bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of Ethanol on Maternal and Offspring Characteristics: Comparison of Three Liquid Diet Formulations Fed during Gestation
Authors: Vavrousek‐Jakuba Eva M. , Baker Ross A. , Shoemaker William J.
Published: April 2006

Maternal blood alcohol levels, weight gain during pregnancy, parturition time, perinatal mortality, and postnatal growth of offspring were compared in groups of pregnant rats fed one of three ethanol‐containing liquid diets (Kahn's formula = BSA diet, Revised Wiener's = RA6 diet, and Lieber‐DeCarli's high protein 82C diet = LDA diet). The three ethanol diets all contained the same amount of ethanol‐derived energy (36% of total energy), but differed in the amount of energy contributed by protein (17, 30, and 25%), fat (36, 24, and 13%), and carbohydrate (12,10, and 27%), respectively. The experimental design also included dams that were pair‐fed isocaloric ethanol‐free versions of the three ethanol diets (designated BSP, RP6, and LDA, respectively) and a group of dams fed a pelleted casein‐based solid diet (PC diet). All experimental diets were fed ad libitum from gestational day 7 to delivery. The effect of ethanol exposure in utero was most severe in mothers and offspring fed the BSA diet. The feed efficiency ratio (maternal weight gain/total dietary energy consumed) of this low‐protein ethanol diet was less than that of RA6 or LDA diets. The feed efficiency ratio calculated for RA6 and LDA diets was not different from that of PC diet. Compared with rats fed RA6 and LDA diets, the rats that were fed BSA diet exhibited deficient maternal weight gain, greater parturition delay, impaired fetal growth, and increased perinatal mortality among the offspring. BSA dams had the highest blood ethanol levels of all groups fed ethanol diets, and exhibited the least difference in blood ethanol concentrations between the day (2 PM) and night (9 PM) periods of the diurnal cycle. These differences in the peak and the day/night pattern occurred despite the observation that all dams ingested equivalent doses of ethanol (∼11 g/kg/day) over the period of the study. It is therefore postulated that the nutritional status of the pregnant animal plays a role in the absorption and/or metabolism of ethanol and thus modulates the exposure of the developing fetus to high blood ethanol levels.
Effects of Ethanol on Inositol 1,3,4,5‐Tetrakisphosphate Metabolism by Rat Brain Homogenates
Authors: Chandler L. Judson , Kurian Pawels , Crews Fulton T.
Published: April 2006

The hydrolysis of membrane phosphoinositides is widely recognized as an important signal transduction pathway in brain. One of the products of phosphoinositide hydrolysis, Ins (1,4,5)P3, is thought to participate in signal transduction by mobilizing intracellular calcium and it is now clear that Ins(1,4,5)P3 metabolism is a complicated process that may be highly regulated. In addition to being dephos‐phorylated by the action of a 5‐phosphatase, Ins(1,4,5)P3 can be phosphorylated by a 3‐kinase to Ins(1,3,4,5)P4. Although the physiological significance of the higher inositol polyphosphates is not clear, recent evidence suggests that Ins(1,3,4,5)P4 may also have important second messenger function. Since ethanol is known to have potent effects on synaptic transmission, we investigated the in vitro effects of ethanol on [3H]Ins(1,3,4,5)P4 metabolism by rat whole brain homogenates. Ins(1,3,4,5)P4 was rapidly hydrolyzed to Ins(1,3,4)P3, inositol bisphosphates [Ins(3,4)P2 and Ins(1,3)P2], inositol monophosphates [Ins(l)P/Ins(B)P and Ins(4)P], and to inositol by sequential dephosphorylation. No [3H]Ins(1,4,5)P3 was detected. Ethanol (500 mM), significantly accelerated the dephosphorylation of Ins(1,4,5)P3, resulting in a more rapid formation of inositol bisphosphates, monophosphates and inositol. However, intoxicating and sedative‐hypnotic concentrations of ethanol (30‐100 mM) had no effect upon Ins(1,3,4)P3 dephosphorylation, suggesting that pharmacologically relevant concentrations of ethanol do not directly effect the enzymes involved in the dephosphorylation of Ins(1,3,4,5)P4 to free inositol in brain.
Acetaldehyde Metabolism in Different Aldehyde Dehydrogenase‐2 Genotypes
Authors: Enomoto Nobuyuki , Takase Shujiro , Yasuhara Minoru , Takada Akira
Published: April 2006

In order to clarify the relationships between acetaldehyde (Ac‐CHO) metabolism and low Km (mitochondrial) aldehyde dehydrogenase (ALDHP) genotypes, hepatic ALDHS activity was determined and serial changes of blood Ac‐CHO levels after ethanol administration were analyzed in the individuals homorygous for the normal ALDH2 genes, heterozygous for the normal and mutant ALDH2 genes, and homozygous for the mutant ALDH2 genes. Genomic DNA was extracted from white blood cells and genotyping of ALDH2 was performed using the polymerase chain reaction technique and slot blot hybridization with synthesized oligonucleotide probes specific to the normal and mutant ALDH2 genes.

ALDH2 activity was not detectable in the liver in two cases of the mutant homozygote. In four out of eight cases of the heterozygote, hepatic ALDH2 activity was measurable, although the activity was lower compared with that in the normal homozygote. Blood ethanol levels after alcohol administration were not different among the three different ALDH2 genotypes. Blood Ac‐CHO levels after drinking of alcohol were significantly higher in the heterorygotes and the mutant homozygotes than in the normal homozygotes. The levels after a moderate amount of ethanol (0.8 g/kg of body weight) in a case of the mutant homozygote were not different from those of the heterozygotes. However, the levels after a small amount of ethanol (0.1 g/ kg of body weight) were significantly higher in the mutant homorygotes than in the heterozygotes.

