bluuebunny/crossref_metadata_2025 huggingface dataset:
Reduced Hypothalamic POMC and Anterior Pituitary CRF1 Receptor mRNA Levels After Acute, but Not Chronic, Daily “Binge”Intragastric Alcohol Administration
Authors: Zhou Yan , Franck Johan , Spangler Rudolph , Maggos Christopher E. , Ho Ann , Kreek Mary Jeanne
Published: May 2006

Background:

Endogenous corticotropin‐releasing factor (CRF), its pituitary CRF1 receptor, and proopiomelanocortin (POMC) may be involved in the hypothalamic‐pituitary‐adrenal (HPA) responses to alcohol.

Methods:

Alcohol (1.5 g/kg) or water was administered intragastrically to male Fischer rats after the “binge'’pattern regimen, that is, three times daily at 1 hr intervals at the beginning of the light cycle. The levels of CRF, CRF1 receptor, and POMC mRNAs in the hypothalamic‐pituitary axis were measured after acute (1 day) or chronic (14 days) binge pattern alcohol administration. Plasma levels of ACTH and corticosterone were measured to examine time‐dependent alterations of HPA responses.

Results:

Plasma ACTH and corticosterone levels were elevated dramatically after 1 day of acute binge pattern alcohol administration. After 14 days of chronic alcohol, however, no elevation in plasma ACTH levels and an attenuated elevation in plasma corticosterone levels were found. CRF mRNA levels in the hypothalamus were not altered after either acute or chronic alcohol administration. CRF1 receptor mRNA levels in the anterior pituitary were decreased significantly after acute administration, with no change after chronic alcohol administration. POMC mRNA levels in the anterior pituitary were not altered by either acute or chronic alcohol administration. In the hypothalamus, POMC mRNA levels were decreased significantly after acute but not chronic binge alcohol administration.

Conclusions:

These results suggest that (1) rats exposed to chronic binge alcohol develop tolerance in HPA activity, as shown by no elevation of ACTH and an attenuated corticosterone response to chronic alcohol after initial dramatic elevations by acute alcohol administration; (2) a concurrent acute decrease in CRF1 receptor mRNA levels in the anterior pituitary is associated with increased HPA activity, and (3) alterations of POMC gene expression in the hypothalamic region may have implications for a molecular understanding of the neuroendocrine response to alcohol.
Chronic, But Not Acute, Nicotine Exposure Attenuates Ethanol Withdrawal‐Induced Hippocampal Damage In Vitro
Authors: Prendergast Mark A. , Harris Barton R. , Mayer Sveta , Littleton John M.
Published: May 2006

Background:

Long‐term ethanol use and long‐term tobacco use frequently occur together, which suggests concurrent dependence on ethanol and nicotine. Consequences of this form of polydrug dependence are not well understood, however. Previous evidence suggests detrimental effects of long‐term ethanol and beneficial effects of nicotine exposure on neuronal viability. Thus, the present study was designed to use an organotypic hippocampal slice culture model to examine the ability of chronic and acute nicotine exposure to reduce neurotoxicity associated with withdrawal from long‐term ethanol exposure.

Methods and Results:

Twenty‐four hours of withdrawal after continuous 10 day ethanol exposure (50 or 100 mM in culture medium) resulted in cytotoxicity in hippocampal slice explants obtained from neonatal rat, most notably in pyramidal cell layers of the CA1 region. Exposure of slices to theN‐methyl‐d‐aspartate receptor blocker MK‐801 during ethanol withdrawal significantly reduced this toxicity. Exposure of slices to nicotine (0.1–10.0 μM) during the 24 hr withdrawal period did not reduce hippocampal damage. However, treatment of slices with nicotine (0.1–10.0 μM) during 10 days of ethanol exposure was associated with significant reductions in subsequent withdrawal‐induced cytotoxicity, an effect reduced by mecamylamine coexposure with nicotine and ethanol.

Conclusions:

These findings indicate the development of marked hippocampal neurotoxicity during withdrawal from long‐term ethanol exposure that is mediated, in part, by overactivation ofN‐methyl‐d‐aspartate receptors. Furthermore, these data suggest that one consequence of concurrent dependence on ethanol and nicotine may be reduced neurological damage associated with ethanol withdrawal.
Involvement of Nicotinic Receptors in Alcohol Self‐Administration
Authors: Lě A. D. , Corrigall W. A. , Watchus J. , Harding S. , Juzytsch W. , Li T.‐K.
Published: May 2006

Background:

Alcohol and nicotine, in the form of tobacco, are commonly co‐abused. Nicotinic receptors also have been implicated in alcohol action. We designed the present study to examine the possible involvement of nicotinic receptors in alcohol self‐administration.

Methods and Results:

Pretreatment with lower doses (0.1–0.4 mg/kg) of nicotine, administered acutely or chronically, did not affect alcohol consumption, whereas a higher dose (0.8 mg/kg) initially suppressed alcohol consumption but stimulated alcohol consumption on repeated treatment. We observed the same pattern of nicotine effects on alcohol self‐administration using an operant procedure. A dose of 0.8 mg/kg of nicotine initially suppressed operant responding for alcohol. Such suppression of alcohol self‐administration was more pronounced during the first 20 min of the 60 min operant session. Responding for alcohol in the nicotine treated group, however, was significantly increased above the saline treated group by the 5th day of treatment. Mecamylamine, a noncompetitive nicotinic receptor antagonist, reduced alcohol consumption, whereas dihydro‐β‐erythroidine (DHβE), a competitive nicotinic receptor antagonist, did not modify alcohol consumption.

