bluuebunny/crossref_metadata_2025 huggingface dataset:
Development of Tolerance to and Physical Dependence on Ethanol: Daily Versus Repeated Cycles Treatment with Ethanol
Authors: Pohorecky Larissa A. , Roberts Patricia
Published: April 2006

We examined the effect of various treatment schedules with ethanol on the development of tolerance and the severity of withdrawal in rats. Tolerance to ethanol was examined after a challenge dose of ethanol using rectal temperature, dowel performance, and tail flick response; open field activity and the startle response were determined during withdrawal. Animals treated daily with ethanol developed greater tolerance, and also lost it faster, compared with animals subjected to repeated cycles of 3 days of ethanol treatment followed by 3 drug‐free days. Also, the severity of withdrawal was greater in animals treated daily with ethanol. In the second study, we examined the development of tolerance and withdrawal severity of animals subjected to three different schedules of daily ethanol administration. Overall, the animals receiving continuous infusion of ethanol showed the most severe withdrawal and had, except for dowel performance, the fastest loss of tolerance to ethanol.
The Effects of Piracetam on Lipofuscin of the Rat Cerebellar and Hippocampal Neurons after Long‐Term Alcohol Treatment and Withdrawal: A Quantitative Study
Authors: Paula‐Barbosa M. M. , Brandão F. , Pinho M. C. , Andrade J. P. , Madeira M. D. , Cadete‐Leite A.
Published: April 2006

There is a growing body of evidence indicating that chronic alcohol consumption induces morphological changes in the central nervous system (CNS) similar to those observed during brain senescence, including an increased formation of lipofuscin. In addition, it was also found that alcohol withdrawal does not reverse these changes. On the contrary, most of the alterations observed during alcohol consumption worsen as happens with the increased lipofuscin formation. Thus, using our model of alcohol feeding and withdrawal, we decided to examine the effects of different drugs said to offer neuronal protection during CNS degenerative processes. The action of piracetam, a cyclic derivate of GABA and commonly used as a nootropic agent, was tested by studying the lipofuscin accumulation on the cerebellar Purkinje and hippocampal CA3 pyramidal cells in alcohol‐treated and withdrawn rats. Piracetam was found to markedly decrease the formation of neuronal lipofuscin. Whatever the functional implications of this pigment, its reduction in piracetam‐treated animals might be related either to a protective effect on the intraneuronal membranous system or to an antioxydant property of this molecule.
Ethanol Preference in the Harrington Derivation of the Maudsley Reactive and Non‐Reactive Strains
Authors: Adams Nelson , Shinabi Z. K. , Blizard David A.
Published: April 2006

Ethanol intake was explored in the Harrington derivation of the Maudsley Reactive and Maudsley Non‐Reactive rat strains (MR/Har and MNRA/Har). When 5% and 10% ethanol solutions were presented as the sole source of fluid (1‐bottle test), MR/Har rats, respectively, ingested 15% more, or 9% less, than their baseline water intake, whereas MNRAs ingested 6% less, or 42% less than their baseline intake. However, because MNRA/Har rats drank significantly more water than MR/Har's under ad libitum conditions (MNRA/Har, 46.6 ± 1.83 ml; MR/Har 32.45 ± 1.64 ml/24 hr), males and females of the two strains ingested a similar amount of ethanol in the 1‐bottle test (5% ethanol, 4–7; 10% ethanol, 6–12 g/kg body weight/24 hr). In 2‐bottle free‐choice tests administered after an extended period of forced ethanol consumption, MR/Har male and female rats exhibited a strong ethanol preference (X = 80%) and consumed a larger amount of ethanol (MR/Har, 7–13; MNRA/Har, 6–9 g/kg body weight/24 hr) than MNRA/Har's. Across all conditions, females of both strains ingested a greater relative amount of ethanol than males. The strain difference in ethanol preference was found to be independent of prior exposure to ethanol because it was also found when 2‐bottle free‐choice tests were carried out in naive animals (Experiment 2). The pattern of development of ethanol preference in individual animals was characterized by abrupt onset, after variable periods of exposure to the 2‐bottle choice test, and maintenance of strong ethanol preference thereafter. The extensive behavioral and biological definition of the Maudsley strains is a valuable asset in attempting to elucidate the biobehavioral correlates of ethanol preference.
The Effects of Progressive Abstinence from Alcohol on Red Blood Cell Proton NMR Relaxation Times and Water Content
Authors: Besson J. A. O. , Craig E. , Ebmeier K. P. , Foster M. A. , Wheatley D. N.
Published: April 2006

Red blood cell proton relaxation times T1 and T2 were measured in samples from chronic alcoholic patients abstinent for varying periods from 1 week to over 6 months. T1 and T2 were elevated in the early stages of abstinence and declined to the values of controls after 8 weeks. Changes in the water content of the red blood cells and the mean corpuscular volume paralleled these changes but were more closely associated with T2. It is suggested that T1 and T2 may reflect different aspects in water content and free‐to‐bound ratio of water. The significance of these findings is discussed in the context of changes previously observed in the brains of alcoholic patients, and in rats fed a diet supplemented with alcohol for 6 months.
The Metabolism of Ethyl Esters of Fatty Acids in Adipose Tissue of Rats Chronically Exposed to Ethanol
Authors: DePergola Giovanni , Kjellström Christer , Holm Cecilia , Conradi Nils , Pettersson Per , Björntorp Per
Published: April 2006

