bluuebunny/crossref_metadata_2025 huggingface dataset:
Strategies for Mapping and Identifying Quantitative Trait Loci Specifying Behavioral Responses to Alcohol
Authors: Buck Kari J.
Published: April 2006

Most responses to alcohol in both humans and animals are heritable, and this genetic sensitivity to ethanol is determined by multiple genes. However, the number of genes, their identities, and just how they determine susceptibility to the actions of alcohol are unknown. Herein, we describe a multistage strategy for mapping quantitative trait loci (QTLs) using recombinant inbred strains and F2 mice. Precise mapping of the chromosome positions of these QTLs should increase our understanding of the genetic causes for individual differences in behavioral sensitivity to alcohol by (1) identifying genomic markers associated with sensitivity to alcohol, (2) allowing the genes specifying behavior to be cloned by position, and (3) elucidating “candidate” genes demonstrating linkage to markers associated with behavioral responses to alcohol. Syntenic conservation between the mouse and human genomes should facilitate the eventual mapping and cloning of human homologs of these QTLs. Ultimately, cloning of these genes may allow the development of gene therapies or other therapeutic interventions for management or prevention of alcoholism and alcohol abuse.
Classical and Neoclassical Approaches to the Genetic Analysis of Alcohol‐Related Phenotypes
Authors: Dudek Bruce C. , Tritto Theresa
Published: April 2006

Theoretical descriptions are given for two breeding methods in animal genetics that might be of use In alcohol research. These methods are marker‐based selection and marker‐based development of congenic strains, both using DNA markers such as polymerase chain reaction‐detectable polymorphisms as the criteria for breeding. Such designs would utilize these markers as Indicators of adjacent Quantitative Trait Loci (QTL) that are influential on alcohol‐related phenotypes. Issues in the logic and implementation of these methods, such as proximity of the markers and the QTL allele, are explored. A third method, development of congenic strains with phenotypic screening, is also described. This method is currently being used to create two sets of congenic lines on a C57BL/6 inbred mouse background. The criterion phenotype is locomotor activation to 1.5 g/kg (ip) ethanol. Data are reported on the success of transferring the activation phenotype from two strains, DBA/2Abg and MOLD/Rk‐Abg, onto the nonactivated C57BL/6Abg background. The value of these methods in alcohol research is outlined with regard to both identification of relevant genes and for their use as tools in basic research on mechanism of alcohol action.
Continuous Exposure of Cultured Rat Cerebellar Macroneurons to Ethanol‐Depressed NMDA and KCl‐Stimulated Elevations of Intracellular Calcium
Authors: Zou J.‐Y. , Cohan C. , Rabin R. A , Pentney R. J.
Published: April 2006

This series of experiments measured ethanol‐induced changes In levels of tree Intracelular calcium. Cerebellar macroneurons, harvested from rat embryos on embryonic day 17, were cultured In the presence of 75 mM ethanol for 24,48, or 96 hr. Intracellular calcium concentrations in control and ethanol‐exposed neurons did not differ after 24 hr, but they were significantly elevated In the neurons exposed to ethanol for 48 or 96 hr. Similarly, Increases In intracellular calcium elicited by stimulation wk 50 μM NMDA were not significantly different In control and ethanol‐exposed neurons after 24 hr. After 48 and 96 hr, however, NMDA‐stimulated Increases in Intracellular calcium levels in control neurons were significantly greater than in the ethanol‐exposed neurons. These results showed that, when calcium levels were elevated by prolonged exposure to ethanol, the neurons were significantly less responsive to NMDA stimulation. Increases in intracelular calcium elicited by stimulation with 30 mM KCI were not significantly different in the control and treated neurons after 24 and 48 hr of ethanol exposure. After 96 hr of exposure to ethanol, however, them was a significant Increase In intracellular calcium levels In control neurons following KCI stimulation, but not in the ethanol‐exposed neurons. The fact that neuronal responses to KCI stimulation were depressed only following 96 hr of exposure to ethanol makes it unlikely that voltage‐regulated channels were the primary mediators of the ethanol‐induced elevations in intracellular calcium in chronically exposed neurons.
NMDA Prevents Alcohol‐Induced Neuronal Cell Death of Cerebellar Granule Cells in Culture
Authors: Pantazis Nicholas J. , Dohrman Douglas P. , Luo Jia , Thomas Jennifer D. , Goodlett Charles R. , West James R.
Published: April 2006

Neuronal cell loss is one of the most debilitating effects of alcohol exposure during development of the nervous system. In this study, primary cultures of neuronal cells (cerebellar granule cells) were wed to examine mechanisms of alcohol‐induced neuronal cell death. Previously, we established that (Pantazis et al., Alcohol Clin Exp Re8 17:1014–1021,1993): (1) alcohol exposure caused neuronal cell death in cultures of cerebellar granule cells and this cell loss was both time‐dependent and dose‐dependent; and (2) the vulnerability of cerebellar granule cells to alcohol‐induced loss changed with the length of time the cells were in culture before Initiating alcohol exposure—that is, younger cultures (1 day in vitro) were much more susceptible to alcohol‐induced neuronal cell death than older cultures (4 or 7 days in vitro). The primary goal of the present study was to examine the potential role of the NMDA receptor in alcohol‐induced death of cerebellar granule cells in culture. Experiments were performed to test the hypothesis that the alcohol‐induced death of cerebellar granule cells can be prevented or reduced by NMDA treatment Our results Indicate that stimulation of the NMDA receptor has a neuroprotective effect and can significantly reduce the alcohol‐induced neuronal cell death of newly established cerebellar granule cell cultures. This neuroprotective effect of NMDA is blocked by 2‐amlno‐5‐phosphonovalerate, a come inhibitor of the NMDA receptor, Confirming that this neuroprotective effect is mediated via the NMDA receptor. This is the first report that alcohol's neurotoxic effect can be ameliorated by activation of the NMDA receptor.
Structural Reorganization in the Supraoptic Nucleus of Withdrawn Rats following Long‐Term Alcohol Consumption
Authors: Sousa N. , Madeira M. D. , Ruela C. , Paula‐Barbosa M. M.
Published: April 2006