Conclusions:

The stimulation of alcohol intake induced by nicotine treatment and the suppression of alcohol intake induced by mecamylamine provide evidence for the involvement of nicotinic receptors in alcohol consumption and/or self‐administration. The failure of DHβE to reduce alcohol consumption, however, suggests that ethanol‐nicotine interaction is mediated by other nicotinic receptor subtypes rather than α4β2 receptor subtype, or that mecamylamine acts through a nonnicotinic mechanism.
Neurocognitive Functioning of Adolescents: Effects of Protracted Alcohol Use
Authors: Brown Sandra A. , Tapert Susan F. , Granholm Eric , Delis Dean C.
Published: May 2006

Background:

The present study examined associations between alcohol involvement in early to middle adolescence and neuropsychological (NP) functioning.

Methods:

Alcohol‐dependent adolescents (n= 33) with over 100 lifetime alcohol episodes and without dependence on other substances were recruited from alcohol/drug abuse treatment facilities. Comparison (n= 24) adolescents had no histories of alcohol or drug problems and were matched to alcohol‐dependent participants on age (15 to 16 years), gender, socioeconomic status, education, and family history of alcohol dependence. NP tests and psychosocial measures were administered to alcohol‐dependent participants following 3 weeks of detoxification.

Results:

Alcohol‐dependent and comparison adolescents demonstrated significant differences on several NP scores. Protracted alcohol use was associated with poorer performance on verbal and nonverbal retention in the context of intact learning and recognition discriminability. Recent alcohol withdrawal among adolescents was associated with poor visuospatial functioning, whereas lifetime alcohol withdrawal was associated with poorer retrieval of verbal and nonverbal information.

Conclusions:

Deficits in retrieval of verbal and nonverbal information and in visuospatial functioning were evident in youths with histories of heavy drinking during early and middle adolescence.
Evidence of a Structural Effect for Alcohol Outlet Density: A Multilevel Analysis
Authors: Scribner Richard A. , Cohen Deborah A. , Fisher William
Published: May 2006

Background:

Ecological studies reveal that alcohol‐related outcomes tend to occur in high alcohol outlet density neighborhoods. The ecological design of these studies limits the interpretation of the findings in terms of the level of the effect. The effect of alcohol outlet density could be related to greater individual access to alcohol, an individual level effect, or to the grouping of drinkers by neighborhood, a structural effect at the neighborhood level.

Methods:

To differentiate between individual and neighborhood level possibilities, we conducted a multilevel study. Individual distance to the closest alcohol outlet was the individual level measure of the effect of alcohol outlet density, whereas the mean distance to the closest alcohol outlet for all individuals within a census tract was the neighborhood level measure for the effect of alcohol outlet density. We analyzed telephone surveys of 2604 telephone households within 24 census tracts stratified by poverty status and alcohol outlet density. Individual distance to alcohol outlets, age, sex, race/ethnicity, and level of education were entered as individual level covariates, and their corresponding aggregated means were entered as census tract level covariates (i.e., mean distance to outlets, mean age, percentage male, percentage Black, mean education).

Results:

Analysis of variance revealed that 16.2% of the variance in drinking norms and 11.5% of the variance in alcohol consumption were accounted for at the census tract level. In multivariate hierarchical analysis, individual distance to the closest alcohol outlet was unrelated with drinking norms and alcohol consumption, whereas mean distance to the closest alcohol outlet demonstrated a negative relation with drinking norms (βc= ‐5.50 ± 2.37) and with alcohol consumption (βe= ‐0.477 ± 0.195); that is, the higher the mean distance to the closest alcohol outlet, the lower the mean drinking norms score and mean level of alcohol consumption.

Conclusions:

The findings suggest that the effect of alcohol outlet density on alcohol‐related outcomes functions through an effect at the neighborhood level rather than at the individual level. Problem drinkers tend to be grouped in neighborhoods, an effect predicted by alcohol outlet density.
Maternal Ethanol Exposure Is Associated With Decreased Plasma Zinc and Increased Fetal Abnormalities in Normal but Not Metallothionein‐Null Mice
Authors: Carey Luke C. , Coyle Peter , Philcox Jeffrey C. , Rofe Allan M.
Published: May 2006

Background:

Ethanol profoundly affects fetal development, and this is proposed to be due primarily to a transient fetal zinc (Zn) deficiency that arises from the binding of Zn by metallothionein (MT) in the maternal liver. Zn homeostasis and fetal outcome were investigated in normal (MT+/+) and metallothionein‐null (MT‐/‐) mice in response to ethanol exposure.

Methods/Results:

Mice were treated with saline or ethanol (0.015 ml/g intraperitoneally at 0 and 4 hr) on day 8 of gestation (Gd8), and the degree of fetal dysmorphology was assessed on Gd18. The incidence of external abnormalities was significantly increased in offspring from MT+/+ dams exposed to ethanol, where 27.4% of fetuses were affected. MT‐/‐ ethanol‐, MT+/+ saline‐, and MT‐/‐ saline‐treated dams had fetuses in which the frequencies of abnormalities were 2.2, 6.4, and 6.9%, respectively. To investigate Zn homeostasis, nonpregnant mice were killed at intervals over 16 hr after ethanol injection. Liver MT concentrations in MT+/+ mice were increased 20‐fold by 16 hr, with a significant elevation evident by 4 hr, whereas liver Zn levels were also significantly increased by 2 hr and maintained for 16 hr. In parallel with these changes, plasma Zn concentrations in MT+/+ mice decreased by 65%, with minimum levels of 4.5±0.3 μmol/liter at 8 hr. Conversely, MT‐/‐ mice exhibited increased plasma Zn concentrations, with peak values of 20.8±0.3 observed at 4 hr.

