bluuebunny/crossref_metadata_2025 huggingface dataset:
Toward an Alcohol Treatment Model: A Comparison of Treated and Untreated Respondents with DSM‐IV Alcohol Use Disorders in the General Population
Authors: Grant Bridget F.
Published: April 2006

The purpose of this study was to compare characteristics of person with alcohol use disorders who sought alcohol treatment with those who did not using data from a nationally representative sample of the United States. Applying an organizing framework from the larger literature on service utilization, a logistic regression analysis was conducted to examine the interaction among factors influencing treatment. The results identified unemployment status and lower educational level as barriers to alcohol treatment, but the impact of these factors differed depending on whether the respondent had previous experience with alcohol treatment. The major findings of this study are discussed in terms of consumer satisfaction, minimizing barriers to alcohol treatment services, and the need to examine individual determinants of alcohol treatment within the larger context of organizational and sociopolitical factors.
Ethanol Alters Spatial Processing of Hippocampal Place Cells: A Mechanism for Impaired Navigation When Intoxicated
Authors: Matthews Douglas B. , Simson Peter E. , Best Phillip J.
Published: April 2006

This study describes a new mechanism by which ethanol alters brain function and may impair performance on tasks requiring spatial navigation. Recording electrophysiological activity from single neurons in the awake, freely behaving animal, the present study shows that ethanol impairs the ability of place cells in the hippocampus to process spatial information. The impairment by ethanol in spatial processing of place cells was remarkably similar to the impairment produced by lesions of afferents to the hippocampus, except that the effect of ethanol was reversible. Since lesions to hippocampal afferents that alter spatial processing of place cells concomitantly impair spatial navigation, the present results suggest that ethanol similarly impairs spatial navigation by altering spatial processing of place cells. The present results have implications for the observation that ethanol impairs performance on navigational tasks that require spatial processing, such as automobile driving.
A Nonhuman Primate Model of Type II Excessive Alcohol Consumption? Part 1. Low Cerebrospinal Fluid 5‐Hydroxyindoleacetic Acid Concentrations and Diminished Social Competence Correlate with Excessive Alcohol Consumption
Authors: Higley J. D. , Suomi S. J. , Linnoila M.
Published: April 2006

Developmental, biochemical, and behavioral concomitants of excessive alcohol consumption were investigated using a nonhuman primate model. The variables of interest were: (1) interindividual stability of cerebrospinal fluid (CSF) 5‐hydroxyindoleacetic acid (5‐HIAA) from infancy to adulthood, (2) effect of parental deprivation early in life on adult CSF 5‐HIAA concentrations; (3) correlations between CSF 5‐HIAA and 3‐methoxy‐4‐hydroxyphenylglycol (MHPG) concentrations and alcohol consumption; and (4) correlation between the frequency of competent social behaviors and alcohol consumption. Twenty‐nine rhesus macaques were reared for their first 6 months either with their mothers or without adults in peer‐only conditions. At 6 and 50 months of age, each subject underwent a series of four, 4‐day social separations. Cisternal CSF was sampled before and during the first and last separations; concomitantly, observational data were collected on social dominance behavior in the home‐cage. When they reached 50 months of age, the monkeys were provided free access to a palatable alcohol solution daily for 1‐hr periods before, during, and after the social separations. Before and after the 50‐month separations, data were collected on all types of social behavior in the home‐cage. Results showed that peer‐reared subjects consumed more alcohol than mother‐reared subjects during baseline conditions. Mother‐reared subjects, however, increased their rates of consumption to equal peer‐reared subjects' rates of consumption during the conditions of a social separation stressor. Peer‐reared subjects also exhibited lower CSF 5‐HIAA concentrations in infancy and adulthood than their mother‐reared counterparts. With rearing condition held constant, interindividual differences in CSF 5‐HIAA, MHPG, and homovanillic acid were stable from infancy to adulthood, and high rates of alcohol were consumed by the young adult monkeys with low CSF 5‐HIAA and MHPG concentrations, particularly when the CSF was obtained during the social separations. High rates of alcohol consumption were also observed in subjects with infrequent social interactions and less competent social behaviors. In contrast to the human data, we found no gender differences in rates of alcohol consumption, nor in the correlations between alcohol consumption and the other variables. With some exceptions, findings from the study are generally consistent with predictions from Cloninger's type II model of excessive alcohol consumption in men with low CSF 5‐HIAA, who also exhibit impaired impulse control and violent and antisocial behaviors.
A Nonhuman Primate Model of Type II Alcoholism? Part 2. Diminished Social Competence and Excessive Aggression Correlates with Low Cerebrospinal Fluid 5‐Hydroxyindoleacetic Acid Concentrations
Authors: Higley J. D. , Suomi S. J. , Linnoila M.
Published: April 2006