The concentration of ethyl esters of fatty acids as well as the activity of the enzyme synthesizing these esters (fatty acid ethyl ester synthase) were determined in adipose tissue of rats ingesting ethanol (9–16 g/kg body weight/day) for different periods of time. After 10 and 17 weeks of ethanol exposure about 300 nmol of ethyl esters of oleic, palmitic, stearic, and linoleic acids were found per gram adipose tissue. The ethyl esters disappeared after 1 week of abstinence. Closer analyses, using radioactive ethanol, revealed a half‐life of the esters of less than 24 hr. The bulk of the esters was found in a membrane preparation of isolated adipocytes. Hormone‐sensitive lipase hydrolyzed emulsified ethyl oleate as efficiently as that of trioleoylglycerol, but in mixed ethyl oleate/trioleoyl glycerol particles the hydrolysis of ethyl oleate was slower, suggesting a decreased accessibility. Synthase activity was found in adipose tissue from rats not exposed to ethanol. It doubled after 10 and 17 weeks of ethanol and decreased with a half‐life of at least a week after abstinence.

It was concluded that ethyl esters of fatty acids are formed in rat adipose tissue as previously shown in other tissues. They seem to be stored mainly in membranous parts of the adipocytes. Synthase activity is induced by ethanol. The elevated activity has a longer half‐life, and may be useful as an indicator of alcohol abuse.
GM1 Ganglioside Protection Against Ethanol‐Induced Gastric Mucosal Injury
Authors: Slomiany Bronislaw L. , Piotrowski Jerzy , Ismail Akram , Klibaner Michael , Murty Varahabhotla L. N. , Slomiany Amalia
Published: April 2006

The gastroprotective properties of GM,‐ganglioside, an indigenous component of epithelial cell membrane, was investigated. The experiments were conducted with groups of rats with and without indomethacin pretreatment. The animals received intragastrically either a dose of GM1 as emulsion in 5% gum arabic or vehicle alone, followed by ethanol given at various time intervals up to 3 h after the GM1. The animals were sacrificed 30 min after the ethanol dose and their gastric mucosa subjected to macroscopic and histologic assessment, and physicochemical measurements. In the absence of GM1, ethanol caused extensive gastric hemorrhagic lesions which were significantly reduced by pretreatment with GM1 at dose as low as 70 μg/100 g body weight. Removal of sialic acid from GM1 led to the loss of gastroprotection. Furthermore, the effect of GM1 was not thwarted by indomethacin. The maximal protection was achieved 1 following GM1 dose and this protective effect persisted at least 2.5 hr. The results of physicochemical measurements revealed that GM1 was capable of preventing the detrimental effect of indomethacin on the adherent mucus gel dimension, and on its content of sulfo‐ and sialomucins, protein, and phospholipids. The effects brought by GM1 were also accompanied by a significant (40–60%) increase in mucus gel viscosity, hydrogen ion retardation capacity (35–46%) and hydrophobicity (70–94%). The results indicate that the gastroprotective action of GM1 occurs through the enhancement of the physicochemical characteristics of the mucus layer, and does not appear to be mediated by endogenous prostaglandins.
Quantitation of β‐Sitosterol in Bourbon
Authors: Rosenblum E. R. , Van Thiel D. H. , Campbell I. M. , Gavaler J. S.
Published: April 2006

Four phytoestrogens have previously been isolated and identified in alcoholic beverages. Before studies to evaluate the degree of estrogenicity of these substances can be performed, it is necessary to determine appropriate doses to be administered to experimental animals. Because β‐sitosterol is the most plentiful, being present in bourbon at μg/dl quantities, we have chosen to begin our quantitation work with this compound. The variability of the amount of β‐sitosterol contained in various brands of bourbon and in different lots of the same brand of bourbon have been assessed using combined gas chromatography/mass spectrometry (GC/MS) for quantitation following a simplified procedure to extract compounds of interest from bourbon.
Effect of Chronic Ethanol Feeding on High Density Lipoprotein Subfractions in Rats
Authors: Lin Renee C. , Lumeng Lawrence
Published: April 2006

We have reported previously that chronic alcohol consumption in the rat produced elevated total serum high density lipoprotein (HDL) fraction, but HDL particles of the alcohol‐fed rat were deficient in apolipoprotein (apo) E. In that report, serum HDL particles were prepared by successive ultracentrifugation method and there were concerns that the apo E deficiency in HDL particles was artificially produced by centrifugal forces. In the present report, apo Al affinity column chromatography was used instead of successive ultracentrifugation and it likewise yielded HDL particles from alcohol‐fed rats that exhibited lower apo E: apo Al ratio than HDL from control rats (0.185 ± 0.016 vs. 0.303 ± 0.017, respectively). When the total serum lipoprotein fraction (d < 1.21) was analyzed by high performance liquid chromatography (HPLC), both HDL and VLDL peaks were higher in alcohol‐fed rats than controls. The size of apo E deficient HDL particles from alcohol‐fed rats determined by HPLC did not differ from that of normal HDL particles. When HDL (1.063 < d < 1.21) was subfractionated into HDL2 (1.063 < d < 1.125) and HDL3 (1.125 < d < 1.21), only HDL2 of alcohol‐fed rats showed lowered apo E: apo Al ratio when compared with same HDL subfraction of control animals. Therefore, the molecular structure of only HDL2 (but not HDL3) was affected by alcohol‐feeding. Another HDL subpopulation which is enriched with apo E, i.e. HDL1 (1.054 < d < 1.063), was also prepared. HDL1 of alcohol‐fed rats was increased by 50% over the controls but its apo E: apo Al ratio was unchanged when compared with control rats. In conclusion, chronic alcohol consumption in the rat produces increased total HDL fraction, decreased apo E: apo Al ratio in the HDL2 subfraction (1.063 < d 1.125), and increased HDL1 (1.054 < d < 1.063) subpopulation.
Ethanol‐Induced Changes in Chloride Flux are Mediated by Both GABAA and GABAB Receptors
Authors: Allan Andrea M. , Burnett Donald , Harris R. Adron
Published: April 2006

