bluuebunny/crossref_metadata_2025 huggingface dataset:
Ambient Temperature Effects on Taste Aversion Conditioned by Ethanol: Contribution of Ethanol‐Induced Hypothermia
Authors: Cunningham Christopher L. , Niehus Jill S. , Bachtold Joseph F.
Published: April 2006

Six experiments examined the effects of low (5–10°C), normal (21°C), or high (32°) ambient temperature on conditioned taste aversion and body temperature changes produced by ethanol, lithium chloride, or morphine sulfate. Fluid‐deprived rats received five to seven taste conditioning trials at 48‐hr Intervals. On each trial, access to saccharin at normal ambient temperature was followed by injection of drug or saline and placement for 6 hr into a temperature‐controlled enclosure. Exposure to low ambient temperature facilitated, whereas exposure to high ambient temperature retarded acquisition of ethanol‐induced conditioned taste aversion. The ability of an alteration in ambient temperature to influence conditioned taste aversion varied as a function of ethanol dose and was related to ambient temperature's effect on ethanol‐induced hypothermia. More specifically, strength of conditioned taste aversion was negatively correlated with core body temperature after ethanol injection. Alterations in ambient temperature alone did not affect ingestion of a paired flavor solution in the absence of drug. Moreover, alterations in ambient temperature did not appear to influence conditioned taste aversion by changing ethanol pharmacokinetics. Finally, high and low ambient temperature did not affect development of taste aversion conditioned by lithium chloride or morphine sulfate. The overall pattern of data presented by these experiments supports the hypothesis that ambient‐temperature influences strength of ethanol‐induced conditioned taste aversion by altering the hypothermic response to ethanol. More generally, these data support the suggestion that body temperature change induced by ethanol is related to ethanol's aversive motivational effects and may be involved in modulating ethanol intake.
Localization of Protein‐Acetaldehyde Adducts on Cell Surface of Hepatocytes by Flow Cytometry
Authors: Lin Renee C. , Sidner Richard A. , Fillenwarth Michael J. , Lumeng Lawrence
Published: April 2006

Acetaldehyde, a highly reactive intermediate of ethanol metabolism, has been shown to form adducts with liver proteins (e.g., a cytosolic 37 kDa protein and the microsomal cytP450IIE1) in rats fed alcohol chronically. In this study, flow cytometry was utilized to test for the presence of protein‐acetaldehyde adducts (‐AAs) on the surface of hepatocytes and immunotransblot was used to detect for the 37 kDa protein‐AA in cytosol as was previously described. For flow cytometric analysis, rabbit anti‐hemocyanin‐AA IgG and fluorescein isothiocyanate‐conjugated goat anti‐rabbit serum IgG were used as the primary and secondary antibodies to label surface protein‐AAs on hepatocytes at 0° to 4°C. After labeling and washing, hepatocytes were fixed with paraformaldehyde‐cacodylate and analyzed with a flow cytometer. In an experiment wherein hepatocytes isolated from rats pair‐fed liquid diets with and without ethanol were treated by adding both the primary and secondary IgGs, some hepatocytes from both alcohol‐fed and control rats exhibited positive fluorescence but no significant difference in fluorescence intensity was noted. In another experiment, hepatocytes were isolated from rats pair‐fed cyanamide (a selective aldehyde dehydrogenase inhibitor) with and without ethanol. The number of hepatocytes showing positive fluorescence in the presence of both primary and secondary IgGs was significantly higher in rats fed cyanamide plus ethanol than in rats fed cyanamide only. Of note, the 37 kDa protein‐AA could be detected by immunotransblot in liver cytosol of alcohol‐fed rats but not in the controls of both experiments with and without cyanamide supplementation. When hepatocytes from rats fed cyanamide plus ethanol were incubated with 0.5% trypsin for 5 min at 37°C after being labeled with fluorochrome, the population of cells with positive fluorescence disappeared. Our data thus indicate that hepatocytes contain surface protein‐AAs when in vivo acetaldehyde concentration is elevated by feeding alcohol and cyanamide simultaneously but not by feeding alcohol alone. The implication is that at least in the rat, only high concentrations of acetaldehyde in vivo can lead to presentation of protein‐AAs to liver cell surface to serve as neoantigens.
Effects of Ethanol and Control Liquid Diets on the Hypothalamic‐Pituitary‐Thyroid Axis of Male Fischer‐344 Rats
Authors: Mason George A. , Noonan Linda R. , Garbutt James C. , Caldwell Jack D. , Shimoda Kazutaka , Walker Cheryl H. , Li Li , Prange Arthur J.
Published: April 2006

The effects of a high dextrose liquid diet containing ethanol and two different control liquid diets on serum and brain thyroid axis hormones and liver and brain deiodinase activities were studied in groups of adult male Fischer‐344 (F‐344) rats. Rats received either lab chow, ad libitum; a nutritionally complete 10% (w/v) ethanol liquid diet, ad libitum; a volume of either a high carbohydrate (HC) or a high fat (HF) isocaloric control liquid diet equal to the volume of diet consumed by rats given the ethanol diet; or the HC control diet, ad libitum. Consumption of liquid diets was measured daily and body weights recorded every other day throughout the study. Hormones were measured after 2, 4, or 8 weeks and deiodinase activities after 4 or 8 weeks. Also, groups of rats were given the 10% ethanol diet, ad libitum, or pair‐fed the HC control diet intermittently for 8 weeks, and thyroid hormones and thyroid‐stimulating hormone (TSH) response to thyrotropin‐releasing hormone (TRH) were determined.

