bluuebunny/crossref_metadata_2025 huggingface dataset:
Alcohol and Secobarbital Effects as a Function of Familial Alcoholism: Extended Intoxication and Increased Withdrawal Effects
Authors: McCaul Mary E. , Turkkan Jaylan S. , Svikis Dace S. , Bigelow George E.
Published: April 2006

Response differences following administration of alcohol between adult males with a positive (FHP) versus negative (FHN) family history of alcoholism have been demonstrated in previous research and are thought to be related to risk for developing alcoholism. If this is so, the pharmacological breadth of addiction risk conferred by a positive family alcoholism history might be studied by determining whether FHP subjects show different responses than FHN to drug classes other than alcohol. We have previously reported on the acute effects of ethanol as compared with secobarbital in FHP and FHN subjects and found that FHP subjects showed greater sensitivity across a variety of subjective measures than FHN subjects for both drug classes. The data reported here are based on an extended data collection period of 3 to 18 hr postingestion, following completion of the acute laboratory portion of the study. Specifically, in the present study, dose‐effect timecourse functions for a variety of physiological (heart rate, blood pressure, and breath alcohol level), subjective (analog mood, drug effect, and withdrawal, Subjective High Assessment Scale (SHAS)), and psychomotor measures (Digit Symbol Substitution Test and numeric recall) were examined in FHP and FHN college‐aged males for secobarbital (0, 100, 200 mg daily) and ethanol (1g/kg daily). FHP and FHN subjects were matched on light‐to‐moderate drinking patterns, anthropometric dimensions, age, years of schooling, and drug use. FHP subjects reported more extended intoxication and greater withdrawal effects following both ethanol and the high dose of secobarbital than did FHN subjects. In addition, these intoxication and withdrawal effects reported by FHP subjects persisted longer than effects reported by FHNs; this was true both for ethanol and the higher secobarbital dose. No differences in physiological responses emerged between the two groups in any drug condition. The present study is the first demonstration of extended intoxication and withdrawal differences between these groups and points to the need to further examine extended time periods following drug ingestion, as this may reveal additional parameters across which these family history groups differ.
Symptoms of Anxiety in Inpatient Alcoholics with and without DSM‐III‐R Anxiety Diagnoses
Authors: Thevos Angelica K. , Johnston Amanda L. , Latham Patricia K. , Randall Carrie L. , Adinoff Bryon , Malcolm Robert
Published: April 2006

Self‐ and observer‐rating scales were administered to alcohol‐dependent inpatients during acute withdrawal and regularly for 3 weeks. Following a structured diagnostic interview (SCID) at the end of the 3rd week of hospitalization, subjects were divided into two groups: a dual‐diagnosed group (alcohol dependence and anxiety disorder) and an alcohol‐only group (no other current Axis I diagnosis). The results demonstrated that the dual‐diagnosed subjects experienced higher anxiety levels during and after acute alcohol withdrawal. All rating scales (i.e., Sheehan Patient Rated Anxiety Scale, Spielberger State Anxiety Inventory, Zung Rating Scale for Anxiety, and Hamilton Rating Scale for Anxiety) were analyzed to obtain the best combination of sensitivity and specificity. Taken together, the results indicate that it may be possible to identify alcoholics who require additional psychiatric evaluation early in treatment. This would allow a treatment plan which could be used to address both psychiatric and substance abuse problems.
Alterations in Splanchnic Blood Flow After Low and High Doses of Ethanol
Authors: Piano Mariann R. , Holm Karyn , Melchior Christine L. , Ferguson J. L.
Published: April 2006

The purpose of this investigation was to determine the effect of various acute doses of ethanol (1.0,3.0,4.0 g/kg) on the distribution of cardiac output (%CO) and blood flow to the splanchnic vascular bed in conscious male Wistar rats. Regional blood flow and cardiac output (CO) were measured by the reference microsphere technique. Mean arterial pressure and CO were significantly reduced 60 min after 3.0 g/kg and 4.0 g/kg of ethanol, while no changes occurred over time in total peripheral vascular resistance or heart rate. Acute ethanol administration produced an early non‐sustained increase in portal vein blood flow, that was most pronounced after a low dose of ethanol, and was attenuated after the 3.0 g/kg and 4.0 g/kg doses of ethanol. The early increase in portal vein blood flow produced a corresponding increase in total liver blood flow. Additionally, we found increases in hepatic arterial blood flow after the higher doses. The combined increase in portal vein and hepatic arterial supply to the liver may serve to increase oxygen delivery, more than the singular increase in portal vein blood flow. This early increase in total liver blood flow after high doses of ethanol may be important for protecting hepatocyte function in the presence of high blood ethanol levels.
Development of Tolerance to Inhibitory Effect of Ethanol on Endothelium‐dependent Vascular Relaxation in Ethanol‐fed Rats
Authors: Hatake Katsuhiko , Wakabayashi Ichiro , Kakishita Eizo , Taniguchi Tadaaki , Ouchi Harumi , Hishida Shigeru
Published: April 2006

