bluuebunny/crossref_metadata_2025 huggingface dataset:
Selective and Enduring Deficits in Spatial Learning After Limited Neonatal Binge Alcohol Exposure in Male Rats
Authors: Johnson Timothy B. , Goodlett Charles R.
Published: April 2006

Background: In rats, heavy bingelike alcohol exposure during the neonatal brain growth spurt [postnatal days (PD) 4–9] can impair development of spatial learning. This study tested whether binge exposure limited to the latter half of this period (PD 7–9) produced selective spatial learning deficits that endured into adulthood.

Methods: On PD 7 to 9, Long‐Evans rats were given intubations of alcohol (5.25 g/kg/day), sham intubations, or no intubations. Rats were tested as adults (≥PD 70) in the Morris water maze under one of three different conditions: place (submerged escape platform in the same location each trial), random (submerged platform in a different, random location each trial), or redundant (visible platform that protruded above the water, in the same location for each trial). A 60‐sec probe trial (with no platform present) followed the last acquisition trial.

Results: The mean peak blood alcohol concentration was 401 mg/dl on PD 7. Neonatal alcohol treatment significantly impaired acquisition and reduced place biases on the probe trial in place‐trained males, but not females. Neonatal alcohol treatment had no significant effects on acquisition performance of the random or redundant groups. Redundant training yielded rapid acquisition for all groups. The visible cue overshadowed place cues for all treatment groups, but small place biases were evident in controls. After random training, no group showed place biases.

Conclusions: Heavy alcohol exposure in rats limited to the last half of the neonatal brain growth spurt caused enduring deficits in spatial learning, but only in males. The deficits were specific to place learning in the Morris water maze and emerged only when learning and performance depended on the use of distal place cues.
Chronic Effects of Prepubertal Ethanol Administration on Steroidogenic Acute Regulatory Protein in the Rat Ovary
Authors: Srivastava Vinod K. , Hiney Jill K. , Dearth Robert K. , Les Dees W.
Published: April 2006

Background: A mitochondrial protein, steroidogenic acute regulatory protein (StAR), plays an essential role in steroidogenesis by facilitating delivery of cholesterol across the mitochondrial membrane. Because ethanol (EtOH) causes suppressed estradiol (E2) secretion in prepubertal female rats and rhesus monkeys, we evaluated the effects of chronic EtOH administration on prepubertal ovarian StAR.

Methods: Rats were implanted with a gastric cannula on day 24 and began receiving control or EtOH diets on day 28. At 0800 hr on day 33, the experimental groups were subdivided. Half of the EtOH‐treated animals received a subcutaneous injection of pregnant mare serum gonadotropin (PMSG; 15 IU), and the other half received an injection of saline. The chow‐fed and liquid‐diet control groups were also subdivided, with half receiving the PMSG and the other half receiving saline. Eight hours after the respective injections, the animals were killed, and their ovaries and blood were collected.

Results: The ovaries from EtOH‐treated rats showed decreased basal expression of both the 3.8‐kb (p < 0.05) and 1.7‐kb (p < 0.01) StAR transcripts. PMSG‐stimulated animals not exposed to EtOH showed a more than 2‐fold increase (p < 0.01) in the ovarian levels of both transcripts. Western blot analysis revealed that EtOH exposure decreased (p < 0.001) the basal expression of StAR protein, which paralleled the decrease in basal StAR messenger RNA. PMSG induced an increase (p < 0.001) in the levels of StAR protein, and this effect was blunted (p < 0.01) by EtOH. These changes observed in ovarian StAR protein were paralleled by decreases in serum pregnenolone and E2.

Conclusions: These results demonstrate for the first time that ovarian StAR is a target for the chronic action of EtOH to alter prepubertal steroidogenesis, resulting in suppressed serum E2 secretion during a critical time of development.
Involvement of Acetaldehyde in Alcohol Addiction
Authors: McBride William J. , Li Ting‐Kai , Deitrich Richard A. , Zimatkin Sergey , Smith Brian R. , Rodd‐Henricks Zachary A.
Published: April 2006

This article presents the proceedings of a symposium at the 2001 RSA Meeting in Montreal, Canada. The organizers and chairs were William J. McBride and Ting‐Kai Li. The presentations were (1) Metabolism of ethanol in the brain and the behavioral consequences, by Richard A. Deitrich and Sergey Zimatkin; (2) Catalase production of acetaldehyde as a possible mediator of the psychopharmacological effects of ethanol, by Brian R. Smith; (3) The reinforcing actions of acetaldehyde in the ventral tegmental area, by Zachary A. Rodd‐Henricks; and (4) Salsolinol and alcohol addiction, by William J. McBride.
Molecular Pathology and Clinical Aspects of Alcohol‐Induced Tissue Injury
Authors: Molina Patricia E. , McClain Craig , Valla Dominique , Guidot David , Diehl Anna Mae , Lang Charles H. , Neuman Manuela
Published: April 2006

Proceedings of a symposium at the 2001 RSA Meeting in Montreal, Canada; organized and co‐chaired by Patricia E. Molina and Manuela Neuman. The presentations were (1) Mechanisms of alcohol‐induced cell injury by Craig McClain; (2) Cytokines in alcoholic steatohepatitis and non‐alcoholic steatohepatitis by Manuela Neuman; (3) Combination of alcohol and hepatitis C virus and liver injury by Dominique Valla; (4) Chronic ethanol exposure potentiates lipopolysaccharide liver injury, despite inhibiting Jun N‐Terminal kinase and caspase 3 activation by Anna Mae Diehl; (5) Glutathione homeostasis in alcoholism: Role in alveolar epithelial barrier and lung injury by David M. Guidot; (6) Metabolic and inflammatory contribution of alcohol to trauma‐induced tissue injury by Patricia E. Molina; (7) Growth factor and protein synthesis dysregulation: Role in alcoholic myopathy by Charles H. Lang.
Possible Pleiotropic Effects of Genes Specifying Sedative/Hypnotic Sensitivity to Ethanol on Other Alcohol‐Related Traits
Authors: Owens Jeremy C. , Bennett Beth , Johnson Thomas E.
Published: April 2006