We have recently shown in the supraoptic nucleus (SON) of the rat that prolonged ethanol consumption induces cell degeneration and enlargement of the surviving neurons and of their subcellular organelles. We analyzed the SON of withdrawn rats to evaluate whether it displays any evidence of morphological reorganization following abstinence from ethanol, inasmuch as in this condition the ethanol‐Induced changes in the plasma levels of neurohormones and plasma osmolality are no longer detectable. A group of 18 month‐old withdrawn rats was compared with age‐matched, pair‐fed control and ethanol‐treated rats. To differentiate between the effects of withdrawal and the effects of rehydration, a group of 18‐month‐old rehydrated rats was also included in this study and compared with age‐matched, pair‐fed control and dehydrated rats. We estimated the volume of SON, and the total number and mean volume of its neurons. The cross‐sectional areas of the vasopressinergic and oxytocinergic populations were also evaluated. At the ultra‐structural level, we determined the volumes and surface areas of the rough endoplasmic reticulum and Golgi apparatus, and the volumes of neurosecretory granules and nucleoli. In withdrawn animals, the total number of SON neurons was smaller than in controls, although the neuronal volume was greater. The number of SON neurons did not differ between withdrawn and ethanol‐treated rats, despite the reduced volume of SON the former animals. The decrease of SON volume correlated with and was caused by a reduction in the volume of SON neurons and in the size of the organelles involved in neuro‐hormone synthesis. Thus, withdrawal from ethanol stops the ethanol‐Induced neuronal degeneration of the SON and partially reverses the ethanol‐induced enlargement of SON neurons and their organelles. We suggest that the larger volume of SON neurons in with dawn animals relative to controls represents a compensatory mechanism, triggered by the reduced number of neurons, to allow the maintenance of adequate levels of circulating neurohormones.
Possible Role of Striatal Adenosine in the Modulation of Acute Ethanol‐Induced Motor Incoordination in Rats
Authors: Meng Zhi‐Hong , Dar M. Saeed
Published: April 2006

Several reports from our laboratory have suggested the involvement of the brain adenosinergic system in ethanol‐induced motor incoordination (EIMI). This study is an extension of the previous work and pertains to the evaluation of the role of the striatal adenosine in EIMI in male Sprague‐Dawley rats. Using the motor incoordination induced by 1.5 g/kg of ethanol (ip) as a test response, the possible behavioral interactions between ethanol and adenosine agonists and antagonists in the striatum were investigated. Intrastriatal (IST) administration of adenosine A1‐, A1= A2‐, and A2‐selective agonists, R(‐)N6‐(2‐phenylisopropyl)adenosine (R‐PIA), 5′‐N‐ethylcarbox‐amido‐adenosine (NECA), and 5′‐(N‐cyclopropyl)‐carboxamidoad‐enosine, respectively, significantly and dose‐dependently accentuated EIMI when evaluated by rotorod test, suggesting the striatal adenosinergic modulation of EIMI. No significant change in normal motor coordination was noted, even when the highest IST doses of adenosine agonists were followed by saline instead of ethanol, suggesting that the observed behavioral interactions of these drugs were selective to ethanol. Hippocampus, which is known not to be involved in the normal motor functions, was selected as a control brain area because of the presence of high density of adenosine receptors, as well as the high levels of adenosine. Intrahippocampal NECA failed to alter EIMI, indicating the specific role of striatal and not hippocampal adenosinergic system in the modulation of EIMI. The potentiating effects of adenosine agonists N6‐cyclohexyladenosine (CHA) and CGS‐21680 on EIMI were blocked by adenosine A1‐ and A2‐selective antagonists, 8‐cyclopentyl‐1,3‐dipropylxan‐thine and 3,7‐dimethyl‐1‐propargylxanthine, respectively, suggesting the participation of specific adenosine receptors in this functional interaction. A role for the adenosine A1 receptor in the striatal adenosinergic modulation of EIMI was favored based on the rank‐order potency of adenosine agonists. IST pretreatment with pertussis toxin (PT), but not with PT β‐oligomer, nearly completely eliminated the accentuation of EIMI by CHA, further supporting the favored role of adenosine A1 receptors in EIMI. Histological and IST [3H]R‐PIA distribution data confirmed that the observed behavioral effects were caused by exclusive striatal distribution of intrastriatally microinjected drugs. Data obtained suggested modulation of acute EIMI by striatal adenosine receptor‐mediated mechanism(s) and the coupling of these adenosine receptors to the PT‐sensitive G1 protein.
Ethanol as a Possible Cofactor in the Development of Murine AIDS
Authors: Fitzpatrick E. A. , Rhoads C. A. , Espandiari P. , Kaplan A. M. , Cohen D. A.
Published: April 2006

