bluuebunny/crossref_metadata_2025 huggingface dataset:
Intra‐Amygdala Infusion of the NPY Y1 Receptor Antagonist BIBP 3226 Attenuates Operant Ethanol Self‐Administration
Authors: Schroeder Jason P. , Olive Foster , Koenig Heather , Hodge Clyde W.
Published: December 2003

Background: Neuropeptide Y (NPY) is the most abundant and widely distributed peptide in the mammalian central nervous system. Evidence suggests that NPY transmission at Y1 receptors may regulate alcohol self‐administration in rodent models. The purpose of the present study was to test the involvement of NPY Y1 receptors in the amygdala in the reinforcing effects of alcohol.

Methods: Long‐Evans rats were trained to self‐administer ethanol (10% v/v) vs. water on a concurrent FR‐1 schedule of reinforcement using a sucrose fading procedure. After a 1 month baseline period, bilateral injector cannulae were surgically implanted to terminate 1 mm dorsal to the central nucleus of the amygdala. Daily (Monday through Friday) operant self‐administration sessions were conducted for 6 months after surgery. Then, the effects of intra‐amygdala infusion of the high‐affinity nonpeptide NPY Y1 receptor antagonist BIBP 3226 (1, 10, or 20 μMg) were determined on parameters of operant alcohol self‐administration.

Results: Intra‐amygdala administration of 10 μM or 20 μM BIBP 3226 decreased total alcohol‐reinforced responding and dose of self‐administered ethanol (g/kg) without significantly altering total water responses or intake compared with vehicle control. Response onset was unaffected. Analysis of the temporal pattern of ethanol‐ and water‐reinforced responding showed that BIBP 3226 decreased cumulative ethanol‐reinforced responding during the 30 to 60 min period of the sessions. Water‐reinforced responses were increased by the low dose of BIBP 3226 (1 μM) during the 50 to 60 min period.

Conclusions: Results from this study indicate that alcohol‐reinforced responding is reduced by acute blockade of NPY Y1 receptors in the amygdala of rats with a long‐term history of alcohol self‐administration. These data are consistent with the hypothesis that alcohol self‐administration is maintained by NPY neurotransmission at Y1 receptors in the central nucleus of the amygdala.
Serotonergic Agents and Alcoholism Treatment: A Simulation
Authors: Stoltenberg Scott F.
Published: December 2003

Background: Those with early‐onset alcoholism may better respond to ondansetron (a 5‐HT3 receptor antagonist) than to selective serotonin reuptake inhibitor (SSRI) treatment, whereas those with late‐onset alcoholism may present the reverse response pattern. Johnson and colleagues proposed a model that attempts to explain the observed treatment response patterns of those with early and late alcoholism onset by focusing on the influence of a common genetic variant in the serotonin transporter regulatory region (5‐HTTLPR) on serotonin (5‐HT) and dopamine (DA) system function.

Methods: The present study formalizes and extends Johnson's descriptive model into a computer simulation consisting of differential equations. For each of 16 conditions defined by genotype, drinking status, diagnostic status, and drug treatment, data were generated by 100 simulation runs.

Results: In every condition, the S/_ genotype (S/S and S/L) had higher extracellular 5‐HT levels than did the L/L genotype. The S/_ genotype also had higher rates of postsynaptic DA firing than did the L/L genotype with the exception of the SSRI treatment condition, where the firing rates were similar. Drinking generally increased levels of extracellular 5‐HT, reduced rates of presynaptic 5‐HT firing, and increased rates of postsynaptic DA firing. Drinking produced increases in DA activation that were greater for the L/L genotype in the SSRI treatment condition and for the S/_ genotype in the ondansetron treatment condition.

Conclusions: Genotype at 5‐HTTLPR may influence relative reward of drinking alcohol while a person is under pharmacological treatment for alcoholism. Alternatively, 5‐HTTLPR genotype may influence pathways of alcohol craving. Clinical studies should examine these hypotheses.
Prenatal Ethanol Exposure Modifies [3H]MK‐801 Binding to NMDA Receptors: Spermidine and Ifenprodil
Authors: Honse Yumiko , Randall Patrick K. , Leslie Steven W.
Published: December 2003

Background: It has been suggested that abnormalities seen in fetal alcohol syndrome are linked with NMDA receptor malfunction. Our laboratory has previously shown that prenatal ethanol treatment decreases [3H]MK‐801 binding density at postnatal day 21, when NMDA receptor subunit protein levels were unaltered. Thus, the focus of the present study was to examine whether prenatal ethanol modifies native NMDA receptor levels.

Methods: Cerebral cortices were taken from offspring born to three treatment groups of pregnant Sprague Dawley® rats: an ethanol group given an ethanol liquid diet during the gestational period, a pair‐fed control group that received a liquid diet without ethanol, and an ad libitum group fed rat chow and tap water. Western blot studies were carried out at postnatal days 1, 7, 14, and 21 to examine total protein expression of NR1 and NR1b splice variants. NR2 subunit levels were examined by [3H]MK‐801 binding studies using spermidine, an endogenous polyamine, and ifenprodil, a selective NR2B antagonist.