These results indicate that hepatic ALDH2 activity is lacking completely, and metabolism of Ac‐CHO in the liver is severely impaired in the homozygotes of the mutant ALDH2 genes. On the other hand, the lack of hepatic ALDH2 activity is partial, and impairment of hepatic Ac‐CHO metabolism is mild, in the heterozygotes of the ALDH2 genes. Clear differences of blood Ac‐CHO levels after a small amount of ethanol suggest that blood Ac‐CHO levels after a small amount of ethanol are good markers for the evaluation of ALDH2 genotypes.
Ethanol Consumption Inhibits Fetal DNA Methylation in Mice: Implications for the Fetal Alcohol Syndrome
Authors: Garro Anthony J. , McBeth Dani L. , Lima Viera , Lieber Charles S.
Published: April 2006

Acute ethanol administration (3 g/kg twice a day) to pregnant mice, from the 9th thru the 11th day of gestation, resulted in hypomethylation of fetal deoxyribonucleic acid (DNA). Nuclei isolated from the fetuses of the ethanol‐treated mice had lower levels of methylase activity relative to controls even in the presence of excess S‐adenosylmethionine, which serves as the methyl donor for the enzyme DNA methyltransferase. Acetaldehyde, at concentrations as low as 3 to 10 μM, inhibited DNA methyltransferase activity in vitro. Since DNA methylation is thought to play an important role in the regulation of gene expression during embryogenesis, ethanol‐associated alterations in fetal DNA methylation may contribute to the developmental abnormalities seen in the fetal alcohol syndrome.
Ro15‐4513 Attenuates the Consumption of Ethanol in Deprived Rats
Authors: June Harry L. , Lummis Guy H. , Colker Richard E. , Moore Timothy O. , Lewis Michael J.
Published: April 2006

This research investigated the effects of Ro15‐4513 (Ro15), a partial inverse benzodiarepine agonist, on the drinking behavior of 23‐1/2 hr fluid deprived rats. Water‐deprived rats were maintained on a two‐bottle regimen of a saccharin‐ETOH solution along with tap water available for 30 min/day for several days. Following this acclimation period, animals were pretreated with either Ro15 (1.0, 2.5, and 5.0 mg/kg) or Tween‐80 vehicle injections. Pretreatment with Ro15 at all doses tested resulted in a significant reduction of the saccharin‐ETOH solution; however, Ro15 did not alter the rats’ consumption of water. The effects of Ro15 on general fluid consumption was investigated in Experiment 2. Following acclimation to a two‐bottle regimen of a saccharin‐solution and tap water 30 min/day, naive animals were pretreated with Tween‐80 vehicle or Ro15 injections. Ro15 failed to alter saccharin or water consumption. The results of this study support previous reports suggesting that Ro15 attenuates the oral consumption of ETOH; however, this effect does not appear to be due to a general suppression of fluid intake.
Changes with Age in the Proliferative Response of Splenic T Cells from Rats Exposed to Ethanol in Utero
Authors: Norman Dean C. , Chang Mei‐Ping , Wong Carol M. K. , Branch Berrilyn J. , Castle Steven , Taylor Anna N.
Published: April 2006

The fetal alcohol syndrome is associated with altered immunity. Several laboratories have confirmed that rodents exposed to ethanol in utero demonstrate both diminished proliferative responses of T cells to mitogens and diminished proliferative responses of T‐blast cells to human recombinant interleukin 2 (rIL2). We examined the developmental time course of these altered immune responses by testing the immune function of in utero ethanol‐exposed rats at various ages. We found that while diminished splenic T cell proliferative responses could not be detected at 2 weeks, they were present at 6 weeks after birth and suppression was maximal at 6 weeks and 3 months. Thereafter, at 5 and 7 months, the altered immune responses gradually declined and normalized at 8 months of age. Thus, both altered T cell mitogenesis and the blunted IL2‐induced proliferative response of T‐blast cells could serve as bio‐markers of fetal exposure to ethanol.
Blood Pressure Dysregulation Associated with Alcohol Withdrawal
Authors: King Andrea C. , Errico Austin L. , Parsons Oscar A. , Lovallo William R.
Published: April 2006

Alcoholics' blood pressures (BP) are typically elevated during withdrawal. Do such elevations predict future blood pressure dysregulation or are they simply a transitory effect of alcohol toxicity? Thirty‐two patients admitted to the hospital for alcohol detoxification were tested to examine the relationship between admission BP and response to isometric handgrip administered 4 to 5 days (session 1) and 3 to 4 weeks (session 2) postdetoxification. Alcoholics were divided into three groups based on admission BPs: Hypertensive (HT, ≥ 160/95 mmHg), Borderline Hypertensive (BHT, 140/90‐159/94 mmHg), and Normotensive (NT, < 140/90 mmHg). In sessions 1 and 2, the groups no longer differed on resting BP or heart rate (HR) but did differ on BP and HR response to handgrip: Compared with the NT group, the HT and BHT groups had greater rises in systolic and diastolic BP and HR. There was a trend for HT alcoholics to report a positive parental history of hypertension (91%) compared to BHT and NT alcoholics (64% and 60%, respectively), suggesting the existence of premorbid factors to this exaggerated cardiovascular response. Further, alcohol consumption, based on a quantity‐frequency index, was significantly higher in the HT group than in the NT group. The results suggest that transitory elevations in blood pressure observed during alcohol withdrawal may predict future BP abnormalities.
Individual Mood Profiles in Alcohol Withdrawal
Authors: Bokström Katarina , Balldin Jan , Långström Göran
Published: April 2006

