal genetics. The B300 X Hampshire Red cross exhibited pronounced cell death within cardiac neural crest populations but had normal development of the heart and aortic arches. Neural crest migration and differentiation into the distal outflow tract were also normal in these embryos, which suggested a capacity to repair earlier losses. The DeKalb White X Hampshire Red cross also did not exhibit cardiac defects. Hearts of the B300 strain had a unique phenotype with respect to ethanol exposure and exhibited a thin ventricular compact layer, dilatation, and reduced myosin/deoxyribonucleic acid and myosin/protein content, a phenotype that indicates disrupted myocardial maturation and inductive cues. The deficit was only observed when ethanol exposure occurred at stages 15 or 18 and apparently was independent of neural crest cell death. Such ventricular thinning might go undetected in the absence of extensive screening.

Conclusions:

Results add to the increasing evidence that genetic background strongly modulates the effects of prenatal alcohol exposure. The results also suggest that embryos have a varying capacity to repair and recover from earlier neural crest losses.
Differences in the Fatty Acid Composition of Fatty Acid Ethyl Esters in Organs and Their Secretions
Authors: Laposata Michael , Kabakibi Ayman , Walden Michael P. , Cluette‐Brown Joanne E. , Nanji Azra A. , Refaai Majed A. , Werner Jens , Nanji Amin A.
Published: May 2006

Background:

Fatty acid ethyl esters (FAEE) are nonoxidative ethanol metabolites that have been shown to be long term markers of ethanol intake and have been implicated as mediators of ethanol‐induced cell injury. Previous studies have indicated that the fatty acid composition of the FAEE found in the plasma of human subjects after ethanol ingestion is predominantly ethyl palmitate and ethyl oleate. This raised the possibility that there is some selectivity toward the fatty acid used for FAEE to be exported from the liver into the blood.

Methods:

To address the hypothesis that the fatty acid composition of FAEE secreted from organs, such as the liver and pancreas, differs from the fatty acid composition of FAEE in the organs, this study was performed using rats that received ethanol by intra‐arterial infusion.

Results:

It was found that the fatty acids in FAEE differed significantly in plasma versus liver, bile versus liver, and pancreatic secretions versus pancreas.

Conclusions:

These results indicate that organs selectively export certain FAEE species.
The Neuropsychological Consequences of Abstinence Among Older Alcoholics: A Cross‐Sectional Study
Authors: Munro Cynthia A. , Saxton Judith , Butters Meryl A.
Published: May 2006

Background:

The older alcoholic has been distinguished from the younger alcoholic with regard to both the acute effects of alcohol and also the recovery of functioning with abstinence. Few studies, however, have included samples of exclusively older subjects. In this investigation we examined the recovery of functioning in an older cohort of recovering alcoholics (age range 55–83) to determine which neuropsychological functions improve and which remain impaired with abstinence.

Methods:

We used a cross‐sectional design, comparing three demographically matched groups on a battery of neuropsychological tests: (a) older alcoholics who had been abstinent for greater than 6 months, (b) older alcoholics who had been abstinent for less than 6 months, and (c) a control group of older subjects without alcohol abuse histories.

Results:

In almost all tasks, the alcoholics who were abstinent for less than 6 months performed worse than the control group. In contrast, the alcoholics who had been abstinent for more than 6 months differed from the control group on learning and recall of a word list, immediate and delayed recall of a complex figure, initial letter fluency, and clock drawing.

