bluuebunny/crossref_metadata_2025_split huggingface dataset:
Increased Ethanol Self‐Administration in δ‐Opioid Receptor Knockout Mice
Authors: Roberts Amanda J. , Gold Lisa H. , Polis Ilham , McDonald Jeffrey S. , Filliol Dominique , Kieffer Brigitte L. , Koob George F. 
Published: April 2006

Background: The role of the δ‐opioid receptor in ethanol drinking has remained unclear despite the use of traditional pharmacological and correlational approaches. The results of several studies suggest that pharmacological blockade of these receptors results in decreases in ethanol drinking behavior, but an approximately equal number of reports have failed to observe an effect of δ‐receptor antagonism on ethanol drinking. It is clear that alternative approaches to understanding opioid‐receptor involvement in ethanol drinking are needed.Methods: In this study, ethanol drinking was examined in δ‐opioid receptor knockout (KO) mice by using first a two‐bottle–choice test, then an operant self‐administration paradigm and a second two‐bottle–choice test, in that order. In addition, because KO mice were previously shown to display enhanced anxiety‐like behavior relative to wild‐type (WT) mice, the effect of ethanol self‐administration on anxiety‐like responses was determined.Results: δ KO mice initially showed no evidence of a preference for ethanol in the first two‐bottle–choice drinking test; however, after an experience of operant self‐administration of ethanol, a preference for ethanol developed in the second two‐bottle–choice test. KO mice also showed a preference for ethanol over water and self‐administered more ethanol than WT mice in the operant self‐administration paradigm. The ethanol self‐administered in this procedure was sufficient to reverse the innate anxiety‐like response observed in this strain.Conclusions: δ KO mice showed a greater preference for ethanol and consumed more ethanol than their WT counterparts, suggesting that a decrease in δ‐receptor activity is associated with increased ethanol‐drinking behavior. It is hypothesized that δ receptors may influence ethanol self‐administration at least partly through an effect of these receptors on anxiety‐like behavior.
Health Problems in Adolescents With Alcohol Use Disorders: Self‐Report, Liver Injury, and Physical Examination Findings and Correlates
Authors: Clark Duncan B. , Lynch Kevin G. , Donovan John E. , Block Geoffrey D. 
Published: April 2006

Background: Although adolescent alcohol consumption has been found to be positively correlated with self‐reported health problems, few studies have examined other health indicators. This study compared adolescents with alcohol use disorders (AUDs) and a community reference group on self‐reported health problems, serum liver enzymes, and physical examination findings. The relevance of negative emotionality to understanding these health problems was also investigated.Methods: The subjects were adolescents with AUDs recruited from clinical programs and classified as having DSM‐IV alcohol dependence (n= 71) or alcohol abuse (n= 57) and reference adolescents without AUDs recruited from community sources (n= 131). The assessment of health status included self‐reported health problems in 15 areas; serum liver enzyme assays, including γ‐glutamyl transpeptidase, alanine aminotransferase, and aspartate aminotransferase; and physical examination findings. Negative emotionality was determined by systematically combining scores from the Hamilton Anxiety Rating Scale, the Beck Depression Inventory, the Child Behavior Checklist, and the Multidimensional Personality Questionnaire.Results: Adolescent AUDs were associated with more self‐reported health problems, higher γ‐glutamyl transpeptidase and alanine aminotransferase levels, and more physical examination abnormalities. Negative emotionality was highly correlated with self‐reported health problems, mediated the relationship between AUDs and self‐reported health problems, and was not correlated with serum liver enzyme levels or physical examination abnormalities.Conclusions: These results indicated that AUDs during adolescence were associated with health problems, including modest but demonstrable liver injury. Self‐reported health problems were probably best understood, in this context, as a negative emotionality manifestation.
Alcohol Impairs Protein Synthesis and Degradation in Cultured Skeletal Muscle Cells
Authors: Hong‐Brown Ly Q. , Frost Robert A. , Lang Charles H. 
Published: April 2006

