bluuebunny/crossref_metadata_2025 huggingface dataset:
Acute Alcohol Effects on Opiomelanocortinergic Regulation
Authors: Rasmussen Dennis D. , Bryant Carrie A. , Boldt Brian M. , Colasurdo Elizabeth A. , Levin Nancy , Wilkinson Charles W.
Published: May 2006

To assess acute effects of alcohol on forebrain and pituitary opiomelanocortinergic regulation, a model was developed in which “experienced” (previously introduced to ethanol administration, so the subjective response was not a novel stimulus) male Sprague‐Dawley rats received pulsatile intragastric ethanol infusions during the dark (active) photophase to produce and sustain (for 3 hr) behaviorally relevant (0, 40 to 70, 80 to 110, or 120 to 150 mg/dl) plasma ethanol levels. The effects of alcohol on hypothalamo‐pituitary‐adrenal (H‐P‐A) axis function were biphasic with respect to dosage (inhibition with low dosage and stimulation with higher dosages) and time (initial stimulation with higher dosages was followed by rapid return to control levels even though elevated plasma ethanol levels were maintained). The effects of alcohol on H‐P‐A activation were also inconsistent; some of the animals did not appear to respond even though elevated (i.e., > 100 mg/dl) plasma ethanol levels were produced. Induction of moderate (80 to 110 mg/dl) plasma ethanol levels acutely (within 30 min) increased immunoreactive (i) β‐endorphin concentrations in the ventral tegmental area of the brain; higher (120 to 150 mg/dl) plasma ethanol levels increased iβ‐endorphin concentrations in both the ventral tegmental area and the nucleus accumbens, whereas iβ‐endorphin concentrations were not significantly altered in other brain areas. High (120 to 150 mg/dl) plasma ethanol levels also increased mediobasohypothalamic pro‐opiomelanocortin (biosynthetic precursor of forebrain β‐endorphin) mRNA concentrations at 3 and 6 hr after initiation of ethanol infusions. Results demonstrate that atraumatic induction of physiologically meaningful plasma alcohol levels by gastric ethanol infusion activates the forebrain opiomelanocortinergic opioid system and exerts complex effects on the interrelated H‐P‐A system, consistent with evidence that these systems may interact to mediate or modulate some responses to alcohol ingestion.
Mechanism of Action of Acamprosate. Part I. Characterization of Spermidine‐Sensitive Acamprosate Binding Site in Rat Brain
Authors: Naassila Mickaël , Hammoumi Saloua , Legrand Elisabeth , Durbin Philippe , Daoust Martine
Published: May 2006

It has been suggested that the anticraving drug, acamprosate, acts via the glutamatergic system, but the exact mechanism of action is still unknown. The aim of this study was to characterize [3H]acam‐prosate binding and establish whether this showed any relation to sites on the NMDA receptor complex. We found saturable specific binding of [3H]acamprosate to rat brain membranes with a KD of 120 μM and a Bmax of 450 pmol/mg of protein. This acamprosate binding site was sensitive to inhibition by spermidine (IC50: 13.32 ± 1.1 μM; Hill coefficient = 1.04), and arcaine and glutamate both potentiated the inhibitory effect of spermidine. Acamprosate binding to the acamprosate binding site was also sensitive to inhibition by divalent cations (Ca2+, Mg2+, and Sr2+). Conversely, acamprosate displaced [14C]spermidine binding from rat brain membranes with an IC50, of 645 μM and a Hill coefficient = 1.74. This inhibitory effect of acamprosate was not affected by arcaine, and was associated with a significant reduction in Bmax and binding affinity for spermidine, suggesting an allosteric interaction between acamprosate and a spermidine binding site. These data are consistent with an effect of acamprosate on the NMDA receptor protein complex, and acamprosate was also found to alter binding of [3H]dizocilpine to rat brain membranes. When no agonists were present in vitro (minimal NMDA receptor activation), acamprosate markedly potentiated [3H]dizocilpine binding at concentrations in the 5 to 200 μ range. However, under conditions of maximal receptor activation (100 μM glutamate, 30 μM glycine), acamprosate only inhibited [3H]dizocilpine binding (at concentrations concentrations > 100 μM). When these binding studies were performed in the presence of 1 μM spermidine, the enhancing effects of acamprosate on [3H]dirocilpine binding were inhibited. The results show that acamprosate binds to a specific spermidine‐sensitive site that modulates the NMDA receptor in a complex way. Together, with data from al Quatari et al. (see next paper), this work suggests that acamprosate acts as “partial co‐agonist“ at the NMDA receptor, so that low concentrations enhance activation when receptor activity is low, whereas higher concentrations are inhibitory to high levels of receptor activation. This may be relevant to the clinical effects of acamprosate in alcohol‐dependent patients during abstinence.
GABAA, Receptor α1, α4, and β3 Subunit mRNA and Protein Expression in the Frontal Cortex of Human Alcoholics
Authors: Mitsuyama Hiroki , Little Karley Y. , Sieghart Werner , Devaud Leslie L. , Morrow A. Leslie
Published: May 2006

