bluuebunny/crossref_metadata_2025_split huggingface dataset:
Expression of c‐Fos in Alko Alcohol Rats Responding for Ethanol in an Operant Paradigm
Authors: Weitemier Adam Z. , Woerner August , Bäckström Pia , Hyytiä Petri , Ryabinin Andrey E. 
Published: April 2006

Background: Identification of the brain regions involved in ethanol administration is important for understanding the neurobiology of ethanol addiction. Animal studies with different brain mapping techniques found that voluntary ethanol self‐administration leads to changes in activity of specific brain regions in patterns that only partially overlap with patterns of brain regions affected by involuntary (i.e., experimenter‐administered) ethanol administration. As an extension of studies mapping changes in neural activity after voluntary ethanol drinking, this study analyzed expression of the inducible transcription factor c‐Fos after ethanol consumption in an operant procedure.Methods: AA (Alko alcohol) rats were trained to operantly respond for water, 0.2% saccharin, 0.2% saccharin/10% (w/v) ethanol, or 10% ethanol in a 30‐min limited‐access procedure. Animals were allowed to self‐administer solutions for at least 40 ethanol response sessions and were killed 1.5 hr after beginning of the last session. Forty‐seven brain regions were immunohistochemically analyzed for c‐Fos expression.Results: In this paradigm, ethanol dose‐dependently increased c‐Fos expression in the Edinger‐Westphal nucleus (EW) and decreased expression in the dorsal tenia tecta compared with no‐ethanol controls. No effects of saccharin on c‐Fos expression were found.Conclusions: Our results extend previous findings of preferential sensitivity of EW to alcohol in voluntary self‐administration procedures to operant responding for ethanol and warrant further investigation of ethanol's effects on the EW. The finding that ethanol attenuated c‐Fos expression in the tenia tecta is novel. Taken together, these findings confirm that voluntary ethanol self‐administration leads to changes in activity of a limited number of brain regions with previously unexamined roles in ethanol sensitivity and addiction.
Can Encouraging Substance Abuse Patients to Participate in Self‐Help Groups Reduce Demand for Health Care? A Quasi‐Experimental Study
Authors: Humphreys Keith , Moos Rudolf 
Published: April 2006

Background: Twelve‐step‐oriented inpatient treatment programs emphasize 12‐step treatment approaches and the importance of ongoing attendance at 12‐step self‐help groups more than do cognitive‐behavioral (CB) inpatient treatment programs. This study evaluated whether this difference in therapeutic approach leads patients who are treated in 12‐step programs to rely less on professionally provided services and more on self‐help groups after discharge, thereby reducing long‐term health care costs.Methods: A prospective, quasi‐experimental comparison of 12‐step‐based (N = 5) and cognitive‐behavioral (n= 5) inpatient treatment programs was conducted. These treatments were compared on the degree to which their patients participated in self‐help groups, used outpatient and inpatient mental health services, and experienced positive outcomes (e.g., abstinence) in the year following discharge. Using a larger sample from an ongoing research project, 887 male substance‐dependent patients from each type of treatment program were matched on pre‐intake health care costs (N = 1774). At baseline and 1‐year follow‐up, patients’ involvement in self‐help groups (e.g., Alcoholics Anonymous), utilization and costs of mental health services, and clinical outcomes were assessed.Results: Compared with patients treated in CB programs, patients treated in 12‐step programs had significantly greater involvement in self‐help groups at follow‐up. In contrast, patients treated in CB programs averaged almost twice as many outpatient continuing care visits after discharge (22.5 visits) as patients treated in 12‐step treatment programs (13.1 visits), and also received significantly more days of inpatient care (17.0 days in CB versus 10.5 in 12‐step), resulting in 64% higher annual costs in CB programs ($4729/patient, p < 0.001). Psychiatric and substance abuse outcomes were comparable across treatments, except that 12‐step patients had higher rates of abstinence at follow‐up (45.7% versus 36.2% for patients from CB programs, p < 0.001).Conclusions: Professional treatment programs that emphasize self‐help approaches increase their patients’ reliance on cost‐free self‐help groups and thereby lower subsequent health care costs. Such programs therefore represent a cost‐effective approach to promoting recovery from substance abuse.
MK‐801 Can Exacerbate or Attenuate Behavioral Alterations Associated With Neonatal Alcohol Exposure in the Rat, Depending on the Timing of Administration
Authors: Thomas J.D. , Fleming S.L. , Riley E.P. 
Published: April 2006