Rats were maintained on liquid diets containing ethanol (35% of total calories) or an equicaloric volume of sucrose instead of ethanol for 10 wk. Vascular strips of isolated rat aortas were mounted in organ chambers to record isometric tension. Ethanol in vitro inhibited the endothelium‐dependent relaxation responses to acetylcholine and ATP in both pair‐fed control and ethanol‐fed rats. The inhibitory effect of ethanol was greater in the pair‐fed rats. In addition, the magnitudes of these relaxation responses in the absence of ethanol in vitro in pair‐fed rats were similar to those in the presence of ethanol in ethanol‐fed rats. In the absence of ethanol in vitro, the relaxations in response to acetylcholine and ATP in the ethanol‐fed rats were greater than in the pair‐fed rats. These results suggest that chronic ethanol consumption can induce tolerance to ethanol‐induced inhibition of endothlium‐dependent relaxation responses to acetylcholine and ATP, and that the relaxations can become adapted to the presence of plasma levels of ethanol, which may inhibit the relaxation in vivo. The augmented relaxation in the ethanol‐fed rats may result from the mechanism causing tolerance to the inhibitory effect of ethanol.
Intoxication after an Acute Dose of Alcohol: An Assessment of Its Association with Alcohol Consumption Patterns By using Twin Data
Authors: Heath Andrew C. , Martin Nicholas G.
Published: April 2006

We examined the hypothesis that genetically determined differences in sensitivity to alcohol explain some of the genetic variation in alcohol consumption pattern. Self‐report data on average weekly alcohol consumption and self‐ratings of intoxication after a standard dose of ethanol (0.75 g/kg body weight), used as an index of sensitivity, were obtained on 206 Australian twin pairs. Significant genetic covariance between weekly consumption and level of intoxication after alcohol intake was found in males, lower ratings of intoxication being associated with increased consumption. However, when direction of causation models were fitted to the male twin data, the hypothesis that decreased sensitivity was a cause of increased consumption was rejected. The major causal effect was that of weekly consumption on level of sensitivity. A similar, although nonsignificant, trend was observed in females. The strength of the association between self‐report of average weekly consumption and level of intoxication after a standard dose of alcohol supports the validity of the former measure.
Differential Modulation by the Stress Axis of Ethanol Withdrawal Seizure Expression in WSP and WSR Mice
Authors: Roberts A. J. , Chu H.‐ P. , Crabbe J. C. , Keith L. D.
Published: April 2006

Withdrawal from both acute and chronic ethanol (EtOH) exposure is associated with increased neural excitability and increased activity of the hypothalamic‐pituitary‐adrenal axis. There is some evidence that glucocorticoids are necessary for EtOH withdrawal seizure expression. Lines of mice that were selected for severe (WSP) and minimal (WSR) EtOH withdrawal (as estimated from handling‐induced convulsion scores) have been shown to differ in their stress response following an acute dose of EtOH. In this study we provide evidence that these lines of mice also differ in their sensitivity to the excitatory effects of glucocorticoids. EtOH withdrawal seizures of WSP mice were significantly increased by chronic and acute corticosterone treatment, whereas those of the WSR mice were unaffected. Neural excitability was decreased in the WSP mice when aminoglutethimide, a glucocorticoid synthesis blocker, was administered. Thus, it appears that genetic differences in EtOH withdrawal seizure severity may be due, in part, to differences in sensitivity to the excitatory effects of glucocorticoids.
Trauma in Cirrhosis: An Indicator of the Pattern of Alcohol Abuse in Different Societies
Authors: Israel Y. , Orrego H. , Schmidt W. , Popham R. E. , Escartin P. , Ishii H. , Kelly D. , Long J. P. , Malizia G. , Mezey E. , Pagliaro L. , Poynard T. , Salaspuro M. , Tanikawa K.
Published: April 2006

While some morbidities associated with the excessive use of alcohol are related to the total amount of alcohol consumed—cirrhosis being an example—other pathologies, such as trauma and those of psycho‐social origin, are mainly related to the frequency of acute alcoholic intoxication rather than to the total amount consumed. The balance between these two types of alcohol‐associated morbidities can provide an indication of the relative frequency of intoxication, and thus of the pattern of alcohol abuse in a population. Since trauma is highly associated with acute alcoholic intoxication, the prevalence of bone fractures was determined in cirrhotics in nine countries. The prevalence of rib and vertebral fractures on routine chest x‐rays showed a 17‐fold variation in the different countries, from 2% and 6% in Spain and Italy to 30% and 34% in Canada and the USA, suggesting marked differences in the pattern of alcohol abuse to intoxication. Conversely, the prevalence of cirrhosis is twice as high in Spain and Italy than in Canada and the USA. A strong positive correlation between per capita consumption and cirrhosis mortality (r= 0.86; p < 0.01) exists among the nine countries studied, while the correlation between per capita alcohol consumption and the prevalence of trauma is not statistically significant (r= ‐ 0.40). Supporting a strong association between trauma and alcoholic intoxication, the prevalence of trauma was found to be highly correlated: r= 0.88, p < 0.002, with the degree of concern for the psycho‐social consequences of alcohol abuse in the different countries. Data indicate that trauma can be used as an objective indicator to assess the pattern of alcohol abuse in a population.
Stress and Alcohol Interaction: An Update of Human Research
Authors: Pohorecky Larissa A.
Published: April 2006