The purpose of this study was to develop an animal model for behavioral features of type II, early‐onset alcohol abuse. To perform this research, cerebrospinal fluid (CSF) monoamine metabolite concentrations and home‐cage social behaviors of 29 rhesus macaque subjects were examined in a 4‐year longitudinal study. Half of the monkeys were reared for their first 6 months with their mothers, and the other half were reared without adults, instead with access only to monkeys of similar age. When the subjects were 6 months old, and again when they were 50 months old, they underwent a series of four, 4‐day social separations. We obtained cisternal CSF before and during the first and last separation of each series to quantify 5‐hydroxy‐indoleacetic acid (5‐HIAA), 3‐methoxy‐4‐hydroxyphenylgycol (MHPG), and homovanillic acid concentrations. After the 6‐month separations, subjects were placed into social groups, and social dominance rankings were assessed. Before and after the 50‐month separations, social dominance rankings were evaluated again, and home‐cage aggression and social behavior data were collected. Over the 3 1/2 years between CSF samplings, records were maintained of subjects' removal from their social groups for excessive aggression or treatment for wounding. Our results showed that among infants, reduced CSF 5‐HIAA was correlated with low social dominance. As young adults, subjects from both rearing groups with low CSF 5‐HIAA and MHPG concentrations exhibited reduced rates of social interaction and low social dominance rankings. In addition, peer‐reared subjects with low CSF 5‐HIAA concentrations exhibited inept social behaviors, and were frequently removed from their social groups for excessive aggression and deviant social behaviors. From these results, we conclude that the peer‐rearing paradigm aggravates the untoward social consequences associated with low CSF 5‐HIAA concentrations over and beyond reducing CSF 5‐HIAA concentrations, suggesting that early experiences may contribute to CNS serotonin changes that increase the disposition to type II‐related behaviors.
Effects of Alcohol Exposure and Artificial Rearing During Development on Septal and Hippocampal Neurotransmitters in Adult Rats
Authors: Kelly Sandra J.
Published: April 2006

The effect of alcohol exposure during the early postnatal period in the rat on the hippocampus and septal region was investigated. The alcohol group was given 5 g/kg/day of ethanol from postnatal days 4 to 10 via an artificial rearing procedure. Control groups consisted of a gastrostomy control group that was treated in the same manner as the alcohol group, but not exposed to alcohol and a suckle control group that was reared normally by dams. Between 90 and 100 days of age, the hippocampus and septal region were assayed under non‐stressed or stressed conditions using HPLC with electrochemical detection. Alcohol‐exposed female rats exhibited increased hippocampal noradrenaline concentrations under stressed conditions, increased septal serotonin, and 5‐hydroxyindoleacetic acid (5‐HIAA) concentrations under nonstressed conditions, and decreased septal dopamine concentrations under stressed conditions. Artificially reared male rats (regardless of alcohol exposure) exhibited an increase in hippocampal noradrenaline concentrations under stressed conditions; a decrease in hippocampal 5‐HIAA concentrations under nonstressed conditions; and a decrease in septal noradrenaline, serotonin, 5‐HIAA, and dopamine concentrations under nonstressed conditions. The results suggest that female rats may be more susceptible to alcohol exposure during the postnatal period than male rats and that male rats may be more susceptible to the effects of artificial rearing than female rats.
Correlated Responses to Selection in FAST and SLOW Mice: Effects of Ethanol on Ataxia, Temperature, Sedation, and Withdrawal
Authors: Shen Elaine H. , Dorow Janet D. , Huson Mary , Phillips Tamara J.
Published: April 2006

A replicated bidirectional selective breeding program has produced lines of mice that differ in locomotor response to ethanol (EtOH). FAST mice were bred for high locomotor activation, whereas SLOW mice were bred for low or depressed locomotor activity in response to 2.0 g/kg of EtOH. We tested FAST and SLOW mice for differences in sensitivity to the incoordinating (1.5 to 2.5 g/kg), hypothermic (3.0 g/kg), and sedative (4.0 g/kg) effects of EtOH, and for differences in sensitivity to withdrawal after acute and chronic EtOH exposure. SLOW mice were more ataxic in a grid test and developed greater tolerance than FAST mice at 2.0 g/kg of EtOH, were more hypothermic than FAST mice, and were more sensitive to the sedative effects of EtOH than FAST mice, as measured by latency to and duration of loss of righting reflex, and by blood ethanol concentrations at regain of the righting reflex. FAST mice had more severe withdrawal seizures after chronic exposure, but did not differ from SLOW mice in withdrawal severity after an acute injection of EtOH. These data suggest that FAST mice are generally more sensitive to central nervous system excitation, and SLOW mice are generally more sensitive to central nervous system sedation by EtOH, and further suggest genetic overlap with respect to genes that mediate locomotor responses to EtOH and genes determining sensitivity to EtOH‐induced ataxia, hypothermia, sedation, and withdrawal severity after chronic exposure. Our current observations are in contrast to observations made earlier in selection, in which few line differences in sensitivity to EtOH effects other than locomotor activity were found. Thus, it seems that continued selection for differences in locomotor response to EtOH has produced genetically correlated differences in other EtOH responses.
Relative Risk for the Development of Hepatocellular Carcinoma in Alcoholic Patients with Cirrhosis: A Multiple Logistic‐Regression Coefficient Analysis
Authors: Tsutsumi Mikihiro , Ishizaki Masao , Takada Akira
Published: April 2006

The hepatitis B virus (HBV) or hepatitis C virus (HVC) markers are frequently positive in alcoholic patients with hepatocellular carcinoma (HCC). However, the role of the relationship between HBV or HCV infection and alcohol drinking in the development of HCC has not been clearly documented. In the present study, the relative risk in 1200 cirrhotic patients with different etiologies who were admitted to five different hospitals in Japan was calculated using the multiple logistic‐regression coefficient analysis. In the HCV+ alcohol group, HCC patients tended to be younger, and the odds ratio for the development of HCC was significantly higher compared with the HCV‐alone group. Furthermore, the interaction coefficient of alcohol and HCV for the development of HCC was significant statistically. However, the interaction between HBV and alcohol was not significant. Because the proportion of male patients with HCC was significantly higher in the alcohol‐alone and HBV‐related groups than in the HCV‐related group, the multiple logistic‐regression analysis was also performed in male patients only. The results were nearly the same as those in male and female patients combined. These results suggest strongly that alcohol and HCV together accelerate the development of HCC. However, a similar relationship was not found between alcohol and HBV.
Prenatal Alcohol Exposure and Academic Achievement at Age Six: A Nonlinear Fit
Authors: Goldschmidt Lidush , Richardson Gale A. , Stoffer David S. , Geva Diklah , Day Nancy L
Published: April 2006