Daily self‐reports of moods, using a Swedish Mood Adjective Check List with six bipolar dimensions, were performed in patients with alcohol dependence. One group (n = 13), consisting of inpatients in late withdrawal at a home for addicts, was studied for 6 weeks; another group (n = 12), consisting of outpatients in full remission, was studied for 1 week. The results of the ratings on the check‐list were used to test a statistical model for its capacity to describe the individual courses of mood states during the recovery process. Time Series Analysis revealed that the individual courses of moods fitted an autoregressive statistical model and could thereby be summarized in numerical measures for individual baselines, amplitudes, and lengths of recovery. Such individual profiles of the alcohol recovery process, may be useful for both clinical and research purposes, making it possible, for instance, to predict points in time for an individual's recovery with respect to his total well‐being, as well as the various dimensions of his mood states.
A Revised Conservative Estimate of the Incidence of FAS and its Economic Impact
Authors: Abel Ernest L. , Sokol Robert J.
Published: April 2006

We have conducted a new analysis of the incidence of fetal alcohol syndrome (FAS) and its economic impact based on prospectively gathered data of consecutive pregnancies. This more conservative analysis reflects our concern over possible inclusion of “false positives” in our previous estimate and now puts the overall rate in the western world at 0.33 cases per 1000. The estimate among whites is 0.29 per 1000 compared with 0.48 per 1000 for blacks. We did not include estimates for native Americans owing to the absence of prospectively gathered data on FAS for this group. Retrospective studies suggest larger disparities. Both prospective and retrospective studies may be influenced by examiner bias especially for minorities since minorities are often evaluated against standards derived from whites. Based on our estimates and the number of black and white children born each year, we estimate that about 1200 children are born with FAS each year in the United States. This is a probable lower limit based on considerations of ascertainment and absence of relevant information for other minorities such as native Americans. In calculating economic costs, we have now adjusted our estimates to take into account costs that would he incurred whether cases were FAS or not, and also have now included estimated costs for anomalies in FAS cases not considered in previous estimates. Based on these considerations, we now estimate the incremented annual cost of treating this disorder at $74.6 million. About three‐quarters of this economic burden is associated with care of FAS cases with mental retardation. This estimate is strictly limited to FAS and not specific alcohol‐related birth defects, the prevalence of which is probably much higher. Nevertheless, the extent of the problem and its economic consequences are still substantial.
Vitamin B12 and Folate Status in Rats after Chronic Administration of Ethanol and Acute Exposure to Nitrous Oxide
Authors: Koblin Donald D. , Everman Barbara W.
Published: April 2006

The chronic administration of ethanol or brief exposure to nitrous oxide (N2O) decreases the activity of hepatic methionine synthase and disrupts normal metabolic processes that require folate and vitamin B12. This combination of drugs has clinical relevance since alcoholic patients often require surgery and receive N2O as a component of their anesthetic. To assess this clinical problem using a rodent model, rats were given a liquid ethanol diet (35% of calories as ethanol) and control rats were pair‐fed a liquid diet with carbohydrate substituting for the caloric content of ethanol. After receiving liquid diets for 6 weeks, rats were exposed to 60% N2O/40% 02 for 6 hr. Urinary excretions of formic acid and formiminoglutamic acid (FIGLU) were used as indirect markers of folate status. In both the ethanol‐fed and control groups, excretion of formic acid and FIGLU markedly increased the first day after N2O and returned towards background values by the second day after N2O exposure. Ethanol treatment alone decreased methionine synthase activities in liver, but not kidney or brain. Exposure to N2O further decreased methionine synthase activities, and recovery of methionine synthase activity after N2O occurred over a period of 4 days at the same rate in both the ethanol‐fed and control groups. Ethanol treatment for 6 weeks combined with acute exposure to N2O did not deplete the rats of vitamin B12 in blood, liver, kidney, or brain. We conclude that in this animal model, chronic treatment with ethanol does not markedly exacerbate the disturbances in folate/vitamin B12 metabolism caused by brief exposure to N2O.
Serum β‐Hexosaminidase Isoenzyme: A Sensitive Marker for Alcohol Abuse
Authors: Hultberg B. , Isaksson A. , Berglund M. , Moberg A.‐L.
Published: April 2006

Serum β‐hexosaminidase (Hex) isoenzymes analyzed by enzyme immunoassay were investigated in a group of alcoholics (n = 38) hospitalized for detoxication, in another group of alcoholics (n = 22) abstinent between 6 days and 10 years and in a reference group (n = 20). Hex ‘B’ isoenzyme was elevated in all 38 patients hospitalized for detoxication but only 35 of these had total Hex values above the upper limit of the reference group. The Hex A isoenzyme, γglutamyltransferase, and aspartate aminotransferase showed considerable overlap between these patients and the reference group. In the group of 22 abstinent patients only one had an increased level of Hex A, Hex ‘B,’ and total Hex, whereas 10 had γ‐glutamyltransferase values above the upper limit of the reference group. It is concluded that Hex ‘B’ is a useful marker for alcohol abuse.
Plasma Norharman (β‐Carboline) Levels are Elevated in Chronic Alcoholics
Authors: Rommelspacher Hans , Schmidt Lutz G. , May Torsten
Published: April 2006

Based on the hypothesis that condensation products of neurotransmitters with aldehydes are involved in the pathogenesis of alcoholism, aromatic β‐carbolines (norharman and harman) were measured in the blood plasma of alcoholics and nonalcoholics. The identity of the extracted compounds was confirmed by various elution conditions of the high performance liquid chromatography (HPLC), newly developed radioreceptor assays, and the mass spectrum of norharman. The levels of norharman and harman in nonalcoholics were unchanged after a load with ethanol (1 g/kg body weight). The norharman levels of the alcoholics were significantly higher than that of the nonalcoholic controls (99.5 ± 26.6 pg/ml vs. 26.9 ± 10.7 pg/ ml; p < 0.001) and did not change significantly during a 3‐week detoxication period. In the subgroup of alcoholics with delirium or hallucinosis, a slight increase of norharman during detoxication could be detected while in alcoholics with vegetative withdrawal symptoms norharman levels dropped slightly over time (p = 0.07). No difference was found with respect to harman between nonalcoholics and alcoholics. These results suggest disturbed regulatory processes in the formation and/or metabolism of norharman in alcoholics. Further investigations are needed to reveal a possible marker function of norharman in alcoholic patients.
Diazepam Preference in Males with and without an Alcoholic First‐Degree Relative
Authors: de Wit Harriet
Published: April 2006