Low concentrations of ethanol (10–30 mM) in the presence of a GABAB receptor agonist, baclofen, promoted 36Cl‐ uptake into membrane vesicles (microsacs) prepared from mouse cortex. Neither ethanol nor baclofen alone altered chloride influx. The GABAB antagonists, phaclofen and 2‐hydroxy‐saclofen, completely blocked the increase in chloride flux produced by ethanol in the presence of either baclofen or GABA. Ethanol increased the chloride conductance produced by the GABAA agonists muscimol, isoguvacine, imidazolacetic acid and amino‐propane sulfonic acid and this action of ethanol was blocked by phaclofen. The specific GABAA antagonist, bicuculline, blocked ethanol‐induced increase in chloride flux in the presence of either baclofen or GABA, GABA‐activated chloride channels were also studied in Xenopus oocytes expressing mouse brain mRNA. In this preparation, GABA action was enhanced by ethanol, pentobarbital, and diazepam, and 2‐hydroxy‐saclofen partially antagonized the action of ethanol without altering the effects of pentobarbital or diazepam. These results suggest that ethanol enhancement of GABAA receptor‐chloride channel function also requires activation of GABAB receptors.
Specific Alterations in the Cerebellar GABAA Receptors of an Alcohol‐Sensitive ANT Rat Line
Authors: Uusi‐Oukari M. , Korpi E. R.
Published: April 2006

The AT (alcohol‐tolerant) and ANT (alcohol‐nontolerant) rat lines, selected for differential sensitivity to the acute motor‐impairing effects of ethanol, have been shown to differ in the ligand binding characteristics of their cerebellar GABAA receptors. In the present study, we characterized these binding differences further and determined whether similar differences are present in other rodent line pairs produced by selective breeding for differences in ethanol sensitivity. The alcohol‐insensitive AT rats had more high‐affinity [3H]muscimol binding sites in the cerebellum than the alcohol‐sensitive ANT rats. The cerebellar “diazepam‐insensitive”[3H]Ro 15–4513 binding sites were displaced by several benzodiazepine agonists (diazepam, lorazepam, clonazepam, and midazolam) at micromolar concentrations with greater efficacy in the ANT than the AT rats. Analyses of the displacement curves indicated that the “diazepam‐insensitive”[3H] Ro 15–4513 binding sites have 30 to 300 times higher affinity to benzodiazepine agonists in the ANT than AT rats. There was no difference between the rat lines in the displacing potency of Ro 15–1788, a weak partial agonist; Ro 15–4513, a partial inverse agonist; or Ro 5–4864, a peripheral‐type benzodiazepine receptor ligand. Thus, the affinity difference seen in the cerebellar [3H]Ro 15–4513 binding sites seems to be specific for benzodiazepine agonists. This difference in affinity may explain the behavioral difference in sensitivity to lorazepam between the rat lines. No differences in [3H]muscimol binding or in the sensitivity of [3H]Ro 15–4513 binding to micromolar diazepam concentrations were found between other rodent line pairs tested (LS/SS, HAS/LAS, HOT/COLD, FAST/SLOW, AA/ANA). The displacement of [3H]Ro 15–4513 binding from the cerebellar membranes by diazepam was significantly greater in the ANT than in Mixed (M) rats (the starting population for the selection of the AT and ANT rats), whereas there was no difference in this displacement between the AT and M rats. Thus, the selection of the AT and ANT rats has produced an alcohol‐sensitive ANT rat line with specific alterations in its cerebellar GABAA receptors.
Genetic Analyses of the Biphasic Nature of the Alcohol Dose‐Response Curve
Authors: Dudek Bruce C. , Phillips Tamara J. , Hahn Martin E.
Published: April 2006

Ethanol (ETOH)‐induced locomotor activation and depression were studied in 23 genotypes of mice. This included a diallel cross of four inbred strains tested with a range of ETOH doses from 0 to 2.75 g/kg. The diversity in shapes of the biphasic ETOH dose‐response curves was both qualitative and quantitative, and additive gene action characterized the genetic control of the dose‐response curve. Small dominance effects were typically directional in the direction of more activation, or resistance to sedation. No evidence was found for maternal effects, sex linkage, or epistasis. Sex differences were seen in the increased susceptibility of male mice to locomotor sedation at higher ETOH doses. In the diallel cross, there was no correlation between the degree of activation produced by low ETOH doses and sedation produced by higher doses. This indicates that while considerable genetic influences exist for both activational and sedative domains of ETOH effects, these genetic influences are relatively independent.
The Effects of Ethanol Initiation Procedures on Ethanol Reinforced Behavior in the Alcohol‐Preferring Rat
Authors: Schwarz‐Stevens K. , Samson H. H. , Tolliver G. A. , Lumeng L. , Li T.‐K.
Published: April 2006