Background Initial sensitivity to ethanol is a predictor of alcohol abuse that has been studied extensively in both human and animal populations. Selection for initial sensitivity to the sedative/hypnotic effects of ethanol resulted in the long‐sleep and short‐sleep lines of mice. Some of the genes selected in these lines could also specify differential responses in other ethanol‐related phenotypes and, perhaps, for other drugs of abuse. We assessed congenic mice carrying a single quantitative trait locus (QTL) from the inbred long‐sleep (ILS) or inbred short‐sleep (ISS) strain on the reciprocal background for a number of ethanol‐ and pentobarbital‐related phenotypes.

Methods Each congenic strain was tested for ethanol elimination rates at 4.1 g/kg, ethanol‐induced ataxia at 2.0 g/kg, ethanol‐induced hypothermia at 4.1 g/kg, and pentobarbital‐induced loss of righting reflex (LORR) at 60 mg/kg. Additionally, the ILS.ISS congenics were tested for low‐dose ethanol‐induced activation (LDA) at five doses ranging from 0.6 to 1.2 g/kg ethanol, and the ISS.ILS congenics were tested for LDA at 1.8 g/kg of ethanol.

Results There was little difference in the ethanol elimination rate between congenics and background strains, although a modest sex effect was found, with the females eliminating ethanol more rapidly than the males. We were unable to replicate previous differences found in LDA for the Lore1 congenic on the ISS background, because none of the congenics differed from controls for LDA. Lore5 congenics showed a differential effect of pentobarbital‐induced LORR in the expected directions. The Lore1 congenics on the ISS background showed more ethanol‐induced ataxia than the ISS controls. Additionally, the hypothermic response seems affected by Lore4 and Lore5 and maybe others.

Conclusions At least two regions carrying a QTL specifying sensitivity to high doses of ethanol cospecify altered sensitivity in other measures of alcohol action. Specifically, these QTLs clearly affect ethanol‐induced hypothermia and pentobarbital‐induced LORR and possibly ethanol‐induced ataxia.
A Three‐Stage Alcohol Clamp Procedure in Human Subjects
Authors: Subramanian Marappa G. , Heil Sarah H. , Kruger Michael L. , Collins Karen L. , Buck Philip O. , Zawacki Tina , Abbey Antonia , Sokol Robert J. , Diamond Michael P.
Published: April 2006

Background Multiple factors can influence blood alcohol levels (BALs) after oral ethanol intake. To minimize the variability in BALs, an alcohol “clamping” method in which alcohol is administered intravenously has been previously reported. We have modified this method and developed a multistage alcohol clamp procedure in humans.

Methods Infusion of alcohol to achieve sequentially increasing steady‐state BALs at 50, 100, and 150 mg/dl (e.g., an alcohol clamp procedure) was performed in five subjects. The method used intravenous infusion of 6% alcohol in saline and followed a protocol generated by a physiologically based pharmacokinetic model for alcohol infusion. Real‐time measurement of BALs was used to base decisions for necessary adjustments in the infusion rates on a negative feedback principle to achieve and maintain the desired BALs. Additionally, in three of these subjects, breath alcohol levels were determined simultaneously with BAL measurements.

Results A three‐stage alcohol clamp procedure was used to achieve BALs of 50, 100, and 150 mg/dl. The intra‐assay and interassay variations for measurement of BALs were 1.6 and 2.1%, respectively. The coefficients of variation for the 50, 100, and 150 mg/dl alcohol clamps were 9.8, 5.6, and 4.6%, respectively. The deviation from target BALs for the three clamps were less than 5%. Breath alcohol levels were lower than BALs across all time points, with the mean ratio between the two being 0.84. Correlation analysis showed a very strong correlation between the two alcohol measurement methods (r= 0.96;p < 0.001).

Conclusions A three‐stage alcohol clamp procedure (50, 100, and 150 mg/dl) has been developed by following a protocol generated with a physiologically based pharmacokinetic model for alcohol infusion in human subjects. This is a suitable procedure to examine the responses on cognitive measures and physiologic parameters under steady states of desired BALs.
Saccadic Eye Movements Are Associated With a Family History of Alcoholism at Baseline and After Exposure to Alcohol
Authors: Blekher Tanya , Ramchandani Vijay A. , Flury Leah , Foroud Tatiana , Kareken David , Yee Robert D. , Li Ting‐Kai , O'Connor Sean
Published: April 2006

Objective To evaluate the influence of family history of alcoholism (FHA) on the response of saccadic eye movements to alcohol.

Method Saccadic performance was evaluated in 54 healthy adult subjects with a FHA (family history–positive) and 49 controls (family history–negative). Alcohol and placebo sessions were presented in counterbalanced order. Alcohol was administered intravenously to achieve and maintain a target breath alcohol concentration of 60 mg/100 ml (60%) for 160 min in each subject. During each session, saccadic eye movement testing was performed at baseline (before infusion of alcohol) and twice during the steady‐state target breath alcohol concentration. The saccadic testing elicited visually guided saccades (VGS) and antisaccades (AS). Saccadic latency and velocity and the percentage of AS errors were quantified and analyzed using multivariate analysis of variance.