Chronic ethanol (EtOH) abuse in humans leads to a variety of immuno‐modulatory events that can alter resistance to a number of infectious agents. Whether alcohol abuse affects the susceptibility to human immunodeficiency virus infection or the subsequent development of acquired immune deficiency syndrome (AIDS) is a matter of extreme importance; however, available information in humans or animal models is limited. The goal of this study was to evaluate the effect of chronic EtOH feeding in mice on the development of immunodeficiency in the murine model of AIDS (MAIDS). C57BV6 mice were placed on the Lieber‐DeCarli liquid EtOH diet pS% or 31% total caloric intake) or a nutrient‐matched isocaloric Quid control diet. Seven days later, mice were infected with the LP‐BMS murine leukemia virus mixture, and groups of infected and noninfected mice were assayed at defined time points postinfection for antigen‐specific and nonspecific immune responses. In the absence of retroviral infection, chronic EtOH feeding (5–8 weeks) led to reductions in spleen weights, compared with isocaloric controls. In spite of reduced spleen size, mitogenic responses of spleen cells to concanavalin A (ConA) and lipopolysaccharide (LPS) were elevated in EtOH‐fed mice, as compared with mice fed the control diet. Chronic EtOH feeding also enhanced the allogeneic mixed lymphocyte response and increased antigen‐specific priming of both B‐cells and CD4+ T‐cells to the antigen, sheep red blood cells. In MAIDS‐infected mice, chronic EtOH feeding delayed but did not prevent the onset of virus‐induced immunodeficiency and MAIDS‐induced autoantibody synthesis. In contrast to mice with MAIDS infection alone, infected mice fed an EtOH diet displayed significant mitogenic responses to ConA and LPS at 4 weeks postinfection; however, at 8 weeks postinfection, both groups were completely immunosuppressed. Liver damage was detected in all groups of EtOH‐fed mice, as indicated by the elevated liver enzymes, ALT and‘ASR moreover, MAIDS infection did not alter the extent of liver damage caused by EtOH feeding. These data suggest that chronic feeding of the Lieber‐DeCarli EtOH diet in mice can lead to immune enhancement and that under these conditions causes a delay in the onset of MAIDS. Whether these results are caused by the effects of chronic exposure of the immune system to EtOH or to elevated Went levels in the standard Lieber‐DeCarli liquid EtOH diet is discussed.
Changes in Blood Alcohol Levels as a Function of Alcohol Concentration and Repeated Alcohol Exposure in Adult Female Rats: Potential Risk Factors for Alcohol‐Induced Fetal Brain Injury
Authors: Maier Susan E. , Strittmatter Marla A. , Chen Wei‐Jung A. , West James R.
Published: April 2006

Fetal alcohol syndrome and alcohol‐related birth defects are the result of heavy maternal alcohol consumption during gestation. The magnitude of deficit manifested by the offspring is invariably a consequence of several risk factors that may result in high peak blood alcohol concentrations (BACs), such as the duration, timing, or pattern of alcohol consumption. In addition, the alcohol content of the consumed beverage may play a role in determining offspring developmental consequences. Because higher BACs are positively correlated with risk and severity of brain injury early in postnatal lie, initially it was important to determine how BAC is influenced by alcohol concentration and whether that influence is constant over repeated alcohol treatments. Groups of female Sprague‐Dawley rats received daily intragastric intubations of 5 g/kg alcohol in one of several concentrations: 45% (v/v), 30% (v/v), 22.5% (v/v), or 15% (v/v) for a duration of 18 consecutive days. Blood samples were taken at various times postintubation on days 3,8,13, and 18 of treatment, and analyzed by headspace gas chromatography. Multivariate analyses of peak BAC, average BAC, and time to reach peak BAC revealed some noteworthy results. First, peak BAC and average BAC were significantly lower in the 45% group, compared with the other concentration groups, whereas this group also took a longer time to reach peak BAC than the other three groups. Second, peak BAC and averege BAC were higher on the last day of treatment than any of the other treatment days. These results suggest that alcohol concentration and repeated alcohol exposure can influence BAC and, as such, are important risk factors to be considered in the appraisal of alcohol‐induced fetal brain injuries.
Conditioned Taste Aversions Induced by Alcohol and Lithium in Rats Selectively Bred for Ethanol Neurosensitivity
Authors: Kulkosky P. J. , Carr B. A. , Flores R. K. , LaHeist A. F. , Hopkins L. M.
Published: April 2006

Rats that were selectively bred for differences in alcohol‐induced sleep time (alcohol neurosensitivity) were tested for differences in formation and extinction of alcohol‐ and LiCl‐induced conditioned taste aversions. Male rats bred for high, control, or low alcohol sensitivity (HAS, CAS, and LAS rats, respectively) were deprived of water and given daily 30 min access to water for a baseline period of 7 days. Rats were then given a novel 0.125% sodium saccharin solution, followed by an intraperitoneal injection of either saline, 2 g/kg of ethanol (at 10% w/v), or 50.9 mg/kg of LiCl(0.15 M) on 3 conditioning days. Each saccharin exposure was followed by a recovery day of BCCBSS to water. The ethanol‐induced saccharin aversion extinguished more rapidly in LAS rats than in CAS or HAS rats (p < 0.05), but LiCl conditioned equivalent aversions in each group. Also, ethanol injection results in large differences in observed resting behavior in these rats (HAS > CAS > LAS), but LiCl injection produced no reliable group differences in resting. The weaker alcohol‐Induced M e aversion in LAS rats accords with their previously measured higher oral consumption of alcohol (Kulkosky et al., Alcoholism 17: M‐651, 1993) and the idea that alcohol intake is limited by an expectancy of postingestive consequences. The weaker ethanol induced aversion in LAS rats reflects selective breeding of an alcohol‐specific trait and not a general difference In aversive conditioning or chemical neurosensitivity.
Task Persistence after Alcohol Consumption Among Children of Alcoholics
Authors: Baer John S. , Novick Natalie J. , Hummel‐Schluger Andrew O.
Published: April 2006