The literature on alcohol and stress in human subjects carried out since 1981 is reviewed. The review covers selected aspects of the interaction of alcohol and stress. (1) Most of the review focuses on the role of stress on alcohol ingestion. Retrospective research based on data from the Health and Nutrition Examination Survey indicated an increase in alcohol consumption with anxiety in certain groups of, as yet not well characterized, individuals. For example, although still insufficiently documented, stress does not appear to play a significant role in alcohol ingestion by women and the elderly. By contrast, stress does appear to play a role in the control of alcohol ingestion by adolescents. Prospective studies employing questionnaire‐interview formats generally support an effect of stress on alcohol ingestion. However, studies employing male college aged social drinkers did not find a correlation between levels of stress and ingestion of alcohol. Alcoholics also differ in the reasons for drinking alcohol, but generally ingest alcohol to lessen anxiety/stress. It is clear that the Tension Reduction Hypothesis as originally postulated is no longer adequate. Many new models based on an interaction of alcohol and stress have been proposed to explain the control of alcohol consumption. Considering the multidimensionality of factors that appear to contribute to the control of alcohol ingestion, it is unlikely that a single model could possibly be relevant to alcohol ingestion under all conditions. More likely different models may be relevant to alcohol consumption under specific conditions, or for specific populations. (2) Alcohol has been reported to decrease anxiety in agoraphobics. The self‐medication by agoraphobics may contribute significantly to their alcohol abuse. (3) Alcohol has also been reported to decrease tremor of the hands in stressed subjects as well as in patients with essential tremor. (4) Although a number of studies have employed electrodermal activity in studies aimed at the interaction of alcohol and stress, the results have been rather inconsistent. (5) The controversy on the purported beneficial effect of alcohol on the cardiovascular system persists. A number of studies have shown a J‐ or U‐shaped relationship between alcohol ingestion and incidence of coronary heart disease. Alcohol may also influence stress‐induced changes in blood pressure. Although a number of studies have demonstrated lower blood pressure in individuals ingesting less than two drinks per day compared with abstainers or heavy alcohol imbibers, the evidence is not conclusive. (6) It is not clear whether the interaction of alcohol and stress involves alterations in plasma catecholamines. Alcohol may lower elevated plasma catecholamines induced by some, but not all, stressors.

The inconsistencies in data in the reviewed literature most likely reflect some of the many variables associated with alcohol and stress research. These are also briefly reviewed and include subject‐, drug‐ and stress‐related variables.
Neuroadaptive Responses to Chronic Ethanol
Authors: Buck Kari J. , Harris R. Adron
Published: April 2006

Cellular responses of neuronal tissue to chronic ethanol exposure are reviewed. Evidence for adaptive responses to the acute actions of ethanol is available for five systems: GABA‐activated chloride channels, voltage‐sensitive calcium channels, NMDA‐activated cation channels, receptors coupled through stimulatory guanine nucleotide binding proteins, and membrane lipid order. We suggest that at least some of these adaptive responses occur because of ethanol actions at the level of gene expression.
Ethanol Inhalation and Dietary N‐6, N‐3, and N‐9 Fatty Acids in the Rat: Effect on Platelet and Aortic Fatty Acid Composition
Authors: Engler Marguerite M. , Karanian John W. , Salem Norman
Published: April 2006

The effects of 18‐carbon n‐6, n‐3, and n‐9 fatty acid diets and ethanol exposure on the fatty acyl composition of platelets and vascular tissue were examined. An experimental design was devised to control the dietary content of 18‐carbon fatty acids. The levels of 18:3n6, 18:3n3 and 18:1n9 were varied by a formulation of dietary oils which contained similar proportions of 18:2n6. Male Sprague‐Dawley rats were fed a purified diet containing 11% by weight of either borage oil (BOR) rich in 18:3n6, linseed/safflower oil (LSO) rich in 18:3n3, or sesame oil (SES) rich in 18:ln9 for 7 weeks and exposed to ethanol vapors by means of inhalation for the final 6 days of the dietary regimen. Moderate blood ethanol levels of 118 k 6.6 mg/dl were obtained. Total lipids were extracted from platelets and aortae, and the fatty acid distributions were analyzed by gas chromatography. BOR feeding resulted in increases in the proportion of 17‐6 fatty acids (18:3n6, 20:3n6, 204n6) in platelets and aorta. Animals fed the LSO diet had increased levels of n‐3 fatty acids (18:3n3, 20:5n3, 22:6n3). The SES‐based diet resulted in an increase in 18:ln9 in both aorta and platelets. Following ethanol exposure alone, the most marked change in the fatty acid profile was a decrase in 20:4n6 in the platelet. This effect was not observed in rats supplemented with BOR. No significant changes were observed in the aortic fatty acid content at this level of ethanol exposure. The results suggested that, in the rat, a diet enriched with BOR effectively prevented ethanol‐induced alterations in platelet fatty acid composition.
Effects of Chronic Ethanol on Currents Carried through Calcium Channels in Aplysia
Authors: Treistman Steven N. , Wilson Andrew
Published: April 2006

Voltage clamp techniques were used to monitor the effects of chronic exposure to ethanol (EtOH) on current carried through calcium channels in an identified neuron of cultured abdominal ganglia from Aplysia californica. Exposure to 200 mM EtOH for periods up to 3 weeks did not change the baseline characteristics of current carried through calcium channels, nor did it alter its acute sensitivity to either 100 mM or 300 mM EtOH challenge. The currents that we examined were equivalent when carried by calcium or barium, and EtOH had similar effects on currents carried by these two ions. The population of voltage‐dependent calcium channels studied here does not show development of tolerance after chronic exposure to EtOH.
Estimation of Blood Alcohol Concentrations in Young Male Drinkers
Authors: Martin Christopher S. , Rose Richard J. , Obremski Karen M.
Published: April 2006