The relationship between family history of alcoholism and risk for benzodiazepine abuse was examined by assessing the reinforcing and subjective effects of diazepam (DZ; 4‐28 mg) in 14 normal (i.e., nonalcoholic) males with a first‐degree alcoholic relative (family history positive; FHP) and in 13 control subjects without alcoholic relatives (FHN). Reinforcing effects were measured using a double‐blind preference procedure in which subjects first sampled DZ and placebo (PL) and then chose the substance they preferred. Subjects were also allowed to select the dose of drug they preferred on each choice session. The subjective effects of DZ were assessed using standardized self‐report questionnaires. Neither group chose the DZ more often than PL. The FHP group chose DZ slightly (but not significantly) more often than the FHN group (mean choices FHP 1.42 vs. FHN 1.15 out of 3 choice options), and they chose slightly (but not significantly) more doses of DZ within sessions (FHP 25 mg vs. FHN 18 mg). The groups did not differ in their responses to DZ on other measures (e.g., subjective drug effects or drug liking). To the extent that laboratory procedures such as the one used here provide a model for assessing the abuse liability of drugs, these results do not provide strong evidence that males with a family history of alcoholism have an elevated risk for developing benzodiazepine abuse or dependence.
Alcohol‐Related Efficiency Deficits Using an Ecologically Valid Test
Authors: Nixon Sara Jo , Parsons Oscar A.
Published: April 2006

This study investigated whether male and female alcoholics and controls differed in their ability to solve an ecologically valid measure of abstraction. Ninety‐one alcoholics (39 females, 52 males) and 61 community controls (36 females, 26 males) completed a battery of abstraction tasks including a Piagetian‐type task, the Plant Task. The Plant Task demands that subjects predict the outcome of an unseen plant given a specific treatment regime. No group differences in the ability to correctly predict the unseen plant's outcome were obtained. Alcoholics were significantly poorer than controls in isolating the relevant variable (χ2 (1) = 8.24, p = 0.004). There were no sex differences in the ability to isolate the relevant variable. However, there was a sex effect in the number of irrelevant explanations (χ2 (3) = 15.58, p = 0.001) with females producing more than males and female alcoholics more than any of the other three cells. These data suggest that (1) alcoholics may exhibit subtle abstraction deficits most readily observed in tasks examining process as opposed to final performance, (2) males and females differ in their response patterns regarding irrelevant material, and (3) further empirical study of the Plant Task may support its use in experimental and clinical settings.
Multimodality Exploration of Event‐Related Potentials in Chronic Alcoholics
Authors: Cadaveira Fernando , Grau Cartes , Roso Margarita , Sanchez‐Turet Miquel
Published: April 2006

Short‐ and long‐latency auditory evoked potentials (SAEPs and LAEPs), visual‐evoked potentials (VEPs), and contingent negative variation (CNV) were studied in 32 chronic alcoholics and their age‐, sex‐, and education‐matched control subjects. The alcoholics exhibited a delayed SAEP peak V and an increase in the III‐V and I‐V intervals, increased VEP P100 latency, increased LAEP N2 and P3 latencies and increased LAEP N1‐P2 amplitude. The analysis of the anomalies at a clinical level indicates a differential sensitivity of the event‐related potentials. The parameters most sensitive to chronic alcohol consumption were (in descending order) P3 latency, peak V latency, the I‐V and III‐V intervals, and P100 latency.
Personality, Alcohol Consumption, and Menstrual Distress in Young Women
Authors: Tate Douglas L. , Charette Lina
Published: April 2006

There has been a longstanding hypothesis that some women develop alcohol dependence as a result of drinking to alleviate premenstrual dysphoria. This study investigated the relationship between personality factors, alcohol consumption, and menstrual distress symptoms in nonalcoholic drinking young women. Normally menstruating women monitored their alcohol intake and physical and affective distress symptoms daily for two consecutive menstrual cycles. Subjects were unaware that their menstrual cycles and symptoms were being monitored. Subjects also completed the Minnesota Multiphasic Personality Inventory (MMPI), the Eysenck Personality Questionnaire (EPQ), Cattel's Sixteen Personality Factor Questionnaire (16PF), and the Vando Reducer‐Augmenter Scale. The MMPI scales were factor analyzed to reduce the number of variables. Four derived MMPI factors were added to the VANDO, the three EPQ factors, and the four higher order factors of the 16PF to provide a total of twelve personality predictors. Separate regression analyses were carried out between personality factors and both alcohol consumption and menstrual distress. The results revealed that the women who drank more tended to be significantly more extroverted, spontaneous, carefree, and open to change. By contrast, women who reported greater over‐all menstrual distress tended to be less capable, secure, and well‐adjusted and reported a greater number of emotional and psychological problems. There was no correlation between alcohol consumption and menstrual distress. It was concluded that the results contradict the alcoholism‐menstrual cycle hypothesis.
Effects of in Utero Ethanol Exposure on the Developing Serotonergic System
Authors: Druse Mary J. , Kuo Alison , Tajuddin Nuzhath
Published: April 2006

Previous work in this laboratory demonstrated that the 19‐ and 35‐day‐old offspring of ethanol‐fed rats have a significant deficiency of cortical serotonin (5‐HT) and 5‐hydroxyindoleacetic acid (5‐HIAA), as well as a decrease in the number of total 5‐HT1 receptors in the motor and somatosensory cortex. The present studies extend our previous reports by demonstrating that there is also a deficit of 5‐HT and 5‐HIAA in the motor cortex but not in the somatosensory cortex. In addition, we have shown that a deficit of 5‐HTlA receptors in the motor and somatosensory cortices contributes to the deficit of total 5‐HT1 receptors. In contrast, we did not observe any changes in the binding to 5‐HT1B receptors in these cortical regions from the 19‐day‐old offspring of ethanol‐fed rats.