Background: Acute and chronic alcohol intoxication decreases skeletal muscle protein synthesis under in vivo conditions. We investigated whether ethanol (EtOH) and its major metabolites, acetaldehyde and acetate, can directly modulate protein balance under in vitro conditions.Methods: Human myocytes were incubated with different doses of EtOH for varying periods of time (i.e., 4–72 hr). Alternatively, cells were incubated with acetaldehyde, acetate, insulin, insulin‐like growth factor‐I (IGF‐I), or with a combination of EtOH plus insulin or IGF‐I. Rates of protein synthesis or degradation were determined by 35S‐methionine/cysteine incorporation into or release from cellular protein.Results: A significant, 15% to 20%, decrease in basal protein synthesis was observed after 24 hr, but not at earlier time points, in response to 80 mM EtOH. Incubation of myocytes for 72 hr decreased synthesis in cells incubated with EtOH ranging between 60 and 120 mM. The ability of IGF‐I or insulin to stimulate protein synthesis was impaired by 30% and 60%, respectively, in cells incubated with 80 mM EtOH for 72 hr. Exposure of cells to 200 μM acetaldehyde or 5 mM Na‐acetate also decreased basal protein synthesis. In contrast, neither EtOH, acetaldehyde, nor acetate altered the basal rate of protein degradation. However, EtOH completely impaired the ability of insulin and IGF‐I to inhibit proteolysis. Finally, EtOH did not impair IGF‐I receptor autophosphorylation, but inhibited the ability of insulin to phosphorylate its own receptor. EtOH also did not alter the number of insulin or IGF‐I receptors or the formation of insulin/IGF‐I hybrid receptors.Conclusions: We have demonstrated that EtOH can directly inhibit muscle protein synthesis under in vitro conditions. Neither EtOH nor its metabolites altered basal protein degradation, although EtOH did compromise the ability of both insulin and IGF‐I to slow proteolysis. This impairment seems to be mediated by different defects in signal transduction.
Moderate Alcohol During Pregnancy: Learning and Behavior in Adolescent Rhesus Monkeys
Authors: Schneider Mary L. , Moore Colleen F. , Kraemer Gary W. 
Published: April 2006

Background: Although high‐dose prenatal alcohol exposure is related to cognitive and behavioral impairments in children and adolescents with fetal alcohol syndrome, there is relatively little research on the effects of moderate drinking during pregnancy. We examined learning, memory, and behavior in adolescent rhesus monkeys prenatally exposed to moderate levels of alcohol, psychological stress, or both alcohol and stress.Methods: Forty adolescent rhesus monkey subjects were derived from four groups of female rhesus monkeys that (1) consumed alcohol throughout gestation; (2) experienced prenatal stress; (3) experienced prenatal stress and alcohol consumption; or (4) control group (no alcohol, no stress). The subjects were assessed for number of trials required to reach 90% criterion of correct responses on nonmatching‐to‐sample task (NMS), followed by trials with delays of 30, 60, or 120 sec. Ratings of behavior during testing were made after each session.Results: Subjects exposed to moderate prenatal alcohol required significantly more trials to reach criterion on the acquisition phase of the NMS task but had no difficulty with delays. Prenatally stressed monkeys showed lower response inhibition or less behavioral restraint, whereas prenatal alcohol plus stress monkeys showed higher activity level and stereotypies compared with controls. High scores on neonatal measures of orientation (attending to novel stimuli) and motor maturity and low scores on irritability, activity, stereotypies, and impulsivity during acquisition were correlated with fewer trials to criterion on acquisition of NMS.Conclusions: NMS trials required to reach criterion and behavior during testing are sensitive to moderate‐level prenatal alcohol exposure in monkeys. The most adverse behavioral outcomes (hyperactivity and stereotypies) were associated with prenatal alcohol plus stress, raising concerns that environmental stress might provide the context within which fetal alcohol exposure could promote adverse behavioral outcomes. These effects occurred in the absence of either facial deformities or retarded physical growth.
Association of Polymorphism in the Alcohol Dehydrogenase 2 Gene With Alcohol‐Induced Testicular Atrophy
Authors: Yamauchi Masayoshi , Takeda Kunihiko , Sakamoto Kazuhiko , Searashi Yasuyuki , Uetake Shinichiro , Kenichi Hashimoto , Toda Gotaro 
Published: April 2006