Background: We have reported that administration of MK‐801, an NMDA receptor antagonist, during ethanol withdrawal in the developing rat attenuates ethanol's adverse effects on behavioral development. In the present study, we altered the timing of MK‐801 delivery in relation to the last alcohol dose to determine if its protective effects were specific to the ethanol withdrawal phase.Methods: Five groups of rats were artificially reared and exposed to alcohol in a binge‐like manner on postnatal day (PD) 6, producing peak blood alcohol levels of 335 mg/dl that cleared to 0 mg/dl by 33 hours. Four groups received MK‐801 at various times after alcohol treatment (0, 9, 21, or 33 hr post‐ethanol). The fifth alcohol‐treated group received saline. Two artificially reared control groups were included: one was injected with saline and the other injected with 0.5 mg/kg MK‐801. Finally, a normally reared suckle control group was also included. Activity level and performance on a spatial discrimination reversal‐learning task were evaluated at PD 18 and PD 40, respectively.Results : Administration of MK‐801 at the same time as ethanol treatment (0 hr) produced a high rate of mortality. Ethanol exposure on PD6 increased activity level relative to controls. Administration of MK‐801 at 0 hr exacerbated this ethanol‐induced overactivity, whereas administration of MK‐801 at 21 and 33 hr reduced the severity of ethanol‐related overactivity. Similarly, ethanol exposure on PD 6 significantly increased the number of errors committed on a spatial discrimination reversal‐learning task. MK‐801 injections 9 hrs after ethanol exacerbated this effect, whereas MK‐801 treatment 33 hrs after ethanol attenuated this effect. Thus, MK‐801 administration at the time of ethanol treatment was highly toxic, whereas during the withdrawal period it was protective.Conclusion : These data are consistent with the hypothesis that ethanol exposure in the neonatal rat inhibits the NMDA receptor, producing a subsequent rebound in NMDA receptor activation and possible excitotoxicity during withdrawal. Both the acute inhibitory effects of ethanol and the excitatory effects of withdrawal may contribute to fetal alcohol effects.
Hypothalamic Function in Response to 2‐Deoxy‐d‐Glucose in Long‐Term Abstinent Alcoholics
Authors: Umhau John C. , Petrulis Sarah G. , Diaz Rosalyn , Biddison James R. , George David T. 
Published: April 2006

Background: The body adapts to diverse stressful stimuli with a response characterized by activation of the hypothalamic‐pituitary‐adrenal (HPA) axis. Chronic alcohol consumption can cause changes in the function of this neuroendocrine system. Although many studies have examined this phenomenon in drinking and recently sober alcoholics, few studies have examined HPA axis function in long‐term sober alcoholics.Methods: To characterize HPA axis function in long‐term sober alcoholics, we used a challenge paradigm with 2‐deoxy‐d‐glucose (2‐DG). An infusion of 2‐DG (a nonmetabolizable glucose analog) induces a well‐characterized stress response. In a previous study, our laboratory found an exaggerated corticotropin and cortisol response in alcoholics abstinent 3 weeks; in this investigation we compared the effects of an infusion of 2‐DG on 19 healthy volunteers and 20 community‐living alcoholics who had been abstinent more than 6 months.Results: In contrast to the previous study, long‐term sober alcoholics did not have an exaggerated corticotropin and cortisol response after 2‐DG.Conclusions: Previously observed abnormalities in cortisol regulation in 3‐week‐sober alcoholics may be related to the acute effects of recent alcohol consumption and withdrawal. Future investigations into the metabolic function of alcoholics, particularly investigations involving the HPA system, should consider the possibility that normalization may not occur until long‐term abstinence has been achieved.
Comparison of Global Brain Gene Expression Profiles Between Inbred Long‐Sleep and Inbred Short‐Sleep Mice by High‐Density Gene Array Hybridization
Authors: Xu Yan , Ehringer Marissa , Yang Fan , Sikela James M. 
Published: April 2006