Rats from the alcohol preferring (P) line developed at Indiana University were initiated to self‐administer ethanol orally without food or water restriction using either a sucrose‐fading or a secondary‐conditioning procedure. Following initiation, they were tested under a variety of operant conditions to examine the ability of ethanol to reinforce lever pressing behavior. Regardless of initiation procedure, the animals maintained lever pressing behavior with ethanol reinforcement, even at ethanol concentrations as high as 40% (v/v). Slightly higher daily session intakes (g/kg) were found at the higher ethanol concentrations following the secondary‐conditioning initiation procedure compared with the sucrose‐fading technique. When both ethanol and water were concurrently available, the rats showed a high preference for ethanol reinforcement. When varying concentrations of sucrose were substituted for water, the amount of ethanol ingested decreased as the concentration of the alternative sucrose increased. However, if the response requirement for the sucrose was substantially greater than that for ethanol, the rats shifted their responding to the lever associated with ethanol presentation. The results are discussed in relation to prior work using similar procedures with Long‐Evans non‐selected rats and with the alcohol non‐preferring (NP) rat line.
Effects of Protein Size on the Rate of Import of the Precursors of Aldehyde Dehydrogenase and Ornithine Transcarbamylase into Rat Liver Mitochondria
Authors: Wang Thomas T. Y. , Wang Yi , Weiner Henry
Published: April 2006

It is known that a signal peptide is required for the import of a protein into mitochondrial matrix. It is also known that a signal peptide can be attached to any protein and allow it to be imported. We recently reported that the rate of import of rat liver mitochondrial aldehyde dehydrogenase precursor was slower than that of ornithine transcarbamylase precursor (Wang TTY, Farrés J, and Weiner H. Arch Biochem Biophys 272, 440–449, 1989). It was not known if the difference in the rate of import was related to the fact that the mature portion of aldehyde dehydrogenase is larger (500 amino acids compared with 322 amino acids) or because the signal peptides were different. We further showed that treatment of the mitochondria with alcohols caused an inhibition of the import of the precursor of aldehyde dehydrogenase but not that of ornithine transcarbamylase. In the present study we constructed chimeric proteins that contained the signal peptide from one precursor protein and the mature portion from the other. We found that the rate of import was related to the overall size of the precursor protein. Consistent with this observation was finding that a truncated aldehyde dehydrogenase precursor, which contained 317 amino acids, was imported more rapidly than was the authentic precursor. Consistent with this finding was the fact that butanol caused the inhibition of only the large precursor proteins. Thus, it appears that size of the protein being imported is a major determinant of the rate at which a precursor protein is imported into mitochondria.
Physical Exercise after Alcohol Intake: Effect on Plasma Catecholamines and Lymphocytic β‐Adrenergic Receptors
Authors: Heikkonen Erkki , Mäki Tiina , Kontula Kimmo , Ylikahri Reino , Härkönen Matti
Published: April 2006

The combined effects of alcohol intoxication and intense physical exercise on the adrenergic system were studied in eight healthy male volunteers. Ethanol (0.8 g/kg body weight) was administered perorally to bring about a mean serum concentration of 21 mmol/ liter (0.1%); each subject also participated in an identical control session without alcohol. Acute alcohol intake alone did not change the concentrations of plasma adrenaline or noradrenaline or the density, affinity, and functioning (ability to mediate catecholaminestimulated production of cAMP) of lymphocytic β‐adrenergic receptors. In contrast, acute ergometer exercise brought about an approximately 10‐fold increase of plasma adrenaline and noradrenaline concentrations, a 2‐ to 3‐fold increase of β‐adrenergic receptor density and an enhancement of isoproterenol‐stimulated cAMP production. Alcohol intake immediately before the ergometer exercise did not modify these changes. In conclusion, acute physical exercise activates the human adrenergic system, with an increase of both plasma catecholamines and lymphocytic β‐adrenergic receptors. Moderate alcohol intoxication does not affect exercise‐induced alterations of these parameters.
Acetaldehyde dehydrogenase (Ahd‐2)‐Associated DNA Polymorphisms in Mouse Strains with Variable Ethanol Preferences
Authors: Bond S. L. , Wigle M. R. , Singh S. M.
Published: April 2006

The genotype‐dependent response of mice to ethanol has been well documented. Cytosolic acetaldehyde dehydrogenase (ALDH‐2) increases in some strains while decreasing in others with ethanol treatment. Further work suggests that the mRNA for ALDH‐2 (Ahd‐2 mRNA) levels are altered following ethanol feeding in a straindependent fashion. This report identifies differences in Ahd‐2 at the genomic DNA level among different strains of mice. Restriction fragment length polymorphisms (RFLPs) associated with the Ahd‐2 locus were found for the restriction enzymes EcoRI, Hindill, Pstl and Rsa I. The mouse strains included in this study could be categorized into two groups based on their overall Ahd‐2 associated DNA banding patterns. Strains C57BL/6J, C57BL/6J*, C57BL/10J and BALB/c form group 1 while strains C3H/HeJ, C3H/HeSnJ, 129/ReJ, Csb, SW and DBA/2J form group 2. With the exception of BALB/c, group 1 represents alcohol preferring strains while group 2 are alcohol avoiding strains. Additional work will be required to determine the physiological significance (if any) of these RFLPs and their possible relationship to ethanol preference and avoidance.
Comparative Effects of Chronic Ethanol Consumption on the Properties of Mitochondria from Rat Brain and Liver
Authors: Thayer William S. , Rottenberg Hagai
Published: April 2006