Animal studies have shown that chronic ethanol consumption produces physical dependence upon ethanol and alters γ‐aminobutyric acid‐A (GABAA) receptor subunit gene expression in brain. Although extensive investigation has been conducted in animal models, relatively little work has been performed directly on human alcoholic brain tissue to determine if there are alterations in GABAA, receptor gene expression. In this study, GABAA, receptor α1, α4, and β3 subunit mRNA and peptide expression in postmortem frontal cortex from human alcoholics (n= 15) and age‐ and sex‐matched controls (n= 13) were measured by quantitative, competitive reverse transcription polymerase chain reaction and Western blot analysis. GABAA, receptor β3 subunit mRNA expression was 35% greater (p < 0.05) in alcoholics, compared with nonalcoholic controls. We found no significant difference in α1, and α4, subunit mRNA levels between groups. However, there was a trend toward greater (21%) α1 subunit mRNA expression. There was no difference in α1, α4, or β2/3 subunit peptide levels in frontal cortex between controls and alcoholics. Neither the age of the subjects nor the postmortem interval correlated with mRNA or peptide levels. Blood ethanol content also did not correlate with mRNA or peptide expression in alcoholic samples. These data suggest that GABAA, receptor adaptations, resulting from prolonged alcohol consumption in human alcoholics, may differ from animal models of alcohol dependence. These differences may be related to the longevity of alcohol exposure in human alcoholics, as well as variability in the dependence/withdrawal state of the human subjects. Therefore, further studies in human postmortem brain tissue are warranted.
Carbohydrate‐Deficient Transferrin and Conventional Alcohol Markers as Indicators for Brief Intervention among Heavy Drinkers in Primary Health Care
Authors: Sillanaukee Pekka , Aalto Mauri , Seppä Kaija
Published: May 2006

Brief intervention is a promising treatment for heavy drinking. The present study examined the diagnostic value of carbohydrate‐deficient transferrin (CDT), mean corpuscular volume (MCV), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and γ glutamyltransferase (GGT) in detecting early‐phase heavy drinkers for brief intervention treatment in primary health care. Laboratory data were collected from consecutive 20‐ to 60‐year‐old, early‐phase heavy drinkers (329 males and 136 females), who were willing to undergo brief intervention treatment in five primary health care outpatient clinics. An elevated value of at least 1 of the 5 markers studied was found in 75% of the male and in 76% of the female heavy drinkers. The sensitivities of CDT, MCV, AST, ALT and GGT values were low; in men, respectively, 39%, 28%, 12%, 28%, and 33%. and in women 29%, 40%, 20%, 29%, and 34%. However, marker combinations, including CDT, reached a good level of sensitivity; the best triple combination (CDT or MCV or GGT) was positive in 69% of the men and 70% of the women. According to logistic regression, the age of the patient had an increasing effect on MCV, ALT and GGT. High body mass index increased all transaminases and decreased CDT and MCV. Smoking increased MCV and decreased AST. Thus, primary health care marker combinations, especially those including CDT, should be considered for the detection of early‐phase heavy drinkers for brief intervention treatment.
Effect of Fetal Alcohol Exposure on Adult Symptoms of Nicotine, Alcohol, and Drug Dependence
Authors: Yates William R. , Cadoret Remi J. , Troughton Edward P. , Stewart Mark , Giunta Trista S.
Published: May 2006

Objectives: The objective of this study is to examine the effect of fetal alcohol exposure on later substance dependence using an adoption study method. Methods: One hundred ninety‐seven adoptees were interviewed for substance abuse disorders, including nicotine, alcohol, and drug dependence. Twenty‐one adoptees had mothers who drank during pregnancy. Adoptees with fetal alcohol exposure were compared with those without fetal alcohol exposure for symptoms of adult nicotine, alcohol, and drug dependence. Results: Adoptee symptom counts for alcohol, drug, and nicotine dependence were higher for those exposed to alcohol in utero. The effect of fetal alcohol exposure remained after controlling for gender, biological parent alcohol dependence diagnosis, birth weight, gestational age and other environmental variables. Conclusions: Fetal alcohol exposure may produce increased risk for later nicotine, alcohol, and drug dependence. Possible effects of fetal alcohol exposure on development of adult substance use patterns needs attention in genetic studies of substance abuse.
Influence of Age and Body Mass Index on γ‐Glutamyltransferase Activity: A 15‐Year Follow‐Up Evaluation in a Community Sample
Authors: Daeppen Jean‐Bernard , Smith Tom L. , Schuckit Marc A.
Published: May 2006

Most clinicians and researchers view serum γ‐glutamyltransferase (GGT) activity as a measure that can be interpreted equally in patients regardless of their demography. The present study evaluates the concurrent influence of age and body mass index (BMI) on GGT in a sample of 133 high functioning young men, with detailed assessment of the pattern of alcohol use at ages 20 [time 1 (T1)], 30 [time 2 (T2)], and 35 [time 3 (T3)]. GGT increased between T1 and T2 (15.4 ± 9.65 units/liter vs. 20.1 ± 12.07 units/liter, t= 4.17, p < 0.001), and between T2 and T3 (20.1 ± 12.07 units/liter vs. 27.3 ± 24.69 units/liter, t= 4.11, p < 0.001). Controlling for drinking quantity and frequency did not change the finding. The relationship between GGT and BMI was estimated after splitting the sample into normal (BMI ≤ 25 kg/m2), and overweight (BMI > 25 kg/m2), subjects. The correlation between GGT and BMI in normal weight men at T1 was r= 0.15, p= 0.09, at T2 r= 0.00, p= 0.96, and at T3 r= 0.09, p= 0.09. In overweight subjects, correlation at T1 was r= 0.40, p= 0.20, at T2 r= 0.36, p < 0.05, and at T3 r= 0.44, p < 0.001. Controlling for the effect of alcohol consumption and/or age did not alter these conclusions. Testing for the interaction of age, BMI, and alcohol consumption did not yield relevant results. We concluded that GGT is positively related to age in the 20s to late 30s and to BMI in overweight subjects; both relationships of age and BMI were independent of alcohol consumption. The interpretation of GGT should take age and BMI into account when suspecting subclinical alcohol problems in young men.
Effect of Prenatal Ethanol Exposure on the Developmental Profile of the NMDA Receptor Subunits in Rat Forebrain and Hippocampus
Authors: Hughes Peter D. , Kim Young‐Nam , Randall Patrick K. , Leslie Steven W.
Published: May 2006