Conclusion:

These findings link the teratogenic effect of ethanol to the induction of maternal MT and the limitation of fetal Zn supply from the plasma.
Effect of Chronic Alcohol Consumption on Total Plasma Homocysteine Level in Rats
Authors: Stickel Felix , Choi Sang‐Woon , Kim Young‐In , Bagley Pamela J. , Seitz Helmut K. , Russell Robert M. , Selhub Jacob , Mason Joel B.
Published: May 2006

Background: Chronic alcoholism in humans is associated with the development of hyperhomocysteinemia, the mechanism of which remains unclear. Among the causes of hyperhomocysteinemia is depletion of folate, vitamin B12, or vitamin B6, Population‐based studies indicate that folate is the strongest vitamin determinant of hyperhomocysteinemia and, in most settings, folate supplementation effectively lowers elevated homocysteine levels. However, it is not clear whether folate deficiency is the cause of alcoholrelated hyperhomocysteinemia.

Methods: In the present study, 10 male Sprague Dawley® rats were fed ethanol‐containing Lieber‐ DeCarli diets with 13 mg of folic acid per kilogram of diet. This represents a folate intake more than 20 times the basal requirement. Ethanol represented 36% of total energy, which yielded a concentration of 6.2% (vol/vol). The same number of rats were pair‐fed with isocaloric control diets that contained an identical level of folate in which ethanol was entirely replaced by maltodextrin.

Results: At the end of 4 weeks, alcohol‐fed rats did not show any significant reduction in plasma or hepatic folate concentrations, plasma pyridoxal‐5′‐phosphate concentration, or plasma vitamin B12 concentration. On the other hand, alcohol‐fed rats were significantly hyperhomocysteinemic (17.24 ± 4.63 μmol/liter,p < 0.01) compared to the nonalcohol group (10.73 ± 2.76 μmol/liter). Alcohol‐fed rats also had a significantly lower hepatic S‐adenosylmethionine and higher hepatic S‐adenosylhomocysteine levels.

Conclusions: Chronic alcohol consumption produces hyperhomocysteinemia by a mechanism that is related to interference with one‐carbon metabolism, and not through vitamin depletion.
Early Postnatal Ethanol Exposure Has Long‐Term Effects on the Performance of Male Rats in a Delayed Matching‐to‐Place Task in the Morris Water Maze
Authors: Girard T. A. , Xing H.‐C. , Ward G. R. , Wainwright P. E.
Published: May 2006

Background: There is concern that, in the absence of full‐blown fetal alcohol syndrome, binge drinking during pregnancy might produce long‐term cognitive deficits in offspring. Spatial working memory might be particularly vulnerable in this regard. This is the first study to address this issue in an animal model of binge exposure during the brain growth spurt using a delayed matching‐to‐place (DMTP) task in the Morris water maze.

Methods: Infant male rats were gastrostomized and reared artificially from postnatal days (PD) 5 to 18. From PD 6 to 9 they were fed either 6.5 g · kg−1· d−1 ethanol (EtOH) in a binge exposure model (BAC 302 mg/dl) or an isocaloric maltose‐dextrin solution (MD). The study included a third suckled control group (SC) that was reared normally. The rats were tested on a series of problems in the DMTP task, first as juveniles (PD 35) and then twice again as adults. Each problem included an initial search trial and a subsequent test trial. The first two phases of testing used delays of either 0 sec or 60 sec between these two trials. The third phase increased this delay to 60 sec and 2 hr. In addition, the rats were tested on a cued task in the water maze.

Results: EtOH rats were impaired relative to controls in their ability to relocate the hidden platform on the second trial, which followed the search trial. In Phases I and 2, there was no differential effect of ethanol on performance across the 0‐sec and 60‐sec delay conditions. However, EtOH rats were more affected by the longer 2‐hr delay in Phase 3. There were no group differences on the search trial, in swimming speed, or cued‐task performance.

Conclusions: These findings establish that binge exposure to ethanol during the brain growth spurt results in a long‐lasting impairment on the DMTP performance of rats in the water maze.
Avian Genetic Background Modulates the Neural Crest Apoptosis Induced by Ethanol Exposure
Authors: Debelak Katherine A. , Smith Susan M.
Published: May 2006

Background:Ethanol‐induced neural crest apoptosis likely contributes to the distinctive craniofacial phenotype that results from prenatal alcohol exposure. The mechanism responsible for this apoptosis is incompletely understood. A serendipitous change in poultry production flocks led to the discovery that, in chick, the embryo's genetic background modulates its susceptibility to ethanol‐induced apoptosis.

Methods:We examined the level of ethanol‐induced neural crest apoptosis in 11 chick layer strains or crosses, using acridine orange uptake.

Results:Holding the ethanol dose and exposure stage constant, strains were classified into very sensitive (Babcock ISA, HyLine W98, Babcock B300/Hampshire Red cross [BxHR]), moderately sensitive (Spafas, HyLine W36, Babcock B300), and nonresponsive (DeKalb White and Black, Shaver White and 2000, DeKalb White/Hampshire Red cross). Detailed examination of two susceptible strains (W98, BxHR) and a resistant strain (DeKalb White) revealed that the DeKalb's nonresponse was not caused by a shift in; timing of apoptosis, or to a lower alcohol exposure at either time of injection or time of death. Strains had identical stage distributions at the time of injection and at apoptosis; housing and diet were held constant.