The effects of chronic alcohol consumption on biochemical properties of mitochondria isolated from liver and brain were compared in rats. As has been found in previous studies (reviewed in Thayer WS: Ann NY Acad Sci 492:193–206, 1987) in liver, ethanol consumption M to a 41% decrease in active phosphorylating (state 3) respiration and a 25% decrease in resting (state 4) respiration. These changes resulted in a 23% decrease in the respiratory control ratio (ratio of respiration rate in state 3 to that in state 4). These effects were associated with a 40% decrease in functional cytochrome oxidase content, determined spectrophotometrically as heme aa3. By contrast, in brain mitochondria isolated from the same rats, ethanol consumption did not result in any significant changes in respiration rates, respiratory control ratio, or cytochrome contents. The findings demonstrate a differential pathobiologic response of brain and liver mitochondria to chronic ethanol consumption. Since the liver is predominant in metabolism of ingested ethanol, the findings of this study suggest that the deleterious effects of chronic alcohol consumption on the structure and function of liver mitochondria may be related to ethanol metabolism.
Ethanol Self‐Administration in Deprived Rats: Effects of Ro15‐4513 Alone, and in Combination with Flumazenil (Ro15‐1788)
Authors: June Harry L. , Colker Richard E. , Domangue Kevin R. , Perry Lauren E. , Hicks Leslie H. , June Pamela L. , Lewis Michael J.
Published: April 2006

Previous work in our laboratory demonstrated that Ro15‐4513, a partial inverse benzodiazepine agonist, decreases self‐administration of ethanol (ETOH) in rats maintained on a two‐bottle regmine of a saccharin ethanol solution (ES) and water over a 35‐day consumption period. The present study extended the consumption period to 60 days and examined the effects of Ro15‐4513 (2.5 mg/kg), flumazenil (Ro15‐1788) (8.0 mg/kg), and Ro15‐4513 in combination with Ro15‐1788 on the time course of ETOH self‐administration. High initial intake of ES observed during the first 4 weeks declined significantly over subsequent weeks. Ro15‐4513 pretreatment, however, resulted in significant reduction of ES, while significantly preventing the “normal” reduction of consumption as was observed under control conditions. The antagonistic actions of Ro15‐4513 were blocked/attenuated by the benzodiazepine receptor antagonist, Ro15‐1788, independent of whether consumption of the ES was low or high. Both Ro15‐4513 and Ro15‐1788 affected water intake differentially compared with vehicle‐injected controls. The results suggest that GABA‐benzodiazepine mechanisms may be important in altering chronic ETOH drinking patterns depending upon experience with ETOH, tolerance, or learning.
Distribution of Alcohol Dehydrogenase and the Low Km Form of Aldehyde Dehydrogenase in Isolated Perivenous and Periportal Hepatocytes in Rats
Authors: Chen Ling , Sidner Richard A. , Lumeng Lawrence
Published: April 2006

Hepatic damage induced by chronic alcohol abuse starts in the petivenous (PV) zone of the hepatic lobule. To explain this vulnerability in the PV zone, periportal (PP) and PV hepatocytes were isolated by digitonin‐collagenase perfusion and the distributions of class I alcohol dehydrogenase (ADH) and the low‐Km mitochondrial aldehyde dehydrogenase (ALDH) were studied. ADH was measured by three approaches i.e., specific activity, immunoreactive enzyme content and ADH mRNA level. ALDH was determined by specific activity and immunoreactive enzyme content. When compared with PV hepatocytes, isolated PP cells exhibited higher lactate dehydrogenase (PP/PV = 1.3–1.5), higher alanine aminotransferase (PP/PV = 1.7–1.9), but lower glutamine synthase (PP/PV < 0.01). By prelabeling the PP zone with acridine orange before digitonin‐collagenase digestion, flow cytometry indicated that mainly the isolated PP hepatocytes exhibited fluorescence. ADH activities and AOH mRNA levels did not differ in PP and PV cells. With a polyclonal antibody directed specifically against class I ADH, ADH immunoreactive protein also did not differ in PP vs PV cells. By activity assay, the low Km ALDH activities were found to be lower in the PV hepatocytes (PP/PV = 1.3). This was confirmed by immunotransblot with anti‐ALDH IgG (PP/PV = 1.6). In conclusion: the preferential damage of the PV zone produced by ethanol is not caused by differences of ADH distribution in liver but could be related partly to a decrease in the low‐Km, ALDH in the PV zone.
Delayed Thermoregulatory Changes in the Immature Rat Following a Single Injection of Ethanol
Authors: Spiers Donald E. , Fusco Laura E.
Published: April 2006

Adult rats exhibit rebound hyperthermia within 24 hr following a single injection of ethanol (EtOH). Tests were conducted to determine whether similar changes in thermoregulatory ability occur in the immature rat. Animals were administered saline or EtOH (4 g/kg BW intraperitoneally) at 2 to 3, 8 to 9, or 14 to 15 days of age. Littermates were handled or left undisturbed with the dams to serve as controls, All rats were tested at 24 or 48 hr post‐treatment to measure steady‐state colonic temperature (Tco), tail skin temperature and metabolic rate (MR) at both thermoneutral and cold ambient temperatures (Tas). The youngest group exhibited no delayed change in body temperature or MR at 24 or 48 hr post‐treatment with EtOH. Likewise, thermoregulatory ability of rats pretreated with EtOH at 8 to 9 or 14 to 15 days of age was not significantly different from controls when tested 24 hr post‐treatment at thermoneutral Ta. In contrast, Tco of EtOH‐treated rats in the two older age groups was 1°C above control level when tested 24 hr post‐treatment at cold Ta. This Tco response can be explained by differences in heat transfer to the tail and MR. No altered response to cold Ta was found at 48 hr postinjection, indicating recovery from the EtOH effect. A single injection with EtOH at 2 to 15 days of age results in a change in Tco, which is dependent on postinjection time, age, and Ta.
The Tridimensional Personality Questionnaire in Males at High and Low Risk for Alcoholism
Authors: Zaninelli Rocco M. , Porjesz Bernice , Begleiter Henri
Published: April 2006