Conclusions:

Memory and executive skills appear to be resistant to recovery or at least slower to recover with abstinence in the older alcoholic. The impairment with visuospatial skills reported in prior investigations of alcoholics may be related to compromised executive functions, which interfere with the encoding of more complex visuospatial information and thus affect recall of such information. Studies that involve larger samples of older alcoholics are needed to understand their ability to recover cognitive functioning with abstinence.
Apoptosis and Dysregulated Ceramide Metabolism in a Murine Model of Alcohol‐Enhanced Lipopolysaccharide Hepatotoxicity
Authors: Deaciuc Ion V. , Nikolova‐Karakashian Mariana , Fortunato Franco , Lee E. Y. , Hill Daniell B. , McClain Craig J.
Published: May 2006

Background:

The role of apoptosis in EtOH‐induced liver injury has not been investigated much. Therefore, the question whether apoptosis is a contributory factor to alcoholic liver disease remains to be answered. The purpose of this study was to characterize the liver apoptotic response in a murine model of alcohol‐enhanced lipopolysaccharide (LPS) hepatotoxicity.

Methods:

Mice were fed an alcohol‐containing liquid diet for 49 days followed by an acute LPS challenge. The liver state was judged on the basis of histological appearance, plasma liver enzyme activity (alanine:2‐oxoglutarate and aspartate:2‐oxoglutarate aminotransferases, as markers of hepatocytolysis), and plasma hyaluronan levels (as a marker of the sinusoidal endothelial cell scavenging function). The liver apoptotic response was assessed by DNA fragmentation (TUNEL procedure), and caspases‐3 and ‐8 activity. To determine if ceramide played a role in the liver apoptotic response, the activity of acidic sphingomyelinase and tissue content of ceramide were also quantified.

Results:

Alcohol exposure induced fat accumulation and sensitized the liver to LPS injurious effects. Plasma liver enzyme activity was elevated by alcohol and this effect was potentiated by LPS. Liver apoptosis was augmented by both alcohol and LPS treatment as reflected by high frequency of positive TUNEL staining nuclei and by an increased activity of caspase‐3 and ‐8. Acidic sphingomyelinase activity was also increased and it was associated with an elevated tissue content of ceramide. In addition, LPS also increased plasma TNF‐α levels. These changes were accompanied by elevated plasma hyaluronan, reflecting an impaired sinusoidal endothelial cell scavenging function.

Conclusions:

These results provide a more complete description of the liver apoptotic response to both alcohol and LPS and may constitute the basis for further mechanistic studies on a possible role apoptosis may play in alcoholic liver injury.
Carbohydrate‐Deficient Transferrin in Relation to the Menopausal Status of Women
Authors: Leusink Geraline L. , Smeets‐Goevaers Cecile G. , Breed Simone A. , Keyzer Jules J. , van Pelt Johannes
Published: May 2006

Background:

Carbohydrate‐deficient transferrin (CDT) has been reported as an excellent marker for male alcohol abuse. Little is known about its validity among women, in whom rather conflicting data concerning the efficiency of the CDT marker and its biochemical mechanism have been reported. Moreover, it is not clear why the reference ranges are different for women (0 to 26 Units per liter) and men (0 to 20 Units per liter).

Methods:

In this population‐based study, we examined the normal CDT values measured by CDTect® in 331 healthy female teetotalers, randomly selected from a large cohort. They were divided into four groups: premenopausal women (n= 76), perimenopausal women (n= 86), postmenopausal women (n= 84), and users of estrogens/progestagens (n= 85).

Results:

The mean of the CDT value in the premenopausal group (15.2 Units per liter) was significantly higher than the mean in the postmenopausal group (13.6 Units per liter; p < 0.016). In pre‐ and perimenopausal women, higher CDT levels were associated with the last period of menstruation; for women menstruating less than 1 month ago versus longer ago, the mean serum CDT value was 15.4 vs. 13.0 Units per liter (p < 0.01).

Conclusions:

The premenopausal state seems to increase serum levels of CDT, probably due to the amount and frequency of blood loss during the menstrual period, and should be considered when interpreting CDT values in women.
The Alcohol Use Disorders Identification Test (AUDIT) and Carbohydrate‐Deficient Transferrin (CDT) in a Routine Workplace Health Examination
Authors: Hermansson Ulric , Helander Anders , Huss Anders , Brandt Lena , Rönnberg Sten
Published: May 2006

Background:

Only a few studies on workplaces have examined the Alcohol Use Disorders Identification Test (AUDIT) or carbohydrate‐deficient transferrin (CDT) as screening instruments for the early identification of elevated and risky levels of alcohol consumption. The purpose of this study was to compare the performances of AUDIT, CDT, and γ‐glutamyltransferase (GGT) in a routine health examination (alcohol screening) in the workplace.