Results: [3H]MK‐801 binding density was significantly reduced in prenatal ethanol‐treated groups compared with ad libitum and pair‐fed control groups. Spermidine increased [3H]MK‐801 binding, although potentiation by spermidine was not significantly different among all three experimental groups. Furthermore, no significant differences in total protein expression of NR1 or NR1b splice variants were observed in cortical membrane homogenates at postnatal days 1 through 21. [3H]MK‐801 binding in the presence of ifenprodil showed that prenatal ethanol treatment significantly decreased low‐affinity ifenprodil binding. High‐affinity ifenprodil binding was reduced in both pair‐fed and ethanol‐treated groups.

Conclusions: These results suggest that prenatal ethanol treatment reduces [3H]MK‐801 binding and that this reduction may be due to a decrease in NR2A subunits.
Generation of Aldehyde‐Derived Protein Modifications in Ethanol‐Exposed Heart
Authors: Niemelä Onni , Parkkila Seppo , Worrall Simon , Emery Peter W. , Preedy Victor R.
Published: December 2003

Background: Although excessive ethanol consumption is known to lead to a variety of adverse effects in the heart, the molecular mechanisms of such effects have remained poorly defined. We hypothesized that posttranslational covalent binding of reactive molecular species to proteins occurs in the heart in response to acute ethanol exposure.

Methods: The generation of protein adducts with several aldehydic species was examined by using monospecific antibodies against adducts with malondialdehyde (MDA), acetaldehyde (AA), MDA‐AA hybrids, and hydroxyethyl radicals. Specimens of heart tissue were obtained from rats after intraperitoneal injections with alcohol (75 mmol/kg body weight) with or without pretreatment with cyanamide (0.05 mmol/kg body weight), an aldehyde dehydrogenase inhibitor.

Results: The amounts of MDA and unreduced AA adducts were found to be significantly increased in the heart of the rats treated with ethanol, cyanamide, or both, whereas no other adducts were detected in statistically significant quantities. Immunohistochemical studies for characterization of adduct distribution revealed sarcolemmal adducts of both MDA and AA in the rats treated with ethanol and cyanamide in addition to intracellular adducts, which were also present in the group treated with ethanol alone.

Conclusions: These findings support the role of enhanced lipid peroxidation and the generation of protein‐aldehyde condensates in vivo as a result of excessive ethanol intake. These findings may have implications in the molecular mechanisms of cardiac dysfunction in alcoholics.
Chronic Ethanol Consumption Enhances Interleukin‐1‐Mediated Signal Transduction in Rat Liver and in Cultured Hepatocytes
Authors: Valles Soraya L. , Blanco Ana M. , Azorin Inmaculada , Guasch Rosa , Pascual María , Gomez‐Lechon María Jose , Renau‐Piqueras Jaime , Guerri Consuelo
Published: December 2003

Background: Interleukin‐1 (IL‐1) is a central mediator of the inflammatory process. Increased serum levels of IL‐1 have been reported in alcoholics with liver damage, but it remains unknown whether chronic ethanol intake, in the presence or absence of lipopolysaccharide (LPS), activates IL‐1 release and signaling in the hepatocyte.

Methods: IL‐1β and IL‐10 release, expression of their receptors (IL‐1RI and IL‐10R), and the IL‐1RI signal transduction response were evaluated in livers and cultured hepatocytes from ethanol‐fed or pair‐fed rats exposed in vivo or in vitro to LPS, ethanol, or both.

Results: Chronic ethanol intake increased both the serum levels of IL‐1β and IL‐10 and the expression of IL‐1RI, but not of IL‐10R, in the liver microsomal fraction. In vivo LPS administration potentiated the ethanol‐induced release of plasma cytokines. It is interesting to note that ethanol, either given in a single dose or chronically fed, stimulated IL‐1β and IL‐10 release from cultured hepatocytes. Stimulation of hepatocytes with IL‐1β caused a higher activation of IL‐1‐associated kinase, extracellular receptor‐activated kinases 1 and 2, and nuclear factor‐κB (NF‐κB) in hepatocytes from alcohol‐fed animals than from controls. Furthermore, in the absence of any stimulation, hepatocytes from alcohol‐fed animals showed an activation of both kinases, as well as an increase in NF‐κB binding. Our results suggest the participation of the extracellular signal‐regulated kinase (ERK)1/2 pathway in ethanol‐induced NF‐κB activation, because treatment with PD‐98059, an ERK1/2 inhibitor, partially suppressed IL‐1β‐induced NF‐κB expression.

Conclusions: Chronic ethanol intake potentiates the action of the proinflammatory cytokine IL‐1β, enhancing the release and signaling response of IL‐1β in the hepatocyte, which in conjunction with other cytokines or LPS may exacerbate the inflammatory damage associated with alcoholic liver disease.
Altered Affective Modulation of the Startle Reflex in Alcoholics With Antisocial Personality Disorder
Authors: Miranda Robert , Meyerson Lori A. , Myers Ryan R. , Lovallo William R.
Published: December 2003

Background: Individual differences in neural circuitry that regulate emotional reactivity may be associated with alcoholism and antisocial personality disorder (ASPD), a common comorbid condition. The emotion‐modulated startle reflex was used to investigate emotional reactivity among alcohol‐dependent (AD) men with and without ASPD.

Methods: Sixty‐two men were tested: (1) AD (n= 24), (2) AD‐ASPD (n= 17), and (3) non‐AD, non‐ASPD controls (n= 21). Participants completed self‐report instruments and clinical interviews and had eye‐blink electromyograms measured in response to acoustic startle probes while viewing color photographs rated as affectively pleasant, neutral, and unpleasant.