This is a report on the effects of prenatal alcohol exposure on the academic achievement of children at 6 years of age. In this longitudinal study, women were interviewed at the end of each trimester of pregnancy, at delivery, and at 8, 18, 36, and 72 months postpartum. The women were of lower socioeconomic status, high school‐educated, and moderate users of alcohol. The offspring received age‐appropriate physical and developmental assessments at each follow‐up. Linear regression and nonlinear curve fitting were used to investigate the nature and shape of the relationship between prenatal alcohol exposure and achievement. In addition, the role of child IQ in this relationship was explored. Alcohol exposure during the second trimester predicted deficits in each of the three subtests of the Wide Range Achievement Test‐Revised (WRAT‐R): reading, spelling, and arithmetic. The relationship was partially reduced by the addition of IQ to the model, but prenatal alcohol exposure still predicted significant deficits in achievement, even after controlling for IQ. Tests for the shape of the relationship demonstrated that the effect of prenatal exposure on the arithmetic subtest of the WRAT‐R was a linear or dose‐response relationship. By contrast, the relationships between prenatal alcohol exposure and performance on the spelling and reading subtests of the WRAT‐R were better modeled as threshold effects. The thresholds for both were ˜1 drink/day in the second trimester.
Alcohol, Central Nervous System Injury, and Time to Fatal Motor Vehicle Crashes
Authors: Zink Brian J. , Maio Ronald F. , Chen Bonny
Published: April 2006

Objectives: Motor vehicle crash (MVC) studies have found that alcohol (ALC) is associated with increased mortality and decreased time to death (TTD). Clinical and experimental data suggest that ALC potentiates central nervous system injury (CNSI). We hypothesize that ALC‐intoxicated, MVC fatalities with CNSI are more likely to die in the immediate postinjury period than are sober victims with CNSI. Methods: Design—A retrospective cohort of 401 MVC fatalities from four Michigan counties for the time period 1985 to 1991 was studied. Measurements—Medical examiner records were reviewed to determine age, blood alcohol concentration (BAC), and TTD. Injury severity was calculated with the Abbreviated Injury Scale (1985 version). Anatomical profile scores and G scores were also calculated and used to identify CNSI subjects. Analysis—χ2 and Student's t test were used, and odds ratios with 0.95 confidence intervals (CIs) were calculated. Results: ALC(+) cases (BAC ≥ 100 mg/dl) (n= 99) were significantly younger and more frequently had TTD < 1 hr than ALC(‐) cases (n= 233): odds ratio 1.62 [0.95 CI (1.02 to 2.50)]. Overall, CNSI cases (n= 297) were significantly younger and had fewer thoracic injuries, but did not have significantly shorter TTD, compared with non‐CNSI cases. However, ALC(+) CNSI cases (n= 77) were over twice as likely to have TTD < 1 hr (odds ratio 2.04 [0.95 CI (1.13 to 3.70)]}. For ALC(+) isolated CNSI cases, the odds ratio for TTD < 1 hr, compared with nonisolated CNSI cases was 8.25 (0.95; CI 0.66 to 102.5). Injury Severity Score, anatomical profile, and G scores were not Significantly different for ALC(+) CNSI cases, compared with ALC(‐) CNSI cases, whether isolated or nonisolated. Conclusions: These data suggest that alcohol intoxication is associated with increased frequency of early death in MVC victims with CNSI, despite there being no detectable difference in anatomical injury scoring.
Alcohol Effects on the Heritability of EEG Spectral Power
Authors: Sorbel J. , Morzorati S. , O'Connor S. , Li T.‐K. , Christian J. C.
Published: April 2006

To estimate the effects of a moderate dose of alcohol on heritability of the EEG power spectrum, 53 monozygotic and 38 like‐sexed dizygotic Caucasian twin pairs (aged 30.0 ± 7.0 years) were studied. Subjects were asked not to drink alcohol for 2 days and to fast after midnight before a protocol of: (1) a low fat meal at 8:00 AM; (2) a baseline EEG recording; (3) ingestion of alcohol over 10 min, which raised the breath alcohol concentration to 0.057 ± 0.017% (SD); followed by (4) a postalcohol EEG recording 35.1 ± 5.7 (SD) min after the start of drinking. One previous study (Propping, P., Hum. Genet. 35: 309–334,1977) found that heritability (H2), the fraction of total variance in the EEG power that is attributable to genetic influences, increased after alcohol administration. In the current study, H2 of log‐transformed, body‐weight‐adjusted spectral band power increased after alcohol for the θ‐, α‐slow, α‐fast, β‐slow, and β‐fast bands (from an average of 0.47 to an average of 0.80). The increase in heritability was accompanied by a significant decrease in the within‐pair differences of monozygotic cotwins for all of the same frequency bands except β‐fast. Because within‐pair differences are expected to contain only environmental factors for the genetically identical individuals, it was concluded that alcohol decreases environmental variation of EEG power spectral density, causing the increase in H2.
Fluoxetine Treatment Seems to Reduce the Beneficial Effects of Cognitive‐Behavioral Therapy in Type B Alcoholics
Authors: Kranzler Henry R. , Burleson Joseph A. , Brown Joseph , Babor Thomas F.
Published: April 2006