Background: Alcohol abuse can induce testicular atrophy, but it only occurs in some alcoholics. Alcohol dehydrogenase (ADH) is located principally on the Leydig cells.Methods: To investigate whether genetic polymorphism of alcohol dehydrogenase (ADH) 2 and aldehyde dehydrogenase (ALDH) 2 was related to alcoholic testicular atrophy, we determined restriction fragment‐length polymorphisms of the ADH2 and ALDH2 genes in 43 Japanese male alcoholics and 50 healthy subjects. An orchidometer was used to determine the testicular size.Results: Less than 16 ml in testicular size was defined as testicular atrophy. Testicular atrophy was found in 24 (55.8%) cases out of 43 alcoholics. Digestion with MaeIII and Mbo II after polymerase chain reaction amplification showed that the ADH21 allele frequency was significantly higher in patients with testicular atrophy than in those without testicular atrophy (χ2= 4.665, p= 0.031), whereas no significant association was observed between testicular atrophy and the ALDH2 gene.Conclusions: The ADH21 allele may be associated with alcoholic testicular atrophy.
Effects of Ethanol on L‐Arginine Transport in Rat Ito Cells in Relation to Nitric Oxide Production
Authors: Saibara Toshiji , Ono Masafumi , Iwasaki Shinji , Maeda Takashi , Onishi Saburo , Hayashi Yoshihiro , Enzan Hideaki 
Published: April 2006

Background: Nitric oxide (NO) is a potent mediator of hepatic sinusoidal hemodynamics that is synthesized in the hepatic stellate cells (Ito cells, fat‐storing cells) and affects these cells. NO production may depend on the induction of inducible nitric oxide synthase and on transport of extracellular L‐arginine. The precise mechanism that controls NO production in stellate cells was characterized recently.Methods: Kinetic analysis of L‐arginine transport and reverse transcription‐polymerase chain reaction for cationic amino acid transporter (CAT) were carried out by using stellate cells prepared from the male Wistar rat. The effect of ethanol on L‐arginine transport and NO production of stellate cells was assessed in the presence of tumor necrosis factor (TNF)‐α and interferon (IFN)‐γ.Results: The L‐arginine transport system functioning in the hepatic stellate cells was system y+, possibly mediated by CAT‐1 and CAT‐2B (Km∼50 μM). IFN‐γ in combination with TNF‐α induced NO production with an enhancement in CAT‐2B mRNA expression and L‐arginine transport, whereas L‐arginine transport and NO production were suppressed by coincubated ethanol.Conclusions: In hepatic stellate cells, ethanol has suppressive effects on NO production and extracellular L‐arginine transport in the presence of TNF‐α and IFN‐γ. The estimated Km of L‐arginine transporter in hepatic stellate cells is very similar to the physiological L‐arginine concentration in portal vein. Our findings may support the merit of further studies on the modulation of NO production via access to portal blood L‐arginine concentration to control disturbed hepatic sinusoidal blood flow in patients with alcoholic liver disease.
Polymorphism of the Neuropeptide Y Gene: An Association Study With Alcohol Withdrawal
Authors: Okubo Takehito , Harada Shoji 
Published: April 2006

Background: Neuropeptide Y (NPY) exists in both the central and peripheral nervous system and is thought to modulate many functions such as feeding behavior, anxiety‐associated behavior, circadian rhythm, seizure modulation, and hormone secretion. Recent studies have revealed that NPY influences alcohol consumption in mice and that alcohol‐preferring rats showed lower concentrations of NPY‐like immunoreactivity compared with alcohol‐nonpreferring rats in several brain regions.Methods: In the present study, we analyzed the whole coding region and 5′‐untranslating region of the NPY gene for 163 Japanese male alcoholics with different withdrawal symptoms (93 with delirium tremens, 71 with seizures, 49 with hallucinations) and 98 Japanese male controls. ALDH2 genotypes of all subjects tested were ALDH2*1 homozygote.Results: Three polymorphic nucleotide substitutions, namely −121C/A (promoter), 1258G/A (exon 2), and 5671C/T (exon 3), were detected in both groups. Substituting C to A in the −121 locus produced a putative binding site of GATA‐1 and GATA‐2. Also, −90G/A (promoter) as a rare variant and 5642–5651 single nucleotide repeats T10/T11 (intron 2) were found. Polymorphism (C/T) at the 1128 locus has been reported to be associated with a higher serum cholesterol level in obese white subjects, but such a polymorphism was not found in our samples. The genotypical distributions for these polymorphic loci (−121C/A, 1258G/A, 5642‐5651 T10/T11, and 5671C/T) were not significantly different between the alcoholics and controls. However, frequency of the T allele and frequency of the genotype that possessed T alleles (CT, TT) at the 5671 locus were significantly higher in patients with seizure than in those without seizure (p < 0.05, p < 0.02).Conclusion: Our data suggested that a C to T substitution at the 5671 locus of the NPY gene may be associated with seizure during alcohol withdrawal.
Structural Requirements of Alkanol Interaction Sites on Human α2β4 Neuronal Nicotinic Acetylcholine Receptors Expressed in Xenopus Oocytes: Effects of Linear and Branched‐Chain Alkanols
Authors: Godden Elizabeth L. , Dunwiddie Thomas V. 
Published: April 2006