Two studies examined task persistence after alcohol consumption among young adult offspring of alcoholics [children of alcoholics (COAs)] and young adult offspring of nonalcoholics (NonCOAs). In study I, heavy drinking college seniors (n= 294) participated in a laboratory alcohol challenge in the context of a baseline assessment for a longitudinal study. Subjects completed a computerized administration of the Matching Familiar Figures Test in two halves: the first half sober, and the second half ∼50 min after consuming a 0.8 ml/kg body weight dose of ethanol. COAs demonstrated significantly greater acceleration of response latencies after consumption of alcohol compared with NonCOAs. In study 1, moderate‐to‐heavy drinking volunteers (n= 149) were recruited for a one‐time laboratory alcohol challenge, and completed a circle‐tracing task three times ∼50 min after consuming a 0.8 ml/kg body weight dose of ethanol. COAs displayed significantly less persistence on the second and third circle‐tracing trials compared with NonCOAs. Data are discussed in relation to models of impulsivity and differential alcohol sensitivity among COAs.
Detection of Relapses in Alcohol‐Dependent Patients Using Carbohydrate‐Deficient Transferrin: Improvement with Individualized Reference Levels during Long‐Term Monitoring
Authors: Borg Stefan , Helander Anders , Carlsson Annette Voltaire , Brandt Ann‐Marie Högström
Published: April 2006

The present study examined whether the sensitivity of carbohydrate‐deficient transferrin (CDT) in serum, a biochemical marker of recent excessive alcohol consumption, could be improved during long‐term monitoring by introducing individualized cut‐offs between normal and elevated CDT levels. Alcohol‐dependent male outpatients (n= 22), trying to abstain from alcohol for 6 months, were monitored by comparing weekly measurements of CDT with self‐reports of alcohol consumption three times/week and daily urinary levels of 5‐hydroxytryptophol (5‐HTOL), a new marker of recent alcohol intake. The method used to calculate cut‐offs was based on the intraindividual variation in CDT not dependent on excessive alcohol consumption or analytical variations. An increase in CDT exceeding the minimum level for each patient by 3 and 4 times the mean coefficient of variation for healthy social drinkers (i.e., by 30% and 40%) was compared as an indication of alcohol consumption, even if the value did not exceed the conventional cut‐off. By using individualized CDT cut‐off points, 68 and 41 episodes of drinking were detected in the patients with the cut‐offs of >30% and >40%, respectively, as compared with 25 with the conventional limit. Most episodes could be verified clinically and/or by elevated urinary 5‐HTOL levels during the 2‐week period preceding each serum sampling. The results suggest that the possibility to detect relapses by CDT can be improved during long‐term monitoring of alcohol‐dependent outpatients by introducing individualized cut‐off points between normal and elevated CDT levels.
β‐Carbolines in Chronic Alcoholics Undergoing Elective Tumor Resection
Authors: Spies Claudia D. , Rommelspacher Hans , Schnapper Claus , Muller Christian , Marks Christian , Berger Gerd , Conrad Christian , Blum Susanne , Specht Martin , Hannemann Lutz , Striebel H. Walter , Schaffartzik Walter
Published: April 2006

The prevalence of chronic alcoholism in patients with carcinomas of the upper digestive tract exceeds 60%. The patient's history and laboratory markers, preoperatively, are often not sensitive or specific enough to detect alcohol‐dependent patients, preoperatively, who are at risk of developing alcohol withdrawal syndrome (AWS) during their postoperative intensive care unit (ICU) stay. Previously, it was found that plasma norharman was elevated in chronic alcoholics, suggesting marker characteristics for chronic ethanol misuse and possibly alcohol dependence. We investigated whether β‐carbolines (i.e., harman and norharman) were different between chronic alcoholics and nonalcoholics with carcinoma, and how the levels change in alcohol‐dependent patients during their hospital stay.

Ninety‐seven patients with oral, pharyngeal, laryngeal, or esophageal carcinomas were evaluated regarding their drinking habits. Sixty patients were transferred to the ICU following tumor resection. Chronic alcoholics met the DSM‐III‐R and ICD‐10 criteria for alcohol dependence or chronic alcohol abuse/harmful use. The daily ethanol intake in chronic alcoholics was ≥60 g. Blood samples were collected on admission to the hospital, preoperatively, on admission to the ICU and on days 2, 4, and 7 in the ICU. Harman and norharman were determined by HPLC.

Elevated norharman was found in chronic alcoholics on admission to the hospital, whereas harman did not differ between groups. On admission, the area under the receiver operating characteristics curve was significantly larger for carbohydrate‐deficient transferrin and preoperatively for norharman. The preoperative norharman levels were significantly correlated with the period of mechanical ventilation and the length of ICU stay. Postoperatively, norharman decreased in all patients, except a group of 11 alcohol‐dependent patients who developed AWS during their ICU stay.