Objective: The aim of this study was to test the hypothesis that, because of abnormalities in serotonergic neurotransmission that may underlie craving and impulsive behavior, fluoxetine treatment differentially affects drinking among type B alcoholics, who are characterized by high levels of both premorbid vulnerability and alcohol‐related problems. Methods: Using a k‐means clustering procedure, alcohol‐dependent subjects from a placebo‐controlled trial of fluoxetine were grouped into low‐risk/severity (type A n= 60) and highrisk/severity (type B: n= 35) groups. Multivariate analysis of covariance (with pretreatment measures as covariates) evaluated the effects of Alcoholic Subtype, Medication Group, Treatment Completion, and their interactions on measures of drinking, both during the 12‐week treatment period and a 6‐month follow‐up period. Results: Although there were no main effects of Alcoholic Subtype or Medication Group, subjects who completed the treatment trial showed significantly better drinking‐related outcomes. There was also an interaction of Alcoholic Subtype by Medication Group during treatment. Among type B subjects, fluoxetine treatment resulted in poorer drinking‐related outcomes than placebo treatment. Among type A subjects, there was no effect of Medication Group. This interactive effect did not persist during the 6‐month follow‐up period. Conclusions: Alcoholic subtypes identified by cluster analysis seem to be differentially responsive to the effects of fluoxetine treatment on drinking‐related outcomes. Serotonergic abnormalities previously identified among a subgroup of alcoholics who are also characterized by impulsivity and severity of alcohol dependence may help to explain the differential medication effect. Based on these findings, it is recommended that, in the absence of a comorbid mood or anxiety disorder, fluoxetine not be used to maintain abstinence or reduce drinking in high‐risk/severity alcoholics.
A Comparative Analysis of Alcohol in Fatal and Nonfatal Bicycling Injuries
Authors: Li Guohua , Baker Susan P. , Sterling Sophia , Smialek John E. , Dischinger Patricia C. , Soderstrom Carl A.
Published: April 2006

Bicycling is the leading cause of recreational injury, resulting in more than half a million emergency department visits and about 900 deaths each year in the United States. Previous research on bicycling injury was conducted predominantly in children and focused on the effectiveness of safety helmets. Few studies have examined the role of alcohol in bicycling injuries. This study examined the magnitude of and factors related to alcohol involvement in fatal and nonfatal bicycling injuries, and tested the hypothesis that alcohol intoxication is associated with significantly increased likelihood of fatality given a serious bicycling injury. Medical examiner data on all fatally injured bicyclists aged 10 years or older from 1987 to 1994 in Maryland (fatal cases, n= 63) were compared with trauma registry data on all injured bicyclists who were treated at a regional trauma center during the same time period (nonfatal cases, n= 253) on variables related to blood alcohol concentrations (BACs), demographic characteristics, and injury circumstances. The fatal cases were more likely than the nonfatal cases to have positive BACs (30% vs. 16%, p < 0.01). and to be legally intoxicated (is., BACs ≥ 0.10%) (22% vs. 13%, p < 0.01). For both fatal and nonfatal cases, intoxication was more prevalent among victims who were male, aged 20 to 39 years, or who were injured at nighttime (7:00 PM to 6:59 AM). Bicyclists who died at the scene were four times as likely as those who died at hospitals to be legally intoxicated (35% vs. 9%, p < 0.02). Given a serious bicycling injury, intoxication was associated with significantly increased likelihood of fatality, with an adjusted odds ratio of 2.8 (95% confidence interval, 1.3 to 6.3). This increased likelihood of fatality was probably due in part to the fact that the rate of helmet use at the time of injury among the intoxicated was much lower than among the sober (vs. 31%, p < 0.05). Results indicate that alcohol plays an important role in fatal and serious bicycling injuries. Preventing intoxicated biking should be incorporated into helmet campaigns and other bicycle safety programs.
Models of Treatment Seeking for Alcoholism: The Role of Genes and Environment
Authors: True William R. , Heath Andrew C. , Bucholz Kathleen , Slutske Wendy , Romeis James C. , Schemer Jeffrey F. , Lin Nong , Eisen Seth A. , Goldberg Jack , Lyons Michael J. , Tsuang Ming T.
Published: April 2006

We investigated the relative influence of genes and environment on the decision to seek treatment for alcoholism under three models of health care utilization. Lifetime alcohol dependence and two measures of treatment seeking for alcohol problems were determined from a 1992 telephone administration of the Diagnostic Interview Schedule. Data were analyzed from 1,864 monozygotic and 1,492 dizygotic male twin respondents from the Vietnam Era Twin Registry. Genetlc and environmental contributions to the decision to seek treatment for alcoholism were assessed under competing models for the relationship between genetic influences on alcoholism risk and genetic influences on treatment seeking among those who became alcoholics. Under the best‐fitting model, genetic influence accounted for 41% of the variance in treatment seeking and 55% of the liability for alcoholism. Shared environment explained none of the variance in liability for alcoholism, but 40% of the variance in treatment seeking. The severity of alcoholism alone is an inadequate model of treatment seeking, because decisions to seek alcohol treatment are also influenced by substantial genetic and or shared environmental factors unrelated to the determinants of alcoholism.
Dopamine Receptors in the Medial Prefrontal Cortex Influence Ethanol and Sucrose‐Reinforced Responding
Authors: Hodge Clyde W. , Chappelle Ann M. , Samson Herman H.
Published: April 2006