This research examined individual differences in the ability to self‐monitor the effects of alcohol. Thirty‐nine male subjects consumed 0.75 ml/kg alcohol and estimated their blood alcohol concentrations (BACs) at peak BAC and on the ascending and descending limbs of the blood alcohol curve. Family history of alcohol dependence did not affect the accuracy of estimation of BACs. Subjects who reported lower levels of subjective intoxication underestimated their BACs more than did subjects who reported higher levels of subjective intoxication. Subjects with less behavioral impairment underestimated their BACs more than subjects with greater behavioral impairment on the ascending limb of the blood alcohol curve. Accuracy was better on the ascending limb compared with peak BAC and the descending limb, and accuracy became worse over time on the descending limb. It appears that cues to the effects of alcohol rapidly become unavailable on the descending limb, which may contribute to decisions concerning further alcohol consumption and driving after drinking.
Alterations of ATP Levels and of Energy Parameters in the Blood of Alcoholic and Nonalcoholic Patients with Liver Damage
Authors: Hernández‐Muñoz Rolando , Glender Walter , Díaz‐Muñoz Mauricio , Suárez Jorge , Lozano Jorge , de Sánchez Victoria Chagoya
Published: April 2006

Blood adenine nucleotides were determined in patients with alcoholic and non‐alcoholic liver diseases. They included patients with alcoholic hepatitis (AH), alcoholic liver cirrhosis (ALC), non‐alcoholic liver cirrhosis (NALC), and amoebic liver abscess (ALA) (28 patients). A decrease of 28% to 39% in blood ATP levels was observed among the patients with AH and the cirrhotic groups, respectively (p < 0.05), whereas no significant changes in blood ATP levels were detected in the ALA group. Although total blood adenine nucleotides were significantly diminished in AH, ALC, and NALC groups, the AH patients retained their energy relationships within normal range. On the other hand, the cirrhotic groups, independently of their etiology, failed to maintain an adequate ATP/ADP ratio, energy charge, and phosphorylation potential in the blood, suggesting a decreased energy availability in their blood cells.

Nevertheless, the mechanism involved in these effects remains to be elucidated, a failure of the damaged liver to supply purines to extra‐hepatic tissues might be a major event altering the blood energy parameters.
Disulfiram Implant: A Double‐Blind Placebo Controlled Follow‐Up on Treatment Outcome
Authors: Johnsen Jon , Mørland Jørg
Published: April 2006

Seventy‐six alcohol‐dependent patients participated in a study of the clinical effect of implanted disulfiram (DS). The patients were randomized to a DS group (n = 40), receiving a subcutaneous abdominal implantation of 10 × 100 mg DS tablets and a placebo group (PL group) receiving an implantation of 9 × 100 mg calcium phosphate tablets together with one calcium phosphate tablet containing 1 mg DS. Both groups believed they were receiving DS.

At admission there was no significant difference between the DS and PL groups with regard to demographic characteristics, psycho‐social adjustment, drinking variables, medical disorders, or laboratory results. After a study period of approximately 300 days, 63 patients (33 DS; 30 PL) were assessed using a battery of tests. There was no significant difference between the groups with regard to reduction in average alcohol consumption, number of days to the first alcohol intake after implantation, or level of psychosocial function. Nevertheless, both groups reduced their ethanol consumption significantly, probably due to the psychological deterrent effect. The DS implant did result in a significantly higher incidence of wound complications. This study does not support the idea that a 1‐g DS implant has any significant clinical effect different from the implant containing only 1 mg DS (placebo).
Effects of Alcoholism and Instructional Conditions on Speed/Accuracy Tradeoffs
Authors: Glenn Susan W. , Parsons Oscar A.
Published: April 2006

The speed and accuracy of neuropsychological performance in alcoholics and nonalcoholics were assessed for each item within a four‐test computerized battery. Subjects were randomly assigned to one of three instructional conditions: Speed‐emphasis instructions, Accuracy‐emphasis instructions, or Typical instructions emphasizing speed and accuracy equally. Across conditions, alcoholics were less accurate and took longer to perform than controls. Examining speed and accuracy components separately within each condition, as predicted, the greatest differences in accuracy scores between alcoholics and controls appeared in the Speed‐emphasis condition, while the greatest group differences in speed scores appeared in the Accuracy‐emphasis condition. The results indicate that the relationships between speed and accuracy are dissimilar between alcoholics and controls; alcoholics exhibit speed/accuracy tradeoffs in that they are unable to adjust performance to meet speed or accuracy demands without suffering substantial compromise in the other aspect of performance. These results have implications for future studies concerning methodological approaches to speed and accuracy assessment and provide support for an information‐processing deficit associated with chronic alcohol abuse.
Loss of Control Drinking among First Offender Drunk Drivers
Authors: Gruenewald Paul J.
Published: April 2006

A mathematical model of alcohol consumption, which characterizes individual drinking in terms of frequency of consumption and subsequent loss of control drinking once consumption has been initiated, is introduced. The model provides a conceptual link between behavioral indices of alcohol consumption patterns and theoretical models of the role of loss of control drinking in the genesis of alcohol dependence and alcoholism. Based on data from a large sample of first offender drunk drivers, it is shown that specific measures of consumption patterns can be used to provide individual estimates of parameters of the model. These estimates are shown to be strongly related to one measure of alcohol dependence and to introspective reports of loss of control drinking.
Cognitive Performance of Alcoholics: A Longitudinal Evaluation of the Role of Drinking History, Depression, Liver Function, Nutrition, and Family History
Authors: Schafer Kimberly , Butters Nelson , Smith Tom , Irwin Michael , Brown Sandra , Hanger Philip , Grant Igor , Schuckit Marc
Published: April 2006