The effects of prenatal ethanol exposure on the NMDARl protein expression (postnatal days 1 and 7) and on the developmental profile of the NMDAR2A and NMDAR2B subunits in rat forebrain and hippocampus were investigated. Forebrain and hippocampal membrane proteins were isolated from pups of various ages (postnatal days 1 to 21) from prenatally ethanol exposed, pairfed and ad libitum control groups. A semiquantitative immunoblot procedure was used with antibodies raised against the NMDAR1, NMDAR2A, and the NMDAR2B subunits to assess the NMDA subunit protein expression. In the samples, NMDAR1 protein expression was unaffected by prenatal ethanol exposure at postnatal day 1 or 7 in both the forebrain and hippocampus. NMDAR2A protein expression levels rose rapidly. In both forebrain and hippocampus during the time frame of study. Renatal ethanol exposure caused a significant reduction in protein expression levels of the NMDAR2A in forebrain through postnatal day 14. NMDAR2B protein expression levels were high throughout the study in both forebrain and hippocampus. Prenatal ethanol exposure significantly reduced protein expression of the NMDAR2B in the forebrain (through postnatal day 14) and hippocampus (up to day 7). The results suggest that there may be a link between the depressed expression of the NMDAR2 subunits and the neurodevelopmental disorders associated with fetal ethanol exposure.
Overt Behavior Problems and Serotonergic Function in Middle Childhood Among Male and Female Offspring of Alcoholic Fathers
Authors: Twitchell Geoffrey R. , Hanna Gregory L. , Cook Edwin H. , Fitzgerald Hiram E. , Little Karley Y. , Zucker Robert A.
Published: May 2006

A large body of literature indicates that the serotonergic system is involved in behavioral regulation, as evidenced by the inverse relationship between impulsive aggression and serotonergic function found in adult alcoholics and nonalcoholics. However, studies of this relationship among child and adolescent offspring of alcoholics (COAs) have not previously been done. This study examines the potentially parallel relationship between behavioral dysregulation and low serotonergic function in young COAs. The relationship is of potential interest as a phenotypic marker of biological vulnerability to aggressiveness, which itself has been hypothesized to be a risk factor for later antisocial alcoholism. The present work is part of an ongoing prospective study of the development of risk for alcohol abuse/dependence and other problematic outcomes in a sample of families subtyped by the fathers' alcoholism classification. We examined the relationship between overt behavior problems in middle childhood (mean age = 10.5 ± 1.7 years) and whole blood serotonin (5‐HT) in a subsample of the offspring (N= 32 boys and 12 girls). Using a Child Behavior Checklist (CBCL) index of behavioral under‐control, we obtained results indicating that high total behavior problem (TBP) children had lower levels of whole blood 5‐HT than did low‐TBP children (p < 0.01). These results support the hypothesis that there is an inverse relationship between whole blood serotonin levels and behavior problems in young male and female COAs. A father's alcoholism status was not significantly related to his child's 5‐HT level, i.e., the child's phenotypic expression of behavioral dysregulation was more reliably connected to serotonergic function than was paternal alcoholism.
Relationship of Serum Neutral Endopeptidase E.C.3,4,24.11 Activity to Alcohol Consumption
Authors: Frette Catherine , Pezet Sophie , El Nabout Rita Azzi , Bertrand Jean‐Pierre , Pham Quang Thieu , Kauffmann Francine , Lafuma Chantal
Published: May 2006

Neutral endopeptidase (NEP) is an ubiquitous enzyme that inactivates numerous endogenous peptides in the brain, kidney, and lung in vivo. The origin of the circulating soluble form and its determinants are largely unknown. The relationships of smoking habits and alcohol consumption to serum NEP activity have been explored in a longitudinal epidemiological study conducted in 4 Lorraine coal miners. At both surveys, 4 years apart, NEP activity was significantly related to alcohol consumption (in grams/day) reported by questionnaire, with correlation coefficients of 0.26 (p= 0.001) in 1990 and 0.23 (p= 0.001) in 1994. The correlations of γ‐glutamyltransferase to NEP activity were even stronger with correlation coefficients of 0.71 (p= 0.0001) in 1990 and 0.79 (p= 0.0001) in 1994. Longitudinally, the change in NEP activity between the first and the second surveys was significantly correlated with change in alcohol consumption (r= to 0.18, p = 0.02) and with change in γ‐glutamyltransferase level (r= 0.60, p= 0.0001). Serum NEP activity was unrelated to smoking habits. Results support the hypothesis of a causal role of alcohol on serum NEP activity.
ADH Genotypes and Alcohol Use and Dependence in Europeans
Authors: Whitfield J. B. , Nightingale B. N. , Bucholz K. K. , Madden P. A. F. , Heath A. C. , Martin N. G.
Published: May 2006

We have tested for effects of alcohol dehydrogenase (ADH) genotypes on self‐reported alcohol consumption and symptoms of alcohol dependence, recorded on three occasions up to 15 years apart, in 377 male and female subjects of European descent.ADH2genotype had significant effects on both consumption and dependence in the men, but not in the women. The effects ofADH3genotype were considerably less than those ofADH2, but significant results could be demonstrated when the combined genotypes were considered. The direction of the effects on alcohol consumption and dependence risk were consistent with reports on Asian subjects, and with the in vitro properties of ADH isoenzymes. As with previous studies on the relationship between ADH type and alcohol use, population stratification cannot be excluded as a contributing factor in these results.
The Interaction of Ethanol and Vitamin A as a Potential Mechanism for the Pathogenesis of Fetal Alcohol Syndrome
Authors: Zachman Richard D. , Grummer Mary A.
Published: May 2006