This study tested the role of dopamine receptors in the medial prefrontal cortex (mPFC) in the onset, maintenance, and termination of ethanol and sucrose‐reinforced responding. Two groups of Long Evans rats were trained to lever press on a fixed‐ratio 4 schedule of reinforcement with 10% ethanol (n = 10) or 5% sucrose (n = 5) presented as the reinforcer. After implantation of injector guide cannulae, the D2/3, agonist quinpirole and the D2 antagonist raclopride were administered bilaterally into the mPFC before behavioral sessions. During control conditions, sucrose reinforcement maintained a 2‐fold greater number of responses per session than did ethanol reinforcement. Quinpirole (10.0 μg/μl) reduced total ethanol‐reinforced responses by delaying response onset and decreasing the duration of responding, but had no effect on response maintenance (i.e., response rate). A higher dose of quinpirole (20.0 μg/μl) decreased total sucrose responses by simultaneously decreasing duration and response rate, without altering response latency. Thus, the effects of quinpirole on ethanol and sucrose‐reinforced responding were similar on response total and duration, but differential on response latency and rate. Raclopride (0.05 and 1.0 μgl/μl) decreased total ethanol responding and rate, but doses as much as 400‐fold greater (20.0 μg/μl) did not alter sucrose response totals. Raclopride alone had no effect on response latency or duration measures in either reinforcement condition. Coadministration of raclopride blocked the quinpirole‐induced increase in response latency (ethanol reinforcement) and decrease in response rate (sucrose reinforcement), but had no effect on other response measures. These data are consistent with the interpretation that D2 and D3 receptors in the mPFC are differentially involved in ethanol and sucrose response onset and maintenance, but similarly involved in response termination. However, differences in baseline response parameters and group size may have contributed to the observed effects.
Effect of Chronic Ethanol Consumption on the Atrial Natriuretic System of Spontaneously Hypertensive Rats
Authors: Guillaume Pascal , Jankowski Marek , Gianoulakis Christina , Gutkowska Jolanta
Published: April 2006

There is a lot of discussion on the effects of ethanol (ETOH) on blood pressure (BP). It has been suggested that chronic moderate ETOH consumption prevents the development of age‐dependent hypertension in humans and spontaneously hypertensive rats (SHR). However, the mechanism mediating this effect is unknown. In the present studies, we hypothesized the implication of atrial natriuretic peptide (ANP), a BP‐lowering hormone, on the antihypertensive effect of moderate ETOH consumption. A 20% v/v solution of alcohol was given as drinking fluid to SHR and normotensive Wistar‐Kyoto (WKY) rats for up to 32 weeks. This treatment prevented, at least in part, the age‐dependent increase of BP in SHR and WKY rats. The lower BP was associated with significantly lower levels of circulating atrial natriuretic peptide in both groups. After chronic ETOH administration, total ANP content and concentration were higher in the left and right atria of SHR and WKY rats than in water‐treated controls. Despite the ETOH‐induced increase in atrial ANP content, there was no significant change in atrial ANP mRNA, suggesting decreased atrial release. Chronic ETOH treatment significantly reduced ANP mRNA in the ventricles of SHR but not of WKY rats. Correspondingly, ventricular ANP content and concentration were lowered by ETOH in SHR only. Chronic ETOH administration induced a significant increase of plasma arginine vasopressin and a significant decrease of plasma aldosterone in SHR but not in WKY rats. Thus, chronic ETOH treatment prevented the age‐dependent elevation of BP in both SHR and WKY rats, and altered the activity of heart ANP as well as of the aldosterone and plasma arginine vasopressin systems.
Prenatal Ethanol Exposure Alters the Expression of Intestinal Hydrolase mRNAs in Newborn Rats
Authors: Estrada Gemma , Krasinski Stephen D. , Rings Edmond H. H. M. , Büller Hans A. , Grand Richard J. , López‐Tejero M. Dolores
Published: April 2006

To gain insight into the postnatal growth delay induced by ethanol in utero, we characterized functional impairments of the small intestine of neonatal rats prenatally exposed to ethanol using a well‐described model of gestational alcoholism (25% ethanol w/v in the drinking water). Expression of the intestinal enzymes–lactase‐phlorizin hydrolase (LPH) and intestinal alkaline phosphatase (IAP)‐that are critical for enteral nutrition of neonates was studied. Characteristic patterns of LPH and IAP expression along the proximal‐distal (horizontal) and crypt‐villus (vertical) axes of the small intestine, as well as the intracellular localization of LPH and IAP mRNAs and immunoreactive proteins within absorptive enterocytes, were not altered by prenatal exposure to ethanol. However, a 10‐ to 15‐fold increase in the number of LPH and IAP mRNA molecules per absorptive enterocyte was found throughout the intestine of ethanol‐exposed neonates, compared with controls, whereas lectese and alkaline phosphatase activities per enterocyte remained unchanged. These findings suggest that ethanol in utero alters the mRNA abundance of epithelial enzymes in newborn rat small intestine. Changes in mRNA abundance could be an important aspect of enterocyte adaptation to high ethanol concentrations in gastrointestinal amniotic fluid of ethanol‐exposed fetuses.
Norepinephrine and Serotonin Receptors in the Paraventricular Nucleus Interactively Modulate Ethanol Consumption
Authors: Hodge Clyde W. , Slawecki Craig J. , Aiken Amy S.
Published: April 2006