Conclusions:Factors within the embryo and/or egg environment can affect the susceptibility to ethanol‐induced apoptosis. These sensitive and resistant strains will be important tools to dissect the molecular mechanism of ethanol‐induced apoptosis, and for understanding how these losses affect subsequent development.
Alcohol and Aldehyde Dehydrogenase Genotypes in Korsakoff Syndrome
Authors: Matsushita Sachio , Kato Motoichiro , Muramatsu Taro , Higuchi Susumu
Published: May 2006

Background: Previous studies have suggested a genetic predisposition to the development of Wernicke‐Korsakoff syndrome (WKS), a neuropsychiatric syndrome commonly associated with alcoholism; however, little is known about this genetic risk factor.

Methods: To test the hypothesis that altcrcd alcohol or aldehyde regulation is related to the development of WKS, the genetic polymorphisms of aldehyde dehydrogenase‐2 (ALDH2) and alcohol dehydrogenase‐2 (ADH2) were examined in 47 alcoholic subjects with WKS and compared with those of 342 alcoholic subjects without any WKS symptoms and 175 nonalcoholic controls.

Results: Although the frequencies of the ALDH2 genotypes and alleles did not differ significantly between alcoholic subjects with WKS and alcoholics without WKS, the ADH2*1/2*1 genotype and ADH2*1 allele were significantly increased in WKS.

Conclusions: These findings suggest that the ADH2*1/2*1 genotype is a risk factor for the development of WKS in alcoholic patients.
An Association Study Between Alcoholism and the Serotonergic Receptor Genes
Authors: Himei Akio , Kono Yoshihiro , Yoneda Hiroshi , Sakai Toshiaki , Koh Jun , Sakai Jun , Inada Yasushi , Imamichi Hiroyuki
Published: May 2006

Background: Linkage and association studies of alcoholism using DNA makers have been conducted without conclusive results. The comorbidity of alcoholism with affective disorder indicates that dysfunction of the serotonergic system may play an important role in developing alcoholism.

Methods: We studied the genetic association between alcoholism and alleles of the HTR1A, HTR2A, and HTR2C genes. The subjects were 91 biologically unrelated alcoholics and 90 controls. Polymorphisms of these genes were determined by polymerase chain reaction restriction fragment length polymorphisms, and the data were analyzed by X2 tests.

Results: We found no significant association between alcoholism and the HTR1A, HTR2A, and HTR2C genes.

Conclusions: The study results suggest that these serotonergic receptor genes may not directly contribute to the etiology of alcoholism.
Differential Display of Ethanol‐Induced Gene in N18TG2 Cells
Authors: Nishida Akira , Zensho Hidenobu , Hisaoka Kazue , Miyata Masahiko , Yamawaki Shigeto
Published: May 2006

Background:Recent advances in molecular biology, such as polymerase chain reaction (PCR) differential display, have enabled the screening of mRNAs transcriptionally regulated by chronic ethanol treatment. Screening of gene expression after ethanol exposure will be the most needed for new biological insights into alcoholism.

Methods:We used PCR differential display to detect differentially expressed RNAs in N18TG2 cells treated for 4 days with physiologic concentrations of ethanol (25 mM).

Results:We succeeded in identifying two differentially expressed RNAs in the ethanol‐treated cells. The increase in the expression of the two RNAs was verified by Northern hybridization analysis. Sequence analyses and searches of the sequence databases revealed that one of the RNAs was that of the heat shock cognate protein 73 (HSC73) gene and that the other was the product of a novel gene. The increase in the level of HSC73 mRNA after ethanol administration was consistent with similar reports from other laboratories, and indicated that our assay system would be applicable to the screening of up‐regulated gene expression during ethanol treatment. Rapid amplification of cDNA 5′‐ends (5′‐RACE) allowed us to determine the upstream sequence of the uncharacterized mRNA that would code for a protein of 113 amino acids. A homology search by MPsrch indicated very low homology to the calcium channel L‐type alpha 1 subunit.

Conclusions:The function of this new gene product is presently unknown, but our results indicate that an investigation of the pathophysiological significance of the gene in alcoholism would be worthwhile. Identification of genes that are influenced by chronic ethanol will certainly increase of the molecular mechanisms underlying physiologic dependence.
Acute and Chronic Effect of Alcohol on Ca2+ Channels in Hepatic Stellate Cells
Authors: Oide Hirosumi , Itatsu Tomoko , Hirose Miyoko , Wang Xian‐En , Nishiyama Daisuke , Takei Yoshiyuki , Sato Nobuhiro
Published: May 2006

Background: Hepatic stellate cells have been reported to play important roles in the regulation of hepatic microcirculation via cell contraction. Increase in intracellular calcium concentration is required to induce cell contraction. We have already reported the existence of L‐type voltage‐operated Ca2+ channels (VOCC), such as smooth muscle cells. On the other hand, alcohol has been known to disturb hepatic microcirculation. In this study, we evaluated the effect of acute and chronic treatment of alcohol on VOCC in rat hepatic stellate cells.

Methods: Stellate cells isolated from rats were cultured with or without 100 mM ethanol for up to 14 days. VOCC were detected by the patch clamp technique. Cells cultured for 14 days without ethanol were exposed to ethanol to investigate calcium current during membrane depolarization. α‐Smooth muscle actin (α‐SMA) was stained by indirect immunofluorescence.

Results: In the control model, VOCC were recognized in cells cultured for more than 7 days. Detection of VOCC increased from 9% on day 7 to 55% on day 14. On the other hand, VOCC in cells treated chronically with 100 mM ethanol appeared earlier than in the control and the incidences were significantly higher than those of the control accompanied with an early activation of cells. In contrast, simultaneous exposure to ethanol during the membrane depolarization inhibited Ca2+ current.