The mechanism of the fetal embryopathology resulting from ethanol ingestion during pregnancy is not established. This review summarizes recent research on the interaction of ethanol and vitamin A in models that explore if an interaction between these two compounds might potentially be the mechanism for fetal alcohol syndrome. The rationale for this hypothesis includes the known facts that: (1) in adults, ethanol ingestion alters vitamin A metabolism and tissue distribution; (2) there are many phenotypic similarities between fetal alcohol syndrome and malformations of both vitamin A toxicity and deficiency; and (3) the vitamin A metabolite, retinoic acid (RA), is a potent mediator in embryogenesis and differentiation. One interaction that could possibly alter fetal development is that the synthesis of RA from retinol, catalyzed by alcohol dehydrogenase, might be competitively inhibited by ethanol leading to RA deficiency. Controversy over this hypothesis continues. Another model demonstrates in vivo effects of pregnant rat mother's ethanol consumption on retinol, retinyl ester, RA content, RA receptor (RAR) binding, and the levels of RAR expression in developing fetal organs. The variable responses in this model still need clarification, and specific defects resulting from specific RAR changes have not yet been identified. In a quail embryo model, ethanol treatment mimics vitamin A deficiency, and RA appears to prevent the adverse effects of ethanol. Finally, RA and ethanol reverse or block each other's effects in studies on isolated neuroblastoma cells. Taken together, these experiments show definite interactions between ethanol and vitamin A. Further studies are needed to determine if any of these mechanisms significantly contribute to prenatal ethanol consumption embryopathy; but, clearly this hypothesis is gaining experimental support.
Prenatal Ethanol Exposure Diminishes Activity‐Dependent Potentiation of Amino Acid Neurotransmitter Release in Adult Rat Offspring
Authors: Savage Daniel D. , Cruz Laura L. , Duran Lorina M. , Paxton Linda L.
Published: May 2006

Prenatal ethanol exposure has been associated with long‐lasting intellectual impairments in children. Previous studies suggest that these deficits are, in part, linked to neurochemical abnormalities that reduce the ability to sustain long‐term potentiation (LTP) in hip‐pocampal formation of adult offspring. One presynaptic component of LTP that manifests during the first half‐hour alter tetanic stimulation is an enhancement of amino acid neurotransmitter release. Given that the onset of enhanced neurotransmitter release correlates temporally with the decay of hippocampal LTP in prenatal ethanol‐exposed offspring, we tested the hypothesis that prenatal ethanol exposure reduces tetanus stimulus‐induced potentiation of electrically evoked amino acid release in hippocampal slices. Rat dams consumed 1 of 3 diets throughout gestation: (1) a BioServ liquid diet containing 5% (v/v) ethanol (26% ethanol‐derived calories) that produces a maternal peak blood ethanol concentration of 83 mg/dl; (2) pair‐fed an isocalorically equivalent amount of 0% ethanol liquid diet; or (3) Purina rat chow ad libitum. Hippocampal slices were prepared from adult offspring from each experimental diet group. Neither the amount of hippocampal slice tissue protein nor the incorporation of [3H]‐d‐aspartate (D‐ASP) was affected by prenatal ethanol exposure. Furthermore, spontaneous efflux and electrically evoked D‐ASP release were similar among the three diet groups. However, tetanus stimulus‐induced potentiation of evoked D‐ASP release in prenatal ethanol‐exposed offspring was reduced to about one‐third of the potentiation of D‐ASP release Observed in the control diet groups. These results suggest that prenatal ethanol exposure produces long‐lasting deficits in the neurochemical mechanisms responsible for activity‐dependent potentiation of amino acid transmitter release without affecting the synaptic machinery responsible for amino acid uptake, storage, and release.
Evaluation of the Carbon 13‐Labeled Ketoisocaproate Breath Test To Assess Mitochondrial Dysfunction in Patients with High Alcohol Consumption
Authors: Bendtsen P. , Hannestad U. , Påhlsson P.
Published: May 2006

There are few functional tests for liver function that selectively indicate the toxic effect of alcohol abuse. To explore the long‐term impact of excessive alcohol use on the liver, there is a need for such specific analyses. The Ketoisocaproate breath test has been shown to be a specific marker of mitochondrial function in the liver, which is known to be selectively affected by heavy alcohol intake. This method was evaluated by analyzing 13 male patients with severe alcohol dependence and comparing these with 10 healthy volunteers, 5 women and 5 men. All alcoholic patients reported a heavy intake of alcohol during the last month before the test and all had some form of abnormal liver status as assessed by traditional markers such as aspartate aminotransferase, alanine aminotransferase, or γ‐glutamyltransferase analyses. The results showed that healthy women had a higher percentage exhalation of 13CO2 than both healthy males and alcoholic males. In contrast to previous studies, we found no significant impairment of Ketoisocaproate decarboxylation as an effect of chronic intake of alcohol or alcohol‐induced steatosis. The findings could not be explained completely by concurrent drug intake used in the routine detoxification of the patients. Thus, the value of the Ketoisocaproate breath test as a biological marker of excessive alcohol consumption appears to be limited because of a fast normalization of the values.
Effect of the Type of Beverage and Meat Consumed by Alcoholics with Alcoholic Liver Disease
Authors: Bode Christiane , Bode J. Christian , Erhardt Jürgen G. , French Barbara A. , French Samuel W.
Published: May 2006