Within 2 weeks rats became accustomed to all diets and thereafter weight gain was comparable in all groups. Small differences between serum thyroid hormones of rats fed the ethanol diet and pair‐fed HC or HF controls may have been caused by lower T4 secretion in ethanol‐fed rats. Marked differences in free and total T4 and T3 between F‐344 rats fed liquid diets for 4 or 8 weeks and rats fed lab chow probably resulted from higher liver 5′‐deiodinase activity in rats fed liquid diets. Sprague‐Dawley rats showed similar but less marked dietary‐induced changes in thyroid hormone levels than did F‐344 rats. No differences in cerebral cortical levels of T4 or T3 were observed among F‐344 rats fed the ethanol liquid diet, rats pair‐fed HC control diet, or rats that received lab chow. No significant differences in basal thyroid axis hormones or TSH response to TRH were observed among F‐344 rats intermittently fed ethanol diet, control diet, or lab chow.
Tolerance to Adenosine's Accentuation of Ethanol‐Induced Motor Incoordination in Ethanol‐Tolerant Mice
Authors: Dar M. Saeed , Clark Mike
Published: April 2006

Our previously published reports have provided data that have supported a functional correlation between ethanol‐induced changes in the characteristics of adenosine receptor, adenosine uptake and release in the brain, and ethanol‐induced motor incoordination. The present data demonstrated a cross‐tolerance between ethanol and adenosine further supporting the hypothesis that brain adenosine modulates the motor impairing effects of ethanol. Mice that received (‐)‐N6‐cyclohexyladenosine (CHA) [0.25 mg/kg/day, intraperitoneal (ip)] for 10 days exhibited marked attenuation (cross‐tolerance) to acute ethanol‐induced motor incoordination compared with chronic saline (ip) controls. The attenuation of acute ethanol‐induced motor incoordination was essentially same in animals that received CHA (25 ng/5 μl/day for 10 days) by the intracerebroventricular (icv) route as opposed to the controls that chronically received artificial cerebral spinal fluid by the same route. Similarly, tolerance was exhibited to acute CHA (0.125 mg/kg ip and 12.5 ng/5 μl icv) by animals fed liquid ethanol (19.5 g/kg/24 hr) for 10 days compared with none in the pair‐fed sucrose controls. Scatchard plots using cerebellar tissue homogenates from animals given chronic CHA or chronic ethanol indicated no change in Bmax and/or Kd values for CHA binding when compared with CHA binding in tissues from their respective controls. However, a lack of any change in the binding characteristics cannot rule out the involvement of adenosine receptors in the observed cross‐tolerance between ethanol and CHA. The results may suggest desensitization of adenosine A, receptors due to chronic CHA and ethanol as an alternate possible explanation in the development of cross‐tolerance between adenosine (CHA) and ethanol.
Effect of Chronic Alcohol Ingestion on the Binding of High Density Lipoproteins to Rat Hepatic Membranes: Involvement of Apolipoprotein E
Authors: Lin Renee C. , Miller Barbara A.
Published: April 2006

Feeding alcohol to rats produces high density lipoproteins (HDL) particles that exhibit lowered apolipoprotein (apo) E:apo A1 ratio. In this study, we have carried out experiments to compare the abilities of apo E‐deficient HDL particles of the alcohol‐fed rat and apo E‐sufficient HDL particles of the control rat to bind to hepatic membranes. When rat hepatic membranes were incubated with rat serum HDL of physiological concentrations (≤200 μg HDL‐apo A1/ml), binding of HDL to hepatic membranes showed concentration dependent on HDL‐apo A1. Polyclonal antibodies that specifically recognize apo A1 and apo E inhibited HDL binding to hepatic membrane while the antibody against apo AIV did not. The binding of 125l‐apo A1‐HDL was diminished by adding excess amount of unlabeled HDL to the incubation mixture. Apo E‐deficient serum HDL obtained from alcohol‐fed rats competed less efficiently against radiolabeled HDL for binding to rat hepatic membrane than normal HDL from control animals. The defect in apo E‐deficient serum HDL obtained from alcohol‐fed rats can be corrected by preincubation with added purified apo E. We hypothesize that this weaker binding may result in slower degradation of apo E‐deficient HDL particles by the liver and in part explains the higher plasma HDL levels found in alcohol‐drinking animals.
Women, Work, and Alcohol: Failures of Simple Theories
Authors: Wilsnack Richard W. , Wilsnack Sharon C.
Published: April 2006

When trying to explain how women's employment affects their drinking behavior, oversimplified theories produce weak and inconsistent results. Recent research casts doubt on any simple ideas that paid employment is hazardous for women's mental health and drinking, or that paid employment is beneficial for women's mental health and drinking, or that stressful jobs increase women's risks of problem drinking. Improved, more complex theories could specify which women will modify their drinking behavior as a result of particular employment experiences, predict interaction effects of employment conditions with other aspects of women's lives, and explain how employment may create a context where other variables may increase or reduce risks of problem drinking.
Cognitive Functioning, ASP, and Family History of Alcoholism in Young Men at Risk for Alcoholism
Authors: Gillen R. , Hesselbrock V.
Published: April 2006

Previous research has suggested that individuals with a family history of alcoholism may have cognitive deficits that predate, and possibly predispose, to the onset of alcoholism. However, these deficiencies may result from other factors, e.g., comorbid psycho‐pathology. The current study investigated the neuropsychological functioning of young adult males at high risk for alcohol abuse due to a family history of alcoholism (FH) and/or a personal history of antisocial personality disorder (ASP). A family history of alcoholism (FH+) alone was not associated with neuropsychological impairment. Subjects with ASP, however, exhibited some difficulty with higher level motor control and with verbal concept formation compared with nonASP subjects. No clear pattern of FH × ASP interaction was evident in the measures examined. These findings suggest that previous findings suggesting cognitive deficiencies in FH+ individuals may have been related to a failure to consider co‐morbid ASP. The deficits exhibited by the ASP subjects may reflect both reduced inhibitory control and a deficiency in higher level verbal skills. These deficiencies may leave ASP individuals less capable of utilizing higher level language skills to regulate behavior.
Neuroendocrine, Fluid Balance, and Thirst Responses to Alcohol in Alcoholics
Authors: Collins Gregory B. , Brosnihan K. Bridget , Zuti Rebecca A. , Messina Matthew , Gupta Manjula K.
Published: April 2006