Conclusions: The expression of Ca2+ channels in stellate cells were up‐regulated by the chronic treatment of alcohol accompanied with the transformation to myofibroblast‐like phenotype. However, alcohol itself inhibited Ca2+ current.
Changes in Dopamine Transporter and c‐Fos Expression in the Nucleus Accumbens of Alcohol‐Tolerant Rats
Authors: Yoshimoto Kanji , Ueda Shuichi , Nishi Mayumi , Yang Yimu , Matsushita Hiroko , Takeuchi Yoshihiro , Kato Baku , Kawai Yoko , Noritake Kanae , Kaneda Shigehiro , Sorimachi Yoshihide , Yasuhara Masahiro
Published: May 2006

Background: We have shown that neurochemical functions of 5‐HT3 receptors in regulating dopamine (DA) release in the nucleus accumbens (ACC) after alcohol exposure compensate for the dysfunction of serotonergic activity to restore the original properties in processing alcohol tolerance, and that the development of alcohol dependence may be mediated by ACC 5‐HT3 receptors. In the present study, the effects of chronic alcohol consumption on the functions of the dopamine transporter (DAT) and the expression of c‐Fos proteins were investigated using in vivo brain microdialysis and immunocytochemistry.

Methods: Perfusion of cocaine and 1‐(2‐Bis‐(4‐fluorophenyl) methoxy) ethyl)‐4‐(3‐phenylpropyl) piperizine (GBR 12909) through the microdialysis probe membrane increased the extracellular levels of DA in ACC of alcohol‐treated rats that had developed alcohol tolerance by drinking 10% EtOH for 30 days.

Results: The magnitudes of DA reuptake or DAT inhibitors, cocaine, and GBR 12909 that induced DA availability in the ACC were significantly higher in alcohol‐treated rats than in controls. When compared with control rats, the alcohol‐treated rats exhibited higher levels of DA and its metabolite, DOPAC, in the ACC. Increased expression of the c‐Fos‐like protein was found in the ACC of alcohol‐treated rats. These results show that (1) chronic alcohol consumption desensitizes or decreases the DAT of DA terminals in the ACC and that (2) EtOH causes cellular hyperexcitability of ACC dopaminergic neurons with increased Fos expression during alcohol tolerance.

Conclusion: The findings suggested that an abnormality of the dopaminergic neurons in the ACC that are involved with DAT dysfunction is associated with the development of alcohol tolerance.
Before‐Discharge Intervention Method in the Treatment of Alcohol Dependence
Authors: Ino Aro , Hayasida Motoi
Published: May 2006

Background: Alcoholics have the fundamental problem of denying dependence on alcohol and minimizing their alcohol‐related problems. Therapeutic interventions often fail to help alcoholics become aware of their drinking problem and remain in long‐range treatment programs, which is a prerequisite for recovery from alcohol dependence.

Methods: Inpatients were assigned to either group 1 or 2 depending on which day of the week they were admitted to the hospital. A newly developed structured intervention method (Before‐Discharge Intervention Method, or BDIM) was employed with select (nonrandomized) hospitalized alcoholics in group 1 and their family members before the patients were discharged from the hospital. None of the patients in group 2 received the BDIM. With this intervention method, the alcoholic's family members delivered to him or her verbal messages that conveyed concern about the alcoholic's problem drinking, their observations of the alcoholic's past episodes of drinking problems, and wishes and support for abstinence. Unless patients died during hospitalization or would not be able to attend the hospital follow‐up clinic and local self‐help groups (Danshukai) after discharge, outcome evaluations were carried out on all patients in groups 1 and 2 during two calendar months, 3 months after the last BDIM patient left the hospital. Outcome measures included patient's and family members' attendance at hospital outpatient follow‐up sessions and self‐help group meetings, and patient's abstinence.

Results: Family members' attendance at hospital follow‐up sessions and/or self‐help group meetings was significantly higher in group 1 than in group 2. Among the three subgroups of discharged patients in either group 1 or 2—that is, those who lived with their spouse, those who lived with someone other than their spouse, and those who lived alone—only those in group 1 who lived with their spouse did significantly better than their counterparts in group 2 in three treatment outcome measures. However, patients' maintenance of abstinence was significantly better only when they and their family members both attended hospital outpatient follow‐up sessions and/or self‐help group meetings. We noted no other statistically significant difference between groups 1 and 2 in any of the other two subgroups of discharged or patients in any of the three treatment outcome variables. Irrespective of the BDIM, patients who lived alone did significantly more poorly than either those who lived with their spouse or those who lived with someone other than their spouse in terms of attendance at hospital follow‐up sessions and local self‐help group meetings and abstinence.

Conclusions: This intervention method can help the alcoholic face the reality of his or her drinking problems and alcohol dependence and thus remain longer in long‐range rehabilitation programs, which is a prerequisite for successful recovery from alcohol dependence.
Effect of Acute Ethanol Administration on the Intestinal Absorption of Endotoxin in Rats
Authors: Tamai Hironao , Kato Shinzo , Horie Yoshinori , Ohki Eiji , Yokoyama Hirokazu , Ishii Hiromasa
Published: May 2006

Background: Endotoxin has been implicated in the pathogenesis and progression of alcoholic liver disease. Not only inactivation of reticuloendothelial function, which reduces clearance of endotoxin, but also an increase in absorption of endotoxin from the intestine may be involved in mechanisms of ethanol‐induced endotoxemia. However, it is unclear how ethanol affects absorption of endotoxin from the intestine in vivo.

Methods: We gave 10 mg/kg of lipopolysaccharides to rats with water (group 1), 5% ethanol (group 2), or 20% ethanol (group 3) using an intubation tube to the stomach. Blood samples were collected and plasma endotoxin levels were measured. We used fluorescence spectrophotometer to examine permeability of the gut to macromolecules (fluorescein isothiocyanate‐dextran; 4,000 Da [FD4] or 20,000 Da [FD20]).