Results: Startle blink magnitudes were larger during unpleasant as compared with pleasant slides for control and AD groups, resulting in significant linear trend effects (p < 0.001) and nonsignificant quadratic trend effects. In contrast, AD‐ASPD did not show a significant difference in blink magnitude during unpleasant and pleasant slides and did not show a significant linear valence trend or quadratic trend effect (p > 0.6). Subjective valence and arousal ratings of the photographs were similar across groups.

Conclusions: Adult male alcoholics with ASPD have abnormal emotional responsiveness to both pleasant and unpleasant stimuli relative to alcoholics without ASPD and to controls.
Chronic Ethanol Consumption by C57BL/6 Mice Promotes Tolerance to Its Interoceptive Cues and Increases Extracellular Dopamine, an Effect Blocked by Naltrexone
Authors: Middaugh Lawrence D. , Szumlinski Karen K. , Van Patten Yancy , Marlowe Angela‐Leigh Bandy , Kalivas Peter W.
Published: December 2003

Background: C57BL/6 (B6) mice voluntarily consume ethanol. Although preingestive factors might be accountable, the fact that B6 mice voluntarily consume sufficient ethanol to set the conditions for an ethanol‐deprivation effect suggest that post‐ingestive pharmacological induced changes also occur. In this study, we determined the amounts of ethanol voluntarily consumed by B6 mice and associated blood ethanol levels (BEL), the effects of this consumption on extracellular dopamine (DA) and how this was altered by naltrexone, as well as on its interoceptive discriminative cues.

Methods: In experiment 1, the amounts of 12% ethanol consumed at 2, 4, and 6 hr into the active phase of the circadian cycle and associated BEL were determined. In experiment 2, dialysate samples were collected for 1 hr to establish basal DA levels. Mice were then injected with saline or naltrexone (6 mg/kg) and given access to water and 12% ethanol or to water only, and samples were collected at 20‐min intervals for the next 2 hr. In experiment 3, mice were trained to discriminate ethanol's interoceptive cues via operant techniques, and half were given 3 weeks access to ethanol and water, the other half water only. Ethanol‐consuming and water control mice were again tested for their ability to discriminate the drug's interoceptive cues.

Results: Mice ingested nearly 6 g/kg of ethanol and attained BEL near 100 mg/100 mL by 6 hr into the active phase. Ethanol intake at 2‐hr into the dark phase was approximately 2.5 g/kg, and increased DA to approximately 100% above basal levels. Naltrexone reduced ethanol consumption and blocked the DA increase. Ethanol consumption for 3 weeks attenuated its discriminative cues.

Conclusions: B6 mice voluntarily consume sufficient ethanol (1) to produce intoxicating BEL; (2) to increase DA levels in nucleus accumbens, an effect blocked by naltrexone; and (3) to attenuate its discriminative cues.
A Mouse Model of Prenatal Ethanol Exposure Using a Voluntary Drinking Paradigm
Authors: Allan Andrea M. , Chynoweth Julie , Tyler Lani A. , Caldwell Kevin K.
Published: December 2003

Background: The incidence of fetal alcohol spectrum disorders is estimated to be as high as 1 in 100 births. Efforts to better understand the basis of prenatal ethanol‐induced impairments in brain functioning, and the mechanisms by which ethanol produces these defects, will rely on the use of animal models of fetal alcohol exposure (FAE).

Methods: Using a saccharin‐sweetened alcohol solution, we developed a free‐choice, moderate alcohol access model of prenatal alcohol exposure. Stable drinking of a saccharin solution (0.066%) was established in female mice. Ethanol then was added to the saccharin in increasing concentrations (2%, 5%, 10% w/v) every 2 days. Water was always available, and mice consumed standard pellet chow. Control mice drank saccharin solution without ethanol. After a stable baseline of ethanol consumption (14 g/kg/day) was obtained, females were impregnated. Ethanol consumption continued throughout pregnancy and then was decreased to 0% in a step‐wise fashion over a period of 6 days after pups were delivered. Characterization of the model included measurements of maternal drinking patterns, blood alcohol levels, food consumption, litter size, pup weight, pup retrieval times for the dams, and effects of FAE on performance in fear‐conditioned learning and novelty exploration.

Results: Maternal food consumption, maternal care, and litter size and number were all found to be similar for the alcohol‐exposed and saccharin control animals. FAE did not alter locomotor activity in an open field but did increase the time spent inspecting a novel object introduced into the open field. FAE mice displayed reduced contextual fear when trained using a delay fear conditioning procedure.

Conclusions: The mouse model should be a useful tool in testing hypotheses about the neural mechanisms underlying the learning deficits present in fetal alcohol spectrum disorders. Moreover, a mouse prenatal ethanol model should increase the opportunity to use the power of genetically defined and genetically altered mouse populations.
Effects of Alcohol Withdrawal on 24 Hour Ambulatory Blood Pressure Among Alcohol‐Dependent Patients
Authors: Estruch Ramón , Sacanella Emilio , De la Sierra Alejandro , Aguilera María Teresa , Antúnez Emília , Nicolás José M. , Fernández‐Solá Joaquín , Coca Antonio , Urbano‐Márquez Álvaro
Published: December 2003

Background: Although epidemiologic studies have reported an association between alcohol intake and high blood pressure (BP), the results of intervention studies have shown inconsistent results. We embarked on a study to determine whether different subgroups of alcohol‐dependent patients may be identified in relation to the effect of alcohol on BP.