This study simultaneously evaluated multiple circulating neurohormones, osmolality, thirst, and fluid balance in eight actively drinking, alcoholic males and seven controls before and 12 hr after an ethanol challenge. Basal levels of serum osmolality and thirst were significantly higher in alcoholics compared with controls, yet actively drinking alcoholics at the start of the study had normal vasopressin (AVP) levels, plasma angiotensin II (Ang II), plasma renin activity, plasma aldosterone (Aldo), and plasma catecholamines. In response to ethanol, serum osmolalities rose significantly higher while plasma AVP levels became significantly suppressed in alcoholics. After the ethanol stimulus, plasma Ang II levels of alcoholics were significantly higher than those of controls at 11 AM (12.15 ± 4.49 vs. 1.83 ± 0.6 pg/ml, p < 0.02) and 12 noon (14.93 ± 6.81 vs. 1.37 ± 0.17 pg/ml, p < 0.04). Neither plasma renin activity nor Aldo changed in accordance with the elevated plasma Ang II in alcoholics. Diuresis in the alcoholics, assessed by the sum of urine output following the challenge dose, was significantly less than that of controls. Thirst scores and fluid intakes after the ethanol challenge did not differ between alcoholics and controls. The lack of an Ang Il‐mediated increase in plasma Aldo or thirst response suggests that ethanol may have a specific blunting effect on Ang II receptors. This study demonstrates that ethanol can be used as a provocative test in chronic alcoholics to uncover aberrant hormonal responses for two systems, namely, Ang II and AVP. This type of testing may have diagnostic utility in identifying active alcoholics, especially those who may be engaged in verbal denial, in a clinical setting.
Consistency and Change in Patterns of Social Drinking: A 6‐Year Follow‐Up of the Finnish Twin Cohort
Authors: Kaprio Jaakko , Viken Richard , Koskenvuo Markku , Romanov Kalle , Rose Richard J.
Published: April 2006

In 1975 and again in 1981, all adult twins in the population‐based Finnish Twin Cohort were administered postal questionnaires yielding data on self‐reported frequency and quantity of alcohol use. The longitudinal results provide information on the age‐to‐age stability of social drinking patterns among 13,404 (twin) individuals aged 18 to 43 at baseline; model‐fitting the cross‐temporal consistency of the twins' reported alcohol use yields unique estimates of the contribution of genetic and environmental factors to their individual age‐to‐age stabilities. Mean consumption levels did not change between 1975 and 1981. Patterns of social drinking were more stable in older (aged 24–43 at baseline) than younger (aged 18–23 at baseline) adult twins, and were more stable among men than women. Heritabilities were significant at both baseline and follow‐up for all three alcohol measures in both genders and both age groups, with a median magnitude of 0.48. Both longitudinal genetic and environmental covariances were significant, and both were generally higher among older pairs. Genetic covariances (median magnitude = 0.68) were significantly higher than environmental covariances (median = 0.36). Analyses of absolute changes in alcohol use revealed heritable influences on the disposition to change. We conclude that genes contribute to both consistency and change in patterns of alcohol use from early to midadulthood.
The Effects of Chronic Ethanol Consumption on the Mesolimbic and Nigrostriatal Dopamine Systems
Authors: Pellegrino Susan M. , Druse Mary J.
Published: April 2006

Both the mesolimbic dopamine system, which is involved with the rewarding properties of several drugs of abuse, and the nigrostriatal dopamine system, which is involved with motor function, appear to be sensitive to the effects of ethanol. In order to determine which components of the mesolimbic and nigrostriatal dopamine systems are adversely affected by chronic ethanol consumption, we assessed dopamine and DOPAC (3,4‐dihydroxyphenylacetic acid) concentration and D1 and D2 receptors in several dopaminergic brain areas.

These studies demonstrated that consumption of a 6.6% (v/v) ethanol‐containing lipid diet for 1 month affected several components of the mesolimbic dopamine system in 3‐month‐old Fisher 344 rats and fewer components of the nigrostriatal dopamine system. Specifically, there was a 1.6‐ to 2.6‐fold increase in the concentration of DOPAC in the nucleus accumbens (NA), frontal cortex (FCX), ventral tegmental area (VTA), and substantia nigra (SN). While the increase in DOPAC in the FCX and VTA was paralleled by a similar increase in dopamine, there was a significant deficiency of dopamine in the SN. These results suggest that there is an increase in dopamine turnover in the FCX, VTA, NA, and SN, which is accompanied by increased dopamine synthesis in the former two regions.

Studies of dopamine receptors in control and ethanol‐fed rats demonstrated a 25% loss of Di receptors in the NA. No significant differences were found in D1 receptors in the striatum or globus pallidus. In addition, there were no differences in the number of total D2 receptors or in the conversion of the high to low affinity state of D2 receptors in the nucleus accumbens and striatum. The results of these studies emphasize the different sensitivities of dopaminergic brain areas to chronic ethanol exposure.
Effects of Ethanol on DNA, RNA, and Protein Synthesis in Rat Astrocyte Cultures
Authors: Snyder Ann K. , Singh Sant P. , Ehmann Svetlana
Published: April 2006