We analyzed meat products and alcoholic beverage preference in patients with the three stages of alcoholic liver disease (ALD) compared with controls using diet history data. Daily consumption of total alcohol, types of alcoholic beverages, and types of meat and meat products in grams was obtained by dietary history taken from patients with biopsy proven stage of ALD. A strong association was found between the ALD subjects and total alcohol and beer consumption. There was a significant increase in the consumption of total pig products, pork, and offal in the ALD groups compared with controls. There was a significant positive correlation between beer consumption and pork in alcoholic hepatitis, total pork products in alcoholic hepatitis, and cirrhosis and offal in alcoholic hepatitis and cirrhosis. There was no correlation with the fatty liver stage of ALD. The strongest correlation was between beer and total pig products in the alcoholic hepatitis group. Wine consumption was negatively correlated with the consumption of pig products and beer in the alcoholic cirrhosis group. In conclusion, the association of total pig product consumption with cirrhosis mortality in various countries was validated by personal diet history data obtained from ALD patients in a tested clinical microcosm. The results suggest that this association may be modified by the type of alcoholic beverage that is preferentially consumed.
Crash Responsibility Versus Drug and Alcohol Use Among Fatally Injured and Hospitalized Motor Vehicle Drivers in Sweden
Authors: Timby Niklas , Sjögren Harmeet , Björnstig Ulf , Eriksson Anders
Published: May 2006

The present study was aimed at determining whether drivers testing positive for drugs and/or alcohol were more often responsible for the crash than the test‐negative ones. Data on 241 fatally injured and 102 hospitalized motor‐vehicle drivers was collected in Northern and Western Sweden. Blood samples were taken from these drivers and screened for the presence of alcohol, licit drugs, and illicit drugs. A judgment of responsibility, and assessment of the traffic situation and crash characteristics were based on police reports. Alcohol‐positive drivers (n= 49) were more often (96% vs. 70%, p < 0.0001) judged to be responsible for the crash than test‐negative drivers. Ninety‐three percent of the drug‐positive drivers were judged to be responsible, but they were not significantly more often responsible than the test‐negative drivers. Drug‐positive drivers differed from the alcohol‐positive drivers in that they more often crossed over to the wrong side of the road and crashed into an oncoming vehicle. The findings support previous studies that reducing the number of drug‐positive drivers in traffic is bound to lead to a reduction in crashes resulting in injury. Further analysis with a larger sample is needed to elucidate the association between crash responsibility and drugs other than alcohol.
Alcohol Consumption Alters Antigen‐Specific Th1 Responses: Mechanisms of Deficit and Repair
Authors: Waltenbaugh Carl , Vasquez Kristine , Peterson Jeffrey D.
Published: May 2006

Among the physiological effects associated with excessive alcohol consumption are alterations in immune function. Alcohol impairs T‐helper 1 lymphocyte (Th1) regulated, cell‐mediated immune responses. Antibody responses, regulated by T‐helper 2 lymphocyte (Th2), are either unimpaired or enhanced. Antigen presenting cells are central to the development of both Th1 and Th2 regulated immune responses. We used both T‐cell receptor transgenic and conventionally immunized mice to demonstrate that ethanol consumption directly affects antigen presenting cells that, in turn, determines whether Th1 or Th2 response patterns predominate. Ethanol consumption inhibits Th1 ‐associated interleukin‐12 and interferon‐γ cytokine production and delayed‐type hypersensitivity. Administration of exogenous recombinant interleukin‐12 both restores interferon‐γ levels and delayed‐type hypersensitivity responses in ethanol‐consuming mice.
Long‐Term Reliability and Validity of Alcoholism Diagnoses and Symptoms in a Large National Telephone Interview Survey
Authors: Slutske Wendy S. , True William R. , Scherrer Jeffrey F. , Goldberg Jack , Bucholz Kathleen K. , Heath Andrew C. , Henderson William G. , Eisen Seth A. , Lyons Michael J. , Tsuang Ming T.
Published: May 2006

The long‐term reliability and validity of telephone lay interview assessments of alcoholism were examined in the context of a large national community‐based survey of over 8,000 male Vietnam era veterans. A subsample of 146 men was interviewed twice by telephone using the same structured interview an average of 15 months apart to evaluate the long‐term reliability of alcoholism symptoms and diagnoses. In addition, a search of Department of Veterans Affairs patient treatment files of inpatient hospitalizations between 1970 and 1993 yielded a subsample of 89 interviewed men with a past discharge diagnosis of alcohol dependence. The test‐retest reliability of alcohol abuse and alcohol dependence diagnoses was good, with kappa coefficients of 0.74 and 0.61, respectively. The reliability of individual alcoholism symptoms was fair to good, with kappas of 0.46 to 0.67. Ninety‐six percent of individuals identified by Department of Veterans Affairs patient treatment files as having an alcohol dependence diagnosis were correctly diagnosed by the telephone interview. The results of the present study provide additional evidence for the long‐term reliability and validity of lifetime alcoholism diagnoses, and suggest that the reliability and validity of telephone interview assessments of alcoholism are as good as that of an in‐person interview. Telephone administration of structured psychiatric interviews appears to be an attractive alternative to in‐person interviewing for gathering information about alcoholism and alcohol‐related problems.
Prediction of Drinking Outcomes for Male Alcoholics after 10 to 14 Years
Authors: Powell Barbara J. , Landon Jennifer F. , Cantrell Peggy J. , Penick Elizabeth C. , Nickel Elizabeth J. , Liskow Barry I. , Coddington Theresa M. , Campbell Jan L. , Dale Tamara M. , Vance Mary D. , Rice Audrey S.
Published: May 2006