Methods: Fifty alcohol‐dependent men (mean age, 41.4 years) received 0.4 g of ethanol per kilogram of body weight every 4 hr in 200 ml of orange juice during 24 hr and the same amount of orange juice without ethanol during another 24 hr. Twenty‐four hour ambulatory BP monitoring was performed during ethanol and orange juice intakes, as was hormonal and biochemical analysis.

Results: Thirty‐five (75%) alcohol‐dependent men were normotensive and 15 (30%) hypertensive. Eighteen (51%) normotensive and 12 (80%) hypertensive subjects showed a significant decrease in 24 hr mean BP after ethanol withdrawal (mean decrease of 8.4 mm Hg [95% confidence interval, −11.2 to −5.7] and 12.5 mm Hg [confidence interval, −16.2 to −8.8], respectively) and were considered as sensitive to alcohol. The remaining alcohol‐dependent subjects were considered as resistant to alcohol. Normotensive subjects sensitive to ethanol showed a significantly greater left ventricular mass and a significantly lower ejection fraction than those normotensive patients whose BP did not change after ethanol withdrawal (both p < 0.01).

Conclusions: More than three fourths of the hypertensive and more than half of the normotensive alcohol‐dependent patients showed sensitivity to the pressor effects of ethanol. Impairment also was observed in heart function in normotensive patients sensitive to the pressor effects of ethanol.
Neurokinin Type‐3 Receptor Stimulation Impairs Ethanol‐Associated Appetitive Behavior in Wistar Rats
Authors: Slawecki Craig J. , Roth Jennifer
Published: December 2003

Objectives: Stimulating central neurokinin type‐3 (NK‐3) receptors decreases ethanol intake in rats. Although paraventricular nucleus of the hypothalamus (PVN) has a high density of NK‐3 receptors, their influence on ethanol reinforcement has not been examined. This study's purpose was to assess the effects of intra‐PVN infusion of senktide, a NK‐3 receptor agonist, on ethanol self‐administration. In a follow‐up study, senktide's effects on ethanol self‐administration after intracerebroventricular (ICV) infusion were examined.

Methods: Male Wistar rats were trained to self‐administer 10% ethanol (10E) in the “Sipper Tube” model described by Samson and colleagues, Guide cannula were then aimed bilaterally at the PVN or unilaterally at the lateral cerebral ventricle. Intra‐PVN (5–100 ng/side) or ICV (30–500 ng/rat) effects of senktide on 10E self‐administration were also examined as a preliminary test of senktide's selectivity.

Results: Intra‐PVN and ICV infusion of senktide reduced the average number of consecutive lever presses and increased the time taken to complete the lever press requirement when 10E served as the reinforcer. Increased duration of the lever‐pressing component was observed when senktide was administered prior to 2S self‐administration sessions. Neither PVN nor ICV senktide administration significantly altered 10E or 2S consumption.

Conclusions: These data suggest that stimulation of central neurokinin typ‐3 receptors in the Wistar rat reduces appetitive behavior while having little or no impact on consummatory behavior. Ethanol “seeking” appeared more sensitive to disruption by senktide than sucrose “seeking.” However, further studies assessing the senktide's effects on sucrose‐maintained behavior are needed to verify this hypothesis. Lastly, it is hypothesized that lack of effect of senktide on intake is in part related to the use of outbred Wistar rats in these studies instead of selectively bred rats.
The Effects of Affective, Behavioral, and Cognitive Components of Trait Anger on the Alcohol‐Aggression Relation
Authors: Giancola Peter R. , Saucier Donald A. , Gussler‐Burkhardt Natasha L.
Published: December 2003

Objective: The purpose of this study was to investigate the effects of affective, behavioral, and cognitive components of trait anger on alcohol‐related aggression in men and women.

Methods: Subjects were 300 (150 men and 150 women) healthy social drinkers between 21 and 35 years of age. Trait anger was measured using the ABC Anger Inventory. Following the consumption of either an alcohol or a placebo beverage, subjects were tested on a modified version of the Taylor Aggression Paradigm in which mild electric shocks were received from, and administered to, a fictitious opponent during a competitive task. Aggressive behavior was operationalized as the shock intensities administered to the fictitious opponent under conditions of low and high provocation.

Results: Results indicated that alcohol increased aggression only for men with higher behavioral and cognitive anger scores and only for women with higher behavioral anger scores. Results also showed that when all anger components were taken into account, behavioral anger was the only factor that put one at risk for intoxicated aggression.

Conclusions: Two recent studies demonstrated that the trait of “general” anger is a risk factor for intoxicated aggression (Giancola, 2002a; Parrott and Zeichner, 2002). The present investigation confirmed and extended these findings by examining the role of three different components of anger. The results highlight the fact that alcohol consumption does not increase aggression in all persons and in all situations. An important goal for future research is to identify which individual difference and contextual factors are most important in determining who will, and will not, behave in an aggressive manner when intoxicated.
α4β2* Nicotinic Acetylcholine Receptors Modulate the Effects of Ethanol and Nicotine on the Acoustic Startle Response
Authors: Owens Jeremy C. , Balogh Seth A. , McClure‐Begley Tristan D. , Butt Christopher M. , Labarca Cesar , Lester Henry A. , Picciotto Marina R. , Wehner Jeanne M. , Collins Allan C.
Published: December 2003

Background: Ethanol modulates the functional activity of α4β2 neuronal nicotinic cholinergic receptors (nAChR) when measured in vitro, but the potential role of α4β2 nAChRs in regulating behavioral effects of ethanol is unknown. Recently, Tritto et al. (Tritto T, Stitzel JA, Marks MJ, Romm E, Collins AC (2002) Variability in response to nicotine in the LS×SS RI strains: potential role of polymorphisms in alpha4 and alpha6 nicotinic receptor genes. Pharmacogenetics 12:197–208) reported that a polymorphism (A529T) in the α4 nAChR subunit gene is associated with variability in nicotine's effects on startle in the LS×SS recombinant inbred (RI) strains. Ethanol also alters the acoustic startle response. Thus, we evaluated the potential role of α4β2 nAChRs in modulating ethanol's effects on acoustic startle.