Brain growth retardation is a major feature of the fetal alcohol syndrome (FAS). Insulin and insulin‐like growth factors (IGF‐I and IGF‐II) exert significant growth‐promoting effects on the central nervous system (CNS). The present study examined the effects of ethanol and its interaction with growth factors on the incorporation of labeled precursors into DNA, RNA, and protein in primary astrocyte cultures prepared from term fetal rats. Cultures were exposed to ethanol for 18 hr in serum‐free medium before measuring nucleoside or amino acid incorporation into acid‐precipitable cell constituents. Under basal conditions, ethanol induced dose‐dependent changes in the rates of incorporation of tritiated thymidine, uridine, and valine. The fraction of the total thymidine uptake that was incorporated into DNA was reduced in the presence of 100 and 200 mM ethanol. Effects on uridine and valine incorporation paralleled cell uptake. Insulin (10−6m) and IGF‐I (10−8m) increased (p < 0.01) incorporation of radiolabeled thymidine, uridine, and valine. Analysis of variance indicated highly significant interactions between ethanol and the effects of growth factors on incorporation of both nucleosides and valine. Interference with the action of neurotrophic factors may be a significant factor in fetal brain growth retardation associated with maternal ethanol ingestion.
The Effect of Ethanol Metabolism on Ferritin Uptake by Freshly Isolated Rat Hepatocytes: Is Acetaldehyde Responsible for This Alteration?
Authors: Zhang Hui , Potter Barry J.
Published: April 2006

Alcohol abuse is associated with disturbances to iron metabolism in man, ranging from anemia to siderosis. Also seen in these patients are increased serum ferritin levels. Since the liver not only stores iron in cytosolic ferritin, but has also been shown to take up this molecule from the plasma by an active transport mechanism, it has been suggested that the iron in this circulating ferritin may contribute to the increased incidence of siderosis seen in alcoholics. As part of an ongoing study of these disturbances, using a rat model, we have examined the uptake of ferritin by freshly isolated hepatocyte suspensions to test the hypothesis that increased hepatocyte uptake of ferritin iron contributes to the siderosis seen in some alcoholics.

Incubation of hepatocytes in the presence of ethanol resulted in a progressive reduction in uptake with increasing alcohol concentration, from 1.23 ± 0.05 ng of ferritin/106 cells/min to 0.65 ± 0.02 ng/106 cells/min (mean ± SD) at an ethanol concentration of 100 mM. 4‐Methylpyrarole (0.1 mM) restored 70% of this activity, but higher concentrations also decreased ferritin uptake in the absence of ethanol. The addition of 5 μM cyanamide decreased ferritin uptake slightly in the presence of ethanol (0.82 ± 0.04 ng of ferritin/106 hepatocytes/min vs. 0.86 ± 0.03 ng/106 cells/min for ethanol alone), while having no effect in the absence of ethanol (1.01 ± 0.04 vs. 1.12 ± 0.05 ng/106 cells/min). Preincubation of the hepatocytes with acetaldehyde resulted in a dose‐dependent reduction to a maximum reduction of approximately 25% at 300 μM acetaldehyde.

These data suggest that, contrary to our initial hypothesis, ethanol has an acute inhibitory effect on ferritin uptake by the hepatocyte. This effect appears to be mediated by acetaldehyde production, resulting from ethanol metabolism.
Blood and Serum Thiamin and Thiamin Phosphate Esters Concentrations in Patients with Alcohol Dependence Syndrome Before and After Thiamin Treatment
Authors: Tallaksen C.M.E. , Bøhmer T. , Bell H.
Published: April 2006

The blood and serum concentrations of free thiamin and its three phosphate esters were determined concomitantly by a new high‐performance liquid chromatography (HPLC) method in 30 patients with alcohol dependence syndrome on admission to hospital and 24 hr after thiamin injection. We studied 24 men and 6 women; mean age, 50 years (range 21 to 69); mean ethanol consumption during the last 30 days, 164 ± 119 g/day. A control group included 40 healthy volunteers (25 men, 15 women), of whom 10 were given the same thiamin injection as were the patients. Thiamin monophosphate was significantly reduced in the patients compared with controls before treatment (men 2.9 ± 2.3 and 5.9 ± 3.1 nmol/liter) and after (8.1 ± 5.1 and 19.5 ± 8.1 nmol/liter). On admission, free thiamin and thiamin diphosphate were similar in controls and in patients in whole blood (B) and serum (S) and increased similarly after treatment (mean B‐thiamin diphosphate in male patients: 149 ± 64 to 238 ± 88 nmol/liter, in controls: 179 ± 40 to 289 ± 18 nmol/liter). However, seven patients had extremely high free thiamin values. The phosphorylation ratio was lower in patients than in controls (p < 0.05), before and after treatment. Finally, the mean B‐diphosphate was lower in patients not taking vitamins (116 ± 48 nmol/liter and 172 ± 57 nmol/liter) and in patients with polyneuropathy (118 ± 54 nmol/liter and 173 ± 52 nmol/liter), compared with the other patients. We conclude that the complete blood thiamin status discloses not only deficiency but also impairment of thiamin metabolism in patients with alcohol dependence syndrome, possibly due to altered protein binding, and that thiamin supplementation is effective even in currently abusing patients.
Attenuation of Alcohol Preference in Alcohol‐Preferring Rats by a Novel TRH Analogue, TA‐0910
Authors: Rezvani Amir H. , Garbutt James C. , Shimoda Kazutaka , Garges Patricia L. , Janowsky David S. , Mason George A.
Published: April 2006