To assess the role of drinking history, depression, liver function, nutrition, and family history on cognitive performance, 171 detoxified male alcoholics were administered a brief neuropsychological examination at admission and discharge from an inpatient treatment program and at a 3‐month follow‐up evaluation. Regression analyses showed that at admission, depression and liver function were significant predictors of neuropsychological performance, whereas at discharge 3 to 4 weeks later only age and an estimate of premorbid intelligence were significant predictors. At the 3‐month follow‐up, estimates of drinking following discharge and severity of depressive symptoms were major significant predictors of neuropsychological performance. Indices of drinking prior to admission to the treatment program, nutrition, and family history for alcoholism did not predict performance on any of the three test occasions. These findings indicate that in addition to the chronic neurotoxic effect of alcohol a number of different medical and psychiatric factors, as well as the acute effects of alcohol, contribute to the cognitive scores of patients at various points in the clinical course.
Impulsivity, Sensation Seeking, and Behavioral and Emotional Responses to Alcohol
Authors: Nagoshi Craig T. , Wilson James R. , Rodriguez Lawrence A.
Published: April 2006

Three hundred forty‐two male and female subjects from the Colorado Alcohol Research on Twins and Adoptees returned a mailed questionnaire that included the Eysenck Impulsivity‐Venturesomeness‐Empathy scales. These subjects had previously been tested in a procedure in which they were given a 0.8 g/kg dose of ethanol to bring their peak blood alcohol concentration (BAC) to near 0.10 g/dl, given topping doses to maintain this BAC over a 3‐hr period, and repeatedly tested on a battery of diverse physiological, psychomotor, perceptual speed, and mood measures. Impulsivity was significantly correlated with higher levels of self‐reported alcohol use and the occurrence of alcohol use problems in males, while both impulsivity and venturesomeness (sensation seeking) were significantly correlated with lessened motor impairment following alcohol use in males. These personality measures, however, were not significantly correlated with mood measures following initial alcohol dosing. Impulsivity and venturesomeness were uncorrelated with alcohol use and responses to alcohol in females, but as with males, impulsivity was related to the occurrence of alcohol use problems in females.
Effect of Ibuprofen on Alcohol‐Induced Teratogenesis in Mice
Authors: Randall Carrie L. , Becker Howard C. , Anton Raymond F.
Published: April 2006

The purpose of the present study was to examine the effect of the prostaglandin synthetase inhibitor ibuprofen (IBU) on the teratogenic actions of alcohol. On day 10 of pregnancy, C57BL/6J mice were injected subcutaneously with 25 mg/kg IBU or vehicle control. One hour later, the mice were intubated with 5.8 g/kg alcohol or an isocaloric control solution. A group injected subcutaneously with 150 mg/kg aspirin, followed by 5.8 g/kg alcohol 1 hr later, sewed as a positive control. The results showed that maternal alcohol treatment resulted in significantly decreased fetal weight and an increased number of fetuses with limb and kidney defects. Implantation sites and prenatal mortality were not affected. IBU did not have any effect on these dependent variables. IBU statistically antagonized the teratogenic effects of alcohol on fetal weight and dysmorphology. These effects, however, were not as marked as in the Aspirin‐Alcohol positive control group. These results are discussed in the context of clarifying the role of prostaglandins in the etiology of alcohol‐induced birth defects.
Effects of Alcohol on β‐Endorphin and Reproductive Hormones in the Male Rat
Authors: Adams Michael L. , Cicero Theodore J.
Published: April 2006

In an attempt to examine the relationship between alcohol‐induced alterations in immunoreactive β‐endorphin (i‐βE) levels in the hypothalamic‐pituitary‐gonadal axis and the synthesis and release of reproductive hormones, male rats were treated with either an acute intraperitoneal injection of alcohol or were chronically exposed to an alcohol‐containing liquid diet. Hypothalamic, pituitary, serum, and testicular levels of immunoreactive β‐endorphin (i‐βE) and serum levels of luteinizing hormone (LH) and testosterone were measured at various times after initiation of these treatments. Testicular interstitial fluid (TIF) volumes and levels of TIF i‐βE and testosterone were also measured 4 hr after acute treatment as an index of testicular release of these substances. Acute alcohol decreased pituitary levels of i‐βE and increased serum levels of the peptide for up to 1 hr after its injection, but did not alter hypothalamic or testicular levels. Acute alcohol markedly increased TIF i‐βE and decreased TIF testosterone and TIF volume. Sharp decreases in serum LH and testosterone were observed in association with these acute changes in i‐βE levels in the pituitary, blood, and testes. During chronic alcohol exposure serum testosterone levels were substantially depressed, but tolerance appeared to develop quickly to the chronic effects of alcohol on serum LH. Similarly, tolerance to alcohol's effects on i‐BE levels in the pituitary and serum also appeared to develop during chronic alcohol administration. However, hypothalamic and testicular i‐BE levels were markedly suppressed by chronic alcohol administration in contrast to the lack of effect observed after acute alcohol administration. Our data demonstrate that both acute and chronic alcohol administration alter the functional activity of i‐βE systems in the hypothalamic‐pituitary‐gonadal axis and suggest that these changes may be involved in alcohol's effects on reproductive endocrinology. Whether the effects we have observed are simply correlational in nature or demonstrate cause/effect relationships remains to be determined.
Hormonal Tolerance to Ethanol is Associated with Decreased Expression of the GTP‐Binding Protein, Gsα, and Adenylyl Cyclase Activity in Ethanol‐Treated LS Mice
Authors: Wand Gary S. , Levine Michael A.
Published: April 2006