Methods: The effects of ethanol on acoustic startle were determined in the LS×SS RI strains. In addition, the effects of ethanol and nicotine were also measured in α4 gain of function and β2 null mutant mice. The β2 mutants do not express the major variant of α4 nAChRs, α4β2.

Results: An association between the α4 A529T polymorphism and ethanol's effects on startle was found in the LS×SS RI strains; those strains that express the A529 variant of α4 were more sensitive to ethanol‐induced depression of startle. The α4 gain of function mutants were more sensitive to the effects of both nicotine and ethanol and the β2 null mutants were less sensitive to both drugs.

Conclusions: α4β2‐containing nAChRs may play important roles in modulating the effects of both ethanol and nicotine on the acoustic startle response. We suggest that nAChR subunit genes should be evaluated as potential contributors to both alcoholism and tobacco abuse.
Pain Thresholds in Alcohol Preferring and Non‐preferring Rats: Diurnal and Repeated Trial Line Differences
Authors: Kimpel Mark W. , Brown Matthew M. , Froehlich Janice C.
Published: December 2003

Background: Studies in humans and animals suggest that those with a genetic predisposition toward high levels of alcohol consumption have decreased pain thresholds. The present study explores this association in rat lines selectively bred for alcohol preference or nonpreference.

Methods: 13 HAD1, 11 LAD1, 16 iP5C, and 16 iNP1 rats were tested in the Ugo Basile Plantar Analgesiometer and the IITC Tail Flick device. Five trials were conducted in each test session with one session per device conducted in the light and one in the dark. Trial one latency represents baseline latency. Decline in Latency over Repeated Trials (DLRT) was analyzed using linear regression.

Results: Testing in the Plantar Analgesiometer revealed no significant line differences in baseline latency (iP5C versus iNP1; HAD1 vs. LAD1). The alcohol preferring lines (iP5C and HAD1), however, both demonstrated an increase in baseline latency in the dark phase compared to the light phase (p < 0.05). The iNP1 line demonstrated highly significant DLRT in both the light phase (p < 0.001) and dark phase (p < 0.01) while the iP5C line demonstrated a significant DLRT only at night (p < 0.01). In the tail flick apparatus, the HAD1 line demonstrated a significantly increased baseline latency compared to the LAD1 line in both the light (p < 0.05) and dark (p < 0.01) phases. The HAD1 line also demonstrated a significant increase in baseline latency in the dark compared to the light phase (p < 0.05) and a significant DLRT in the light (p < 0.01) and the dark phase (p < 0.001).

Conclusions: The alcohol preferring HAD1 line demonstrates a significantly increased baseline tail latency compared to the nonpreferring LAD1 line in both light and dark phases. There is a significant diurnal rhythm of paw and tail latency in both of the alcohol preferring lines (iP5C and HAD1) but not in the nonpreferring lines (iNP1 and LAD1). A novel finding of Decline in Latency with Repeated Trials (DLRT) was found in both alcohol preferring and nonpreferring lines; degree of DLRT differed as a function of line and circadian period.
Developmental Differences in the Sensitivity of Hippocampal GABAA Receptor‐Mediated IPSCS to Ethanol
Authors: Li Qiang , Wilson Wilkie A. , Swartzwelder H.S.
Published: December 2003

Background: Ethanol consumption by juveniles and adolescents is a public health problem of massive proportions. Recent studies have indicated that adolescents may be less sedated by ethanol than adults, and may thus be able to consume more ethanol, putting them at greater risk for ethanol addiction and other negative consequences of ethanol use. However, the mechanisms underlying this developmental difference are unknown. One contributing factor may be GABAA receptor‐mediated inhibition, which is known to produce sedation. Ethanol is known to enhance this inhibitory process.

Methods: Using whole cell recording, we tested the response of GABAA receptor‐mediated IPSCs in brain slices of rat hippocampus from animals representing three developmental stages: juvenile, early adolescent, and adult.

Results: We found significantly greater ethanol‐induced enhancement of GABA‐mediated IPSPs in cells from adult animals compared to those from juvenile or adolescent animals.