Cloninger has proposed a tridimensional model as the basis for the classification of personality variants and has developed the Tridimensional Personality Questionnaire (TPQ) as an empirical test of this model. In this study, the TPQ was administered to two groups of young men. One group was comprised of nonalcoholic sons of male alcoholics; the other group consisted of nonalcoholic men with no family history of alcoholism. Since the sons of male alcoholics are considered to be at greater risk to develop alcoholism than the sons of nonalcoholics, it was hypothesized that the two groups would demonstrate differences with regard to one or more personality variants as measured by the TPQ. No statistically significant differences in the three TPQ‐subscale scores of the two groups were found.
New Alcohol Markers—How Useful Are They in Population Studies: The Svalbard Study 1988–89
Authors: Nilssen Odd , Huseby Nils Erik , Høyer Georg , Brenn Tormod , Schirmer Helge , Førde Olav Helge
Published: April 2006

Regular high consumption of alcohol in selected populations have, with high precision, been identified by two new alcohol markers: carbohydrate‐deficient transferrin and mitochondrial aspartate aminotransferase. To test these markers in an unselected population, gamma‐glutamyltransferase (GGT), carbohydrate‐deficient transferrin (CDT), and mitochondrial aspartate aminotransferase (mAST) were measured in the Norwegian population, 310 males and 171 females, aged 18 to 60 years, living at Svalbard. Using self‐reported alcohol intake as gold standard, sensitivity, specificity, positive predictive value, and likelihood‐ratio were estimated according to different cutoff‐points for alcohol intake and for the tests. In contrast to earlier studies, the sensitivity was in general low. With a specificity of 90% or higher, the sensitivity did not exceed 26% for any of the tests. Whereas CDT showed its best discriminatory power at lower intake of alcohol, GGT discriminated best at higher levels. Parallel and serial analysis of CDT and GGT indicated a conditional independence between the tests, as well as at higher and at lower levels of alcohol consumption. mAST was judged as not suitable in population studies.
The Association between Moderate Alcoholic Beverage Consumption and Serum Estradiol and Testosterone Levels in Normal Postmenopausal Women: Relationship to the Literature
Authors: Gavaler Judith S. , Van Thiel David H.
Published: April 2006

The major source of endogenous estrogens in postmenopausal women is the aromatization of androgens to estrogens; because alcohol is known to increase aromatization, the relationship between moderate alcoholic beverage consumption and serum estradiol levels was evaluated in 128 normal postmenopausal women. Alcohol intake was based on a composite of self‐report and food record information. Among the 78.8% of women reporting alcohol use, weekly intake was 4.8 ± 0.6 drinks. Among abstainers, estradiol levels were 100.8 ± 12.1 pmol/liter, significantly lower than in alcohol users, 162.6 ± 11.9 pmol/liter. Significant bivariate correlations were found between the logarithm of estradiol and total weekly drinks. In multiple linear regression analyses inclusion of alcohol as a variable increased the amount of explained variation in estradiol. Similar findings were demonstrable when the crude estimator of aromatization, the estradiol:testosterone ratio logarithm was the dependent variable. Together, these findings suggest that moderate alcohol use is an important factor for postmenopausal estrogen status and may offer a partial explanation for the reported protective effect of moderate alcohol consumption with respect to postmenopausal cardiovascular disease risk.
Human Placental Transfer of Zinc: Normal Characteristics and Role of Ethanol
Authors: Beer William H. , Johnson Raymond F. , Guentzel M. Neal , Lozano Joy , Henderson George I. , Schenker Steven
Published: April 2006

The fetal alcohol syndrome is primarily an impairment of growth and development. Zinc deficiency also causes abnormal fetal growth. Moreover, alcohol has been shown in some rodent studies to impair placental transport of zinc. The purpose of this investigation was to define better normal human placental zinc transport and the effects of alcohol on this process.

To do this we employed the isolated perfused single cotyledon human term placental model, as well as the cultured human cytotrophoblast. In the perfused placental studies, it was shown that zinc is transferred by the placenta very slowly, about 6% of the rate of transport of antipyrine, a freely diffusible marker. The transfer is comparable in both directions, maternal to fetal and the reverse. Zinc does not cross the placenta against a zinc concentration gradient, in either direction. Rather there is good evidence of significant uptake (storage) of the zinc by the placenta on the recirculating compartment side of gradient studies. Moreover, when the perfusion fluid was low (0.2 g/100 ml) in albumin, about twice as much zinc accumulated in the perfused cotyledon and there was less zinc in the maternal compartment, as compared to perfusion with ten‐fold higher (2.0 g/100 ml) albumin concentrations. Thus, ligand binding in the perfusate importantly influences placental zinc uptake. Interestingly, however, the increased placental binding of zinc did not translate into greater transfer of zinc to the fetal compartment.