Results The family history–positive and family history–negative groups showed an overall difference at baseline in AS and VGS latencies and velocities in the alcohol and placebo sessions (p= 0.006). Alcohol delayed saccades such that AS and VGS latencies increased (p= 0.0001) and slowed the execution of saccades such that peak velocities decreased (p= 0.0002). The percentage of AS errors decreased after alcohol administration, but no significant effect of alcohol (alcohol versus placebo session) was observed (p= 0.1). Latency of AS saccades demonstrated a significant overall FHA effect (p= 0.02) and a significant interaction between FHA and response to alcohol over time (p= 0.02).

Conclusions Differences in operational characteristics of the saccadic control system are associated with FHA in adult social drinkers, both at baseline and when the brain is exposed to ethanol at 60 mg/100 ml.
Prenatal Alcohol Exposure Predicts Continued Deficits in Offspring Size at 14 Years of Age
Authors: Day N. L. , Leech S. L. , Richardson G. A. , Cornelius M. D. , Robles N. , Larkby C.
Published: April 2006

Background Growth deficits are among the cardinal features for the diagnosis of fetal alcohol syndrome. Growth deficits have also been noted among those who were exposed to alcohol prenatally but who do not have fetal alcohol syndrome. Few studies have observed subjects past early and middle childhood, however, to evaluate the longer‐term effects of prenatal alcohol exposure on growth in adolescence. This is a report of the effects of alcohol exposure during gestation on the size of the offspring at 14 years of age.

Methods Women were recruited in their fourth prenatal month. These women were interviewed in the fourth and seventh months of pregnancy and at delivery. The women and their children were seen when the offspring were 14 years of age.

Results Growth deficits associated with prenatal alcohol exposure were identified among the offspring at 14 years of age. Weight, height, head circumference, and skinfold thickness continued to be significantly affected by prenatal alcohol exposure after controlling for other significant predictors of size. These effects exhibited a dose‐response pattern, and significant effects were found at levels below one drink per day. For example, first trimester alcohol exposure predicted weights of 152 lbs for the offspring of abstainers, 149 lbs for the offspring of light drinkers (>0 and <0.2 drinks per day), 143 lbs for the offspring of moderate drinkers (>0.2 and <0.89 drinks per day), and 136 lbs for the offspring of heavy drinkers (>0.89 drinks per day).

Conclusions Prenatal alcohol exposure continues to affect size at age 14 years in this cohort of children followed since their fourth month of gestation.
Genetic Dissection of Quantitative Trait Loci Specifying Sedative/Hypnotic Sensitivity to Ethanol: Mapping With Interval‐Specific Congenic Recombinant Lines
Authors: Bennett Beth , Beeson Mary , Gordon Lena , Carosone‐Link Phyllis , Johnson Thomas E.
Published: April 2006

Background Linkage studies alone do not produce sufficient resolution to narrow the location of a quantitative trait locus (QTL) to a small‐enough chromosomal region for gene identification. One solution to this problem is to use interval‐specific congenic recombinant (ISCR) lines to narrow the chromosomal interval known to contain the QTL. In previous work, we mapped four QTLs for differential ethanol sensitivity in the inbred long‐sleep (ILS) and inbred short‐sleep (ISS) strains and generated reciprocal congenic strains in which each full QTL interval from ILS was bred onto the ISS background and vice versa.

Methods ISCR lines were derived by identifying mice carrying recombination events in the congenic interval during backcrossing of the ISS.ILS. Lore congenics to ISS. Recombinant mice were backcrossed to ISS, and progeny carrying the ISCR chromosome were identified and tested to determine whether the ISCR region carried the donor Lore QTL.

Results We developed multiple ISCR lines for each Lore QTL, in which the QTL interval was broken into a number of smaller intervals. For all four QTLs, we reduced the size of the interval, in one case to 3.7 cM.

Conclusions Use of ISCR lines can narrow each Lore candidate region to a few centimorgans. Such an interval size is conducive to brute‐force approaches to identify candidate genes, entailing bioinformatics, gene expression, and DNA sequencing strategies.
Effects of Ethanol Exposure on Subsequent Acquisition and Extinction of Ethanol Self‐Administration and Expression of Alcohol‐Seeking Behavior in Adult Alcohol‐Preferring (P) Rats: I. Periadolescent Exposure
Authors: Rodd‐Henricks Zachary A. , Bell Richard L. , Kuc Kelly A. , Murphy James M. , McBride William J. , Lumeng Lawrence , Li Ting‐Kai
Published: April 2006

Background The current study examined the effects of ethanol (EtOH) drinking during periadolescence on the subsequent acquisition and extinction of operant self‐administration of EtOH and expression of alcohol‐seeking behavior in adult alcohol‐preferring (P) rats to test the hypothesis that alcohol drinking during periadolescence produces enduring alterations that enhance the reinforcing properties of EtOH.

Methods Periadolescent female P rats were given 24 hr free‐choice access to 15% (v/v) EtOH starting at postnatal day (PND) 30 and ending on PND 60 or were similarly housed and received water only. On PND 75, without any prior training, periadolescent alcohol‐drinking and periadolescent alcohol‐naïve rats were placed in standard two‐lever (15% EtOH and water) chambers to examine acquisition of EtOH self‐administration with a fixed ratio (FR) 1 schedule of reinforcement. After the acquisition phase and after stable responding was established on an FR5 for EtOH and FR1 for water, P rats underwent extinction training for both EtOH and water rewards. After extinction training and a 2 week home cage period, rats were returned to the operant chambers in the absence of reward for seven consecutive sessions (Pavlovian spontaneous recovery). After this testing period, animals were maintained in their home cage for a week before being returned to the operant chambers and allowed to respond for EtOH and water (reacquisition).