Background: Inbred long‐sleep (ILS) and short‐sleep (ISS) mice show significant central nervous system–mediated differences in sleep time for sedative dose of ethanol and are frequently used as a rodent model for ethanol sensitivity. In this study, we have used complementary DNA (cDNA) array hybridization methodology to identify genes that are differentially expressed between the brains of ILS and ISS mice.Methods: To carry out this analysis, we used both the gene discovery array (GDA) and the Mouse GEM 1 Microarray. GDA consists of 18,378 nonredundant mouse cDNA clones on a single nylon filter. Complex probes were prepared from total brain mRNA of ILS or ISS mice by using reverse transcription and 33P labeling. The labeled probes were hybridized in parallel to the gene array filters. Data from GDA experiments were analyzed with SQL‐Plus and Oracle 8. The GEM microarray includes 8,730 sequence‐verified clones on a glass chip. Two fluorescently labeled probes were used to hybridize a microarray simultaneously. Data from GEM experiments were analyzed by using the GEMTools software package (Incyte). Differentially expressed genes identified from each method were confirmed by relative quantitative reverse transcription–polymerase chain reaction (RT‐PCR).Results: A total of 41 genes or expressed sequence tags (ESTs) display significant expression level differences between brains of ILS and ISS mice after GDA, GEM1 hybridization, and quantitative RT‐PCR confirmation. Among them, 18 clones were expressed higher in ILS mice, and 23 clones were expressed higher in ISS mice. The individual gene or EST's function and mapping information have been analyzed.Conclusions: This study identified 41 genes that are differentially expressed between brains of ILS and ISS mice. Some of them may have biological relevance in mediation of phenotypic variation between ILS and ISS mice for ethanol sensitivity. This study also demonstrates that parallel gene expression comparison with high‐density cDNA arrays is a rapid and efficient way to discover potential genes and pathways involved in alcoholism and alcohol‐related physiologic processes.
Altered GABAA Receptor Subunit and Splice Variant Expression in Rats Treated With Chronic Intermittent Ethanol
Authors: Petrie Jennifer , Sapp Douglas W. , Tyndale Rachel F. , Park Maenghee Kang , Fanselow Michael , Olsen Richard W. 
Published: April 2006

Background: Intermittent chronic administration of ethanol to rats has been shown previously to produce a hyperexcitable, kindling‐like state, accompanied by reduced inhibitory synaptic transmission in the hippocampus and changes in γ‐aminobutyric acid type A (GABAA) receptors. Further information is needed on the detailed changes in GABAA receptors and their time course and persistence, as is comparison to changes after chronic, continuous ethanol.Methods: GABAA receptors were analyzed in the rat brain after chronic intermittent ethanol (CIE) by using radioligand binding, photoaffinity labeling of polypeptides, and estimates of messenger RNA (mRNA) levels of receptor subunits by reverse transcriptase–polymerase chain reaction (RT‐PCR) and in situ hybridization.Results: CIE rats were confirmed to have increased GABAA receptor binding of the benzodiazepine partial inverse agonist and ethanol antidote ligand Ro15‐4513, due to increased expression of the α6 subunit polypeptide in the cerebellum, shown by photoaffinity labeling. Estimates of mRNA levels by use of RT‐PCR did not reveal any significant increase in α6 or in several other receptor subunits in several brain regions, but a decrease in the ratio of the long and short splice variants (L/S) of the γ2 subunit was detected in the hippocampus, especially the CA1 region.Conclusions: Changes in GABAA receptors were found in rats given CIE. Increased α6 subunit in the cerebellum was demonstrated by using both the binding to diazepam‐insensitive sites for [3H]Ro15‐4513 and increased levels of the 57‐kDa α6 polypeptide after photoaffinity labeling with this ligand. This increase appeared after 30 doses of ethanol and decayed to normal 1 week after ethanol was discontinued. The transient change in cerebellar α6 subunit‐containing receptors, also reportedly seen after chronic continuous ethanol, is thus unlikely to account for the persistently hyperexcitable, kindled, seizure‐susceptible state seen in CIE. However, the significant decrease in γ2 subunit L/S splice variant ratio in the hippocampus implies changes in GABAA receptor function, possibly involving protein phosphorylation by protein kinase C. Altered receptor trafficking and turnover associated with synaptic plasticity may contribute to the observed reduced inhibition in the hippocampus and other signs of alcohol dependence produced by CIE.
4‐Methylpyrazole Decreases Salivary Acetaldehyde Levels in ALDH2‐Deficient Subjects but Not in Subjects With Normal ALDH2
Authors: Väkeväinen Satu , Tillonen Jyrki , Salaspuro Mikko 
Published: April 2006