Thus, normal zinc transfer is slow, equal bidirectionally, and dependent on ligand binding in perfusate and placenta. Equal transport in both directions and absence of accumulation of zinc against a concentration gradient at “physiologic” zinc concentrations are not consistent with active (energy dependent) transfer. Alcohol (400 mg/100 ml) added to the perfusate did not impair placental zinc transfer from the maternal to fetal circuits over 4 h. Also, net uptake of zinc by human placental trophoblast exposed to 200 mg/100 ml alcohol concentration for 48 h was comparable to control values. Thus, alcohol exposure over this time in both experimental systems did not impair zinc transport by the term human placenta.
Abnormalities of Hematologic Parameters in Heavy Drinkers and Alcoholics
Authors: Seppä Kaija , Sillanaukee Pekka , Koivula Timo
Published: April 2006

Hematologic parameters measured by a Technicon H‐1 analyzer and reticulocyte values were studied in three middle‐aged male groups; 184 social drinkers, 88 heavy drinkers, and 106 alcoholics. Erythrocyte mean cell volume (MCV) correlated positively (p < 0.001) with red cell distribution width (r= 0.388) and negatively with red blood cells (r= ‐0.594, p < 0.001), hemoglobin distribution width (r= ‐0.330, p < 0.001), cell by cell counted hemoglobin concentration (CHCM) (r= ‐0.434, p < 0.001), and the ratio between standard deviation of CHCM and CHCM (r= ‐0.375, p < 0.001). In spite of these correlations high red cell distribution width values were also found in alcoholic patients with normocytosis (MCV ≤ 96 fl).

Alcohol induced abnormalities primarily in erythrocytes. The only significant abnormality in the heavy drinker group was a high value of erythrocyte MCV, which was found in 22.7%. In the alcoholic group the MCV value was high in 39.6%, and low erythrocyte values were detected in 16%. A high erythrocyte mean cell distribution width value indicating anisocytosis was found in 40.6% of the alcoholic group. In this material the specificities of these values were also good. The scatter cytogram for red blood cells did not give any valuable visual information in the abuser groups. Thus, certain abnormalities in the Technicon H‐1 system parameters, even other than MCV, can be explained by alcohol abuse.
Delayed Increases in Liver Cirrhosis Mortality and Frequency of Alcoholic Liver Cirrhosis Following an Increment and Redistribution of Alcohol Consumption in Finland: Evidence from Mortality Statistics and Autopsy Survey Covering 8533 Cases in 1968–1988
Authors: Savolainen V. T. , Penttilä A. , Karhunen P. J.
Published: April 2006

Changes in the legal restrictions for alcohol consumption in 1969 liberated purchasing and marketing of low‐alcohol beer. Subsequently, within the space of 5 years, the per capita consumption of absolute alcohol increased from 4.2 to 6.5 liters. To evaluate the possible effects of this change upon liver cirrhosis mortality as well as prevalence of liver cirrhosis in autopsy series, we surveyed mortality statistics and data from 8,533 medicolegal autopsies in 1968 through 1988. Liver cirrhosis mortality statistics revealed a highly significant (p < 0.001) increase from 6.4 to 13.7 per 100,000 during the period, and similarly, the prevalence of liver cirrhosis in the autopsy series showed a highly significant (p < 0.001) increase from 3.0% to 6.1%. More specifically, this increase was attributable to a highly significantly (Chi‐square 15.4, p < 0.001) increased proportion of alcoholic liver cirrhosis occurring at a younger age and almost exclusively in males. The stepwise mode of increase as well as the changes in sex and age distribution of cirrhosis since 1969 could be interpreted as an effect of distribution of consumption to a new generation of consumers. The forensic autopsy series seemed to reflect changes in per capita consumption with a shorter time lag than with mortality statistics. Additionally, only 7% of the 448 cirrhosis singled out from this material exhibited liver cirrhosis as a cause of death and were thus also included in the official mortality statistics, suggesting the greater accuracy of our forensic autopsy series.
Alcohol and Deaths in Police Custody
Authors: Giles H. Gwynne , Sandrin Susie
Published: April 2006

We examined the involvement of alcohol consumption, chronic alcohol abuse or dependence, the soundness of the police determination of alcohol‐related intoxication, and the importance of other drugs in deaths in police custody in a survey of the cases reported to the Chief Coroner of Ontario during the past 10 years. The data suggest no mismanagement by the police. At least 86% of the fatalities were associated with recent alcohol consumption or chronic alcohol abuse/dependence. Use of drugs other than alcohol was far less common. Promoting use and further development of simple tests to estimate blood alcohol concentration, chronic alcohol problems, and suicide risk, before incarceration takes place, may save lives.
The Development of Alcohol‐Related Expectancies from the Age of 12 to the Age of 15 for Two Swedish Adolescent Samples
Authors: Gustafson Roland
Published: April 2006

Two hundred seventy‐four Swedish students from grades six through nine participated in the first study. The purpose was to explore whether 12‐year‐old Swedish students (grade six) have formed alcohol‐related expectancies prior to any own extensive drinking experience and whether alcohol‐related expectancies change from the age of 12 to the age of 15 (grade nine). Results indicated that expectancies are formed at the age of 12 and that most of the expected effects are positive in nature. From the age of 12 to the age of 15 expectancies develop further in a positive direction. Background variables did not affect the results to any major degree. The results from a second, more heterogeneous sample of 146 students from grade six and grade nine, confirmed the general picture. It was concluded that adolescents do hold positive alcohol‐related expectancies and that these expectancies become more positive with increasing age.
Alcoholism and the D2 Receptor Gene
Authors: Cook Brian L. , Wang Zhe Wu , Crowe Raymond R. , Hauser Richard , Freimer Martin
Published: April 2006

The allelic association of the human dopamine D2 receptor gene and alcoholism was evaluated in 20 male alcoholics and 20 controls (sex, race, and geographic place of birth matched). This study further examines the issue of alcoholism severity and A1 allele frequency. No difference in A1 allele frequency was observed between these two groups. Similarly, no relationship between alcoholism severity and A1 frequency within the alcoholics was demonstrated.
Effects of Morphine and Naloxone on Ethanol‐ and Sucrose‐Reinforced Responding in Nondeprived Rats
Authors: Schwarz‐Stevens Karen S. , Files Forrest J. , Samson Herman H.
Published: April 2006