Results Compared with periadolescent alcohol‐naïve rats, periadolescent alcohol‐drinking rats acquired EtOH responding sooner (i.e., in the first acquisition session), displayed a greater resistance to extinguish EtOH responding (i.e., higher levels of responding in sessions 4–6), had higher responding for more sessions on the EtOH lever in the absence of reward after a prolonged home cage rest period, and had a more prolonged elevated level of EtOH responding during reacquisition (four sessions versus one session).

Conclusions Overall, the results suggest that periadolescent EtOH drinking by P rats produced long‐lasting alterations in the reinforcing effects of alcohol, which increased the likelihood that alcohol drinking would be initiated in adulthood, decreased the likelihood that once adult alcohol drinking began it could be extinguished easily, and increased the potential for relapse.
Ethanol‐ and Sucrose‐Reinforced Appetitive and Consummatory Responding in HAD1, HAD2, and P Rats
Authors: Czachowski Cristine L. , Samson Herman H.
Published: April 2006

Introduction Ethanol‐preferring (P) rats and high‐alcohol‐drinking (HAD1 and HAD2) rats have been selectively bred to consume greater amounts of ethanol than nonselected rat strains. These three rat lines also show increased levels of responding for ethanol in operant paradigms that assess a combined appetitive/consummatory response.

Methods The present experiment used a model of reinforced responding that procedurally separates the appetitive, or seeking, response requirement from consummatory responding to compare seeking and intake responding in P and HAD rats. Subjects (n= 7 or 8 per group) were trained to make 25 lever‐press responses, which were followed by 20 min of access to a sipper tube spout containing either 10% ethanol (10E) or (in separate groups of subjects) 3% sucrose (3S). After training, a single nonreinforced session was conducted to assess the limit to appetitive responding under extinction conditions. After this single nonreinforced session, three successive across‐session breakpoint determinations were made for 10E and 3S by increasing the response requirement over days until subjects failed to complete the requirement. A final extinction session was then conducted.

Results Appetitive responding during both the nonreinforced and breakpoint sessions indicated that P rats made significantly more responses overall than HAD rats in both the ethanol and sucrose groups. P rats also consumed more sucrose than HAD rats, with no differences in ethanol consumption between the lines (1.0–1.5 g/kg/20 min). Appetitive responding in the HAD rats in the ethanol groups was comparable to that reported previously for nonselected Long‐Evans rats.

Conclusions These findings indicate that appetitive and consummatory processes are distinct and that P rats have an increased tendency to both seek and drink ethanol and sucrose solutions, making this selected line useful when modeling both “craving” and “loss of control” related behaviors involved in excessive alcohol consumption.
Alcohol Suppresses Insulin‐Like Growth Factor‐1 Gene Expression in Prepubertal Transgenic Female Mice Overexpressing the Bovine Growth Hormone Gene
Authors: Srivastava Vinod K. , Dearth Robert K. , Hiney Jill K. , Chandrashekar Varadaraj , Mattison Julie A. , Bartke Andrzej , Dees W. Les
Published: April 2006

Background Alcohol (ALC) delays puberty in female rats and alters the development of a normal menstrual pattern in rhesus monkeys. These actions are associated with depressed serum levels of growth hormone (GH), luteinizing hormone and insulin‐like growth factor‐1 (IGF‐1). The mechanism of this ALC‐induced depression in IGF‐1 is not known, however, could be due to depressed GH and, possibly, to an alteration in the hepatic GH receptor. To assess whether ALC has a direct action at the liver, we used a transgenic mouse model that overexpresses GH, allowing assessment of potential direct actions of ALC on the level of either the GH receptor or the IGF‐1–synthesizing machinery within the hepatocyte.

Methods One group of transgenic mice was fed a liquid diet containing ALC. The second group was pair‐fed the companion isocaloric control liquid diet. The third group of transgenic mice was fed Lab Chow and water. The fourth group consisted of normal (nontransgenic) littermates fed Lab Chow and water. Animals received their respective diets for 5 days. Mice were killed during their late juvenile stage of development, and tissues and blood collected and frozen.

Results The ALC‐fed transgenic mice showed a decrease (p < 0.01) in hepatic IGF‐1a and IGF‐1b messenger RNA levels compared with transgenic controls, and this paralleled a decrease (p < 0.01) in serum IGF‐1. ALC did not alter the circulating levels of bovine GH held constant by the promotor and did not alter mouse GH receptor protein levels as analyzed by Western blotting.

Conclusions Using this transgenic animal model that maintains circulating GH in the presence of ALC, we found that the ability of ALC to suppress prepubertal Igf1 gene expression can also occur independently of any alterations in the level of circulating GH. This direct effect on the hepatocyte is a postreceptor event because the GH receptor protein levels were not altered by ALC exposure.
β‐Endorphin Modulation of Lymphocyte Proliferation: Effects of Ethanol
Authors: Boyadjieva Nadka I. , Dokur Madhavi , Advis Juan P. , Meadows Gary G. , Sarkar Dipak K.
Published: April 2006

Background We have previously shown that alcohol suppresses the natural killer (NK) cell activity of splenic lymphocytes partly by reducing the secretion of opioid peptide β‐endorphin (β‐EP) and its positive influence on NK‐cell cytolytic activity in rats. The inhibition of NK‐cell cytolytic activity was also associated with a reduced number of NK cells after chronic ethanol administration. Hence, the possibility arises that chronic ethanol may alter NK cell proliferation, survival, or both. In this study, we investigated whether ethanol treatment for 1 to 4 weeks reduces the proliferation of other lymphocyte subsets and whether β‐EP regulates ethanol's effect on lymphocyte proliferation.