Experiments were performed to characterize the acute effect different doses of a novel thyrotropin‐releasing hormone (TRH) analogue (TA‐0910) on ethanol intake in rats. Selectively bred alcohol‐preferring (P) rats received a single intraperitoneal injection of normal saline or 0.083, 0.25 and 0.75 mg/kg of TA‐0910 at 9:30 AM, and their consumption of ethanol, water, and food was measured for hr. TA‐0910 dose‐dependently attenuated ethanol intake and commensurately increased water consumption. Only the highest dose TA‐0910 increased the total caloric intake. TA‐0910 did not affect the pharmacokinetics of ethanol. These findings indicate involvement of TRH systems in ethanol preference and suggest that centrally acting TRH analogues may be therapeutic in the treatment of alcoholism.
Corticosterone Induces Rat Liver Alcohol Dehydrogenase mRNA But Not Enzyme Protein or Activity
Authors: Qulali Mona , Crabb David W.
Published: April 2006

Glucocorticoids induced ADH activity and mRNA 2‐ to 4‐fold in rat hepatoma cells (H4IIE and H4IIEC3), but were reported not to alter ADH activity in rat liver. The failure of corticosteroids to induce ADH may have been due to the short‐term treatment of the rats or the dose of steroid used. To reevaluate the effect of glucocorticoids in vivo, we studied animals 4.5 weeks after adrenalectomy so that ADH activity and mRNA should have reached a new steady‐state level; the dose of glucocorticoid used was estimated to provide physiological replacement. Male Wistar rats were injected with a single daily dose (10 mg/kg/day) of corticosterone‐21‐acetate or vehicle subcutaneously for 10 days. Liver extracts were assayed for ADH activity, ADH protein, and ADH mRNA. Nuclei were isolated for nuclear run‐on assays. Adrenalectomy did not reduce the activity of ADH in liver. Subsequent corticosterone treatment did not alter ADH enzyme activity, nor did it affect ADH protein levels as analyzed on Western blots. However, Northern blot analysis of ADH mRNA indicated a 2‐fold increase in ADH mRNA in the treated animals when the data were normalized to the level of the 28S ribosomal RNA or CHO‐B mRNA. The rate of transcription of the ADH gene in nuclei isolated at the end of 10 days of treatment from corticosterone‐treated adrenalectomized rats was not statistically different from that in the oil‐treated adrenalectomized ones. The disparity between ADH activity and protein levels and the mRNA level may have resulted from other effects of corticosterone, e.g., stimulation of protein degradation or effects on translation.
Time Dependency of IgA Nephropathy Induction in Alcohol Ingestion
Authors: Smith Suzanne Meleg , Tsukamoto Hidekazu
Published: April 2006

We investigated the influence of the alcohol ingestion period on the incidence of IgA nephropathy in an animal model. A group of 41 rats received a continuous infusion of liquid diet and alcohol: “alcoholics.” A further group of 41 control rats received an isocaloric diet in which the alcohol was replaced by glucose. IgA nephropathy was diagnosed by the presence of intense IgA deposition in the mesangium. At 6 weeks, 60% of the alcoholic rats had IgA nephropathy. The incidence increased until 100% of the alcoholic rats presented the renal disease at 16 weeks. IgA nephropathy was not found in any of the control animals. We conclude that, in this animal model, the incidence of IgA nephropathy is dependent on the time frame of the alcohol ingestion.
Ethanol Induces Marked Changes in Lymphocyte Populations and Natural Killer Cell Activity in Mice
Authors: Meadows Gary G. , Wallendal Michele , Kosugi Atsushi , Wunderlich John , Singer Dinah S.
Published: April 2006

Treatment of mice in vivo with 5% w/v ethanol given in a liquid diet causes marked changes in spleen, peripheral blood, and thymus lymphocytes. In both the thymus and spleen, there is an acute cellular depletion resulting in a significant decrease in gross tissue size and cell number. In spleen and peripheral blood, the percentage of T lymphocytes is increased relative to B lymphocytes, but the ratio of CD4+/CD8+ T cell sub‐populations remains unchanged. Splenic natural killer (NK) cell activity is increased in ethanol‐consuming mice, although the percentage of NK1.1+ cells is relatively unchanged.
Brain Region‐Dependent Sensitivity of GABAA Receptor‐Mediated Responses to Modulation by Ethanol
Authors: Proctor William R. , Allan Andrea M. , Dunwiddie Thomas V.
Published: April 2006

Simultaneous extracellular and intracellular electrophysiological recordings were made from the CA1 region of rat hippocampal brain slices during superfusion with ethanol. Ethanol (80 mM) had a biphasic effect on the extracellularly recorded population spike, with an initial increase followed by a significant reduction (38%) in this response, which was maximal 10 to 15 min after the start of ethanol application. Concurrent intracellular recordings in the CA1 showed small (0.7 mV) hyperpolarization of the resting membrane potential, with no significant change in the input impedance, EPSP, GABAA and GABAB IPSPs, or after hyperpolarization (AHP) following depolarizing current injection. Ethanol reduced the amplitude and duration of depolarizing responses to brief, localized pressure‐ejection of N‐methyl‐D‐aspartate (NMDA) onto pyramidal neuron dendrites, but did not affect the GABAA receptor‐mediated depolarizing responses to the dendritic application of GABA. In parallel studies, the effect of ethanol on GABA‐stimulated 36Cl− flux was measured in microsac preparations from rat hippocampus, cerebellum, and cerebral cortex. Ethanol application caused substantial enhancement of the chloride uptake from cerebellar and cerebral cortical microsacs, but had no effect on 36Cl− influx in hippocampel microsacs. These results suggest that there are important brain region‐dependent differences in the sensitivity of the GABAA receptor/chloride channel to modulation by ethanol.
Audiogenic Seizure Susceptibility and Auditory Brainstem Responses in Rats Prenatally Exposed to Alcohol
Authors: Berman R. F. , Beare D. J. , Church M. W. , Abel E. L.
Published: April 2006