The finding that elevated norharman levels were found in chronic alcoholics on admission to the hospital and preoperatively supports the view of a specific marker for alcoholism. Preoperative norharman was superior to carbohydrate‐deficient transferrin and was associated with a prolonged ICU stay and a prolonged period of mechanical ventilation. Further studies are required to determine whether norhaman aids in the preoperative diagnosis of chronic alcohol misuse with respect to the prevention of postoperative complications.
Predictors of Mortality in Alcoholic Men: A 20‐Year Follow‐Up Study
Authors: Lewis Collins E. , Smith Elizabeth , Kercher Carman , Spitznagel Edward
Published: April 2006

This study investigates the predictors of mortality in 158 male alcoholics who were psychiatrically hospitalized between 1907 and 1968 and followed for >20 years. The findings showed that an older age, liver cimhosis, and separation or divorce at intake were all associated with a shorter time to death. These results corroborate those of other follow‐up studies that have identified age, health, and social support as independent correlates of mortality in alcoholics. From a therapeutic standpoint, the most alterable predictor is social support. Thus, the establishment of a salutary social network and social support system should be an integral part of the alcoholic's treatment plan.
EEG Dimension in Sons of Alcoholics
Authors: Ehlers Cindy L. , Havstad James W. , Schuckit Marc A.
Published: April 2006

Recent advances in the field of nonlinear dynamics have provided new conceptual models, as well as novel analytical techniques applicable to studies in alcohol research. One measurement technique, which has been developed in an attempt to characterize nonlinear systems in physics and biology, is the estimation of attractor dimension. This dimension may be seen as a measure of the information required to describe the current behavior of a system. We have applied these techniques to the analysis of EEG collected from 17 men with alcoholic fathers and 19 men with no alcoholic relatives. The men with alcoholic fathers were found to have a lower EEG attractor dimension than their matched controls. This suggests that the EEG of young men with alcoholic fathers may be “more organized” or “less complex” than men with no alcoholic relatives. Although more studies will be needed to explore this hypothesis, these studies suggest that further development of nonlinear approaches to the analysis of brain systems are likely to generate new clinical measures, as well as new ways of viewing brain electrical function and alcoholism. Key Words: EEG, Power Spectral Analysis, Nonlinear Dynamics, Alcohol, Family History of Alcoholism.
Effectiveness of the Alcohol Use Disorders Identification Test in Occupational Health Screenings
Authors: Seppä Kaija , Mäkelä Rauno , Sillanaukee Pekka
Published: April 2006

This study evaluated the effectiveness of the 10‐item Alcohol Use Disorders Identification Test (AUDIT) among occupational health screenings. AUDIT was available from 32 male and 93 female employees, mainly of academic organizations; 22 alcoholic men reporting to treatment at a detoxification clinic served as a reference group. Two other structured questionnaires, the Malmö modified Michigan Alcoholism Screening Test (Mm‐MAST) and the CAGE, were compared with the AUDIT, and comparisons were also made to the self‐reported weekly alcohol consumption. The total score on the AUDIT correlated equally with the self‐reported alcohol consumption, especially when the alcoholics were excluded (r= 0.73, p < 0.001) as the Mm‐MAST (r= 0.58, p < 0.001) and CAGE (r= 0.33, p= 0.005). All three questionnaires were good at detecting male alcoholics: using the cut‐off point of at least 8 positive answers on the AUDIT, 3 on the Mm‐MAST, and 3 on the CAGE. The sensitivities were 100%, 100%, and 91%, respectively. In the AUDIT, however, there was a clearer difference related to the cut‐off level than with the Mm‐MAST and CAGE. With the cut‐off of 8 points, 31% of the male and 11 % of the female employees were classified as suspect heavy drinkers. The AUDIT was significantly more often accurate than the two other questionnaires, especially among female employees in detecting suspect early‐phase heavy drinkers and thus seems to be suitable for health screenings.
Delayed P3A in Abstinent Elderly Male Chronic Alcoholics
Authors: Biggins Christie A. , MacKay Shane , Poole Nancy , Fein George
Published: April 2006

Significant central nervous system toxicity in frontal brain regions has been demonstrated with chronic alcohol consumption both on autopsy and using neuropsychological testing. This study examined the latency of an objective and reproducible brain event‐related potential measure of frontal cortex function in chronic elderly male alcoholics who were abstinent 3 months‐2 years, a patient group in whom the central nervous system effects of chronic alcohol abuse are thought to be largest and most persistent. We examined the latency of the P3A event‐related potential component, which reflects a frontal maximum orienting response to novel stimuli. Twelve elderly abstinent chronic alcoholic males and 11 elderly male controls were studied in an auditory and a visual paradigm, each of which included target, nontarget, and novel rare nontarget conditions. In both modalities, the P3A response to the novel rare nontarget stimuli was significantly delayed in the chronic alcoholics. P3B delays to the target stimuli were also present in the alcoholics, with the P3A and P3B effects being independent of each other. For both P3A and P3B, the effects were larger and more consistent in the visual compared with the auditory modality. Our conclusions are as follows: (1) both P3A and P3B latency delays are evident in elderly abstinent chronic alcoholics; (2) separate mechanisms are responsible for these effects; (3) these effects are more sensitively detected in the visual versus the auditory modality; and (4) delayed P3A latency may be an objective and reproducible index of the frontal cortex effects of chronic alcohol abuse.
Alcohol Consumption and Physical Fitness Among Young Adults
Authors: Braun Barbara L. , Wagenaar Alexander C , Flack John M.
Published: April 2006