Methods:

The study, carried out over 16 months in a large workplace in the transport sector, was part of an on‐going controlled study. Employees who came to the company health service for a routine health examination were offered the opportunity to undergo an alcohol screening and check their alcohol habits.

Results:

Of the 570 subjects who participated, 105 (18.4%) screened positive according to AUDIT, CDT, or both. Only 7.6% of the persons who screened positive did so according to both instruments. If GGT had been included as a screening instrument, the proportion of positive results would have increased to 22.0%. If we had only used AUDIT in the screening process, the proportion of positives would have fallen by nearly half.

Conclusions:

The present findings suggest that AUDIT and CDT are complementary instruments for alcohol screening in a routine workplace health examination, and each has value for identifying a different segment of the risky drinking population.
Association Between Ethanol and Sucrose Intake in the Laboratory Mouse: Exploration Via Congenic Strains and Conditioned Taste Aversion
Authors: Blizard David A. , McClearn Gerald E.
Published: May 2006

Background: A substantial body of literature indicates that intakes of “sweet’ solutions and ethanol are positively correlated across inbred strains of rats and mice but there has been speculation that the correlation is fortuitous and there is no agreement on the underlying mechanism.

Methods and Results: We assessed the correlation between intake of sucrose and ethanol in congenic mice created by backcrossing alleles favoring sucrose intake from the BXD RI‐5 strain into DBA/2J. In addition, to probe more specifically the interrelationship between intake of the two solutions, we examined aversion generalization from sucrose to ethanol in C57BL/6J mice. Among the congenic mice, a statistically significant product‐moment correlation of r= 0.36 (p < 0.02) was found between 6‐hr intake of sucrose corrected for differences in baseline water intake and preference for 10% ethanol presented in a 96‐hr 2‐bottle test. Furthermore, C57BL/6J male mice conditioned to avoid a 0.2 M sucrose solution generalized their aversion to a 10% ethanol solution presented in the same 2‐bottle test, drinking 42.1 ± 9.38% (mean ± SE) of their total fluid intake from the ethanol tube, compared with the control group mean of 69.86 ± 8.84%.

Conclusions: The positive association between intake of sucrose and ethanol in congenic mice provides strong evidence that the previously demonstrated genetic correlation between intake of these solutions is not the result of fortuitous fixation of unrelated alleles and provides suggestive evidence that, at least in the B6/D2 lineage, the genetic association between intakes of the two solutions reflects close linkage or the pleiotropic effects of the same genes. The demonstration that a conditioned taste aversion to sucrose generalized to ethanol in the C57BL/6J inbred mouse strain is an extension of similar observations in outbred rats and specifically demonstrates that intake of the two solutions is controlled by some of the same physiologic or neurological processes and thus is consistent with the pleiotropic interpretation of the genetic correlation.
P Rats Develop Physical Dependence on Alcohol Via Voluntary Drinking: Changes in Seizure Thresholds, Anxiety, and Patterns of Alcohol Drinking
Authors: Kampov‐Polevoy Alexey B. , Matthews Douglas B. , Gause Lee , Morrow A. Leslie , Overstreet David H.
Published: May 2006

Background: It has been proposed that the alcohol‐preferring P rat meets many of the criteria for an animal model of alcoholism. However, the development of alcohol dependence has not been explored in rats that self‐administer ethanol for less than 15–20 weeks. The present study investigated the development of physical dependence upon alcohol after 2–6 weeks of voluntary alcohol intake. Changes in bicuculline‐induced seizure thresholds, microstructure of alcohol drinking, and anxiety‐related behavior were used as indices of alcohol dependence. In addition, we evaluated the microstructure of alcohol drinking associated with the development of physical dependence upon alcohol.