Using the proopiomelanocortin (POMC) system as a marker, long sleep (LS) and short sleep (SS) lines of mice were investigated to explore the cellular events that occur during the acquisition of hormonal tolerance to ethanol. Four‐day ethanol exposure (1.8 g/ kg/24 hr) increased anterior pituitary POMC mRNA levels 4‐fold in the LS line and 2‐fold in the SS line. Following 7 days of ethanol exposure (1.8 g/kg/24 hr), anterior pituitary POMC levels returned to basal values in the LS line but remained elevated (2‐fold) in the SS line. In this setting, the loss of ethanol's ability to sustain elevated POMC mRNA levels in the LS line is defined as hormonal tolerance. Since POMC biosynthesis is primarily regulated through adenylyl cyclase, ethanol‐induced alterations in this signal transduction system were explored. Paralleling the effects of ethanol on POMC mRNA levels, ethanol exposure reduced GTP‐γ‐S, AIF3‐, and MnCl2‐stimulated adenylyl cyclase activity by 35%, 21%, and 24%, respectively, in the LS line without effecting adenylyl cyclase activity in the SS line. To determine whether ethanol‐induced changes in adenylyl cyclase activity in LS mice could result from alterations in G proteins, protein levels of Gsα and Giα were determined by western analysis before and after ethanol exposure. Paralleling the effect on POMC mRNA levels and adenylyl cyclase activity, ethanol induced a 35% reduction in Gsα protein levels in LS mice but did not alter Giα levels. Neither Gsα nor Giα levels were altered in the SS line. The genetic specificity of ethanol‐induced alterations in Gsα protein levels in LS mice was not limited to the anterior pituitary. Ethanol exposure reduced Gsα protein levels in cerebellar membranes in the LS line with no effect on cerebellar G Gsα levels in the SS line. Differential regulation of G proteins could be a critical molecular event in the pathogenesis of ethanol tolerance. These observations underscore that the threshold for tolerance to ethanol is in part genetically determined.
The Relationship between Brain Temperature during Intoxication and Ethanol Sensitivity in LS and SS Mice
Authors: Finn Deborah A. , Bejanian Marina , Jones Brenda L. , Babbini Mario , Syapin Peter J. , Alkana Ronald L.
Published: April 2006

The present study characterized the relationship between brain temperature, rectal temperature, and ethanol sensitivity in the selectivity bred long‐sleep (LS) and short‐sleep (SS) mice. Radiotelemetric brain probe implanted and nonimplanted LS/lbg and SS/lbg male mice were injected with 2.5 and 4.9 g/kg ethanol, respectively, before exposure to ambient temperatures of 15°C, 22°C, or 34°C. Ambient temperature significantly affected rectal temperature, brain temperature, and ethanol sensitivity, measured by impairment of righting reflex. Brain and rectal temperatures at return of righting reflex (RORR) were highly correlated. In SS mice brain and rectal temperatures at RORR were significantly positively correlated with loss of righting reflex (LORR) duration and significantly negatively correlated with blood ethanol concentration (BEC) at RORR. In LS mice rectal temperature at RORR was significantly negatively correlated with LORR duration, while both brain and rectal temperature at RORR were significantly positively correlated with BEC at RORR. The strength of the correlations and r2 values generated from linear regression analysis indicates that body temperature during intoxication can explain up to 52% of the variability in ethanol sensitivity in SS mice, but only 19% of the variability in ethanol sensitivity in LS mice. The correlational analyses are consistent with previous results based on comparisons between rectal temperature and ethanol sensitivity and extend to direct brain temperature measurement the evidence that decreasing temperature during intoxication decreases ethanol sensitivity in SS mice and increases ethanol sensitivity in LS mice. Further, the present results indicate that the differential effects of temperature on ethanol sensitivity in LS and SS mice do not reflect line differences in the effects of ambient temperature challenge on brain temperature during intoxication.
Electrophysiological Response to Ethanol in P and NP Rats
Authors: Ehlers C. L. , Chaplin R. I. , Lumeng L. , Li T. K.
Published: April 2006

Event‐related potentials (ERPs) have been successfully used in human subjects to evaluate alcoholics as well as those at risk for the future development of alcoholism. In the present study, two lines of rats, those with a preference for ethanol consumption (P) and those not preferring (NP) to drink ethanol were studied using ERP‐producing stimuli. Rats were implanted with electrodes in the frontal cortex and dorsal hippocampus (DHPC). A passive auditory “oddball” paradigm was used to record ERP responses following saline and two doses (0.5, 1.0 g/kg) of ethanol. P and NP rats differed under the saline condition in that P rats had smaller N1‐like ERP components and larger P2 waves in both cortex and hippocampus. P and NP rats were also found to differ in response to ethanol administration. NP rats evidenced dose‐dependent reductions in ERP component amplitudes such as the N1 recorded from cortical sites. P rats did not have such reductions in N1 amplitudes and in fact, displayed increased N1 amplitudes in hippocampal sites. These studies provide further electrophysiological evidence that rats with a genetically influenced preference for ethanol consumption differ from nonpreferring rats at baseline and have a less intense depressant or more stimulating response to ethanol challenge.
Ethanol Influences Class I and Class II MHC Antigen Expression on Human Fetal Islet‐Like Cell Clusters
Authors: Ruhland Bernd , Walker Liberty , Wollitzer Alison Okada , Peterson Charles M.
Published: April 2006