The relationship between alcohol consumption and physical fitness was analyzed using data from the baseline examination of the Coronary Artery Disease Risk Development In Young Adults study (CARDIA), a longitudinal study of the evolution of risk factors for cardiovascular disease in Black and White men and women aged 18–30 years. Two parameters of submaximal exercise treadmill testing were evaluated time to heart rate 130 and duration of the treadmill test. In men and women qualified for treadmill testing, time to reach heart rate 130 was positively associated with ethanol intake. The relationship between fitness and ethanol intake persisted in sex‐specific analysis after adjustment for age, ethnicity, systolic blood pressure, sum of subscapular and triceps skinfolds, and physical activity level. The magnitude and strength of the relationship were greater in women than in men. A negative interaction between ethanol intake and smoking status was evident. Linear regression coefficients in men were 0.29 sec to heart rate 130/ml ethanol/day in nonsmokers and −0.06 sec to heart rate 130/ml ethanol/day in smokers. Linear regression coefficients in women were 1.07 sec to heart rate 130/ml ethanol/day in nonsmokers and 0.23 sec to heart rate 130/ml ethanol/day in smokers. Men and women who smoked showed 31 sec longer time to heart rate 130, regardless of ethanol intake. Mean daily ethanol intake was positively associated with duration of treadmill testing in women, but weakly associated with duration in men. These results show increased physical fitness as ethanol intake increased in women and nonsmoking men and mildly decreased physical fitness as ethanol consumption increases among men who smoke. The positive association of physical activity with ethanol intake among nonsmokers combined with downregulation of β‐adrenergic receptors in smokers may partially explain these results. Physical activity levels increase as ethanol consumption increases in nonsmokers, whereas smokers have a constant physical activity level. This alcohol‐fitness relationship may change as physical activity levels decline with age or as the association of ethanol with physical activity changes.
Variability of Ethanol Absorption and Breath Concentrations During a Large‐Scale Alcohol Administration Study
Authors: Friel Patrick N. , Baer John S. , Logan Barry K.
Published: April 2006

Ethanol disposition was evaluated in 77 female and 97 male college seniors during an alcohol challenge study. All were regular drinkers who exceeded legal intoxication levels at least twice a month by history. A standard ethanol dose (females, 0.43 g/kg; males, 0.51 g/kg) was administered over 10 min, after a 4‐hr fast, and breath alcohol concentrations (BrACs) were measured for 2 hr. Intersubject variability in BrACs was greatest early in the study, during ethanol absorption; the coefficient of variation decreased from 39% at 14 min to 14% at 125 min after the start of drinking. The time to peak BrAC varied from 10 to 91 min after the start of drinking (mean 39.6 min). Mean BrACs were significantly lower in females than males; mean peak BrACs were 0.054 g/210 liters in females and 0.058 g/210 liters in males (p= 0.031). The β and r‐values for both genders were higher than those typically used in ethanol dose calculation formulas. Data are discussed to direct future research. The constants used in Widmark's formula need to be revised differentially for males and females in this population to reach specific target BrACs. Furthermore, substantial variability in absorption rates must be accounted for when assessing rising versus falling limb BrAC phenomena.
Reduced Activities of Thiamine‐Dependent Enzymes in Brains of Alcoholics in the Absence of Wernicke's Encephalopathy
Authors: Lavoie Joël , Butterworth Roger F.
Published: April 2006

The relative roles of alcohol per se, thiamine deficiency, and liver disease in the pathogenesis of alcohol‐related brain damage have not been fully elucidated. In particular, the extent to which alterations of brain thiamine metabolism contribute to cognitive dysfunction in alcoholism in the absence of Wernicke's encephalopathy has not been established. In the present study, thiamine diphosphate‐dependent enzymes were measured using standard spectrophotometric techniques in homogenates of brain tissue obtained at autopsy from eight alcoholic patients, all of whom died in hepatic coma without clinical or neuropathological evidence of Wernicke's encephalopathy and six nonalcoholic, age‐matched controls, matched for autopsy delay time and free, at the time of death, from gross malnutrition or other neurological or psychiatric disorders. Transketolase activities were reduced in cerebellum (by 35%, p < 0.01), thalamus (by 35%, p < 0.01), frontal cortex (by 22%, p < 0.01), temporal cortex (by 20%, p < 0.01), and prefrontal cortex (by 19%, p < 0.01). Activities of the pyruvate dehydrogenase complex were selectively reduced in prefrontal cortex by 25% (p < 0.01). Activities of α‐ketoglutarate dehydrogenase were within normal limits in all brain regions of alcoholic patients. The generalized reductions of transketolase activity undoubtedly result from thiamine deficiency. Previous studies suggest that the presence of liver disease may exacerbate thiamine deficiency in alcoholics. A sustained loss of transketolase activity in brain could result in disruption of pentose shunt activity and concomitant reductions in reducing equivalents and lipid metabolism within the cell. The selective loss of pyruvate dehydrogenase activity in prefrontal cortex of alcoholic cirrhotics could relate to the phenomenon of hepatic coma. Pyruvate dehydrogenase is a rate‐limiting enzyme, and loss of activity could result in a cerebral energy deficit. Reductions of thiamine diphosphate‐dependent enzymes could thus be implicated in the pathogenesis of alcoholic brain damage in patients in the absence of overt Wernicke's encephalopathy.
Significant Increase of Blood Alcohol by Cimetidine after Repetitive Drinking of Small Alcohol Doses
Authors: Gupta Anand M. , Baraona Enrique , Lieber Charles S.
Published: April 2006