Methods Male rats were ad libitum–fed rat chow, pair‐fed with isocaloric liquid diet, or fed with ethanol‐containing liquid diet for 1, 2, 3, or 4 weeks. Groups of these rats were infused with β‐EP with or without the δ‐receptor antagonist naltrindol into the paraventricular nucleus of the hypothalamus. Splenocytes were isolated and used for flow cytometric analysis of the changes in the number of various lymphocyte subsets. Lymphocyte proliferation was determined by mitogen stimulation assays.

Results Ethanol consumption resulted in a reduction of the number of CD161+ NK cells, CD3+ T lymphocytes, CD4+ T‐helper cells, and CD8a+ cytotoxic T cells in a time‐dependent fashion. Alcohol consumption also suppressed the proliferative response of lymphocyte subsets to concanavalin A, phytohemagglutinin, and lipopolysaccharide. β‐EP promoted the lymphocytes’ proliferative response to mitogens, whereas naltrindol blocked the effects of the opioid. Chronic alcohol consumption reduced the proliferative response of lymphocytes to β‐EP.

Conclusions These results suggest that chronic alcohol administration reduces immune function partly by decreasing the opioid‐regulated mitogen‐stimulated proliferation of lymphocyte subsets.
A Proline‐Threonine Substitution in Codon 351 of ADH1C Is Common in Native Americans
Authors: Osier Michael V. , Pakstis Andrew J. , Goldman David , Edenberg Howard J. , Kidd Judith R. , Kidd Kenneth K.
Published: April 2006

Background The alcohol dehydrogenase (ADH) genes have been repeatedly associated with protection against alcoholism. Until now, only four protein coding variants have been identified (ADH1C Arg271Gln, Ile349Val, ADH1B Arg47His, and Arg369Cys), and only two of these (ADH1C Ile349Val and ADH1B Arg47His) have been routinely tested in association studies with alcoholism.

Methods The new ADH1C*351Thr allele was identified by direct sequencing of DNA samples that gave different typing results for the ADH1C Ile349Val polymorphism with different typing protocols.

Results A new coding variant has been identified at codon 351 of ADH1C. This allele is found in most Native American populations that we have studied with allele frequencies of the new ADH1C*351Thr allele as high as 26%. Only two instances of this allele have been seen in a large survey of African and Eurasian populations.

Conclusions The changes in charge, size, and rotational mobility caused by this amino acid substitution should be significant. Because this new variant codes for a new enzyme form in Native Americans, the kinetics of this enzyme should be studied and considered in studies of the role of ADH1C in the protection against alcoholism in Native Americans.
Binge Drinking in Jewish and Non‐Jewish White College Students
Authors: Luczak Susan E. , Shea Shoshana H. , Carr Lucinda G. , Li Ting‐Kai , Wall Tamara L.
Published: April 2006

Background In the United States, religious commitment, as measured by service attendance, has an inverse relationship with alcohol consumption, heavy use, and problem use. This association, however, has not been found consistently in Jewish Americans. The present study examined the relationship between religious variables and binge drinking in Jewish and non‐Jewish white college students. In addition, the association among genetic, cultural, and religious variables and binge drinking was examined in the Jewish sample alone.

Methods Participants were 132 Jewish and 147 non‐Jewish white college students. All participants completed the Time‐Line Follow‐Back, had blood drawn for genotyping at the alcohol dehydrogenase locus ADH2, and reported their religious affiliation and the number of religious services attended in the past year. Jewish subjects also completed the Jewish Identity Scale.

Results As hypothesized, more frequent religious service attendance related to lower rates of binge drinking in non‐Jews but was not related to binge drinking in Jews. Within the Jewish sample, individuals who were religiously affiliated had approximately one third the risk of binge drinking as those who were secularly affiliated, but identification with Jewish culture was not related to binge drinking. In the total sample, individuals who possessed a variant alcohol dehydrogenase allele ADH2*2 were approximately half as likely to binge drink as those who did not possess this allele.

Conclusions These results are consistent with previous studies that find an inverse relationship between religious service attendance and heavy alcohol use in Christian but not Jewish college students. Findings within the Jewish sample support theories that suggest religious, not just cultural, Jewish affiliation relates to lower levels of alcohol behavior. More research is needed to identify additional factors, including other religious, cultural, genetic, and biological influences, that protect Jewish Americans from heavy drinking.
Long‐Term Effects of and Physiological Responses to Nitrous Oxide Gas Treatment During Alcohol Withdrawal: A Double‐Blind, Placebo‐Controlled Trial
Authors: Alho Hannu , Methuen Taina , Paloheimo Markku , Strid Nuria , Seppä Kaija , Tiainen Juha , Salaspuro Mikko , Roine Risto
Published: April 2006

Background Nitrous oxide gas (N2O) has been proposed to be effective in the treatment of the alcohol withdrawal syndrome (AWS). This has not been proved, however, in studies performed according to good clinical practice guidelines. Moreover, previous studies have not measured end tidal N2O concentrations or physiologic responses during N2O treatment. We have recently reported that in a double‐blind, randomized, controlled setting, N2O was not superior to placebo in relieving AWS symptoms. In this previous study, we did not find significant differences between the treatments either in the Clinical Institute Withdrawal Assessment of Alcohol scores or in the total use of benzodiazepines (diazepam and temazepam). The aim of the present study was to characterize other effects and side effects of the N2O treatment using several objective measures and to study the possible long‐term efficacy of the treatment.