The present studies also examined the effects of in utero ethanol exposure on the early development of the serotonergic system. The results of these studies demonstrated a deficit of 5‐HT and/or 5‐HlAA in the brain stem as early as the 15th day of gestation (G15) and in the cortex as early as G19. In addition, we demonstrated a delay in both the normal developmental decline of 5‐HT1A receptors in the brain stem and in the acquisition of cortical 5‐HT1A receptors. No changes were found in the binding of [125]cyanopindolol to 5‐HT1B receptors in either region of fetal or neonatal rats exposed to ethanol in utero. Given the important role of serotonin for normal central nervous system (CNS) development, it is possible that these early serotonergic abnormalities contribute to altered CNS development in ethanol‐exposed rats.
Differential Effects of Ethanol on Punished Responding in the P and NP Rats
Authors: Baldwin Helen A. , Wall Tamara L. , Schuckit Marc A. , Koob George F.
Published: April 2006

The effects of ethanol administration (0, 0.25, 0.5, 0.75 and 1.0 g/kg intraperitoneal) were examined in a conflict test in 24 alcohol‐preferring (P)‐rats, 17 alcohol‐nonpreferring (NP)‐rats, and 24 heterogeneous Wistar rats. The conflict test was a modified Geller‐Seifter procedure employing an unpunished random interval 30‐sec component and an incremental shock conflict component. Heterogeneous Wistar rats displayed significant increases in punished responding with doses of 0.5, 0.75, and 1.0 g/kg of ethanol. P‐rats did not show a significant increase in punished responding until 0.75 g/ kg ethanol. NP rats displayed significant increases in punished responding with all doses tested (0.25, 0.5, and 0.75 g/kg). There were no group differences in the effects of ethanol on unpunished responding. Thus NP‐rats were more sensitive and P‐rats were less sensitive to the anticonflict effects of ethanol than heterogeneous Wistar rats. The results suggest that the P and NP rats may show a profile of sensitivity to the anticonflict effects of ethanol similar to the sensitivity to the intoxicating effects of ethanol observed in family history positive and family history negative human subjects.
Effects of Prenatal Ethanol Exposure on Glucocorticoid Receptors in Rat Hippocampus
Authors: Weinberg Joanne , Petersen Thomas D.
Published: April 2006

Animals exposed to ethanol in utero are typically hyperresponsive to stressors in adulthood as indicated by increased adrenocortical activation and/or deficits in response inhibition or recovery following stress. In the present study we reasoned that a deficit in feedback control of pituitary‐adrenal activity might underlie this hyperresponsiveness in fetal ethanol‐exposed (FEE) animals. Further, we hypothesized that a long‐term decrease in hippocampal glucocorticoid receptor concentration, induced by prenatal ethanol exposure, might mediate such a deficit in pituitary‐adrenal feedback regulation. Male and female Sprague‐Dawley rats from prenatal ethanol (E), pair‐fed (PF), and control (C) treatment groups were tested in adulthood for determination of cytosolic hippocampal glucocorticoid receptor binding. No significant differences in specific binding (Bmax) or binding affinity (Kd) of either type I or type II glucocorticoid receptors were found among animals from E, PF, and C conditions. There were, however, significant sex differences in receptor concentration and binding affinity; females showed significantly greater maximal binding and significantly lower binding affinity than males. These data do not support the hypothesis that prenatal ethanol exposure induces a long‐term decrease in hippocampal glucocorticoid receptors in animals tested under basal nonstressed conditions. However, these data do not preclude the possibility that receptor binding capacity may be differentially affected in E, PF, and C animals during stress.
Effect of Chronic Ethanol on Apolipoprotein (Apo) E Synthesis and Glycosylation in Rats
Authors: Ghosh Pradeep , Chirtel Stuart J. , Lakshman M. R.
Published: April 2006

We have previously shown in rats that chronic ethanol feeding significantly inhibits the incorporation of labeled leucine into Apo E secreted into the liver perfusate (p < 0.01). Fish oil has been shown to counteract many of the adverse effects of ethanol. In order to explore whether this inhibitory effect of ethanol was due to the decreased synthesis and/or defective glycosylation of this glycoprotein, we have determined the effects of chronic ethanol and fish oil on the synthesis and glycosylation of Apo E in vivo. Four groups of male Wistar rats were pair‐fed the following liquid diets for 8 weeks: (1) Ethanol Regular Fat, (2) Control Regular Fat, (3) Ethanol Fish Oil, and (4) Control Fish Oil. At the end, the rats were intraportally injected with a single dose of [U‐14C]leucine (0.2 μCi/g body weight) and/or [2‐3H]mannose (1 μCi/g body weight) and killed after 30 min. The incorporation of the labeled precursors into the immunoprecipitable Apo E was measured in the liver and its microsomal and Golgi fractions. The results showed marked decreases in mannose incorporation into total glycoproteins and specifically of Apo E in whole liver, microsomal, and Golgi fractions under ethanol treatment. In contrast, the leucine incorporation into liver Apo E increased 11% (p < 0.048) by ethanol treatment. As a result, the [3H]mannose/[14C] leucine incorporation ratio also decreased 41% to 47% at the whole liver, microsomal, and Golgi fractions indicating a marked inhibition in glycosylation of Apo E in the ethanol group. Thus, we conclude that it is the defective glycosylation of Apo E and not its synthetic rate, that may be responsible for the decreased hepatic secretion of Apo E caused by chronic ethanol feeding. On the other hand, fish oil partially reverses these deleterious effects of chronic ethanol.
Effect of Concentration of Ingested Ethanol on Blood Alcohol Levels
Authors: Roine Risto P. , Gentry R. Thomas , Lim Robert T. , Baraona Enrique , Lieber Charles S.
Published: April 2006