Several autoimmune diseases have been linked to an aberrant expression of major histocompatibility complex (MHC) products Ethanol enhances Class I and Class II products on a variety of cell types, and there is evidence for an autoimmune etiology in numerous pathologies associated with alcoholism. We examined whether ethanol alters the expression of Class I and Class II MHC products on human fetal islet‐like cell clusters. Incubation of islet‐like clusters for 48 hr in ethanol at a starting concentration of 1.5% increased the percentage of single cells expressing Class 1. The percentage of cells expressing Class II did not change, but their relative mean fluorescence increased significantly. These findings suggest that alcohol ingestion could alter MHC expression on pancreatic islet cells in vivo perhaps affecting the development of diabetes in genetically predisposed individuals. These findings also support the hypothesis that the rising incidence of type 1 diabetes seen in areas of the world where the per capita consumption of alcohol is also increasing may be a consequence of the immunological effects of alcohol intake.
Ethanol Fails to Modify [3H]GR65630 Binding to 5‐HT3 Receptors in NCB‐20 Cells and in Rat Cerebral Membranes
Authors: Hellevuo Kaisa , Hoffman Paula L. , Tabakoff Boris
Published: April 2006

Low concentrations of ethanol have been found to enhance the electrophysiologic effect of serotonin (5‐HT) acting at 5‐HT3 receptors on NCB‐20 cells. To determine whether this action of ethanol reflects a change in the agonist‐receptor interaction, the effect of ethanol (100 mm) on agonist and antagonist binding to 5‐HT3 receptor was studied in vitro in membranes from NCB‐20 cells and from cortex plus hippocampus of rat. The antagonist [3H]GR65630 was used to label 5‐HT3, recognition sites. Ethanol did not change the characteristics of saturable [3H]GR65630 binding in either membrane preparation. In competition studies, the agonists 5‐HT and 2‐methyl‐5‐HT completely inhibited the binding of [3H]GR65630 to NCB‐20 cell membranes, while in brain membranes the maximum displacement of specific [3H]GR65630 binding by 5‐HT was approximately 30%. Ethanol decreased the affinity of the receptor for 2‐methyl‐5‐HT, but not to 5‐HT in NCB‐20 cells, and had no effect on agonist binding in brain membranes. The results indicate that enhancement of 5‐HT responses at 5‐HT3 receptors by ethanol is not a result of changes in the equilibrium binding characteristics of the agonist.
Increased Ventricular Vulnerability in a Chronic Ethanol Model Despite Reduced Electrophysiologic Responses to Catecholamines
Authors: Patel Ravindra , McArdle Joseph J. , Regan Timothy J.
Published: April 2006

An increased incidence of sudden death has been reported in chronic alcoholism. To assess electrical vulnerability of the heart, action potential responses, and the role of the sympathetic system, a well‐nourished canine model has been studied intact under chloralose anesthesia after 1 year of ethanol consumption at 36% of caloric intake. Two alcoholic groups were compared with controls (Group 1). In Group 2 myocardial vulnerability was assessed after chronic EtOH and superimposed acute administration. In Group 3 basal vulnerability was related to circulating norepinephrine and release of neurohormone from the myocardium. Subsequently the responsiveness to catecholamine infusion was determined. To assess vulnerability an electrode catheter was placed in the right ventricular apex. The basal ventricular fibrillation threshold (VFT) was reduced to 27 ± 3 ma in Group 2 versus 43 ± 1.0 in Group 1. Acute infusion of ethanol in Group 2 further reduced the threshold. Group 3 had a reduced basal VFT. Baseline arterial plasma levels of norepinephrine were 8‐fold higher and coronary venous levels 13 times higher in the alcoholic group than in Group 1. However, VFT was not responsive to infused epinephrine, compared with Group 1 controls. In vitro study of superfused ventricular tissue from Group 3 revealed that basal action potential amplitude, overshoot, and resting potential were comparable with normals. Basal repolarization time (90%) was 198 ± 12 msec in Group 3 versus 215 ± 6 msec in Group 1 (p < 0.05). After acute EtOH, repolarization time was shortened to 170 ± 8.6 in Group 1 at 90 mg% ethanol (p < 0.002), with minimal further change up to 280 mg%. There was no significant change in Group 3. Isoproterenol (10‐8 to 10‐8) shortened repolarization time maximally to 74% of basal in Group 1, and 85% of basal in Group 3 (p < 0.01). Thus, despite reduced in vivo and in vitro electrophysiologic responses to exogenous catecholamines in this chronic ethanol model, an increase of circulating NE appeared to promote increased ventricular vulnerability.
Altered Expression of HLA Antigens and CD16 Fc Receptors on Leukocytes of Alcoholic Subjects and Uremic Patients
Authors: Jones Joe M. , Veech Richard L. , Abbasi Fatima , Yu Kai , Yeralan Olcay , Briefel Gary R. , Anderson John , Mezey Esteban
Published: April 2006