Methods A total of 105 inpatients who had AWS and were admitted to the A‐Clinic detoxification center were included in the study. The subjects were randomly assigned to one of the following three treatments: (1) N2O/oxygen (from 30 to 70% in oxygen), (2) air/oxygen (30%/70%), and (3) medical (normal) air. During the single 45‐min treatment period, end‐tidal N2O, carbon dioxide, and oxygen concentrations were measured. The physiologic responses were studied by measuring heart rate, blood pressure, pulse oximetric saturation, frontal muscle electromyographic activity, and plethysmographic pulse amplitude. Long‐term effects were studied by measuring craving with the Obsessive‐Compulsive Drinking Scale; severity of dependency with Severity of Alcohol Dependence Data; and liver enzymes with aspartate aminotransferase, alanine aminotransferase, and γ‐glutamyltransferase 3 and 6 months after the treatment.

Results Patients in the N2O group demonstrated significantly higher facial muscle electromyographic activity and higher pulse amplitude than the air‐treated subjects. Self‐reported side effects between the gas treatments, however, did not differ between the groups. Regarding long‐term effects of the treatments, there were no differences between the groups.

Conclusions Contrary to previously published data, N2O treatment did not decrease craving or liver enzymes during the 6‐month follow‐up. At the concentration used, N2O treatment produced signs of arousal instead of strong sedation.
Reciprocal Congenics Defining Individual Quantitative Trait Loci for Sedative/Hypnotic Sensitivity to Ethanol
Authors: Bennett B. , Beeson M. , Gordon L. , Johnson T. E.
Published: April 2006

Background: We have identified four major genes or quantitative trait loci (QTLs) that determine duration of loss of righting reflex (LORR), induced by sedative doses of ethanol:Lore1, Lore2, Lore4, and Lore5. Together these genes explain more than 50% of the phenotypic variance for sensitivity to the sedative/hypnotic effects of ethanol between the Inbred Long Sleep (ILS) and Inbred Short Sleep (ISS) strains of mice. The derivation of these strains is reviewed here.

Methods: Each QTL has been bred onto the opposite background (ILS or ISS) through 10 rounds of backcrossing by using QTL‐marker‐assisted counter selection to produce reciprocal congenic strains. Mice were genotyped for markers that flanked each of the QTLs. Selection for the donor at the desired QTL, and against donor markers at the other four QTLs, allowed rapid fixation of the genetic background. Phenotypic assessment in the ISS‐recipient congenic strains was conducted throughout the backcross.

Results: By the N5 generation, phenotypic assessments failed to detect significant effects in some sublines; these sublines were discarded and positive lines split to create new replicate sublines. In the N10, all sublines retained the phenotypic difference between heterozygotes and ISS homozygotes; however, the expected additive effect was not found in the Lore1 congenics. On the ILS background, each Lore was captured, as shown by the expected differential LORR. Two strains on the ILS background, and one on the ISS, exhibited the differential effect on blood ethanol concentration associated with the donor strain.

Conclusions: Congenic strains represent an important resource for confirmation of previously identified QTLs, for identification and mapping of additional phenotypes, and for exclusion of candidate genes. QTL‐marker‐assisted selection rapidly stabilized the genetic background within four generations (based on phenotypic assessments); however, phenotypic selection during the backcrossing to generate congenic strains did not contribute to the successful capture of the ISS QTLs.
Effect of Gender and Estrous Cycle on the Pharmacokinetics of Ethanol in the Rat Brain
Authors: Robinson Donita L. , Brunner Lane J. , Gonzales Rueben A.
Published: April 2006

Background: Aspects of ethanol pharmacokinetics in the blood, such as elimination, are known to vary by gender in the rat. Ethanol concentrations reaching the brain, which are relevant in affecting behavior, have not been measured rigorously by gender. This study used quantitative microdialysis to measure ethanol pharmacokinetics in the nucleus accumbens after a moderate dose of ethanol, comparing males with females and females across the estrous cycle.

Methods: We administered 1 g/kg ethanol intravenously or intragastrically to male and female rats. We measured ethanol concentrations in the nucleus accumbens by use of microdialysis with in vivo probe calibration and compared them with concentrations in jugular venous blood.

Results: After intravenous delivery, apparent ethanol elimination was approximately 15% faster in females than males from both brain and blood. After intragastric delivery, blood ethanol concentrations peaked faster in females than males by approximately 20 min, suggesting faster absorption or diffusion from the stomach. Likewise, accumbal ethanol concentrations peaked faster in females than males by approximately 25 min, indicating faster distribution to the brain. These pharmacokinetic parameters did not vary across the estrous cycle, nor were they influenced significantly by body water.