Methods: Alcohol (10% ethanol solution) was measured in graduated drinking tubes with both alcohol and water available continuously. Microstructure of alcohol intake was monitored by a computerized drinkometer. Physical dependence upon alcohol was determined by measuring bicuculline‐induced seizure thresholds after alcohol withdrawal. Anxiety‐related behavior of P rats after alcohol withdrawal was determined by the social interaction and elevated plus maze tests.

Results: Initial alcohol intake in the alcohol‐preferring P rat was relatively modest (3.9 ± 0.4 g/kg/day). Four days of forced alcohol exposure (initiation) followed by 6 weeks of voluntary drinking resulted in an increase of alcohol intake to 5.5 ± 0.2 g/kg/day. Ethanol self‐administration for 6 weeks, but not for 2 or 4 weeks, produced a significant reduction (30%; p < 0.05) in bicuculline‐induced seizure thresholds during alcohol withdrawal. Alterations in the microstructure of alcohol intake (i.e., 90% increase in the size of alcohol drinking bouts compared to the baseline [p < 0.001] with no change in bout frequency) were associated with the development of alcohol dependence. Termination of alcohol intake after 6 weeks of voluntary alcohol consumption resulted in increased anxiety according to both the social interaction and elevated plus maze tests.

Conclusions: The results of this study indicate that 6 weeks of voluntary alcohol intake are sufficient for the development of physical dependence upon alcohol in the alcohol‐preferring P rats as measured by susceptibility to bicuculline‐induced seizures. This time is much shorter than the 15–20 weeks reported earlier. Development of physical dependence to alcohol was associated with an increase in daily alcohol intake (40% over the baseline), an increase in alcohol intake during each drinking bout (90% over the baseline), and elevated anxiety during alcohol withdrawal.
MK‐801 Blocks the Development of Behavioral Sensitization to Ethanol
Authors: Camarini Rosana , Frussa‐Filho Roberto , Monteiro Maristela Goldnadel , Calil Helena Maria
Published: May 2006

Background: Studies have indicated that MK‐801 (a noncompetitive N‐methyl‐d‐aspartate receptor antagonist) participates in the long‐term neural changes responsible for sensitization to stimulant drugs. It is known that repeated administration of low doses of ethanol sensitizes animals to its stimulant effect. In this work we investigated whether MK‐801 alters the development of behavioral sensitization to ethanol.

Methods: Groups of male Swiss mice were treated with saline or ethanol (2.0 g/kg) plus saline or MK‐801 (0.25 mg/kg) for 21 days. On day 25, all animals received an ethanol challenge injection (2.0 g/kg). We measured locomotor activity on days 1, 7, 14, 21 and 25. In addition, we assessed the effects of different doses of MK‐801 on the response to a low dose of ethanol (2.0 g/kg).

Results: Ethanol‐treated mice developed sensitization to the locomotor‐stimulating effect of the drug, whereas those concomitantly receiving ethanol and MK‐801 did not. All doses of MK‐801 that were used stimulated the locomotor activity of both ethanol and saline‐treated animals.

Conclusions: The findings support the hypothesis that N‐methyl‐d‐aspartate receptors have an important role in the development of sensitization to drugs of abuse.
Effect of Ethanol on Brain Metallothionein in Transgenic Mice
Authors: Suzuki Yutaka , Cherian M. George
Published: May 2006

Background: Three isoforms of metallothionein (MT‐I, ‐II, and ‐III) have been detected in mice brain but little is known on their inducibility. Therefore, changes in MT levels in brain were investigated in MT‐I overexpressing transgenic mice (MT‐I*) and wild type mice of the same strain (C57BL/6J) after oral administration of ethanol.