This study reports on the long‐term outcomes of 360 men who were hospitalized for alcoholism during 1980 to 1984 and followed at 12 months and again 10 to 14 years later. At the 10/14‐year follow‐up, 96 (26.7%) men were confirmed as deceased; 255 (70.8%) men participated in the assessment/interview battery completed during baseline hospitalization. The battery consisted of psychosocial, alcohol‐related, and psychiatric measures. Two distinct but highly correlated outcome measures were selected: a clinical rating scale and a factor score. Overall, predictors from baseline and 12‐month follow‐up included age at intake hospitalization, alcoholism severity, social stability, drinking days, and antisocial personality disorder. Approximately 37% of the assessed survivors were either totally abstinent or drinking nonabusively throughout the 10/14‐year follow‐up, whereas another 37% continued to drink abusively. Men who abstained or reduced alcohol intake reported better physical health at follow‐up than those who continued to drink. Although our findings did not directly link alcoholism to death, they strongly indicate that chronic alcohol abuse may lead to premature death.
Platelet Monoamine Oxidase Activity in Subgroups of Alcoholics and Controls: Results from the Collaborative Study on the Genetics of Alcoholism
Authors: Anthenelli Robert M. , Tipp Jayson , Li Ting‐Kai , Magnes Les , Schuckit Marc A. , Rice John , Daw Warwick , Nurnberger John I.
Published: May 2006

Objective: Platelet monoamine oxidase (MAO) B activity levels were evaluated to determine whether low platelet MAO activity is a marker for alcoholism, correlates of alcoholism (e.g., cigarette smoking), or a subtype of alcoholism. Methods: Adult women (n= 788) and men (n= 685) participating in the Collaborative Study on the Genetics of Alcoholism study were evaluated with a semistructured interview, and blood samples were obtained for determination of platelet MAO activity using tryptamine (0.1 mM) as substrate. DSM‐III‐R alcohol‐dependent individuals were subgrouped using four currently available methods (e.g., two variations of the type 1/type 2 scheme, primary versus secondary typology, type A/type B dichotomy). Results: In the overall sample, subjects'gender, cigarette smoking status, and the Collaborative Study on the Genetics of Alcoholism site at which their platelets were prepared explained 22% of the variance in platelet MAO activity levels, and multivariate analysis showed that carrying a broad diagnosis of alcohol dependence did not uniquely explain any additional variance in platelet MAO activity levels. Furthermore, within each of the alcoholic subgrouping methods tested, there were no significant differences in platelet MAO activity for type 1 versus type 2, type A versus type B, or primary versus secondary alcoholics. Conclusions: Cigarette smoking and male gender are associated with decreased platelet MAO activity levels. After considering these factors, a diagnosis of alcohol dependence does not predict any additional variance in MAO‐B activity. Phenotypes of alcoholics (e.g., type 1 versus type 2, type A versus type B, primary versus secondary) do not differ in platelet MAO activity. The results suggest that decreased platelet MAO activity is not a trait marker of alcoholism or one of its subtypes; but, rather, is a state marker of cigarette smoking.
Acute Ethanol Effects on Focal Cerebral Ischemia in Fasted Rats
Authors: Zhao Yong‐Jie , Yang Guo‐Yuan , Ben‐Joseph Oded , Ross Brian D. , Chenevert Thomas L. , Domino Edward F.
Published: May 2006

The effects of acute ethanol intoxication were investigated in a rat model of unilateral middle cerebral artery occlusion. Groups of 5 to 8 male Sprague‐Dawley rats were subjected to 4 hr of left middle cerebral artery occlusion. All groups were deprived of food overnight and were pretreated intraperitoneally with 5% dextrose solution (10 ml/kg), 20% ethyl alcohol in 5% dextrose solution (2 g/kg), or 30% ethyl alcohol in a 5% dextrose solution (3 g/kg) 1 hr before middle cerebral artery occlusion. Regional cerebral blood flow during ipsilateral occlusion was ˜9.1 to 10% of baseline in all groups. The mean % brain water content in control, 2 g/kg ethanol‐treated groups, and 3 g/kg ethanol‐treated groups were: in the ischemic core–81.6, 81.2, and 82.4; intermediate zone–80.5, 80.6, and 81.7; and outer zone–79.7, 79.7, and 80.8, respectively. Brain Na+ and K+ content in the three groups was related to water content, but much greater with ethanol pretreatment. The water content of the intermediate zones in the 3 g/kg ethanol‐treated animals was significantly greater than in the control (p < 0.01 and 0.001) and the 2 g/kg ethanol‐treated groups. One‐way analysis of variance indicated a significant dose–effect relationship in which the lower dose of ethanol tended to reduce ischemic core water content, and the larger dose increased ischemic core water, compared with the control. None of the overnight fasted groups had any significant hyperglycemia. The group given 3 g/kg ip ethanol 1 hr before had exacerbated edema formation with a mean whole blood level of ethanol of ˜230 mg/dl. The neurotoxic effects of high concentrations of ethanol were unrelated to any change in plasma glucose concentrations.
Measuring Quantity, Frequency, and Volume of Drinking
Authors: Rehm Jürgen
Published: May 2006

This paper is based on the first sessions of the same name that were held on May 12,1997 at the International Workshop on Consumption Measures and Models for Use in Policy Development, Bethesda, MD. The session chair was Jürgen Rehm; presenters were Susan Bondy, Deborah Dawson, Kaye Fillmore, Thomas Greenfield, Deborah Ha‐sin, Jürgen Rehm, Anders Romelsjö, and John Searles; and discussants were Eckart Kühlhorn and Linda Sobell.
Measuring Drinking Practices: How Far We'e Come and How Far We Need to Go
Authors: Room Robin
Published: May 2006