The homeostatic function of the hypothalamus has long been recognized. In particular, the role of the paraventricular nucleus (PVN) in regulating ingestive behavior has been of interest. Infusions of serotonin and norepinephrine into the PVN are correlated with nutrient selective decreases and increases in consumatory behavior, respectively. Given the wide range of homeostatic functions of the hypothalamus, it is plausible that similar hypothalamic mechanisms may also be involved in the regulation of ethanol intake. This study examined the effects of PVN infusions of serotonin (5‐HT) and norepinephrine (NE) on ethanol intake in a 1‐hr limited‐access two‐bottle paradigm. When intake of 6% (v/v) ethanol versus water stabilized, male Wistar rats were implanted with stainless steel guide coannulae aimed at the PVN. After recovery, NE (20.50, and 100 nmol), 5‐HT (5 and 25 nmol), and their combination (NE 50 nmol + 5‐HT 5 nmol) were microinjected into the PVN in a volume of 0.5 μl/side over 1 min. Baseline ethanol intake was approximately 1.0 g/kg and ethanol preference (milliliters ethanol per total milliliters) was approximately 60%. Both 20 and 50 nmol of NE significantly increased absolute ethanol intake by 50% and relative ethanol intake by approximately 30%. Corresponding decreases were observed in water intake. Neither dose of 5‐HT when administered alone altered ethanol or water consumption, but the 5‐nmol dose of 5‐HT attenuated the increase observed after NE (50 nmol) administration. These data demonstrate that NE and 5‐HT receptors in the PVN interact in the modulation of ethanol ingestion. This finding suggests that homeostatic regulatory functions of the hypothalamus are involved in ethanol intake, and a perturbation of this system may influence excessive drinking.
Hepatic Saturation Mechanism of Ethanol: Application of Mathematical Models to Ethanol Outflow Profiles in the Perfused Rat Liver
Authors: Matsumoto Hiroshi , Fukui Yuko
Published: April 2006

The saturation mechanism of hepatic ethanol (EtOH) elimination was studied in the perfused rat liver. EtOH outflow profiles after the instantaneous administration of 3 (mg/ml) × 0.4 (ml), 12 × 0.1, 24 × 0.1, and 3 × 0.1 mg (as a dose concentration × a volume) through the portal vein were analyzed by the statistical moment analysis and mathematical models (i.e., dispersion models). Results for 3 × 0.1 and 12 × 0.1 mg doses by moment analysis were similar. This demonstrated that the elimination exhibits linear kinetics. Recovery ratio and hepatic volume of distribution for 3 × 0.4 and 24 × 0.1 mg were larger than those for 3 × 0.1 and 12 × 0.1 mg doses and were similar. Kinetics after administration of 3 × 0.4 and 24 × 0.1 mg may be nonlinear. A difference in the relative dispersion (CV2) obtained by moment analysis between 3 × 0.4 and 24 × 0.1 mg doses indicated different properties of the nonlinear elimination kinetics. There were no differences in all the parameters in the one‐compartment dispersion model between 3 × 0.4 and 24 × 0.1 mg doses. In the two‐compartment dispersion model, there were differences in the blood volume (VB) and the forward partition rate constant (K12) between 3 × 0.4 and 24 × 0.1 mg (p < 0.05), whereas the elimination rate constant (ke) and the dispersion number values for these doses were similar. These findings demonstrated that there is difference in the no‐equilibrium process between 3 × 0.4 and 24 × 0.1 mg doses. Therefore, we suggest that the continuous EtOH input into the liver causes the saturation of enzyme pathways and the change of the nonequilibrium process.
Metabolism of Acetaldehyde to Acetate by Rat Hepatic P‐450s: Presence of Different Metabolic Pathway from Acetaldehyde Dehydrogenase System
Authors: Kunitoh Satoru , Asai Hirohide , Imaoka Susumu , Funae Yoshihiko , Monna Takeyuki
Published: April 2006

NADPH‐dependent activity of acetaldehyde oxidation was investigated in microsomes by assaying [14C]acetic acid produced from [14C]acetaldehyde with ion‐exchange column. Rat hepatic microsomes exhibited acetaldehyde oxidation activity in the presence of NADPH. This activity was induced 2‐fold by the treatment of rats with ethanol. We designated this NADPH‐dependent oxidation system as microsomal acetaldehyde‐oxidizing system (MAOS), to distinguish from the NAD‐dependent acetaldehyde oxidation system by acetaldehyde in mitochondria and cytsol. We further investigated essential enzymes contributing to MAOS activity. Acetaldehyde oxidation activity was investigated in eight forms of purified P‐450 in a reconstituted system. Cytochrome P‐450 (CYP) 2E1 had the highest oxidation activity and CYP1A2 and CYP4A2 had the next highest activity. Other forms had low activity. To assess the contribution of these forms to MAOS activity, immunoblot was done. CYP2E1 was induced 2‐fold by ethanol treatment, but CYP1A2 and CYP4A2 were not, reflecting the MAOS activity increased by ethanol treatment. These results suggest that CYP2E1 is the essential enzyme in the MAOS of rats.
Analysis of CA Repeats in First Intron of Class I ADH Gene in Long‐Evans Cinnamon Rats Developing Fatal Intoxication after Ethanol Intake
Authors: Katsuki Shinichi , Kato Junji , Nakajima Masahiro , Inui Noriaki , Sasaki Katsunori , Kohgo Yutaka , Niitsu Yoshiro
Published: April 2006