The effect of the concentration of ingested ethanol on the resulting blood alcohol concentrations (BAC) was tested in both humans and rats. In humans, when 0.3 g/kg body weight ethanol was ingested postprandially, the mean area under the blood alcohol curve (AUC) and the mean peak BAC were significantly lower with a concentrated (40% w/v) than with a dilute (4%) solution. Similarly, rats in the fed state exhibited decreasing mean AUCs with increasing concentrations (4%, 16%, and 40%) of intragastrically administered ethanol (1.0 g/kg). Pharmacokinetic analysis comparing intragastric and intraperitoneal administration of ethanol to rats indicated that the more concentrated solution resulted in less alcohol reaching the systemic circulation (4%: 0.896 ± 0.071 g/kg; 16%: 0.772 ± 0.072 g/kg; 40%: 0.453 ± 0.037 g/kg) and suggested that this effect could be attributed to two factors: increased gastric retention of ethanol (4%: 0.109 ± 0.024 g/kg; 16%: 0.102 2 0.016 g/kg; 40%: 0.214 ± 0.042 g/kg) and a large increase in first‐pass metabolism (4%: 0.004 ± 0.054 g/kg; 16%: 0.145 ± 0.048 g/kg; 40%: 0.329 ± 0.044 g/kg).

In contrast to the results in the fed state, in humans fasted overnight the concentration of alcohol consumed (4%, 16%, and 40%) had no significant effect on mean AUCs. In fasted rats, mean AUCs after intragastric intubation of the two lower concentrations of ethanol (4% and 16%) were comparable to those found after intraperitoneal injection, and only the highest ethanol concentration (40%) produced a lower mean AUC.

Our results demonstrate that the consumption of a concentrated solution of ethanol results in lower blood alcohol levels than does a dilute solution, when subjects are tested in the fed state. This effect is associated with more first pass metabolism and less bioavailability with the high ethanol concentrations. These findings now raise the issue whether ethanol in low concentration beverages such as beer and wine has a greater bioavailability than in distilled spirits.
Polymorphism of the Rat Liver Mitochondrial Aldehyde Dehydrogenase cDNA
Authors: Carr L. G. , Mellencamp R. J. , Crabb D. W. , Weiner H. , Lumeng L. , Li T.‐K.
Published: April 2006

In humans, a deficiency in mitochondrial aldehyde dehydrogenase (Class 2 ALDH) activity due to a single base‐pair exchange in its structural gene serves as a deterrent to excessive alcohol consumption. Differences in Class 2 ALDH isozyme patterns on isoelectric focusing gels have been observed in the selectively bred, alcoholpreferring (P) and alcohol‐nonpreferring (NP) lines of rats. To determine whether the differences are the result of sequence variation in the structural gene, we sequenced the cDNAs for Class 2 ALDH from P and NP rats. A synonymous exchange was seen in the codon for amino acid 473 in both lines, when compared with published sequences. Additionally, when the cDNA from P rats was used as reference, a substitution (G for A) was identified in the cDNA of NP rats which changes amino acid 67 from Gln (CAG codon; ALDH2Q allele) to Arg (CGG codon; ALDH2R allele). The Arg for Gln substitution makes the enzyme more basic and could account for the different electrophoretic mobilities. To determine whether the polymorphism was associated with drinking behavior, we genotyped the ALDH2 locus by amplifying rat genomic DNA encompassing the nucleotide exchange followed by probing with allele‐specific oligonucleotides. There are highly significant differences in the frequencies of the two alleles in the P and NP rat lines. The frequency of the ALDHR allele is 63% in the NP line and only 18% in the P line, whereas the frequency of the ALDH2Q allele is 82% in the P line and 37% in the NP line.
Chronic Alcoholism Impedes the Recovery of Renal Function following Renal Ischemia
Authors: Ishigami Masaaki , Ohnishi S. Tsuyoshi , Yabuki So
Published: April 2006

The recovery of renal function following renal ischemia was studied using rats fed for 1‐, 3‐, and 5‐week periods with an alcoholic diet (ethanol provided 36% of total calories). Renal ischemia was produced by clamping the renal artery and vein for 20 min. Renal function was determined 24 hr after the ischemia. In the absence of ischemic insult, the renal function of rats fed with an alcoholic diet for 1, 3, and 5 weeks was not significantly different from those of nonalcoholic rats. In nonalcoholic rats, renal function (24 hr postischemia) were: glomerular filtration rate (GFR) 430.4 ± 29.6 μl/min/g KW (kidney weight), renal plasma flow rate (RPFR) 1.4 ± 0.17 ml/min/g KW, and fractional sodium excretion (FENa) 2.0 ± 0.04% (mean ± SE). Postischemic renal function of rats on 1‐ and 3‐week alcoholic diets were essentially the same as that of the control rats. However, the 24‐hr postischemic renal function of 5‐week alcoholic diet rats was significantly depressed. The values were only 117.2 ± 35.2 μl/min/g KW (p < 0.05) for GFR, 0.31 ± 0.12 ml/min/g KW (p < 0.05) for RPFR, and 7.46 ± 3.59% for FENa. The present results demonstrate that the rat kidney subjected to prolonged alcohol ingestion was more susceptible to renal insult than a nonalcoholic kidney.
Impaired Autonomic Nervous System in Alcoholics Assessed by Heart Rate Variation
Authors: Yokoyama Akira , Takagi Toshikazu , Ishii Hiromasa , Muramatsu Taro , Akai Junichiro , Kato Shinzo , Hori Shingo , Maruyama Katsuya , Kono Hiroaki , Tsuchiya Masaharu
Published: April 2006