Conclusions: We conclude that the sensitivity of GABAA receptor‐mediated inhibitory processes to ethanol increases with development from the juvenile period to adulthood.
Multiple Variable First Exons: A Mechanism for Cell- and Tissue-Specific Gene Regulation
Authors: Zhang Theresa , Haws Peter , Wu Qiang
Published: December 2003

A large familyof neural protocadherin (Pcdh) proteins is encoded bythree closelylinked mammalian gene clusters (α, β, and γ). Pcdh α and γ clusters have a striking genomic organization. Specifically, each “variable” exon is spliced to a common set of downstream “constant” exons within each cluster. Recent studies demonstrated that the cell-specific expression of each Pcdh gene is determined bya combination of variable-exon promoter activation and cis-splicing of the corresponding variable exon to the first constant exon. To determine whether there are other similarlyorganized gene clusters in mammalian genomes, we performed a genome-wide search and identified a large number of mammalian genes containing multiple variable first exons. Here we describe several clusters that contain about a dozen variable exons arrayed in tandem, including UDP glucuronosyltransferase (UGT1), plectin, neuronal nitric oxide synthase (NOS1), and glucocorticoid receptor (GR) genes. In all these cases, multiple variable first exons are each spliced to a common set of downstream constant exons to generate diverse functional mRNAs. As an example, we analyzed the tissue-specific expression profile of the mouse UGT1 repertoire and found that multiple isoforms are expressed in a tissue-specific manner. Therefore, this variable and constant genomic organization provides a genetic mechanism for directing distinct cell- and tissue-specific patterns of gene expression.
Mutational and Selective Pressures on Codon and Amino Acid Usage in Buchnera, Endosymbiotic Bacteria of Aphids
Authors: Rispe Claude , Delmotte François , van Ham Roeland C.H.J. , Moya Andres
Published: December 2003

We have explored compositional variation at synonymous (codon usage) and nonsynonymous (amino acid usage) positions in three complete genomes of Buchnera, endosymbiotic bacteria of aphids, and also in their orthologs in Escherichia coli, a close free-living relative. We sought to discriminate genes of variable expression levels in order to weigh the relative contributions of mutational bias and selection in the genomic changes following symbiosis. We identified clear strand asymmetries, distribution biases (putative high-expression genes were found more often on the leading strand), and a residual slight codon bias within each strand. Amino acid usage was strongly biased in putative high-expression genes, characterized by avoidance of aromatic amino acids, but above all by greater conservation and resistance to AT enrichment. Despite the almost complete loss of codon bias and heavy mutational pressure, selective forces are still strong at nonsynonymous sites of a fraction of the genome. However, Buchnera from Baizongia pistaciae appears to have suffered a stronger symbiotic syndrome than the two other species.
Fluorescent Detection and Isolation of DNA Variants Using Stabilized RecA-Coated Oligonucleotides
Authors: Rice Michael C. , Heckman Brandy M. , Liu Yi , Kmiec Eric B.
Published: December 2003

Several genome resequencing strategies have been developed to detect genetic variation in populations and correlate diversity with phenotypic consequences. Commonly used methods of detecting single nucleotide polymorphisms (SNPs) use PCR amplification and indirect analysis, which can create template biases and enable user contamination. Here we present a novel assay to detect and isolate DNA variants using stabile nanostructures formed directly on duplex DNA. The assay incorporates the well-established RecA-catalyzed strand invasion process witha novel stabilizing hybridization step. First, short RecA-coated oligonucleotide filaments invade duplex DNA to form a synaptic intermediate or “D-loop.” Sequentially, chemically modified oligonucleotide probes anneal to the displaced DNA strand of the complex to form a stable “double D-loop.” These joint molecules resist dissociation when both oligonucleotides are completely complementary to the target duplex; however, if the probes are mismatched, the complex is inherently instable and rapidly dissociates. SNPs are identified by detecting the fluorophore assimilated into stable complexes produced by homologous probes compared to unstable differentially labeled mismatched probes. Furthermore, this strategy can be used to isolate specific allelic variants by affinity purification from complex populations. Stabilized double D-Loop intermediates accordingly offer the promise of haplotyping and pharmacogenomic analysis directly in double-stranded DNA samples.
CONREAL: Conserved Regulatory Elements Anchored Alignment Algorithm for Identification of Transcription Factor Binding Sites by Phylogenetic Footprinting
Authors: Berezikov Eugene , Guryev Victor , Plasterk Ronald H.A. , Cuppen Edwin
Published: December 2003

Prediction of transcription-factor target sites in promoters remains difficult due to the short length and degeneracy of the target sequences. Although the use of orthologous sequences and phylogenetic footprinting approaches may help in the recognition of conserved and potentially functional sequences, correct alignment of the short transcription-factor binding sites can be problematic for established algorithms, especially when aligning more divergent species. Here, we report a novel phylogenetic footprinting approach, CONREAL, that uses biologically relevant information, that is, potential transcription-factor binding sites as represented by positional weight matrices, to establish anchors between orthologous sequences and to guide promoter sequence alignment. Comparison of the performance of CONREAL with the global alignment programs LAGAN and AVID using a reference data set, shows that CONREAL performs equally well for closely related species like rodents and human, and has a clear added value for aligning promoter elements of more divergent species like human and fish, as it identifies conserved transcription-factor binding sites that are not found by other methods. CONREAL is accessible via a Web interface at http://conreal.niob.knaw.nl/.
Whole-Genome Discovery of Transcription Factor Binding Sites by Network-Level Conservation
Authors: Pritsker Moshe , Liu Yir-Chung , Beer Michael A. , Tavazoie Saeed
Published: December 2003