Background: Carcinogenic acetaldehyde is produced from ethanol locally in the upper digestive tract via alcohol dehydrogenases (ADHs) of oral microbes, mucosal cells, and salivary glands. Acetaldehyde is further oxidized into less harmful acetate mainly by the aldehyde dehydrogenase‐2 (ALDH2) enzyme. ALDH2‐deficiency increases salivary acetaldehyde levels and the risk for upper digestive tract cancer in heavy alcohol drinkers. 4‐methylpyrazole (4‐MP) is an ADH‐inhibitor which could reduce the local production of acetaldehyde from ethanol in the saliva.Methods: Five ALDH2‐deficient subjects and six subjects with normal ALDH2 ingested a moderate dose of alcohol (0.4 g/kg of body weight), whereafter their salivary acetaldehyde levels, heart rate, skin temperature, and blood pressure were followed for up to four hours. Blood acetaldehyde and ethanol levels were determined at 60 min. The experiment was repeated after a week. Two hours before the second study day, the volunteers received 4‐MP, 10–15 mg/kg of body weight orally.Results: Total ethanol elimination rate decreased with 4‐MP by 38–46% in all subjects. 4‐MP also reduced blood acetaldehyde levels and suppressed the cardiocirculatory responses of the ALDH2‐deficient volunteers. In addition, salivary acetaldehyde production in ALDH2‐deficient subjects was significantly reduced when correlated with salivary ethanol levels. On the contrary, 4‐MP did not have any effect on salivary or blood acetaldehyde levels in subjects with normal ALDH2.Conclusions: A single dose of 4‐MP before ethanol ingestion reduces ethanol elimination rate, the flushing reaction, and both blood and salivary acetaldehyde levels in ALDH2‐deficient subjects but not in subjects with the normal ALDH2 genotype. These results suggest that the role of oral mucosal and glandular ADHs in salivary acetaldehyde production is minimal and support earlier findings indicating that salivary acetaldehyde production is mainly of microbial origin in subjects with normal ALDH2.
Ethanol‐Induced Impairments in Spatial Working Memory Are Not Due to Deficits in Learning
Authors: Hoffmann Sarah E. , Matthews Douglas B. 
Published: April 2006

Background: Acute ethanol administration impairs spatial reference memory and spatial working memory. However, the experimental designs previously used to test spatial working memory fail to make a distinction between the acquisition, or learning, of spatial information and the retention of this information. This study demonstrates that acute ethanol administration impairs spatial working memory, by using a novel experimental design that eliminates the confound between the learning of new spatial information and the testing of this information.Methods: Long‐Evans male rats received three forced trials to the same place for food reward on an elevated radial arm maze. Subjects were then given six free‐choice trials in the first acquisition session, followed by a 30‐min consolidation period before an additional six free‐choice trials were administered—the retention session. Animals were trained to a criterion of five of six correct in both the acquisition and retention over 2 consecutive days. Once criteria were obtained, subjects received either saline or one of three ethanol doses immediately after the acquisition session to investigate whether ethanol alters retention of the learned spatial information.Results: Acute ethanol administration impaired spatial working memory. Rats tested under saline and low‐dose ethanol (1.0 g/kg) made significantly more place choices than rats tested under moderate‐ or high‐dose ethanol (1.5 and 2.0 g/kg, respectively). Ethanol produced a temporary impairment in that no significant differences were found when subjects were retrained and retested 24 hr after initial testing.Conclusions: These results demonstrate that acute ethanol administration impairs spatial working memory and that such a deficit is not contingent on a learning impairment. These results support earlier findings that acute ethanol administration impairs spatial working memory but provide a significant advance by validating a novel training procedure that allows for direct investigation of working memory. Ethanol's impairment of both spatial working memory and spatial reference memory strengthens the similarities between memory impairments due to ethanol administration and memory impairments due to hippocampal lesions.
In Utero Ethanol Exposure Causes Mitochondrial Dysfunction, Which Can Result in Apoptotic Cell Death in Fetal Brain: A Potential Role for 4‐Hydroxynonenal
Authors: Ramachandran Vinitha , Perez Antonio , Chen Juanjuan , Senthil Duraisamy , Schenker Steven , Henderson George I. 
Published: April 2006