The possible influences of ethanol and its metabolic product acetate on the surface expression of HLA class I and class II antigens and CD 16 Fc receptors were examined. Fluorescent‐labeled monoclonal antibodies and flow cytometry were used to measure these antigens on leukocytes from reference controls, subjects admitted for alcohol detoxification, uremic patients undergoing hemodialysis using Cuprophan dialyzers and fluids containing 4 to 37 mm acetate, and uremic patients that were not hemodialyzed. In comparison to the controls, the mean intensity of staining for class I antigens was not changed significantly on lymphocytes or monocytes from alcoholics but was depressed on cells from eight of 12 uremic patients. Interferon‐γ above 5 units/ml was detected in less than 15% of plasma samples from controls, uremic patients or alcoholics on admission but was detected in four of eight samples from alcoholics at discharge (2‐4 days after admission). The intensity of staining for class II antigens was depressed by more than 50% on lymphocytes from alcoholics and uremic patients. The expression of HLA class I and class II antigens was depressed whether uremic patients were hemodialyzed or not. The percentage of lymphocytes expressing CD16 was depressed in three of seven alcoholics and five of seven hemodialyzed patients. In contrast, the percentage of monocytes expressing CD 16 was increased in six of seven hemodialyzed patients and three of five uremic patients not undergoing hemodialysis suggesting activation of monocytes in these patients. Plasma levels of beta 2‐microglobulin were elevated by 61% in alcoholics, 50‐fold in hemodialyzed patients, and 26‐fold in nonhemodialyzed uremic patients. Although alcoholics and hemodialyzed patients exhibited similar alterations in some of the parameters measured, the results did not indicate a significant role for acetate or hemodialysis with Cuprophan membranes in the alterations of membrane antigen expression.
Flow Cytometric and Immunohistochemical Evaluation of Ethanol‐Induced Changes in Splenic and Thymic Lymphoid Cell Populations
Authors: Saad Assad Joe , Jerrells Thomas R.
Published: April 2006

Ethanol‐induced alterations in the immune system are thought to play a major role in increasing the susceptibility of alcoholics to infections and tumors. One important change in the immune system is the noted loss of lymphoid cells from the thymus and spleen. To examine these alterations we used a model system where C57B1/6 mice were pair‐fed either a Leiber‐DeCarli diet containing 7% (v/v) ethanol or an isocaloric control diet. Mice receiving ETOH for 7 days showed a loss of cells from the spleen and thymus; this loss was even more severe after withdrawal for 1 day. The most profound changes were seen after 2 weeks of ETOH. Spleen and thymus cell numbers were reduced to 36% and 6.2%, respectively compared to control mice. Staining of thymocytes with monoclonal antibodies to lymphocyte surface markers and evaluation with flow cytometry revealed that immature thymocytes (PNA+, CD4+/CD8+) were most reduced. Mature thymocytes (CD4+/CD8‐ or CD4‐/CD8+) were depleted, and the CD4+ to CD8+ ratio was increased. Sections of thymus stained with hematoxylin and eosin or with immunohistochemical methods showed atrophy and lymphoid cell depletion. No cortex was histologically identifiable after 2 weeks of ETOH. The spleen cells most affected by ETOH were the B cells. They were reduced to 8.2 × 106 cells/spleen (31.5% of the lymphocytes), as compared to 38.5 × 106 cells/spleen (50.3% of the lymphocytes) in the control mice. The spleen was atrophic, but the immunoarchitecture was preserved. Ethanol causes a depletion of lymphocytes from the spleen and thymus with alterations in lymphocyte subpopulations. Immature cells in the thymus are most susceptible, and the changes are more severe with longer periods of consumption.
Chronic Ethanol‐Induced Impairments in Receptor‐Mediated Endocytosis of Insulin in Rat Hepatocytes
Authors: Tuma Dean J. , Casey Carol A. , Sorrell Michael F.
Published: April 2006

The effects of chronic ethanol administration on the receptor‐mediated endocytosis of insulin were investigated in isolated hepatocytes. When hepatocytes were isolated from rats that were fed an ethanol liquid diet for 5‐6 weeks, these cells bound 25% less insulin to their surface membrane than did cells from the chow‐fed or pairfed controls. This decreased binding was likely a result of reduced surface receptor number rather than changes in receptor affinity. Rates of insulin degradation were also reduced by 25‐30% in hepatocytes from the ethanol‐fed animals. In addition, chronic ethanol feeding induced a defect in the internalization of the receptor‐insulin complex and altered the hepatocellular processing of the internalized insulin. These results indicate that chronic ethanol administration impairs both the surface binding and the endocytosis of insulin by the liver.
The Phytoestrogens Present in De‐Ethanolized Bourbon Are Biologically Active: A Preliminary Study in a Postmenopausal Woman
Authors: Van Thiel D. H. , Galvao‐Teles A. , Monteiro E. , Rosenblum E. , Gavaler J. S.
Published: April 2006

Bourbon and some other alcoholic beverages have been shown to contain phytoestrogens which, as a result of an excessive intake and alcohol associated liver disease, have been suggested as contributing to the feminization of chronic alcoholic men. To evaluate this hypothesis directly, de‐ethanolized bourbon was prepared and orally administered to a single postmenopausal woman. Serum or plasma levels of luteinizing hormone, follicle stimulating hormone, sex steroid binding globulin, high density lipoprotein cholesterol, and estradiol were monitored before, during, and after administration of the de‐ethanolized bourbon at a dose equivalent to 4 ounces of bourbon for 20 days. The changes observed for each parameter during the injection of the bourbon extract are consistent with the presence of a biologically active estrogenic substance being present in the bourbon extract. These observations provide the first direct evidence in man for the presence of a biologically active estrogenic substance(s) in bourbon.