To assess effects of repetitive alcohol drinking and pre‐existing first‐pass metabolism on the cimetidine induced increase in blood alcohol concentrations, 20 healthy men (aged 20 to 40) of varied ethnicity and consuming less than 60 g alcohol per week underwent baseline quantitation of first‐pass metabolism of alcohol. This was followed by oral administration of 0.6 g/kg ethanol given postprandially in 3 to 4 drinks spread over 135 min, before and after cimetidine (400 mg twice a day for 7 days). Blood alcohol concentrations were determined by breath analysis. First‐pass metabolism was quantified by applying Michaelis‐Menten kinetics to blood alcohol curves after intravenous or oral administration of equal alcohol doses. At baseline, 15 subjects had a substantial first‐pass metabolism (over one sixth of the dose); their alcohol levels increased with repeated doses with a mean peak of 27 ± 3 mg/dl before and 39 ± 5 after cimetidine (P < 0.01), an effect much greater and longer than after a single alcohol dose. Three subjects exceeded 50 mg/dl, the legal limit for driving in several countries. By contrast, in the five subjects with minimal first‐pass metabolism, cimetidine did not increase alcohol levels. Thus, under conditions mimicking social drinking, cimetidine increased blood alcohol to concentrations known to impair psychomotor skills and they persisted at those levels over prolonged periods of time. In a minority of subjects, no such interaction was found, but their first‐pass metabolism at baseline was absent or minimal and thus no inhibition by the drug was to be expected.
Alcohol Inhibits Epidermal Growth Factor‐Stimulated Progesterone Secretion from Human Granulosa Cells
Authors: McKenzie Pamela P. , McClaran Joseph D. , Caudle Michael R. , Fukuda Aisaku , Wimalasena Jay
Published: April 2006

In this study, luteinized human granulosa cells (GC) obtained during in vitro fertilization procedures were used as a model system to evaluate the effects of ethanol (EtOH), a well‐known reproductive toxin, on epidermal growth factor (EGF) and gonadotropin‐stimulated steroidogenesis. Our results demonstrate that the basal progesterone (P4) and estradiol (E2) secretion by human GC in vitro was dependent on the ovarian stimulation protocol. EGF significantly enhanced P4, but not E2, secretion in human GC from clomiphene citrate (CC), human menopausal gonadotropin (hMG), and hMG/gonadotropin‐releasing hormone agonist (GnRH‐a)‐treated patients. The effects of EGF plus luteinizing hormone (LH) were additive in cells from the CC group, but less than additive in hMG and hMG/GnRH‐a groups. EtOH at 20 mM or more inhibited EGF stimulated P4 secretion in human GC from all three patient groups. EtOH inhibited P4 secretion stimulated by EGF and LH cotreatment in the CC and hMG/GnRH‐a groups, but not in human GC from the hMG‐treated patients. These results suggest that basal and EGF or LH‐stimulated P4 secretion by human GC, as well as the effects of EtOH, are profoundly influenced by the follicle's hormonal milieu.
Fetal Alcohol Exposure Alters the Induction of Immediate Early Gene mRNA in the Rat Prefrontal Cortex after an Alternation Task
Authors: Nagahara Alan H. , Handa Robert J.
Published: April 2006

The present study examined fetal alcohol effects (FAE) on the induction of the immediate early genes (IEGs) c‐fos, jun B, c‐jun, and zif268 mRNAs in the prefrontal cortex, hippocampus, and other brain regions after testing in an alternation task. Subjects were female offspring of Sprague‐Dawley rats fed either a 35% ethanol‐derived calorie diet, pair‐fed with sucrose, or control‐fed with laboratory chow during the last week of gestation. At 75–85 days of age, rats were food‐deprived and trained in a t‐maze for food reward. Then rats were tested at 5‐sec, 30‐sec, or 60‐sec delays on each of 6 days. On the day of killing, a subset of rats was tested at the 60‐sec delay for 12 trials and killed 30 min after testing. The remaining animals were killed from their home cage and acted as controls. Expression of the four IEG mRNAs was examined in the brains of these animals using in situ hybridization. FAE rats showed a memory deficit at the 60‐sec delay (p < 0.05), but not at the 0‐sec or 30‐sec delays. Testing in the alternation task induced a significant elevation of c‐fos, c‐jun, jun B, and zif268 mRNA expression in the prefrontal cortex, hippocampal subfields CA1 and CA3, and several cortical areas. However, FAE rats showed a significantly smaller elevation of both c‐fos and jun B mRNA levels in the orbital, prelimbic, and anterior cingulate regions of the prefrontal cortex (p < 0.05). FAE animals also showed a lower expression of jun B mRNA in the caudate nucleus. Significant correlations between the mean performance at the 60‐sec delay and mRNA expression of c‐fos, jun B, and zif268 in the prefrontal cortical regions (p < 0.05) were observed. These findings suggest that fetal alcohol exposure produces changes in the adult prefrontal cortex that may contribute to the behavioral deficit in the alternation task.
Ethanol Inhibits Contractility of Esophageal Smooth Muscle Strips
Authors: Fields Jeremy Z. , Jacyno Mark , Wasyliw Roxana , Winship Daniel , Keshavarzian Ali
Published: April 2006