Rats prenatally exposed to alcohol (0%, 17.5%, or 35% ethanol‐derived calories) were tested for audiogenic seizure susceptibility on one of postnatal days 18 to 23, then retested 5 days later. Prenatal alcohol exposure did not influence audiogenic seizure susceptibility or severity. There was, however, a significant increase in seizure incidence on the retest day for all groups, suggesting a priming effect. Auditory brainstem response (ABR) data suggested that prenatal alcohol exposure and acoustic trauma (i.e., exposure to an alarm bell used for eliciting audiogenic seizures) induced measurable sensorineural hearing loss, and that the combined exposure to alcohol and acoustic trauma interacted additively to produce greater hearing loss than either alone.
The Involvement of NMDA Receptors in Acute and Chronic Effects of Ethanol
Authors: Danysz Wojciech , Dyr Wanda , Jankowska Ewa , Glazewski Stanislaw , Kostowski Wojciech
Published: April 2006

Recent evidence indicates involvement of excitatory amino acid receptors sensitive to N‐methyl‐d‐aspartate (NMDA) in the action of ethanol (EtOH). Pronounced inhibition of NMDA receptor function is seen in vitro with concentrations of EtOH corresponding to those present during alcohol intoxication in humans. The present study was devoted to investigate the role of NMDA receptors in the action of EtOH in rats. Acute experiments showed antagonism by EtOH of convulsions induced by intracerebroventricular injection of NMDA. A similar effect was seen with a high dose of diazepam. Convulsions induced by an agonist of another excitatory amino acid receptor subtype, kainate, were also inhibited by EtOH. An uncompetitive antagonist of NMDA receptors, 5‐methyl‐10, 11‐dihydro‐5H‐dibenzo‐cyclohepten‐5, 10‐imine maleate (MK‐801), potentiated EtOH‐induced loss of righting, but attenuated the hypothermic action of EtOH. Moreover, MK‐801 inhibited audiogenic convulsions in EtOH withdrawn rats. At the same time the effect of a proconvulsive dose of NMDA was not enhanced. Tolerance to the myorelaxant action of both EtOH and MK‐801 upon repetitive administration was seen. Also some degree of cross‐tolerance was observed. Moreover, MK‐801 failed to modify EtOH preference in rats. The present results support involvement of NMDA receptors in expression of some acute and subchronic actions of EtOH and in expression of EtOH withdrawal.
Classical Genetic Analyses of Responses to Sedative‐Hypnotic Drugs in Crosses Derived from Long‐Sleep and Short‐Sleep Mice
Authors: de Fiebre Christopher M. , Marley Rodney J. , Miner Lucinda L. , de Fiebre Nancy Ellen C. , Wehner Jeanne M. , Collins Allan C.
Published: April 2006

A classical (Mendelian) genetic analysis of responses to eight sedative‐hypnotic compounds (ethanol, urethane, trifluoroethanol, chloral hydrate, barbital, paraldehyde, methyprylon, pentobarbital) was conducted in crosses derived from mouse lines that were selectively bred for differential duration of anesthesia following ethanol. The sleep‐time responses of these mice, the long‐sleep (LS) and short‐sleep (SS) mouse lines, as well as the F1, F2 and backcross (F1 × LS, F1 × SS) generations were measured. Generally, differences in responses among the generations were greater for water soluble compounds than were differences for more lipid soluble compounds. Also, the inheritance of responses to water soluble compounds could be explained primarily by additive effects of alleles while the inheritance patterns for more lipid soluble compounds were more complex. Genetic correlation with ethanol response decreased with increasing lipophilicity. These results suggest that the selection of the LS‐SS mouse lines was specific for water soluble anesthetic agents. Because several of these agents are known to act at GABA receptors, examination of the interactions of compounds which differ in lipid solubility at GABA receptors from LS and SS mice may prove useful in elucidating the mechanism of the anesthetic actions of ethanol and other drugs.
Alcohol Withdrawal in Rats Is Associated with a Marked Fall in Extraneuronal Dopamine
Authors: Rossetti Zvani L. , Melis Franco , Carboni Susanna , Diana Marco , Gessa Gian Luigi
Published: April 2006

Withdrawal of rats from chronic ethanol (2–5 g/kg, every 6 hr for 6 days) resulted in withdrawal symptomatology and dramatic fall in extracellular dopamine (DA) in the ventral striatum as measured by microdialysis. The changes in DA output paralleled the withdrawal symptomatology and both phenomena were reversed by a challenge ethanol dose (5 g/kg orally). The results suggest that the decrease in DA output may be responsible for the aversive symptoms of withdrawal.
Alterations in EEG Amplitude, Personality Factors, and Brain Electrical Mapping after Alpha‐Theta Brainwave Training: A Controlled Case Study of an Alcoholic in Recovery
Authors: Fahrion Steven L. , Walters E. Dale , Coyne Lolafaye , Allen Thomas
Published: April 2006

A controlled case study was conducted of effects of EEG alpha and theta brainwave training with a recovering alcoholic patient who experienced craving and fear of relapse after 18 months of abstinence. Training consisted of six sessions of thermal biofeedback to increase central nervous system (CNS) relaxation. Effects were documented with pretreatment and post‐treatment personality testing, 20‐channel digitized EEG evaluations both under relaxed conditions and under stress, minute‐by‐minute physiologic recordings of autonomic and EEG data during each training session, blood pressure, and heart rate indications taken both during relaxation and under stress, and by clinical observation.

Results replicated those of a previous controlled study with chronic alcoholic patients not abstinent prior to treatment. New findings include post‐treatment indications of more relaxed CNS functioning under stress, and of reduced autonomic activation both during relaxation and under stress. Brain‐mapping indications of anxiety associated with painful cold‐pressor stimulation were seen only in the pretest readings; at post‐test the brain map indicated pain‐associated EEG activity in the contralateral somatosensory area, but no apparent anxiety‐associated EEG activity.

At 4 months post‐treatment the patient's wife and colleagues report the patient appears to function in a more relaxed way under the impact of stress, and he reports no longer experiencing craving for alcohol.