Comprehensive identification of DNA cis-regulatory elements is crucial for a predictive understanding of transcriptional network dynamics. Strong evidence suggests that these DNA sequence motifs are highly conserved between related species, reflecting strong selection on the network of regulatory interactions that underlie common cellular behavior. Here, we exploit a systems-level aspect of this conservation—the network-level topology of these interactions—to map transcription factor (TF) binding sites on a genomic scale. Using network-level conservation as a constraint, our algorithm finds 71% of known TF binding sites in the yeast Saccharomyces cerevisiae, using only 12% of the sequence of a phylogenetic neighbor. Most of the novel predicted motifs show strong features of known TF binding sites, such as functional category and/or expression profile coherence of their corresponding genes. Network-level conservation should provide a powerful constraint for the systematic mapping of TF binding sites in the larger genomes of higher eukaryotes.
Recombination Has Little Effect on the Rate of Sequence Divergence in Pseudoautosomal Boundary 1 Among Humans and Great Apes
Authors: Yi Soojin , Summers Tyrone J. , Pearson Nathaniel M. , Li Wen-Hsiung
Published: December 2003

Recent studies indicated that recombination is strongly mutagenic. In particular, data from the mouse pseudoautosomal boundary (PAB) suggested that locally intensive recombination increased the nucleotide substitution rate by more than 100-fold and greatly increased the GC content. Here we study the rates of nucleotide substitution in eight introns of the human and great ape XG gene, which spans the boundary between the pseudoautosomal region 1 (PAR1) and the X-specific region. Contrary to what is expected under the above hypothesis, our sequence data from humans and great apes reveal that the PAR1 introns of XG have actually evolved slightly slower than X-specific introns. Only when a New World monkey was compared with hominoids were the rates slightly increased in the PAR1 introns. In terms of base composition, although the intergenic regions of the human PAR1 show a significant increase of G and C nucleotides, the base composition of the surveyed PAR1 introns is similar to that of the X-specific introns. Direct and indirect evidence indicates that the recombination rate is, indeed, much higher in PAR1 introns than in X-specific introns, and that the present PAB has persisted since the common ancestor of hominoids. Therefore, the mutagenic effect of recombination is far weaker than previously proposed, at least in hominoid PABs.
Active labour market policy and employment flows
Authors: Puhani Patrick A.
Published: December 2003

Analyses Polish active labour market policy programmes (ALMP) from a macroeconomic (regional) point of view. The effects of training programmes on the outflows from unemployment into employment and the effects of all ALMP programmes on the outflows from employment into unemployment (to identify displacement effects) are estimated. The empirical evidence gives no support to the view that public training programmes can be used to reduce unemployment, and there is no robust evidence for displacement effects by any ALMP programme. The result that start‐up loans can reduce flows from employment into unemployment is only weakly significant.
The wage structure and wage distribution in Poland, 1994‐2001
Authors: Adamchik Vera , Hyclak Thomas , King Arthur
Published: December 2003

Analyzes the wage structure and wage distribution for male and female Polish workers during a more mature phase of a transition to a market economy, namely 1994‐2001. The results indicate an overall rise in earnings inequality for both genders during this period. Contrary to conventional expectations, changes in the composition of employment caused by a deep restructuring process did not have a significant impact on earnings inequality. Throughout this period, the changes in the wage structure and wage distribution were almost entirely due to the changes in returns to worker characteristics. However, does not observe the “explosion of differentials at all levels,” predicted by many leading models on transition. Wage structures for men and women evolved in different ways. This analysis suggests that the effect of changes in labor supply and institutional factors on the wage structure and wage distribution was relatively unimportant. Demand side factors seem to be far more important in explaining the dynamics of earnings inequality in Poland during 1994‐2001.
Capital subsidies and job creation in rural areas
Authors: Skuras Dimitris , Dimara Efthalia , Stathopoulou Sophia
Published: December 2003

Assesses the job creation effects of capital subsidies provided to small and medium enterprises in rural and lagging areas. The proposed methodology takes account of extensive censoring of job creation among assisted rural firms, endogeneity of the capital stock change resultant from capital subsidies, and the extensive part‐time and seasonal job requirements in rural areas. Capital stock change, as a result of grant aid is negatively related to the decision to create new jobs and to the extent of job creation given that some employment is created. Evidence of this work provides the ground for discussing the effectiveness and implications of using capital subsidies as a job creation instrument within rural development policies.
Earnings and “skill” allocation in the Canadian labor market
Authors: Chu Ng Ying
Published: December 2003

Using the Survey of Labour and Income Dynamics, the incidence of skills mismatches in the Canadian workforce was found to be about 27 percent. The overeducated (undereducated) were found to earn less (more) than their adequately educated counterparts. The overeducated could realize a wage gain by finding the “right” job, while the undereducated would gain by adjusting their skill level. Based on the Oaxaca decomposition, it was concluded that better skills allocation would help to narrow gender wage differentials.
Controlling mouse infestations in domestic properties
Authors: Murphy Gai , Lindley Brian , Marshall Peter
Published: December 2003

Current approaches to the control of house mouse infestations rely heavily on a reactive service, where treatments are undertaken in response to complaints. The impact of buildings on the distribution and persistence of house mouse infestations has received little attention. This paper reports the results of 117 surveys of domestic properties in an urban area of Manchester. Results found that mice were not uniformly distributed within the domestic properties surveyed and that general characteristics and construction of the property, food hygiene within the kitchen area and overall fitness influenced distribution. The paper highlights the need for an integrated approach to control to ensure long‐term eradication of chronic house mouse infestations.
Traditional roofing techniques in the Lake District National Park
Authors: Scott Alan W.
Published: December 2003