Acute ethanol (EtOH) in vivo decreases both the pressure of the lower esophageal sphincter (LES) and the amplitude of contractions of the smooth muscle of the lower esophageal body (LEB) in both man and cat. However, the mechanism of this inhibitory effect of EtOH is unclear. This inhibitory effect could be caused by a direct effect of EtOH on the esophagus or be secondary to known inhibitory effects of EtOH on the central nervous system. To this end, we evaluated the in vitro effect of EtOH on contractility of smooth muscle strips from both LES and LEB. Circular muscle strips from LES and LEB were isolated from cats. Changes in resting tension of LES strips and changes in stimulant‐induced tension of LES or LEB strips were measured in the presence of up to five concentrations of EtOH (12.5–100 mM). Stimulants included electric field stimulation (EFS) and carbachol. EtOH at 75 mM significantly decreased resting LES tension. EtOH also decreased maximal contractile responses to carbachol in both LES and LEB and increased the EC50 of carbachol for LES, but not LEB. EtOH also modulated EFS‐induced esophageal contractility; EtOH potentiated EFS‐induced “on‐response relaxation” in LES and decreased EFS‐induced “off‐response contractions” in LEB. EtOH‐induced inhibition of esophageal contractility seemed to be reversible. EtOH did not result in muscle fatigue. Thus, EtOH can directly inhibit contractility of the esophagus, and does so reversibly and at pharmacologically relevant concentrations.
Association between Low Contents of Dopamine and Serotonin in the Nucleus Accumbens and High Alcohol Preference
Authors: McBride W. J. , Bodart B. , Lumeng L. , Li T.‐K.
Published: April 2006

The contents of dopamine (DA), 3,4‐dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), serotonin (5‐HT), and 5‐hydroxy‐indoleacetic acid (5‐HIAA) were determined in the nucleus accumbens (ACB), frontal cortex (FR), anterior striatum (AST), and hippocampus (HIP) of adult male rats from the F2 generation of P×NP intercrosses. Rats were tested for their alcohol preference and were divided into two groups, depending on their alcohol intake. Rats in the high drinking group (n= 11) had ethanol intakes >5 g/kg/day, whereas the low drinking group (n= 15) had values < 1 g/kg/day. The content of DA in the ACB was lower (p < 0.001) in the high alcohol drinking group (46 ± 2 pmol/mg tissue) than in the low intake rats (61 ± 3 pmol/mg tissue). However, the contents of DOPAC and HVA in the ACB were similar for both groups. There were no differences between the two groups in the contents of DA in the FR or AST. The content of 5‐HT in the ACB was lower (p < 0.05) in high alcohol drinking rats (6.3 ± 0.3 pmol/mg tissue) than in the low intake group (7.0 ± 0.2 pmol/mg tissue). The content of 5‐HIAA in the ACB of the high intake rats was also lower than the level for the low drinking rats. There were no differences in the contents of 5‐HT or 5‐HIAA in the FR, HIP, and AST between the two groups. The results confirm a phenotypic association between abnormal DA and 5‐HT systems projecting to the ACB and high alcohol drinking behavior in the P line of rats.
Heart Mitochondria Response to Alcohol Is Different than Brain and Liver
Authors: Marin‐Garcia Jose , Ananthakrishnan Radha , Goldenthal Michael J.
Published: April 2006

Specific mitochondrial enzyme activities, mitochondrial DNA copy number, and mRNA levels were measured in heart, brain, and liver tissues of a group of alcohol‐fed rats and compared with a control group. The results show a significant increase in mitochondrial enzyme activities (citrate synthase, complex IV, complex III, complex I, and complex V), as well as an increase in mitochondrial DNA in the cardiac tissue of the alcohol‐fed animals. These data are indicative of an increase in mitochondrial number in the cardiac tissue that may occur as the result of an adaptive response to the alcoholic insult. However, in the liver and brain of the alcohol‐treated rat, specific mitochondrial activities were decreased, in particular, complex III and ATP synthase, whereas levels of other mitochondrial enzymes (e.g., citrate synthase, specific mitochondrial transcripts, and mitochondrial DNA levels) do not seem to be affected. These data suggest that a tissue‐specific response to alcohol exists that may have a common molecular mechanism in brain and liver, but is different in the heart.
ADH2 Gene Polymorphisms Are Determinants of Alcohol Pharmacokinetics
Authors: Thomasson Holly R. , Beard James D. , Li Ting‐Kai
Published: April 2006

The class I hepatic alcohol dehydrogenases (ADHs) are primarily responsible for ethanol metabolism in humans. Genetic polymorphism at the ADH2 locus results in the inheritance of isozymes of strikingly different catalytic properties. The most common ADH2 allele, ADH2*1, encodes the low Km isozyme subunit β1. The ADH2*3 allele encodes a high‐activity isozyme subunit of alcohol dehydrogenase, β3, identified in ∼25% of African‐Americans. The Vmax of β3β3‐ADH is 30 times greater than that of the β1β1‐ADH. Therefore, we hypothesized that the rate of ethanol metabolism, an important factor in the toxicity of ethanol, in persons with β3‐containing ADH, either β3β3‐ or β1β3‐ADH, would be faster than that of persons with only β1β1‐ADH. We tested this hypothesis with ethanol administered orally to healthy, young African‐Americans. Three hundred and twenty‐six African‐American men and women were genotyped using polymerase chain reaction amplification of their leukocyte DNA followed by hybridization with allele‐specific probes. One hundred twelve volunteers, selected by genotype, received an oral dose of ethanol designed to produce a blood ethanol concentration of 80 mg/dl (0.080 g/dl), when the blood alcohol concentration‐time curve was extrapolated back to time 0. Ethanol metabolic rates (β60s) were determined in the 112 subjects from the slope of the pseudolinear portion of the blood ethanol concentration‐time curves. The mean β60 of African‐Americans having β3‐containing ADH isozymes had significantly faster ethanol elimination rates than those with only β1β1‐ADH isozymes. There were no significant differences in body weight, ethanol intake in the week before testing, peak breath ethanol concentration, time to peak, or volume of distribution between the genotype groups. Within each of these groups, men had lower ethanol disappearance rates than women. These results demonstrate in vivo the kinetic differences of ADH2 isozymes that may influence individual risk for the effects of ethanol.