Overall, support is provided for the possibility that alpha and theta brainwave training may be a useful intervention for the abstinent alcoholic experiencing stress‐related craving and fear of relapse.
Sedating Effects of Ethanol And Time of Drinking
Authors: Roehrs Timothy , Zwyghuizen‐Doorenbos Ardith , Knox Michaele , Moskowitz Herbert , Roth Thomas
Published: April 2006

Ethanol (0.5 g/kg) was administered to 12 healthy, normal‐sleeping men, aged 21 to 45, at two different times of the day (0900 and 1700 hr). The Multiple Sleep Latency Test (MSLT) was conducted at 1000, 1200, 1400, and 1600 hr in the day drinking condition and at 1800, 2000, 2200, and 2400 hr in the evening drinking condition. On placebo, sleepiness was greater in the daytime testing hours than in the evening, replicating findings on the circadian rhythm of sleepiness/alertness. There was a time of drinking (day versus evening) by ethanol interaction. An ethanol effect on sleep latency was found in the daytime hours, when alertness was relatively low. Ethanol failed to have a significant effect on sleep latency during the evening hours when alertness levels were increasing. Performance on a divided attention task, administered 1 hr postconsumption, was impaired by ethanol consumption, but did not vary as a function of time of drinking (day versus evening). However, at 5 hr postconsumption, mean reaction time on the first 20 min of a 40‐min auditory vigilance task was slowed by ethanol to a greater extent after day drinking then after evening drinking.
Ethanol Intake of Chickens Treated with Fenfluramine, Fluoxetine, and Dietary Tryptophan
Authors: Lu M‐R. , Wagner G. C. , Fisher H.
Published: April 2006

Male, white leghorn chickens fed a standard diet with or without tryptophan supplementation were treated with single injections of 8 mg/kg fenfluramine in one series of experiments, or 8 mg/kg fluoxetine in another series. The birds had been food‐ and water‐deprived prior to injection. They were offered, following the drug or saline injection, water, a 5% ethanol solution, or an isocaloric sucrose solution (8.75%) for 1 hr. Both fluoxetine and fenfluramine significantly reduced consumption of the ethanol solution, an effect exacerbated by tryptophan supplementation. Water or sucrose solution intake was also significantly reduced, but significantly less so than ethanol after fenfluramine injection. Since the birds drank significantly more of the sucrose solution after saline injection than of water, the consumption decrease caused by fenfluramine resulted, nevertheless, in a higher intake than that of either water or ethanol. Body temperature was decreased by ethanol intake and/or fluoxetine injection. Fenfluramine injection had an opposite, body temperature‐increasing effect. It appears that both fenfluramine and fluoxetine decrease ethanol intake in a manner more specific than for water or sucrose, and that this effect is amplified by dietary tryptophan supplementation.
FTIR Evidence for Alcohol Binding and Dehydration in Phospholipid and Ganglioside Micelles
Authors: Yurttaş Lale , Dale Bruce E. , Klemm William R.
Published: April 2006

We theorize that intoxicants and modern anesthetics bind at the membrane‐water interface and displace (dehydrate) bound water molecules by breaking the hydrogen bonds. We tested this hypothesis by examining the effect of butanol on the binding of water to the polar regions of lipids in reversed micelles. Understanding the mechanisms of intoxication requires studies in physiologically relevant systems such as systems containing sialoglycoconjugates, especially gangliosides, which concentrate in the synapses of neural tissue. Therefore, we compared butanol effects on phospholipid with effects on ganglioside.

Hydrogen‐bond breaking activity of 1‐butanol was studied in reversed micelles made of dipalmitoylphosphotidylcholine (DPPC), ganglioside (GM1 and GT1b) or the lipid mixture in a D2O‐CCl4 medium. Fourier transform infrared spectroscopy (FTIR) data indicated that 1‐butanol binds to DPPC and to gangliosides. Adding GM1 to the DPPC micelles introduces a new binding site for the alcohol. GTlb binds more butanol than GM1, because of more binding sites provided by extra sialic acid moieties. Spectral red shifts indicate that both water and butanol bind to the C = O group of sialic acid. Butanol partially releases the surface‐bound water by disrupting hydrogen bonds, as indicated by an appearance of a sharp new free OD stretching band of the released D2O molecules. However, control studies with lipid‐free systems in CCl4 revealed that a free OD peak could occur from a deuterium exchange reaction between D2O and 1‐butanol(ol‐h). Thus, in lipid systems involving D2O and 1‐butan(ol‐h), deuterium exchange and partial release of water take place at the same time, and it is not possible to distinguish one from the other. Nonetheless, we could demonstrate butanol‐induced displacement of bound water with H2O + 1‐butan(ol‐h) and D2O + 1‐butan(ol‐d) in lipid‐free/CCl4 and lipid/CCl4 systems. Here, the alcohol also produced a new and large free OH peak that was larger than the OH peak produced when the same amount of butanol was used in the absence of water. This “free” water probably forms dimers and trimers with unbound butanol.
Evidence for Normal Feedback Inhibition of Triiodothyronine on the Thyrotropin (TSH) Response to Thyrotropin‐Releasing Hormone (TRH) in Abstinent Male Alcoholics
Authors: Garbutt James C. , McDavid Joshua , Mason George A. , Quade Dana , Loosen Peter T.
Published: April 2006