Conclusions: This study provides the first quantitative measurement of ethanol concentrations and, thus, pharmacokinetics in the brain of awake rats. If ethanol distribution to the brain varies between genders, as these results suggest, then differences in the pharmacological response to ethanol can be expected, providing a rationale for studying the pharmacodynamics of ethanol in the brain of the self‐administering rat.
Antagonistic Effects of Dopaminergic Signaling and Ethanol on Protein Kinase A–Mediated Phosphorylation of DARPP‐32 and the NR1 Subunit of the NMDA Receptor
Authors: Edwards Scott , Simmons Diana L. , Galindo David G. , Doherty James M. , Scott Anne M. , Hughes Peter D. , Wilcox Richard E.
Published: April 2006

Background: This article extends our initial investigation of the interactions between dopamine and glutamate receptor systems after acute exposure to ethanol. DARPP‐32 (dopamine and cyclic adenosine monophosphate–regulated phosphoprotein of approximate molecular weight 32 kDa) is an important regulator of protein phosphatase‐1 that in turn regulates a large number of effectors, including the NMDA receptor.

Methods: We measured the protein kinase A (PKA)–mediated phosphorylation of DARPP‐32 and the NR1 subunit of the NMDA receptor. Initially, corpus striatum was assayed after intraperitoneal treatment of mice with the D1 agonist SKF82958, the D2 agonist and anticraving drug bromocriptine, or ethanol. In other experiments we blocked D1 receptors with the selective D1 antagonist SCH23390 or blocked D2 receptors with the selective D2 antagonist eticlopride. Finally, we examined combinations of some dopaminergic drugs with and without ethanol.

Results: SKF82958 alone significantly increased PKA‐mediated phosphorylation of both DARPP‐32 and NR1. Bromocriptine alone had no effect on pDARPP‐32 or on pNR1. However, when D1 receptors were blocked, bromocriptine reduced the PKA‐mediated phosphorylation of both DARPP‐32 and NR1. Coincident treatment with bromocriptine and ethanol reversed both of these effects with D1 receptors blocked. The combination of eticlopride (D2 blocker) and SF82958 (D1 agonist) did not significantly alter either pDARPP‐32 or pNR1.

Conclusions: These data demonstrate antagonistic effects of acute ethanol exposure on D1 signaling in vivo and the potential of acute in vivo challenge protocols to help fill gaps in the understanding of ethanol's effects on protein phosphorylation.
Automating Standard Alcohol Use Assessment Instruments Via Interactive Voice Response Technology
Authors: Mundt James C. , Bohn Michael J. , King Monica , Hartley Michael T.
Published: April 2006

Background: Interactive voice response (IVR) technology integrates touch‐tone telephones with computer‐automated data processing. IVR offers a convenient, efficient method for remote collection of self‐report data.

Methods: Twenty‐six subjects recruited from an outpatient alcohol treatment center completed IVR and paper/pencil versions of a demographic and drinking history questionnaire, Stages of Change Readiness and Treatment Eagerness Scale, Drinker Inventory of Consequences, Obsessive‐Compulsive Drinking Scale, Alcohol Dependence Scale, and two numerical rating scales of craving and desire to drink during the prior week. Administration of the instruments in both formats was repeated 1 week later. The order of administration method was counterbalanced between subjects and reversed across data collection sessions. Scale and subscale scores from both methods were correlated within sessions. Test‐retest correlations were also calculated for each method. A criterion of α= 0.01 was used to control type I statistical error.

Results: Intermethod correlations within each session were significant for all of the instruments administered. Test‐retest correlations for both methods were also significant, except for the numerical ratings. Scores on the Alcohol Dependence Scale obtained via IVR were significantly lower than those collected by paper/pencil. Other differences between the data collection methods or across the sessions were inconsistent. The average IVR call length was 34 min and 23 sec. Paper/pencil forms required an average of 18 min and 38 sec to complete and an additional 10 min and 17 sec for data entry.

Conclusions: IVR technology provides a convenient alternative to collecting self‐report measures of treatment outcomes. Both paper/pencil and IVR assessments provide highly convergent data and demonstrate good test‐retest reliability. Alcohol Dependence Scale score differences between methods highlight special considerations for IVR adaptation of existing paper/pencil instruments. Benefits of IVR include procedural standardization, automatic data scoring, direct electronic storage, and remote accessibility from multiple locations.
Response of Saccadic Eye Movements to Alcohol in African American and Non‐Hispanic White College Students
Authors: Blekher T. , Beard J. D. , O'Connor S. , Orr W. E. , Ramchandani V. A. , Miller K. , Yee R. D. , Li T‐K.
Published: April 2006

Background: The primary goal of this study was to evaluate how race and sex interact with the effects of a moderate dose of alcohol on different ocular control subsystems in African American (AA) and non‐Hispanic white American (WA) college students.

Methods: Horizontal visually guided (VG) saccades and antisaccades (AS) of 80 young adult, healthy, AA and WA college students were recorded with an infrared system. Subjects ingested 10 aliquots of ethanol at 3 min intervals, with the aggregate dose precalculated to yield a peak breath alcohol concentration (BrAC) of 80 mg%. Data from the measures performed at baseline and the ascending and descending limbs of the BrAC at ∼65 mg% were compared across race and sex by multivariate analysis of variance. A no‐alcohol control session, performed in 20 of the subjects, documented test‐retest reliability of the VG and AS measurements.

Results: Both AA and WA groups demonstrated slowing of AS and VG saccades after alcohol administration, but there was no significant effect of 65 mg% alcohol on VG accuracy or AS errors. AS latency recovered toward baseline values, whereas the slowing of VG latency/velocity progressed, during alcohol exposure. There were significant differences between AA and WA groups in the time course of VG latency after alcohol but not in most other dependent measures. No significant effects for sex were observed in any of the saccade measures. The faster disappearance of alcohol in WA compared with AA was replicated, and some measures demonstrated a significant, albeit small, negative correlation between the alcohol disappearance rate and impairing effects of alcohol on saccades.