Background: Nicotine and alcohol are both drugs of abuse that are frequently used concurrently, but little is known about the interactions between these agents at the molecular level. The neuronal subgroup of nicotinic acetylcholine receptors (nAChRs) are members of a neurotransmitter‐gated ion channel superfamily and have been used extensively to characterize the interactions of ethanol with these channels. Previous work has shown that both the direction and the magnitude of the modulatory effects of n‐alcohols and several fluorinated analogs on nAChRs can be predicted based upon the molecular volume of the alkanol. However, size (molecular volume) is only one of several determinants of binding‐site interactions; shape and flexibility of the interacting ligand and/or the site itself (i.e., structural constraints) and alkanol hydrophobicity are also likely to be involved.Methods: Two‐electrode voltage‐clamp electrophysiology was used to investigate the effects of alkanols on the α2β4 human neuronal nicotinic acetylcholine receptor ectopically expressed in Xenopus oocytes.Results: ACh‐induced currents mediated by α2β4 nAChRs were potentiated by 1‐ and 2‐propanol, whereas 1‐pentanol and several branched‐chain pentanol isomers only inhibited channel activity. 1‐Butanol had a biphasic concentration‐response curve, producing a nearly 2‐fold increase in current at lower concentrations and >50% inhibition at higher concentrations. Other four‐carbon alcohols such as 2‐butanol and 2‐methyl‐1‐propanol also facilitated responses at lower concentrations and inhibited at higher concentrations, whereas 2‐butene‐1‐ol and 2‐methyl‐2‐propanol only inhibited responses. The effects of these alkanols on ACh responses were the result of changes in both the potency as well as the efficacy of ACh at these receptors.Conclusions: Although molecular volume and hydrophobicity both correlate well with the potencies of linear alkanols in modulating the activity of α2β4 nAChRs, these relationships break down almost completely when comparing the structural isomers of these agents. The structure of the interacting alkanol significantly affects the potency and efficacy of alkanols at the nAChR, and this occurs independently of differences in molecular volume and hydrophobicity.
Influence of Alcohol Consumption on Serum Immunoglobulin E Levels in Atopic and Nonatopic Adults
Authors: Vidal C. , Armisén M. , Domínguez‐Santalla M. J. , Gude F. , Lojo S. , González‐Quintela A. 
Published: April 2006

Background: Total and specific serum immunoglobulin E (IgE) are routinely used as diagnostic tools in allergy clinics. Several studies have demonstrated an increase of total serum IgE concentrations in alcoholics, but the possible influence of lower quantities of ethanol intake on serum IgE values has not been fully evaluated. This study was aimed at analyzing the influence of alcohol intake on both total and specific serum IgE concentrations in patients studied in an allergy clinic.Methods: A total of 460 patients were included in the study. According to skin‐prick tests to common aeroallergens, 325 were classified as atopics and 135 as nonatopics. Most atopic patients (253; 78%) were allergic to mites. Alcohol consumption was recorded as the number of standard (10‐g) drinking units regularly consumed per week. Two hundred subjects (43%) were abstainers, and 260 (57%) were regular consumers of a median of 30 g of alcohol per week. Total serum IgE was measured in all patients by latex‐enhanced nephelometry. Serum‐specific IgE was assayed by fluoroenzymeimmunoassay.Results: Total serum IgE increased along with ethanol consumption. On multivariate analysis, regular alcohol consumption greater than 70 g per week was associated with increased total serum IgE levels, even when adjusting for age, sex, atopy, and smoking. Among house‐dust mite–allergic patients, specific serum IgE values against the house dust mite Dermatophagoides pteronyssinus were higher in regular alcohol consumers than in abstainers. This difference was not observed among patients allergic to grass pollen (Lolium perenne).Conclusions: Alcohol consumption, even in moderate quantities, is associated with increased total and specific IgE concentrations in subjects studied in an allergy clinic. Alcohol intake should be taken into account in epidemiological studies of total serum IgE levels.
Adduction of Soluble Proteins with Malondialdehyde‐Acetaldehyde (MAA) Induces Antibody Production and Enhances T‐Cell Proliferation
Authors: Willis Monte S. , Klassen Lynell W. , Tuma Dean J. , Sorrell Michael F. , Thiele Geoffrey M. 
Published: April 2006