Results: Plasma endotoxin levels were not different between group 1 (9 ± 2 pg/ml) and group 2 (14 ± 3 pg/ml), whereas they significantly increased in group 3 with a peak at 60 min (87 ± 35 pg/ml). Acute ethanol administration did not affect clearance of endotoxin in rats. Hemorrhagic erosions of the proximal small intestine with epithelial cell loss were observed in group 3 at 4 hr, but no significant histological change was observed at 30 min by light microscopy. Acute ethanol administration (20%) increased the permeability of the small intestine to FD4 and FD20 in 30 min when no hemorrhagic erosions of the proximal small intestine with epithelial cell loss were observed.

Conclusions: Acute ethanol administration increases intestinal permeability before pathological changes are revealed by light microscopy. Acute ethanol ingestion, especially at high concentrations, facilitates the absorption of endotoxin from rats' small intestine via an increase in intestinal permeability, which may play an important role in endotoxemia observed in alcoholic liver injury.
Disulfiram Treatment Increases Plasma and Red Blood Cell Acetaldehyde in Abstinent Alcoholics
Authors: Rosman Alan S. , Waraich Afsar , Baraona Enrique , Lieber Charles S.
Published: May 2006

Background: Much of alcohol's toxicity is due to its product, acetaldehyde. The role of acetaldehyde derived from endogenous sources was assessed in alcoholic patients administered disulfiram, an inhibitor of aldehyde dehydrogenase.

Methods: The first part of the study included 23 subjects without biochemical or clinical evidence of chronic liver disease who were abstinent for 2 weeks; 11 patients were started on disulfiram (250 mg/day), whereas the other 12 were not given disulfiram and served as controls. The second part of the study included 13 alcoholic patients with clinical or pathological evidence of cirrhosis who also were administered disul firam for 2 weeks. Plasma and red blood cell (RBC) acetaldehyde as well as serum transaminases were measured at baseline and after 1 and 2 weeks of treatment.

Results: In the disulfiram‐treated group of alcoholics without known cirrhosis, RBC acetaldehyde levels increased from the pretreatment value of 2.98 ± 0.18 μM to 4.14 ± 0.33 μM after 1 week and to 4.14 ± 0.26 μM after 2 weeks of treatment (p < 0.001). Compared with the pretreatment values (2.07 ± 0.24 μM), plasma acetaldehyde levels also increased after 1 week (3.18 ± 0.32 μM) and 2 weeks (3.15 ± 0.26 μM) of disulfiram treatment (p < 0.001). There were no significant differences in sequential levels measured in either plasma or RBC acetaldehyde levels in patients who were not administered disulfiram. In the group of cirrhotic patients, the mean baseline RBC acetaldehyde value (3.60 ± 0.22 μM) was significantly higher than in noncirrhotics. Disulfiram therapy increased the RBC acetaldehyde after 1 week (4.63 ± 0.27 μM, p < 0.001) and 2 weeks of treatment (4.06 ± 0.28 μM, p < 0.05). Compared with baseline values, plasma acetaldehyde levels were significantly higher after 1 week but not after 2 weeks of disulfiram. There were no significant differences among serum transaminases in alcoholics administered disulfiram, although three cirrhotic patients did have clinically significant elevations.

Conclusions: In abstaining subjects given disulfiram, acetaldehyde concentrations increase, possibly due to diminished catabolism of endogenously generated acetaldehyde. Disulfiram should be given cautiously, especially in patients with cirrhosis.
Basis of Variable Sensitivities of GABAAReceptors to Ethanol
Authors: Mori Takashi , Aistrup Gary L. , Nishikawa Kiyonobu , Marszalec William , Yeh Jay Z. , Narahashi Toshio
Published: May 2006

Background:The GABAAsystem is believed to be one of the crucial target sites for ethanol. However, in the literature, data using various preparations yielded controversial conclusions regarding the ethanol potency to modulate the activity of GABAAreceptors. We have previously shown that the potency ofn‐alcohols to potentiate GABA‐induced currents is correlated with their carbon chain length. This correlation was further compared among four cell types in an attempt to explain the variable potencies of ethanol to potentiate GABA responses.

Methods:Whole‐cell patch clamp experiments were performed to determine and compare the potencies ofn‐alcohols in potentiating GABA‐induced currents in rat dorsal root ganglion (DRG) neurons, human embryonic kidney cells expressing the rat α1β2γ2S or α1β2γ2L subunits, and rat cortical neurons.

Results:The GABAA, receptors of the four cell types tested were all sensitive ton‐alcohols, albeit with different potencies and efficacies. The effective concentration to increase GABA‐induced currents to 125% of control (EC125) was correlated with the carbon chain length ofn‐alcohols, but slopes for this relationship are different among DRG neurons, the α1β2γ2S, and α1β2γ2L subunits. Thus, the potencies of lower alcohols such as ethanol differed among these cell types although higher alcohols such asn‐octanol were almost equally potent. In cortical neurons, however, the relationship was shifted in the direction of longer carbon chains, indicating that their sensitivity was lower than those of the other three cell types. The ethanol EC125values as obtained by experiments or those by extrapolation (in parenthesis) from the EC125‐carbon chain length relationship were: 169 (103) mM for DRG neurons, 501 (333) mM for the α1β2γ2L subunits, 781 (674) mM for the α1β2γ2S subunits, and (1897) mM for cortical neurons.