Conclusions: Prolonged latencies and unchanged percentage of errors reflect a differential effect of alcohol on neural function in specific areas (parietal eye field, superior colliculus, and frontal eye areas). Race may interact with the effect of ethanol on saccadic eye movements in a college student population.
Ethanol, Acetaldehyde, Acetate, and Lactate Levels After Alcohol Intake in White Men and Women: Effect of 4‐Methylpyrazole
Authors: Sarkola Taisto , Iles Matthew R. , Kohlenberg‐Mueller Kathrin , Eriksson C. J. Peter
Published: April 2006

Background: 4‐Methylpyrazole (4‐MP), a selective inhibitor of alcohol dehydrogenase (ADH), recently has been approved for clinical use in humans. The objective was to evaluate the use of 4‐MP in human alcohol research and to study the effect of 4‐MP on various parameters of alcohol metabolism during alcohol intoxication.

Methods: 4‐MP (10–15 mg/kg orally) or placebo was given in double‐blind fashion to 22 premenopausal women, 12 of whom were using oral contraceptives, and 13 men followed by intake of alcohol (0.5 g/kg orally) or placebo.

Results: A 30% to 40% decrease in the ethanol elimination rate was observed in the different groups during pretreatment with 4‐MP. The alcohol‐induced increase in plasma acetate was partially inhibited by 4‐MP. A significant positive correlation was observed between the effect of 4‐MP on the alcohol‐induced lactate and acetate elevations. The acetaldehyde was nondetectable (<1 μmol/liter) in the peripheral venous blood during alcohol intoxication in both women and men. During alcohol intoxication, a decrease in breath acetaldehyde was found with 4‐MP pretreatment in women but not in men.

Conclusion: The alcohol‐induced elevation in blood acetate level is caused, in part, by ADH‐mediated ethanol oxidation. Although no evidence was found for measurable acetaldehyde levels in the peripheral venous blood during alcohol intoxication, the effect of 4‐MP on breath acetaldehyde in women supports the view that ADH‐mediated acetaldehyde elevations reflected in the airways, but too low to be detected in the peripheral venous blood, may occur in women during alcohol intoxication in the present experimental conditions.
The Alcohol Use Disorders Identification Test (AUDIT): A Review of Recent Research
Authors: Reinert Duane F. , Allen John P.
Published: April 2006

Background: Efficient, inexpensive screening for early stage alcohol problems is important in health care settings. The Alcohol Use Disorders Identification Test (AUDIT) has been studied extensively to establish its value in this regard.

Methods: A literature search that used EtOH as a database was conducted to identify studies published on the AUDIT through September 2001. Keywords used for the search were “Alcohol Use Disorders Identification Test” and “AUDIT.” All studies reporting psychometric properties of the measure were reviewed with particular attention being given to the period 1996 and later. A small number of additional references were located by noting their citation in other studies reviewed.

Results: Although more research is needed on non‐English versions to establish their psychometric properties, at least in its English edition, the AUDIT demonstrates sensitivities and specificities comparable, and typically superior, to those of other self‐report screening measures. Test‐retest reliability and internal consistency are also quite favorable. For males, the AUDIT‐C, a shortened version of the AUDIT, appears approximately equal in validity to the full scale.

Conclusions: Recent research continues to support use of the AUDIT as a means of screening for alcohol use disorders in health care settings in the United States.
Ethanol Decreases the Efficiency of Phosphorylation of Thymidine Kinase in a Human T‐Lymphocytic Cell Line
Authors: Prakash Om , Tang Zhen‐Ya , Zhou Peng , Peng Xiaochan , Kolls Jay , Shellito Judd E. , Nelson Steve
Published: April 2006

Background: Thymidine kinase (TK) and thymidylate kinase (TMPK) are the two rate‐limiting enzymes in the cascade of activation of the anti‐human immunodeficiency virus (HIV) drug 3′‐azido‐3′‐deoxythymidine (AZT) to its active triphosphate form. We examined the effect of ethanol and a combination of ethanol and AZT on TK and TMPK activities in human Jurkat T cells.

Methods: Jurkat T cells were exposed to 0.2 and 0.5% (v/v) ethanol concentrations alone or in combination with 5 or 10 μM AZT for 48 hr in growth medium. TK and TMPK activities were determined by measuring the conversion of [3H] substrates (thymidine or AZT for TK and thymidine monophosphate for TMPK) to their respective monophosphate or diphosphate forms. The effect of ethanol on the transcriptional activity of TK was determined by reverse transcription–polymerase chain reaction and on the growth of Jurkat cells by [3H]‐thymidine incorporation and cell‐cycle analysis.

Results: Treatment of Jurkat cells with 0.2 and 0.5% ethanol concentrations resulted in 25 and 50% decreases (p≤ 0.05) in TK activity, respectively. No significant changes were observed in the TMPK activities. However, ethanol decreased the formation of thymidine diphosphate from thymidine in coupled TK/TMPK reactions, suggesting that decreases in TK activity could result in an overall decrease in the phosphorylation of AZT. The effect of ethanol on TK was independent of its transcript level. AZT in combination with ethanol decreased the inhibitory effect of ethanol on TK activity. However, it did not block the ethanol effect even at higher concentrations. Ethanol significantly decreased the proliferative capacity and cell cycle progression of the Jurkat cells.

Conclusions: Our in vitro study in human Jurkat T cells indicates that at physiologically achievable concentrations in humans, ethanol can decrease TK activity through decreases in cell proliferation, and it suggests that ethanol ingestion in HIV‐1–infected individuals could compromise activation of AZT and related drugs through decreased TK activity.