In the following series of experiments, effects of morphine (0.1, 0.3, 1.0, 3.0, and 10.0 mg/kg) and naloxone (0.1, 0.3, and 1.0 mg/kg) were assessed in nondeprived rats trained to leverpress with 10% ethanol, sweetened ethanol, or 5% sucrose and water as the rein‐forcers. Morphine, at doses of 0.1, 0.3, and 1.0 mg/kg had little effect on responding with ethanol or sweetened ethanol available on a fixed ratio 4 (FR4) schedule of reinforcement, but at the 3.0 mg/kg dose, morphine suppressed responding to near zero. Similar results were obtained when 10% ethanol and water were available on a concurrent FR4 FR4 schedule of reinforcement. When 5% sucrose and water were available concurrently, morphine suppressed responding at 3.0 and 10 mg/kg. Naloxone (0.1, 0.3, and 1.0 mg/kg) decreased responding for ethanol, sweetened ethanol, and sucrose solutions in a dose‐dependent manner. Naloxone decreased total number of responses/session by shortening the duration of responding without affecting momentary rate. Overall, the data suggest that the endogenous opioid system plays a role in the ability of ethanol to reinforce operant behavior. However, this role does not appear to be specific to ethanol because similar results were observed with sucrose reinforcement. Failure to find enhanced ethanol intakes following morphine injections in the operant situation suggests that the method used to measure ethanol self‐administration makes a difference in assessing the effects of drugs on ethanol intake.
Low Platelet Gamma‐Aminobutyrate Aminotransferase and Monoamine Oxidase Activities in Chronic Alcoholic Patients
Authors: Sherif Fathi , Hallman Jarmila , Oreland Lars
Published: April 2006

The activities of gamma‐aminobutyrate aminotransferase (GABA‐T) and monoamine oxidase (MAO) were estimated in blood platelets from 25 male chronic alcoholics and from 27 healthy male volunteers without histories of alcohol abuse. Based on clinical criteria, the alcoholics were classified into type 1 or type 2 alcoholism. The activity of GABA‐T was found to be lower both in type 1 and type 2 alcoholics than in healthy volunteers. With regard to MAO, the platelet activity was found to be significantly lower only in type 2 alcoholics in concordance with previous reports. No significant correlation was found between the activities of GABA‐T and MAO in the blood platelets of healthy volunteers. The inhibitory effect of 400 mM ethanol on the platelet MAO activity increased with decreasing concentrations of the substrate phenylethylamine. The degree of inhibition of ethanol on the platelet MAO activity, however, did not differ significantly between alcoholics and controls.
Response to Diazepam in Sons of Alcoholics
Authors: Cowley Deborah S. , Roy‐Byrne Peter P. , Godon Carol , Greenblatt David J. , Ries Richard , Walker R. Dale , Samson Herman H. , Hommer Daniel W.
Published: April 2006

Alcohol exerts several of its actions via the chloride channel associated with the central GABA‐benzodiazepine receptor complex. To explore possible role for this receptor complex in risk for alcoholism, and to determine whether risk for alcoholism is associated with risk for benzodiazepine abuse, the authors administered intravenous diazepam to 18 sons of male alcoholics (SOAs) and 18 control subjects. Four logarithmically increasing doses of diazepam and matched volumes of placebo were given in randomized order on separate days about 1 week apart. SOAs were significantly more likely than controls to report euphoric responses to diazepam. At some diazepam doses, SOAs were more likely to report feeling “high” and “intoxicated.” SOAs and controls did not differ in feeling “drugged.” SOAs and controls may differ in expectations regarding the subjective effects of drugs and/or in the function of the central GABA‐benzodiazepine receptor complex. These findings also add further evidence for increased pleasurable effects, and thus possibly increased risk for benzodiazepine abuse, in subgroup of SOAs.
The Identification and Partial Characterization of Acetaldehyde Adducts of Hemoglobin Occurring in Vivo: A Possible Marker of Alcohol Consumption
Authors: Gross Myron D. , Gapstur Susan M. , Belcher John D. , Scanlan Gale , Potter John D.
Published: April 2006

Chromatographic, peptide mapping and mass spectrometric analysis were used to examine hemoglobin (Hb) from heavy drinkers and abstainers for alcohol consumption‐related modifications. Heavy drinker and abstainer hemoglobin samples contained similar amounts of glycosylated Hb and significantly different (p < 0.05) amounts of “fast” hemoglobin. The presence of higher amounts of “fast” Hb in heavy drinker relative to abstainer samples suggested the presence of alcohol‐consumption related modifications. To further examine Hb for modifications, tryptic peptides of the “fast” hemoglobin HbA1c were isolated and analyzed by plasma desorption mass spectrometry (PDMS). [14Clacetaldehyde (AcH)‐Hb was synthesized in vivo for use as standard. Specific peptides were chosen based on co‐migration with radiolabeled peptides from tryptic digest of the [14C]acetaldehyde‐Hb. The masses obtained by PDMS for two heavy drinker peptides were identical to two radiolabeled peptides; the two pairs of peptides co‐migrated on HPLC. A comparison of the observed mass for the peptides with the theoretical masses for acetaldehyde‐modified Hb peptides suggested that the peptides were AcH‐modified alpha and beta chain N‐termini of Hb. The modified peptides were found in five of six heavy drinker samples. This is the first description of site‐specific AcH‐Hb adducts occurring in vivo. The routine detection of such adducts has potential for characterizing usual alcohol intake.