The suppression of heart rate variation reflects cardiac autonomic nervous dysfunction and is known to be associated with a poor prognosis or sudden death in diabetic patients. We investigated consecutive changes in the heart rate variation in 51 alcoholics using the coefficient of variation of R‐R interval (CVRR). To correct for age effects, a ratio of CVRR to the standard predicted value (CVP) was calculated. On the whole, CVRR/CVP was suppressed on admission and on the 7th day of abstinence and increased on the 30th day. However, alcoholics could be divided into two groups by their CVRR/CVP on the 30th day: one group with transient autonomic dysfunction whose CVRR/CVP was more than 0.8 (n= 32), and the other group with persistent autonomic dysfunction whose CVRR/CVP was less than 0.8 (n= 19). Withdrawal hypertension occurred more frequently (63% vs. 19%) and mean systolic pressure (159 ± 24 mmHg vs. 138 ± 17 mmHg) was higher in the latter group than in the former, suggesting that persistent autonomic damage might, at least in part, contribute to withdrawal hypertension. To investigate further the relationship between the persistent autonomic damage and other complications, the CVRR/CVP on the 30th day of abstinence was analyzed in an additional 85 alcoholics (total n= 136). Persistent suppression of the CVRR/CVP was more frequently found in alcoholics with leg paresthesia (64%, n= 22), the Wernicke‐Korsakoff syndrome (73%, n= 11), or diabetes mellitus (69%, n= 68), than in alcoholics without these complications (31%, n= 35). This suggests that persistent autonomic dysfunction reflects damage in both the peripheral and the central autonomic nervous systems and is exacerbated by the complication of diabetes mellitus. The measurement of CVRR on the 30th day of abstinence is useful to evaluate persistent autonomic dysfunction in alcoholics.
Cerebral Blood Flow and Metabolic Rate in the Conscious, Freely Moving Rat: The Effects of Hypercapnia, and Acute Ethanol Administration
Authors: Ligeti Laszlo , Hines Kirk , Dora Eors , Sinnwell Teresa , Huang Ming‐Tau , McLaughlin Alan C.
Published: April 2006

We propose a simple method that can be used to measure cerebral blood flow (CBF), cerebral oxygen consumption (CMRO2), and cerebral glucose consumption (CMRglu) in the conscious, freely moving rat. The method is based on the classical Kety‐Schmidt approach, and uses a chronic cannula in the confluens sinuum. We tested the method by investigating the response of CBF, CMRO2, and CMRglu to hypercapnia and used the approach to Investigate the effects of acute alcohol administration. Severe hypercapnia (PaCO2∼80 mmHg) increased the CBF by a factor of 3.5, decreased the CMRO2 by 30%, and had no significant effect on the CMRglu. Under normocapnic conditions moderate blood alcohol levels (100–200 mg%) caused no significant effects on CBF, CMRO2, or CMRglu, but high blood alcohol levels (250–400 mg%) decreased all three parameters by approximately 25%. Under hypercapnic conditions high blood alcohol levels had no effect on CBF, CMRO2, and CMRglu.
Ethanol‐Induced Enhancement of Cocaine Bioactivation and Irreversible Protein Binding: Evidence Against a Role of Cytochrome P‐450IIE1
Authors: Boelsterli Urs A. , Atanasoski Suzana , Göldlin Christian
Published: April 2006

Chronic ethanol consumption potentiates cocaine‐induced liver injury in rodents. Since cocaine has to be bioactivated by a cytochrome P‐450‐dependent N‐oxidative pathway to exert its hepatotoxic effects, we studied the role of the ethanol‐inducible P‐450IIE1 for cocaine metabolism. Male Sprague‐Dawley rats were pretreated with either a liquid diet containing ethanol (30% of calories) for 4 weeks or injected with pyrazole (200 mg/kg/day, ip, for 3 days). Both agents induced microsomal p‐nitrophenol hydroxylation which is a probe for the catalytic activity of P‐450IIE1. However, only ethanol, but not pyrazole, increased both microsomal cocaine N‐demethylase activity (by 47%) and the extent of irreversible binding of [3H]‐cocaine to microsomal proteins (by 100%), which was taken as a quantitative endpoint for the formation of a reactive metabolite. Cocaine N‐ demethylation and irreversible protein binding of cocaine were not inhibited by P‐450IIE1 isozyme‐selective substrates, nor was the rate of cocaine metabolism and binding decreased by functionally active polyclonal anti‐rat P‐450IIE1 antibodies. Furthermore, pyrazole pretreatment sensitized cultured hepatocytes to the glutathione‐dependent cytotoxic effects of nontoxic concentrations of cocaine. These results indicate that (a) cocaine is not a major substrate for the ethanol‐inducible P‐450IIE1, (b) the enhancing effects of ethanol on cocaine bioactivation may be due to induction of other P‐450 isoforms, and (c) induction of P‐450IIE1 may potentiate cocaine‐induced hepatocellular toxicity in vitro independently of cocaine metabolism, e.g., by P‐450IIE1‐dependent oxidative stress.
Isoelectric Focusing/Western Blotting: A Novel and Practical Method for Quantitation of Carbohydrate‐Deficient Transferrin in Alcoholics
Authors: Xin Yan , Lasker Jerome M. , Rosman Alan S. , Lieber Charles S.
Published: April 2006