The Long‐Evans Cinnamon (LEC) rat is a mutant strain established from Long‐Evans rats that displays spontaneous hepatitis and liver cancer. We previously demonstrated that LEC rats died of acute ethanol intoxication after being fed a liquid diet containing 5% ethanol. Furthermore, we found that both alcohol dehydrogenase (ADH) and aldehyde dehydrogenase activities were remarkably suppressed in the liver of LEC rat, compared with Wistar rats. In the present study, we further investigated ethanol metabolism in the non‐ADH pathway and what caused the decrease of liver ADH activity in LEC rats. Blood ethanol concentration 5 hr after intraperitoneal administration of ethanol in LEC rats was higher than in the Wistar rats, indicating that ethanol oxidation was impaired in LEC rats. The expression of liver cytochrome P‐450IIE1 in the LEC rat was as much as that in Wistar rats. Regarding decreased ADH activity in the liver of LEC rats, we examined an alternating purine‐pyrimidine (CA) repeatlength polymorphism in the first intron of a class I ADH gene that would play a role in altering ADH activity. A polymerase chain reaction method was used to amplify the CA repeat in the first intron of this class I ADH gene, a nine CA repeat insertion and a point mutation were detected in LEC rats. These results suggest that this alternating sequence would modify transcription of the class I ADH gene in LEC rats. Thus, LEC rats have abnormal ethanol metabolism in the ADH pathway.
Identification of Cholesta‐3,5‐dien‐7‐one by Gas Chromatography‐Mass Spectrometry in the Erythrocyte Membrane of Alcoholic Patients
Authors: Adachi Junko , Hojo Keiko , Ueno Yasuhiro , Naito Takeaki , Ninomiya Ichiya , Imamichi Hiroyuki , Tatsuno Yoshitsugu
Published: April 2006

Lipids and oxidized lipids were analyzed by gas chromatography‐mass spectrometry in the erythrocyte membranes of alcoholic and control subjects. Cholesta‐3,5‐dien‐7‐one and cholesta‐trienes were detected in alcoholic samples examined, but not in significant amounts in controls. Levels of polyunsaturated fatty acids (arachidonic acid, 20:4; docosahexaenoic acid, 22:6; and docosatetraenoic acid, 22:4) in alcoholic samples declined significantly, whereas cholesta‐3,5‐dien‐7‐one levels increased. A high level of total bilirubin was observed in most patients. A possible mechanism of the accumulation of choletsa‐3,5‐dien‐7‐one in the erythrocyte membrane of alcoholics is discussed.
Detection of Activity in the Conditioned Medium of Ethanol‐Treated HepG2 Cells which Stimulates Collagen Synthesis in IMR‐90 Cells
Authors: Inui Noriaki , Kato Junji , Kohgo Yutaka , Katsuki Shinichi , Niitsu Yoshiro
Published: April 2006

Hepatic fibrosis often occurs in alcoholic liver diseases without accompanying tissue necrosis or inflammation. However, the precise mechanism of this fibrosis has not been fully clarified. In the present study, using the hepatoblastoma cell line HepG2 as a model for hepatocytes, we identified a factor that stimulates collagen synthesis of fibroblasts in a conditioned medium of HepG2 cells after treatment with ethanol. Type I procollagen peptide (PIC) in a culture of human fibroblast IMR‐90 markedly increased after incubation with the conditioned medium of ethanol‐treated HepG2 cells. The stimulating activity on the production of PIC by IMR‐90 remained after the dialysis and evaporation of the conditioned medium of HepG2 cells, indicating this factor was not as volatile from low molecular substances such as acetaldehyde, acetate, or lactate. The activity of this factor diminished with heat or trypsin treatment. A gel chromatographic analysis disclosed that the molecular weight of this factor was ˜8000 Da. These results suggest that a polypeptide factor secreted from HepG2 cells by treatment with ethanol stimulates collagen synthesis of fibroblasts.
Usefulness of Technetium‐99m‐Galactosyl Human Serum Albumin Liver Scintigraphy for Assessment of Severity of Alcoholic Hepatitis
Authors: Itano Satoshi , Sata Michio , Kumashiro Ryukichi , Hirai Kenji , Tanikawa Kyuichi
Published: April 2006

We performed a liver scintigraphy using technetium‐99m diethylene‐triaminepentaacetic acid‐galactosyl human serum albumin (99mTC‐GSA), which images the functional liver mass through its binding to the specific receptor asialoglycoprotein receptor in patients with severe alcoholic hepatitis. Receptor index (LHL 15) was significantly lower in patients with alcoholic hepatitis, compared with controls with normal liver. Difference in the isotope uptake patterns between liver and heart varied according to the severity of liver disease, and made it possible to categorize 5 grades. Grading score could discriminate between the eventual outcome of the patients. Furthermore, single photon emission computed tomography showed the variable uptake patterns in the hepatic lobule, wherein there were no evident findings in macroscopic view at autopsy. The results of this study show the usefulness of 99mTc‐GSA scintigraphy in the evaluation and prognosis of alcoholic hepatitis.
Roles of Alcohol, Hepatitis Virus Infection, and Gender in the Development of Hepatocellular Carcinoma in Patients with Liver Cirrhosis
Authors: Miyakawa Happei , Izumi Namiki , Marumo Fumiaki , Sato Chifumi
Published: April 2006

To assess the interaction of alcohol, hepatitis C virus (HCV), and hepatitis B virus (HBV) infection in hepatocarcinogenesis, we prospectively observed 449 patients with liver cirrhosis (LC) who presented to our outpatient clinics in 1 month; 164 patients with habitual drinking [alcoholic liver‐liver cirrhosis (AL‐LC)] who had taken ≥72 g alcohol/day (HCV‐positive 81 cases: HCV + AL; HCV‐negative 83 cases: AL); 176 patients with HCV infection, but without alcohol intake; 34 patients with HBV infection; 6 patients with HCV and HBV coinfection; and 82 patients with liver diseases from other etiologies, such as primary biliary cirrhosis. In the HCV group, the cumulative occurrence rate of hepatocellular carcinoma (HCC) was 9%, 18%, and 23% in the first, second, and third years, respectively. In the HCV + AL group, that was 13%, 17%, and 28%, respectively. There was no difference in the HCC occurrence rate between the two groups. In the AL group, the cumulative HCC occurrence rate was only 1% during the observation period of 3 years. The occurrence rate was significantly lower in the AL group, compared with the HCV and the HCV + AL groups. In the HBV group, the cumulative occurrence rate of HCC during the observation period of 3 years was 17%, which was similar to that of the HBV + AL group, 14%. We also examined some other variables that might be related to the development of HCC. The cumulative occurrence rate of HCC in male patients was 31%, whereas that was 18% in female patients. In the HCV group, there was a significant increase of HCC occurrence rate in male patients. In contrast, no difference was observed in the HCC occurrence rate between male and female patients in the HBV group. The present study suggests that alcohol alone may not be an independent risk factor for HCC, nor does it accelerate HCC development in LC patients with HCV and HBV infection during the prospective observation of 3 years.
Possibility of 5‐HT3 Receptor Involvement in Alcohol Dependence: A Microdialysis Study of Nucleus Accumbens Dopamine and Serotonin Release in Rats with Chronic Alcohol Consumption
Authors: Yoshimoto K. , Yayama K. , Sorimachi Y. , Tani J. , Ogata M. , Nishimura A. , Yoshida T. , Ueda S. , Komura S.
Published: April 2006