Conclusions:It was concluded that the GABAAreceptors of these four cell types were basically sensitive ton‐alcohols including ethanol but the sensitivity curve was shifted to the lower side in the order of decreasing sensitivity of DRG neurons > α1β2γ2L > α1β2γ2S > cortical neurons.
Serotonergic Function, Behavioral Disinhibition, and Negative Affect in Children of Alcoholics: The Moderating Effects of Puberty
Authors: Twitchell Geoffrey R. , Hanna Gregory L. , Cook Edwin H. , Fitzgerald Hiram E. , Zucker Robert A.
Published: May 2006

Background: Serotonergic (5‐HT) dysfunction has been implicated in both behavioral disinhibition and negative affect in adults. Although our group's previous work found decreased whole blood 5‐HT in high versus low behavior problem children of alcoholics, some child/adolescent studies report conflicting results, and 5‐HTs role in negative affect has been largely unexamined. Age‐related developmental factors may play a role in these relationships.

Methods: This report is from an ongoing prospective study of the development of risk for alcohol abuse/dependence and other problematic outcomes in a sample of families subtyped by father's alcoholism classification. The present study extends previous work and examines relationships between whole blood 5‐HT and both child behavioral disinhibition (an aggression index from the Child Behavior Checklist) and negative affect (Child Behavior Checklist Anxious/Depressed scale) in offspring from 47 families (N= 45 boys and 17 girls; mean age = 10.88 ± 2.03 yr).

Results: The most important finding was that puberty moderated relationships between 5‐HT and both behavioral disinhibition and negative affect with a relationship for pubescent children (n= 14, r= ‐0.54, p= 0.05;r= ‐0.57,p= 0.04, respectively) but no relationship for prepubescent children (n= 48,r= 0.05, p= 0.75; r= ‐0.15,p= 0.31, respectively).

Conclusions: The moderating effects of puberty may help clarify inconsistencies in child/adolescent literature. Furthermore, there appears to be a relationship between 5‐HT and negative affect which parallels that between 5‐HT and behavioral disinhibition. Pubertal status may be an important variable to evaluate as a moderator in relation to the developmental context of the role 5‐HT dysfunction may play in various models of behavior related to alcoholism over the early life course.
Decision‐Making Biases, Antisocial Personality, and Early‐Onset Alcoholism
Authors: Mazas Carlos A. , Finn Peter R. , Steinmetz Joseph E.
Published: May 2006

Background: Disinhibited, antisocial traits increase the risk for early‐onset alcoholism. Research also suggests that decision biases which favor immediate large rewards regardless of long‐term consequences may be important mechanisms associated with the biological substrates of antisocial traits. This study tested the hypothesis that early‐onset alcoholism with antisocial personality (ASP) would be associated with favoring immediate larger rewards despite their being associated with long‐term losses.

Methods: Twenty‐seven early‐onset alcoholics with and without a diagnosis of ASP, eight subjects with ASP but no alcohol dependence, and 32 controls were tested on a task that manipulated the magnitude of immediate rewards and the magnitude of long‐term punishments. The sample was recruited from the community via advertisements.

Results: Compared with subjects without ASP, subjects with ASP favored larger immediate rewards despite long‐term losses regardless of alcohol dependence; however, they learned to shift their decisions in a more advantageous direction over time. A disadvantageous decision bias also was associated with drinking greater quantities of alcohol and having a lower IQ.

Conclusions: This study suggests that ASP in a young adult noninstitutionalized sample was associated with a pattern of disadvantageous decision making similar to that observed in patients with antisocial behavioral characteristics associated with lesions in the ventromedial frontal cortex. The data also suggest that this pattern of disadvantageous decision making is associated with consuming larger quantities of alcohol but not consuming alcohol more frequently.
Sertraline Treatment for Alcohol Dependence: Interactive Effects of Medication and Alcoholic Subtype
Authors: Pettinati Helen M. , Volpicelli Joseph R. , Kranzler Henry R. , Luck Gary , Rukstalis Margaret R. , Cnaan Avital
Published: May 2006

Background: Characteristic behaviors of some alcohol‐dependent individuals, e.g., binge drinking, comorbid psychopathology, and some types of alcohol‐related problems, have been linked to abnormalities in serotonergic neurotransmission. However, studies that have evaluated serotonergic pharmacotherapy for reducing drinking have yielded conflicting results. One explanation for these findings is a general failure to distinguish alcohol subgroups that may be differentiated on the basis of serotonergic abnormalities. However, in 1996, Kranzler and colleagues reported that Type B alcoholics, who are characterized by high levels of premorbid vulnerability, alcohol dependence severity, and comorbid psychopathology, showed less favorable drinking outcomes in response to treatment with fluoxetine, a serotonin reuptake inhibitor, than with placebo. This medication effect was not seen in Type A alcoholics, i.e., those with lower risk/severity of alcoholism and psychopathology. The aim of the present study was to explore the validity of differential responding by alcohol‐dependent subtypes using the serotonin reuptake inhibitor, sertraline.

Methods: A k‐means clustering procedure was applied to a sample of alcohol‐dependent subjects enrolled in a 14‐week, placebo‐controlled trial of 200 mg/day of sertraline, classifying them into lower‐risk/severity (Type A: n= 55) and higher‐risk/severity (Type B: n= 45) subgroups.

Results: A significant interaction between alcoholic subtype and medication condition was found, confirming the findings of Kranzler and colleagues that alcoholic subtypes responded differentially to serotonergic medication. Somewhat at variance with their results, however, the present study showed that the lower risk/severity (Type A) subjects had more favorable outcomes when treated with sertraline compared to placebo.