This paper is based on the panel session that was held on May 14, 1997 at the International Workshop on Consumption Measures and Models for Use in Policy Development and Evaluation, Bethesda, MD. The session chair was Robin Room, and presenters were Klaus Mäkelä and Lorraine Midanik.
Alcohol and Cardiac Arrhythmias
Authors: Rosenqvist Mårten
Published: May 2006

Chronic alcohol overconsumption increases the risk for sudden death presumably due to ventricular arrhythmias. This paper is a review of the mechanisms behind alcohol‐induced arrhythmias and describe the incidence of alcohol‐related ventricular arrhythmias.
Alcohol and Risk of Cancer
Authors: Ringborg Ulrik
Published: May 2006

A large number of cohort and case‐control studies have contributed to increased knowledge regarding alcoholic beverages and risk of malignant diseases. A clear association pointing at a causal relationship has been found for cancer of the oral cavity, pharynx, larynx, esophagus, and liver. A suggestive association has been found for cancer of the large bowel and breast. An association is considered unlikely for cancer of the stomach, pancreas, lung, urinary bladder, prostate, ovary, and for malignant melanoma. Studies have also been conducted regarding endometrial cancer, kidney cancer, leukemia, and lymphoma. No associations have been demonstrated, but the number of studies is too small for conclusions.
Acquisition of a Fixed Ratio Schedule in Adult Male Rats Neonatally Exposed to Ethanol and/or Cocaine
Authors: Segar Tracy M. , Klebaur Jennifer E. , Bardo Michael T. , Barron Susan
Published: May 2006

Acquisition of an operant learning task for sucrose reinforcement was examined in rats after neonatal exposure to ethanol and/or cocaine. Subjects were raised using an artificial rearing procedure from postnatal days 4 to 11 and were intragastrically fed a milk diet containing either ethanol (6 g/kg/day), cocaine (60 mg/kg/day), the combination (6 g/kg/day + 60 mg/kg/day), or an isocaloric control diet. There was also a suckled sham control. Adult male offspring (postnatal day 65 to postnatal day 68) were shaped to lever press for sucrose reinforcement and then began daily 1Bmin sessions of fixed ratio (FR) training. The number of days to acquire an FR 20 was measured. Neonatal exposure to the ethanol/cocaine combination significantly increased the number of days to reach the FR 20. There was also a trend for fewer of these subjects to reach the FR 20, although this difference was not statistically significant. These results suggest that subjects neonatally exposed to the ethanol/cocaine combination have difficulty learning an operant task. This impairment was unique to the ethanol/cocaine combination group and suggests that polydrug exposure during development may have a more adverse outcome than exposure to ethanol or cocaine alone.
Effects of Ethanol on α‐Adrenergic and β‐Adrenergic Agonist‐Stimulated β‐Endorphin Release and cAMP Production in Hypothalamic Cells in Primary Cultures
Authors: De Alok , Boyadjieva Nadka Iv. , Sarkar Dipak K.
Published: May 2006

We have previously shown that low concentrations of ethanol rapidly stimulate β‐endorphin (β‐EP) release from hypothalamic neurons in primary cultures and that chronic exposures to these concentrations of ethanol desensitize β‐EP neurons to ethanol challenges. We have also shown that chronic ethanol desensitizes dibutyryl cAMP‐, adenosine‐, and prostaglandin E1‐stimulated β‐EP release and the cAMP content in hypothalamic neurons. In this study, we determined the effects of ethanol (50 mM) on β‐adrenergic agonist (isoproterenol) or α‐adrenergic agonist (l‐phenylephrine)‐induced β‐EP release and cellular contents of cAMP to identify whether ethanol causes heterologous desensitization of the adenylate cyclase system in this neuronal cell population. Both isoproterenol and l‐phenylephrine increased β‐EP levels in culture media and elevated the cAMP content in cell extracts in a concentration (0.1 and 10 μM)‐dependent fashion between 3 to 6 hr. A 50 mM dose of ethanol increased β‐EP and cAMP levels at 3 hr, but it did not elevate β‐EP and cAMP levels after 48 hr of exposure. Acute exposure (3 hr) of these cells to ethanol moderately enhanced the isoproterenol‐stimulated and l‐phenylephrine‐stimulated levels of media β‐EP and intracellular levels of CAMP. However, chronic exposure (48 hr) to ethanol reduced the magnitude of both α‐ and β‐adrenergic receptor agonist‐stimulated β‐EP release and cAMP production. These results confirm our previous findings that the ethanol action on β‐EP secretion is mediated by the cAMP system and further suggest that chronic ethanol causes heterologous desensitization of the adenylate cyclase system in the β‐EP neuronal cell population.
Clinical Use of Benzodiazepines and Decreased Memory Activation in Anxious Problem Drinkers
Authors: Zack Martin , Toneatto Tony , MacLeod Colin M.
Published: May 2006

Clinical use of benzodiazepines (BZDs) may improve treatment outcome in anxious problem drinkers. Decreased activation of alcohol‐related memories by negative affective cues may partly explain the beneficial effects of BZDs. To explore this possibility, the present study assessed semantic priming of alcohol words by negative affective words in anxious problem drinkers who received their standard dose of BZD and in unmedicated controls. Two groups of nine subjects each were matched on levels of anxiety, alcohol use, and alcohol dependence before performing a lexical decision task. Medicated subjects displayed significantly less activation than did unmedicated subjects on trials containing negative affective primes and alcohol‐related targets, but displayed equivalent activation on control trials with neutral, categorized words. Degree of activation also correlated with a drug's affinity for the BZD receptor. These preliminary results suggest that BZD‐induced amnesia may contribute to the therapeutic effects of these drugs in anxious problem drinkers.
Ethanol Actions on Multiple Ion Channels: Which Are Important?
Authors: Harris R. Adron
Published: May 2006

Background: This review is based on a plenary lecture presented at the 1999 meeting of the Research Society on Alcoholism. It provides an overview of the search for sites of action for ethanol in the brain. Initial studies were directed at interaction of ethanol with membrane lipids, but during the past decade, emphasis has been shifted to protein sites, particularly those on ion channels. Molecular biological techniques have provided the opportunity to study isolated channels in cellular expression systems and also provide the opportunity to manipulate these channels in mutant mice.