Methods: All experimental mice were given 4 g/kg of ethanol by gastric intubation. In addition, to account for the stress of animal handling, both groups of mice (MT‐I* and C57) were given distilled water by gastric intubation and used as controls. At different times after ethanol/water treatment, the mice were killed and the brains were dissected into six regions. The total amount of MT in the brain and different regions were measured by a cadmium‐binding assay. Zinc and copper were measured by atomic absorption spectrometry. The results were compared with untreated mice and corresponding control mice.

Results: In C57BL/6J mice, the whole brain MT was increased by ∼1.29‐fold at 12 hr and ∼1.27‐fold at 18 hr after ethanol administration compared with basal levels. In MT‐I* male mice, the whole brain MT was increased by ∼1.64‐fold at 12 hr and ∼1.62‐fold at 18 hr after ethanol administration, whereas in MT‐I* female mice, it was increased by ∼1.57‐fold at 12 hr and ∼1.57‐fold at 12 hr and ∼61‐fold at 18 hr after ethanol administration. Although the zinc and copper levels in the whole brain were not altered, the zinc level in the cerebellum at 12 and 18 hr in male and female MT‐I* mice were increased, and zinc levels in the hippocampus of male MT‐I* mice were increased at 12 and 18 hr after ethanol treatment.

Conclusions: Acute or chronic ethanol administration can cause generation of oxygen free radical and oxidative stress to the brain. The generation of free radicals is thought to be one of the causes of cell injury after ethanol administration. The mechanism of induction of MT in brain after oral ethanol administration may be associated with oxidative stress caused by ethanol or its metabolites, and can be considered as a protective mechanism against ethanol toxicity.
Impaired Protein Synthesis Induced by Acute Alcohol Intoxication Is Associated With Changes in eIF4E in Muscle and eIF2B in Liver
Authors: Lang Charles H. , Frost Robert A. , Kumar Vinayshree , Wu Duanqing , Vary Thomas C.
Published: May 2006

Background: Acute alcohol intoxication in rats decreases protein synthesis in skeletal muscle and, to a lesser extent, in liver. The purpose of the present study was to examine potential mechanisms for the inhibitory effect of acute ethanol exposure.

Methods: Rats were injected intraperitoneally with either ethanol (75 mmol/kg) or saline, and tissues were examined 2.5 hr later. Rates of protein synthesis in vivo were determined by [3H]phenylalanine incorporation into protein, and various eukaryotic initiation factors (eIFs) were quantitated by Western blot analysis to identify possible mechanisms for regulating translation.

Results: Protein synthesis in gastrocnemius and liver was decreased (39% and 21%, respectively) after alcohol administration, compared with saline‐injected control animals. Alcohol administration did not alter tissue RNA content but diminished translational efficiency in muscle (43%) and liver (24%). Hepatic eIF2B activity was decreased 24% in alcohol‐treated rats, and this was associated with a 95% increase in eIF2α phosphorylation. However, alcohol did not alter the amount of 4E‐binding protein 1 (4E‐BP1) bound to eIF4E, eIF4E bound to eIF4G, or the phosphorylation state of either 4E‐BPI or eIF4E. In contrast to liver, neither eIF2B activity nor the phosphorylation of eIF2α was affected in muscle of alcohol‐treated rats. However, acute alcohol intoxication increased binding of 4E‐BP1 to eIF4E (113%), decreased the amount of eIF4E bound to eIF4G (81%), and decreased the amount of 4E‐BP1 in the phosphorylated γ‐form (77%). The plasma concentrations of insulin and insulin‐like growth factor‐I were unchanged by alcohol, but muscle insulin‐like growth factor‐I messenger ribonucleic acid abundance was decreased 35%.

Conclusions: These data suggest that acute alcohol intoxication decreases translation initiation and protein synthesis in liver and muscle via different mechanisms. Changes in eIF2B appear to predominate in liver, whereas alterations in eIF4E availability appear more critical in skeletal muscle for controlling translation initiation.