The present study was performed to examine the involvement of serotonin‐3 (5‐HT3) receptors in the rat nucleus accumbens (ACC) in alcohol dependence. In alcohol‐treated rats, perfusion of 40 mM K+ and 100 mM ethanol (EtOH) through the microdialysis probe increased the extracellular levels of ACC dopamine (DA), compared with controls. Perfusion of the serotonin (5‐HT) uptake inhibitor sertlarine enhanced the extracellular levels of ACC 5‐HT in both groups. Increased 5‐HT availability in the synaptic clefts on the ACC further activated ACC DA release in the alcohol‐treated rats, in comparison with controls. In the final experiments, perfusion of the 5.0 μM 5‐HT3 receptor agonist 2‐methyl‐5‐HT (2‐Me‐5‐HT) through the microdialysis probe enhanced the extracellular levels of ACC DA. Magnitude of 2‐Me‐5‐HT‐induced DA release was significantly higher in alcohol‐treated rats than in controls. On the other hand, 40 mM K+‐ and 100 mM EtOH‐induced extracellular 5‐HT release in alcohol‐treated rats were markedly inhibited. These results show that (1) chronic alcohol intake increases the sensitivity of 5‐HT3 receptors, (2) 5‐HT3 receptors regulate DA release in the ACC, (3) the dopaminergic neuronal systems associated with 5‐HT3 ionophore in the ACC were upregulated after chronic alcohol exposure, and (4) chronic alcohol intake desensitizes the serotonergic neuronal systems in rat ACC. These findings suggest that neurochemical functions of 5‐HT3 receptors in regulating DA release in the ACC after alcohol exposure compensate for the dysfunction of serotonergic activity to restore the original properties in processing alcohol tolerance and that the development of alcohol dependence may be mediated by ACC 5‐HT3 receptors.
Effect of Glutathione on Inositol 1,4,5‐Triphosphate‐Induced Ca2+ Release in Permeabilized Hepatocytes from Control and Chronic Ethanol‐Fed Rats
Authors: Nomura Tomoyuki , Higashi Katsuyoshi , Hoshino Makoto , Saso Katsuhisa , Itou Makoto , Hoek Jan B.
Published: April 2006

The effect of oxidized and reduced glutathione on inositol 1,4,5‐trisphosphate (InsP3)‐induced Ca2+ release from endoplasmic reticular Ca2+ stores was studied in digitonin‐permeabilized hepatocytes from chronically ethanol‐fed rats and pair‐fed control animals. The fractional Ca2+ release induced by a subsaturating concentration of lnsP3 was significantly enhanced in cells from ethanol‐fed rats in the absence of a change in maximal lnsP3‐releasable Ca2+ pool size, and this difference was not affected by preincubation with reduced glutathione. Incubation with oxidized glutathione (1 mM) increased the efficacy of Ca2+ release by subsaturating concentrations of lnsP3 in both control preparations and in cells from ethanol‐fed rats. The shift in the InsP3 dose‐response curve was not significantly different between the two preparations. These findings suggest that the enhanced efficacy of InsP3‐induced Ca2+ release in hepatocytes from ethanol‐fed rats is not caused by the oxidation of protein‐bound thiol groups on the lnsP3 receptor.
Ethanol‐Induced Apoptosis and Oxidative Stress in Hepatocytes
Authors: Higuchi Hajime , Kurose Iwao , Kato Shinzo , Miura Soichiro , Ishii Hiromasa
Published: April 2006

This short review focuses on ethanol‐induced oxidative stress and hepatocyte apoptosis. Apoptosis is increasingly recognized as a fundamental biological process that impacts on an early development, maturation, and acquisition of disease states of multicellular organisms. Although the occurrence of apoptosis has been identified for many decades, relatively recent acceptance of this principle is evidenced by remarkable increases in special conferences and presentations on this topic as well as its rapidly expanding volume of scientific literature. Oxidative stress is well recognized to be a key step in the pathogenesis of ethanol‐associated liver injury. Ethanol administration induces an increase in lipid peroxidation either by enhancing the production of oxygen reactive species and/or by decreasing the level of endogenous antioxidants. Studies in our laboratory using a confocal laser scanning microscopic system strongly suggest that agents which inhibit ethanol‐induced oxidative stress effectively attenuate hepatocyte death, i.e., apoptosis and necrosis. In addition, our investigations demonstrated that inhibitors of intracellular antioxidants exaggerate ethanol‐associated hepatocyte apoptosis. Although the detailed mechanism still remains unknown, it is conceivable that an oxidant‐dependent mechanism is largely involved in the process for ethanol‐induced hepatocyte apoptosis.