This paper considers vernacular roofing practices for natural slate within the Lake District National Park and looks at the application of traditional techniques within the environmentally‐sensitive area. The paper examines the geology of the Lake District, slate production, methods of re‐slating and specific techniques and details. The paper uses case studies of recent roofing projects to illustrate good practice.
Flexural performance of concrete beam splices with different surrounding concretes
Authors: Leung H.Y.
Published: December 2003

In this study, tests were conducted to investigate the effect of different concretes on the behaviour of reinforced concrete beams with central splices. Five beam specimens were prepared using different concrete mixes in their splice regions. Experimental results indicated that the bond failure of the spliced rebars governed the ultimate flexural behaviour of all specimens, except the one cast with steel fibres. A small increase in flexural strength was found for both the spliced beams cast with high‐strength concrete and steel fibres. Moreover, use of high‐strength concrete and steel fibrous concrete led to a remarkable improvement in the beam's displacement capacity. The effect of pulverised fuel ash on the splice performance was insignificant while the introduction of silica fume caused improvements in loading capacity and ductility.
Freeze/thaw durability in concrete with fibre additions
Authors: Richardson A.E.
Published: December 2003

From recent laboratory research monofilament and fibrillated polypropylene fibres were used in structural concrete and have been tested against 150 freeze/thaw cycles. The findings show monofilament fibres to play a significant role in protecting the concrete matrix against the forces encountered. External cube integrity was shown to be a poor indicator of structural condition. A significant aspect of the work is the range of tests applied to the freeze/thaw concrete cubes against the control sample. Strong evidence of condition was obtained from ultrasonic, compressive strength and weight loss. Surface scaling was not a satisfactory indication of the structural condition of the concrete.
Developing future energy‐performance standards for UK housing: the St Nicholas Court project – Part 2
Authors: Lowe Robert , Bell Malcolm , Roberts David
Published: December 2003

This paper and part 1, which appeared in the last issue, set out the results of a housing field trial designed to evaluate the impact of an enhanced energy‐performance standard for dwellings. The project was designed to inform the next review of part L of the Building Regulations for England and Wales, which, following the publication of the UK government's White Paper on energy policy, is expected in 2005. The project reported explores the implications of an enhanced standard in the context of timber frame construction. Although, for programming reasons, it was necessary to terminate the research project at the end of the design phase, the results suggest that the standard investigated is well within the capacity of the industry. It was clear, however, that the whole supply chain will need to take a positive approach to the development of new solutions. The secret to a smooth and cost‐optimised transition is that the necessary development work begins immediately, not when regulation changes.
Redesigning library applications for PDAs: ILS vendor perspective
Authors: McCullough John
Published: December 2003

One of the barometers of the level of demand placed on libraries to evolve their services is the rate at which the library automation vendors release enhancements, new features, and entirely new product lines to serve the library marketplace. An area in which new technology and library needs intersect is in the area of development for PDAs (personal digital assistants) and other handheld devices enabled for wireless communication. There is little doubt about the opportunities presented by PDAs and wireless technology to enhance library services. However, barriers remain to the real‐world adoption of many of these solutions, chief among them the rate of user adoption of these technologies.
PDAs and health sciences libraries
Authors: Peters Thomas A. , Dorsch Josephine , Bell Lori , Burnette Peg
Published: December 2003

The article explores the issues and opportunities for health sciences libraries surrounding the use of personal digital assistants (PDAs) by healthcare professionals. Six general trends, issues, and opportunities are identified, as well as ten potential roles for libraries. Health science librarians need to explore various potential roles, then, based on an assessment of local needs and resources, determine the level and extent of their commitment to PDA support. The underlying support by health sciences libraries for handheld information seeking, information storage, computing, and communication at the point of need and care should remain strong and unflagging.
Supporting PDAs: the experience of a health sciences library
Authors: Garrison Julie A. , Anderson Tiffany L. , MacDonald Marlyse H. , Schardt Connie M. , Thibodeau Patricia L.
Published: December 2003

This paper discusses the Duke University Medical Center Library’s experience in supporting the use of mobile technology. Over the past several years, the library contributed to the formation of a mobile technology infrastructure through surveys, organization of information sharing events, and the development and review of medical center wide proposals and reports.
Hand‐held computers in the classroom and the library: teaching and learning resource issues resulting from widespread deployment at the University of Minnesota Duluth
Authors: Deneen Linda , Allert James
Published: December 2003

The University of Minnesota Duluth (UMD) began requiring all incoming freshmen in computer science and engineering disciplines to purchase hand‐held computers in the Fall of 2001. This article describes how the initiative was implemented and the effects it had on the structure of the teaching and learning environment at UMD. Special attention is paid to its impact on library concerns and the evolution of the relationship between hand‐held computers and electronic reference material.
Unicode: support for multiple languages at the Ohio State University Libraries
Authors: Tull Laura , Straley Dona
Published: December 2003

Unicode is a standard for a universal character set for all of the scripts of the world’s languages It is one of the fundamental technological building blocks for international exchange of textual information, via computers. It is particularly important to libraries that house collections in many languages and written in various scripts. Ohio State University Libraries houses collections written in many non‐Latin scripts including Arabic, Hebrew, Chinese, Japanese, Korean and Cyrillic. Providing patrons with access to these materials has become much easier with the incorporation of Unicode into library systems and software. This article describes what needs to be in place on personal computers and in the library system in order to take advantage of Unicode as well as providing some guidelines to troubleshoot problems when they occur.