Disturbances in the hypothalamic‐pituitary‐thyroid (HPT) axis have been reported in abstinent, noncirrhotic alcoholics, including a reduction in thyrotropin (TSH) response to thyrotropin‐releasing hormone (TRH) and reductions in triiodothyronine (T3). Some evidence has suggested that a portion of alcoholics may also exhibit a disturbance in the feedback inhibition of thyroid hormone on TSH release. To evaluate the function of the HPT axis negative feedback system in abstinent, noncirrhotic alcoholic men we compared the TSH response with TRH before and after a standard suppressive dose of T3. Ten alcoholic subjects were studied and compared with four control subjects from a previous study and to literature values. The mean percent reduction in TSH response in the alcoholic subjects of 74 ± 7% was almost identical to the 71 ± 9% reduction observed in normal subjects. The present findings indicate that noncirrhotic, abstinent alcoholic men exhibit normal suppression of the TSH response to TRH following T3.
Continued Development and Unconditioned Stimulus Characterization of Selectively Bred Lines of Taste Aversion Prone and Resistant Rats
Authors: Elkins Ralph L. , Walters Paul A. , Orr T. Edward
Published: April 2006

This report updates the bidirectional selective breeding of taste aversion (TA) prone (TAP) and TA resistant (TAR) rat lines from the 8th through the 22nd generations. A palatable saccharin solution and the aversive consequences of a cyclophosphamide injection are the respective conditioned stimulus (CS) and unconditioned stimulus (US) of line development. Nonsibling matings within each of the two extremes of TA conditionability have produced TAP and TAR lines having markedly different TA propensities. As previously reported, the substitution of a rotational (i.e., motion sickness) US for cyclophosphamide during TA conditioning also produced characteristic line differences in conditioned taste aversion acquisition. The present report extends the effective line separating USs to include injections of lithium chloride, emetine hydrochloride, and EtOH. A range of EtOH dose levels produced dose‐dependent TAs within TAP rats but failed to induce TAs in TAR rats. Following the conclusion of TA testing, the administration of a hypnotic EtOH dose produced equivalent loss of righting capability and equivalent hypothermia in both TAP and TAR rats. The line differences in EtOH induced TA conditionability therefore do not reflect general line differences in EtOH sensitivity. The lines may be useful within studies of biological bases of TA conditionability and animal analog studies of prevention and treatment of alcohol dependence.
The Alcohol Clinical Index in Lower Socieconomic Alcohol‐Dependent Men
Authors: Alterman Arthur I. , Gelfand Lois A. , Sweeney Karen K.
Published: April 2006

The Alcohol Clinical Index, consisting of a 17‐item Clinical Signs checklist and a 13‐item Medical History questionnaire, was designed to provide an economic screening instrument for alcoholism not subject to self‐report biases. There has been little validation work with this instrument. We therefore administered the Alcohol Clinical Index to a group of 40 alcohol‐dependent men undergoing treatment at a VA Medical Center and a group of 17 nonalcoholic men being treated at an outpatient medical clinic at the same facility. The Clinical Signs checklist had high sensitivity, but poor specificity. Overall accuracy was 70% for a threshold score from 1 to 5. The Medical History questionnaire had more moderate sensitivity, but 100% specificity for a cutoff score of 2 or more. At a cutoff of 2, it had an overall accuracy of 84%. The high specificity of the Medical History questionnaire suggests that it could be used to help discriminate between alcoholics and non‐alcoholics. Further study of these measures and individual items within the measures is recommended with different groups of alcohol users and nonusers.
Dose‐Ranging Study of Depot Disulfiram in Alcohol Abusers
Authors: Phillips Michael , Greenberg Joel
Published: April 2006

The object of this early Phase 2 study was to determine the dosage of depot disulfiram (DSF) required to induce sustained sensitivity to alcohol. Sixteen abstinent alcohol abusers were studied in an un‐blinded ascending‐dose trial of DSF suspended in either (1) 5% methylcellulose or (2) 0.1% polysorbate 80. Five pairs of subjects received a single subcutaneous dose of Formulation A (1.0, 2.0, 2.5, 3.0, or 3.5 g). Three pairs were treated with Formulation B (60, 75, or 90 mg/kg) plus an oral loading dose of DSF (15 mg/kg). Subjects were challenged with oral alcohol (0.15 g/kg) before treatment, and on days 7, 14, 21, and 28. Subjective and objective responses to alcohol challenges (skin temperature, breath acetaldehyde, pulse rate, and blood pressure) were measured, and mobilization of DSF was assessed by carbon disulfide levels in breath. Treatment with Formulation B (75 or 90 mg/kg) plus an oral‐loading dose (15 mg/kg) was consistently followed by sustained sensitivity to alcohol. Some subjects experienced the subjective and objective features of the DSF‐ethanol reaction for 28 days, but these reactions achieved statistical significance only on day 7 for objective changes and on days 7 and 14 for subjective discomfort. Breath carbon disulfide was detectable until day 28 in all subjects receiving more than 1.0 g DSF, demonstrating sustained release of the drug. Treatment with depot DSF merits further study for its potential benefits in chronic alcohol abuse.
Ascites as a Marker for the Hyperdynamic Heart of Laennec's Cirrhosis
Authors: Friedman Howard S. , Fernando Hemal
Published: April 2006

The purpose of this study was to determine the relation of the circulatory findings of cirrhosis to hepatic decompensation. Twenty individuals with biopsy‐proven cirrhosis and 15 aged‐matched controls underwent echocardiographic evaluation of cardiac function. Cardiac dimensions and indicies derived from echocardiograms were related to various measures of liver decompensation. Cirrhotics had a higher heart rate, left ventricular end‐diastolic volume, left ventricular ejection fraction, and cardiac output and a lower mean blood pressure and peripheral resistance than aged‐matched subjects. On multiple regression analyses mean blood pressure, peripheral resistance, and cardiac output were all found to be related to estimates of ascites. Also, cirrhotics with ascites had a lower peripheral resistance than those without this finding. Conclusion: In clinically stable patients with cirrhosis, the presence of ascites indicates an intense vasodilatory state with a hyperdynamic circulation.