Background: In utero ethanol exposure causes abnormal fetal brain development that may partly be due to enhanced cell death. The mechanisms underlying this remain to be defined, but ethanol‐induced oxidative stress may play a role. The following studies investigated the effects of short‐term in utero ethanol exposure on fetal brain mitochondrial events that are known to elicit apoptotic cell death. Evidence is presented suggesting that 4‐hydroxynonenal (HNE), a toxic product of lipid oxidation, is a causal factor in the observed mitochondrial damage.Methods: Mitochondria were isolated from control and ethanol‐exposed fetal brains (days 17 and 18 of gestation). Permeability transition was determined spectrophotometrically, and cytochrome c and apoptosis‐inducing factor (AIF) release were assessed by Western blotting. Caspase‐3 activity and DNA fragmentation were determined both as markers for mitochondrially mediated apoptosis and as consequences of cytochrome c and AIF release.Results: Maternal ethanol intake caused an increase in mitochondrial permeability transition, and this was accompanied by cytochrome c and AIF release from fetal brain mitochondria that exceeded control values by 62 and 25%, respectively (p < 0.05). In utero ethanol exposure resulted in a 30% increase in caspase‐3 activity and a 25% increase in DNA fragmentation (p < 0.05) in the fetal brain. HNE levels were increased by 23% (p < 0.05) in mitochondria by in vivo ethanol exposure. In vitro treatment of fetal brain mitochondria with HNE (25–100 μM) also caused increases in mitochondrial permeability transition, as well as dose‐dependent releases of cytochrome c and AIF.Conclusions: These studies illustrate that in utero ethanol exposure can elicit a cascade of events in the fetal brain that are consistent with mitochondrially mediated apoptotic cell death. Additionally, the increase in mitochondrial content of HNE after ethanol intake and the ability of HNE added to fetal brain mitochondria to mimic these effects of in vivo ethanol exposure support a potential role for HNE in the proapoptotic responses to ethanol.
Effect of Alcohol Consumption on Host Release of Interleukin‐17 During Pulmonary Infection With Klebsiella pneumoniae
Authors: Shellito Judd E. , Zheng Min Quan , Ye Peng , Ruan Sanbao , Shean Mary K. , Kolls Jay 
Published: April 2006

Background: A link between alcohol abuse and bacterial pneumonia has been recognized for centuries, but mechanisms to explain this relationship are unclarified. Interleukin‐17 (IL‐17) is a lymphocyte‐derived cytokine that is part of the inflammatory cytokine cascade. Previous studies from our laboratory indicated that IL‐17 is released in lung tissue in a murine model of bacterial pneumonia caused by Klebsiella pneumoniae. The effects of alcohol consumption on pulmonary release of IL‐17 are unknown.Methods: Mice were maintained on 20% ethanol in drinking water or on a control diet without alcohol. After 2 weeks, alcohol and control mice were challenged with intratracheal K. pneumoniae. Mice were followed for survival after bacterial challenge, neutrophil recruitment was assayed as myeloperoxidase, and IL‐17 was measured in lung lavage fluid by enzyme‐linked immunosorbent assay. In additional experiments, splenocytes from control mice were incubated with ethanol in vitro, and release of IL‐17 was measured in culture supernatants. Finally, control and alcohol mice received intrapulmonary gene transfer of E‐1–deleted adenovirus containing the murine IL‐17 gene. These mice were then challenged with K. pneumoniae and followed for survival and neutrophil recruitment.Results: In these studies, we demonstrate that a 2‐week history of ethanol consumption in mice suppresses release of IL‐17 into lung tissue, decreases neutrophil recruitment, and increases mortality from experimental K. pneumonia. In vitro experiments confirm a direct suppressive effect of ethanol on the release of IL‐17 from splenocytes. In vivo administration of the IL‐17 gene in an adenoviral vector to alcohol‐consuming mice results in release of IL‐17 into lavage fluid and normalizes neutrophil recruitment and mortality after bacterial challenge.Conclusions: The results of these experiments strongly implicate IL‐17 as an important pathway for the immunosuppression associated with alcohol abuse and support gene therapeutic approaches to augment immune function in the alcoholic host or to treat infections associated with alcoholism.