Carbohydrate‐deficient transferrin (CDT) has been described as the single, most accurate marker of chronic alcohol consumption. Rapid, sensitive, and specific measurement of serum CDT levels can thus provide important clinical information concerning patient diagnosis and treatment. To date, however, methods used for assessing CDT concentrations [e.g., analytical isoelectric focusing combined with immunofixation and micro anion‐exchange chromatography followed by radioimmunoassay (RIA)] have not been practical enough for widespread laboratory application. In the present study, we examined the use of a different technique, namely isoelectric focusing (IEF) combined with Western blotting (IEF/WB). Serum proteins (20–40 μg) were first focused according to isoelectric points (pl) on highresolution agarose IEF gels (ampholyte pH range of 5–8) containing nonionic detergent. The focused proteins were transferred electrophoretically to nitrocellulose filters, and then stained immunochemically with antihuman transferrin IgG. IEF/WB completely resolved CDT (focusing at pl 5.7 and 5.9) from other serum transferring isoforms, as assessed with neuramidase‐generated CDT standards. Computerized densitometric scanning of the immunoblots allowed CDT levels to be quantitated directly rather than as a quotient. Serum CDT content determined by IEF/WB was highly correlated (r2= 0.962; n= 17) with values determined previously by RIA. In a larger subject group, CDT levels (mg/liter) measured by IEF/WB were 139 ± 54 in recently‐drinking alcoholics (n= 58), 81 ± 8 in abstaining alcoholics (n= 7), and 68 ± 16 in healthy control subjects (n= 16). These IEF/WB values for serum CDT are highly similar to those reported using other quantitation methods. Importantly, CDT levels as measured by IEF/WB were not influenced by the severity of liver disease among the recently‐drinking alcoholics nor did nondrinkers with liver disease exhibit elevated IEF/WB CDT values. Serum CDT/total transferrin ratios (the latter measured by ELISA) offered no advantage over serum CDT alone to distinguish active and heavy drinking. In conclusion, we have developed a sensitive, accurate, and most importantly, practical method for quantitation of serum CDT, a highly‐reliable marker of chronic alcohol consumption. Routine implementation of this technique by clinical laboratories can rapidly provide the physician with a powerful diagnostic tool.
Event‐Related Potentials in Alcoholic Men: P3 Amplitude Reflects Family History But Not Alcohol Consumption
Authors: Pfefferbaum Adolf , Ford Judith M. , White Patricia M. , Mathalon Daniel
Published: April 2006

Multilead event‐related potentials (ERPs), elicited by auditory and visual stimuli requiring a button press response and by a startling noise requiring no response, were recorded from male alcoholics and age‐matched male controls (26–60 years old). Single‐trial analyses of blink responses to the startling stimuli indicated that alcoholics startle less frequently but with equivalent amplitude as the controls. In contrast, single‐trial analyses of P3 indicated that alcoholics generate a P3 as often as controls, but that their individual P3s are smaller. Alcoholics who reported a positive family history of problem drinking had larger startle blink amplitudes and smaller auditory and visual P3s than did alcoholics who reported a negative family history. Hierarchical regression analysis was used to demonstrate that smaller P3s in family history positive alcoholics were independent of lifetime alcohol consumption.
Six‐ and Twelve‐Month Abstinence Rates in Inpatient Alcoholics Treated with Aversion Therapy Compared with Matched Inpatients from a Treatment Registry
Authors: Smith James W. , Frawley P. Joseph , Polissar Lincoln
Published: April 2006

Two hundred forty‐nine patients who were treated for alcoholism in an inpatient multimodal treatment program that included aversion therapy were matched post hoc on 17 baseline variables with patients from a national treatment outcome registry. The latter patients received inpatient treatment that emphasized individual and group counseling as the primary therapeutic elements but did not include aversion therapy for alcohol. Six‐ and 12‐month abstinence rates from alcohol and all mood‐altering chemicals are reported. The patients treated with aversion therapy for alcohol had higher alcohol abstinence rates at 6 and 12 months (p < 0.01). The abstinence rates from all mood‐altering chemicals were higher in the aversion group at 6 months (p < 0.05) but not at 12 months. The largest differences between treatment groups in 6‐month alcohol abstinence rates were noted for males (p < 0.001), those over 35 (p < 0.001), daily drinkers (p < 0.001), and those with alcohol‐related work performance problems (p < 0.05).
Macrocytosis as a Consequence of Alcohol Abuse among Patients in General Practice
Authors: Seppä Kaija , Laippala Pekka , Saarni Matti
Published: April 2006

Macrocytosis, a common finding in patients without anemia or other hematologic abnormalities, is often ignored. The purpose of this prospective study was to investigate 300 consecutive, adult health‐center patients with a mean cell volume (MCV) value ≥ 100 fl. The incidence of macrocytosis was 2.4%. Of the 177 male and 123 female patients, only 14 (4.7%) were anemic; 80.2% of the men (89.3% of those under 60 years) and 34.1% of the women were alcohol abusers, representing the largest diagnostic group. The highest MCV value found in alcoholics without folate or vitamin B12 deficiency was 120 fl. The most useful laboratory test for identifying alcohol abuse among macrocytic patients was the measurement of serum gammaglutamyltransferase. Of the several morphologic abnormalities in the marrow the only specific finding were vacuoles in the granulocyte or erythrocyte precursors. No underlying cause was found for macrocytosis in 6.8% of the men and 35.8% of the women. Even when it is not associated with anemia, macrocytosis should not be ignored. It may be the only indicator of a disease which often, particularly in young and middle‐aged men, is alcohol abuse.