Background: The alcohol metabolites malondialdehyde and acetaldehyde can combine to form stable adducts (MAA) which are found in the livers of humans and rats after significant alcohol ingestion. While adducted proteins induce antibody responses in the absence of adjuvants, the mechanisms by which these responses occur are unknown. Thus, it was the purpose of these studies to investigate how MAA modification stimulates antibody and T‐cell responses in the absence of adjuvants.Methods: Hen egg lysozyme (HEL) was modified with increasing levels of MAA and was used as an immunogen, and antibody and T‐cell responses were determined. The role of scavenger receptors in the immunogenicity of MAA‐adducted proteins was also investigated.Results: Maximum antibody response was induced after immunization with 1.8 nM MAA/nM HEL, and was primarily an IgG1 response to HEL as determined by inhibition ELISAs. T‐cell proliferative responses after immunization with HEL‐MAA were solely to HEL. Immunization with a scavenger receptor ligand in conjunction with HEL‐MAA increased the predominant IgG1 response and sharply decreased the IgG2a response by approximately 50%. Binding of HEL‐MAA by splenocytes was determined by flow cytometry to be approximately 15% greater than HEL alone, showing a doubling of the geometric mean fluorescence. Also, most of the cells that bound HEL‐MAA were class II positive, indicating that antigen‐presenting cells can bind the MAA‐adducted HEL, and potentially initiate immune responses.Conclusions: MAA modification of proteins induces antibody and T‐cell proliferative responses in vivo. Initial studies suggest that these responses may be mediated by scavenger receptors that recognize MAA‐adducted proteins. This suggests a mechanism by which proteins modified with oxidative products associated with chronic ethanol consumption may alter immune responses that may play an active role in the development and/or progression of alcoholic liver disease.
Acamprosate, MK‐801, and Ifenprodil Inhibit Neurotoxicity and Calcium Entry Induced by Ethanol Withdrawal in Organotypic Slice Cultures From Neonatal Rat Hippocampus
Authors: Mayer Sveta , Harris Barton R. , Gibson D. Alex , Blanchard John A. , Prendergast Mark A. , Holley Robert C. , Littleton John 
Published: April 2006

Background The antirelapse drug acamprosate has previously been reported to inhibit activating effects of polyamines on N‐methyl‐D‐aspartic acid receptor (NMDAR) function. Because increased synthesis of polyamines has been suggested as a mechanism for potentiation of NMDAR function during ethanol withdrawal, we evaluated the effects of acamprosate, MK‐801, and ifenprodil in a cell culture model of ethanol withdrawal–induced neurotoxicity.Methods Organotypic hippocampal cultures from 8‐day‐old neonatal rats were maintained in vitro for 23 days before experimental use. The ethanol withdrawal model consisted of exposing cultures to ethanol (70–100 mM) for 4 days before being “withdrawn” into Calcium‐Locke's buffer for 1 hr and then into minimal medium for 23 hr. Uptake of 45CaCl2 and propidium iodide by damaged cells was assessed 1 hr and 24 hr after the start of ethanol withdrawal, respectively. Additional studies examined effects of exposure to NMDA (50 μM) or spermidine (100 μM) on withdrawal‐induced hippocampal damage. Last, these studies examined the ability of the sodium salt of acamprosate (Na‐acamprosate, 200 μM), ifenprodil (50 μM), or MK‐801 (30 μM) to inhibit neurotoxicity and 45Ca2+ entry produced by these insults.Results Ethanol withdrawal was associated with significantly greater toxicity and 45Ca2+ entry, relative to controls. Exposure to spermidine and NMDA during ethanol withdrawal further increased neurotoxicity and 45Ca2+ entry. Acamprosate, ifenprodil, and MK‐801 almost completely prevented ethanol withdrawal–induced toxicity and 45Ca2+ entry. Acamprosate also reduced spermidine‐induced neurotoxicity during ethanol withdrawal but was ineffective against NMDA‐induced toxicity or 45Ca2+ entry at this time.Conclusions The results support the contention that acamprosate, like ifenprodil, interacts with polyamines and that these compounds may be effective in reducing consequences of ethanol withdrawal. NMDAR activation is also strongly implicated in ethanol withdrawal neurotoxicity, but whether acamprosate causes any of these effects in this preparation directly via the NMDAR remains uncertain.