Conclusions: There is now compelling evidence that multiple ion channels are affected by ethanol and growing support for the idea that ethanol interacts directly with specific sites on ion channels. The key, and unanswered, question is which of these channels are responsible for alcohol‐induced behaviors such as intoxication, tolerance, dependence, or craving. Mutant mice will likely give (some) answers to these questions during the next decade.
Ethanol‐Altered Liver‐Associated T Cells Mediate Liver Injury in Rats Administered Concanavalin A (Con A) or Lipopolysaccharide (LPS)
Authors: Cao Qi , Batey Robert , Pang Gerald , Clancy Robert
Published: May 2006

Background: Recent work from our laboratory implicates T cells in the pathogenesis of alcoholic liver disease. We have studied the role of liver‐associated T cells in acute hepatitis produced in control rats administered Concanavalin A (Con A) after adoptive transfer of T cells from alcohol‐consuming animals.

Methods: Liver‐associated T cells from ethanol‐consuming rats were transferred via tail vein to nonethanol‐consuming rats. They then received Con A (20 mg/kg body weight) intravenously. This produced a severe hepatitis. Serum was collected for the assay of alanine aminotransferase (ALT) and cytokines.

Results: Hepatic necrosis was accompanied by an increase in plasma levels of ALT, interleukin‐6, and tumor necrosis factor‐α. These increases correlated with increased production of interleukin‐6 and tumor necrosis factor‐α in culture of liver‐associated T cells stimulated or unstimulated with Con A. Immunohistology staining showed increased infiltration of inflammatory cells comprised of neutrophils and mononuclear cells, which included greater numbers of CD4+ T cells in the portal tract areas and around the central vein. Focal and lobular necrosis was seen with inflammatory cells in the necrotic area. Hepatocytes isolated from the liver showed increased apoptosis compared with rats that received liver‐associated T cells from nonethanol‐consuming rats. Injection of endotoxin LPS, in the same model, was associated with less hepatocyte injury indicating a distinct role for T cells as opposed to Kupffer cells in this model of liver disease.

Conclusions: Chronic ethanol consumption induces a lesion in a pool of liver‐associated T cells which can mediate liver injury after polyclonal mitogen activation.
Influence of Fetal Alcohol Exposure on the GABAergic Regulation of Growth Hormone Release in Postnatal Rats
Authors: Blaine Kelly , Gasser Kenneth , Conway Sonya
Published: May 2006

Background: Disruption of the growth hormone (GH) axis by maternal ethanol (ETOH) consumption may contribute to abnormalities in offspring. Interestingly, γ‐aminobutyric acid (GABA) neurotransmission, which is vulnerable to fetal ETOH exposure, also regulates the hypothalamic‐pituitary GH axis. This study examines whether GABAergic control of this axis is disrupted by prenatal ETOH exposure.

Methods: Pregnant dams were fed either rat chow ad libitum or a 36% ETOH diet (by calories), or wcre pair‐fed an isocaloric control diet. Hypothalami and pituitarics from offspring were copcrfused, in vitro, with muscimol, a GABAAagonist, either alone or in combination with bicuculline, a GABAAantagonist. Perfusatcs werc analyzed by radioimmunoassay for GH, somatostatin (SRIF), and GH‐releasing factor (GRF).

Results: Normal development of GABA regulation was evaluated first in control offspring. Sensitivity to muscimol (measured by percent increase in GH above basal levels) occurred at all ages and generally was greater in male compared to female tissue. Furthermore, the efficacy of bicuculline in depressing muscimol‐induced GH secretion increased with age in both sexes. In males, this response correlated with increased SRlF rclease. In females, releasing factor data were highly variable relative to the percent change and are not presented.

Maternal ETOH consumption altered the development of GABAergic regulation of the GH axis in offspring. However, because ETOH induced changes in the response of releasing factors to muscimol appcar to offset each other, a disruption in GH release was not evident. More apparent was the reduced capacity of bicucullinc to reverse muscimol‐induced GH release from male tissue. This ETOH effect was evidcnt at 35‐days of age and was associated with reduced SRIF release. In female tissue, a reduced bicuculline response was also suggested at 35 days of age. After puberty no response was elicited by muscimol in either tissue from pair‐fed or ETOH‐exposed female offspring.

Conclusion

: In summary, fetal ETOH exposure influences the development of GABAergic regulation of the hypothalamic‐pituitary GH axis in an age and gender specific manner. Vulnerability of the male axis is expressed by the reduced capacity of bicucullinc to depress GH rcleasc and altered releasing factor sensitivity to GABAA‐receptor stimulation or inhibition. There is also some suggestion that the female axis is less sensitive to bicuculline during early puberty, and, unlike the male, is insensitive to both muscimol and bicuculline after puberty. The latter, however, may be attributable to stress or nutritional deprivation, rather than to the direct effect of prenatal ETOH.