Conclusions: Alcoholic subtypes differentially responded to sertraline when used as a treatment to reduce alcohol drinking, with one subtype having more favorable outcomes. Subtyping alcoholics may help to resolve conflicting findings in the literature on serotonergic treatment of alcohol dependence.
Hospital Morbidity of Alcohol Use Disorders in the Center of France
Authors: Reynaud Michel , Malet Laurent , Facy Françoise , Glanddier Phyllis
Published: May 2006

Background: The Auvergne region of central France has the third highest mortality rate in the country for alcohol‐related disorders and the highest level of alcohol consumption among young people.

Methods: An exhaustive cross‐sectional study of regional hospital morbidity related to alcohol was undertaken on a single day in May 1998, including 9,552 hospital beds. All inpatients age 16 and older in the Departments of Medicine, Surgery, Obstetrics and Gynecology, Psychiatry, and Medium‐Stay Services were studied. The aim was to define alcohol‐related behavior patterns (by using the Diagnostic and Statistical Manual of Mental Disorders [DSM‐IV] criteria of abuse and dependence and the CAGE questionnaire) and to measure the proportion of nonsomatic alcohol‐related care dispensed in hospital.

Results and Conclusions:

The prevalence of alcohol use disorders in all wards was 20%. Half of these patients were alcohol dependent, a quarter were diagnosed as alcohol abusers, and a quarter had an alcohol‐related problem that was not identified during the stay. Alcohol use disorders were more common in male inpatients (34% vs. 8% in female inpatients) and in certain age groups. One male subject in two and one female subject in five between 34 and 45 years had an alcohol‐related problem. Almost 25% of male inpatients studied between the ages of 16 and 20 years had an alcohol‐related problem, but only half had been diagnosed previously.

Hospital care for alcohol‐related health problems was seriously inadequate. On average, 38% of patients diagnosed with an alcohol use disorder received relevant nonsomatic alcohol care, of which 13% were alcohol abusers and 50% were alcohol‐dependent patients.

Significance:

This exhaustive study demonstrates the degree of alcohol‐related morbidity among hospitalized patients, which is particularly high in men, in the Auvergne region of France. The study emphasizes the lack of diagnosis, particularly for the young, and the apparent deficiencies in the hospital management of these patients.
Mitochondrial Glutathione Replacement Restores Surfactant Synthesis and Secretion in Alveolar Epithelial Cells of Ethanol‐Fed Rats
Authors: Guidot David M. , Lou Brown Ann S.
Published: May 2006

Background: Chronic alcohol abuse increases the incidence and severity of acute lung injury in critically ill patients. Previously we determined that ethanol ingestion in rats dramatically decreased alveolar epithelial cellular levels of glutathione and surfactant synthesis and secretion in vitro. Previous studies in alcoholic liver disease suggest that mitochondrial glutathione levels, and not cellular levels per se, are involved in the pathogenesis of ethanol‐mediated hepatotoxicity. Therefore, we hypothesized that alveolar epithelial mitochondrial glutathione depletion mediates the observed defects in surfactant synthesis and secretion in ethanol‐fed rats.

Methods: Male Sprague‐Dawley rats were fed the Lieber‐DeCarli liquid diet with or without ethanol (36% of total calories) for 6 weeks. In some experiments, ethanol‐fed rats were then switched to the control diet for 1 week, with or without glutathione supplementation with either N‐acetylcysteine (NAC) or procysteine (PRO). Alveolar epithelial type II cells were then isolated and glutathione levels (cytosolic and mitochondrial) and surfactant production (synthesis and secretion) were determined.

Results: Ethanol ingestion decreased (p < 0.05) mitochondrial and cytosolic levels of glutathione, and surfactant synthesis and secretion in isolated type II cells when compared to cells from control‐fed rats. NAC treatment restored (p < 0.05) cytosolic but not mitochondrial glutathione levels (p > 0.05), and had no effect (p > 0.05) on surfactant synthesis and secretion in type II cells isolated from ethanol‐fed rats. In contrast, PRO treatment restored (p < 0.05) cytosolic and mitochondrial glutathione levels, and normalized (p < 0.05) surfactant synthesis and secretion in type II cells isolated from ethanol‐fed rats.

Conclusions: These results suggest that mitochondrial, and not simply cytosolic, replacement of glutathione is necessary to improve surfactant function in critically ill patients with a history of alcohol abuse.
Prenatal Alcohol Exposure and Depressive Features in Children
Authors: O'Connor Mary J. , Kasari Connie
Published: May 2006

Background: This study examined the association between prenatal alcohol exposure and self‐report of depressive symptoms in 5‐ to 6‐year‐old children. Higher levels of prenatal alcohol exposure were hypothesized to be associated with endorsement of a greater number of depressive symptoms in children. It was also hypothesized that maternal depression, although associated with drinking behavior, would contribute independently to outcome. Finally, the mother's behavior toward the child, as well as current drinking practices, were postulated to mediate the relationship between prenatal alcohol exposure and child depressive symptoms.

Methods: Participants were 41 mother‐child dyads who had been followed longitudinally since the children were 1 year of age. Self‐report questionnaires for maternal and child depression were used.

Results: Results revealed that prenatal alcohol exposure, maternal depression, and child gender seemed to be highly associated with child depressive symptoms. Girls who had higher levels of prenatal alcohol exposure and whose mothers acknowledged higher levels of depression endorsed the highest number of depressive symptoms. Neither the mother's behavior in interaction with the child nor her current level of alcohol consumption mediated the relationship.

Conclusions: The importance of considering prenatal alcohol exposure as a risk variable in the prediction of childhood‐onset depression and the possible neurological mechanisms underlying depression in children with alcohol exposure in utero are discussed.