bluuebunny/crossref_metadata_2025 huggingface dataset:
Enzymic Catalysis of the Accumulation of Acetaldehyde From Ethanol in Human Prenatal Cephalic Tissues: Evaluation of the Relative Contributions of CYP2E1, Alcohol Dehydrogenase, and Catalase/Peroxidases
Authors: Person Richard E. , Chen Hao , Fantel Alan G. , Juchau Mont R.
Published: April 2006

Background: The human prenatal brain is very sensitive to the toxic effects of ethanol, but very little information is available concerning the conversion of ethanol to the highly cytotoxic metabolite, acetaldehyde, in that organ. Thus, experiments were designed to investigate rates of accumulation of acetaldehyde from ethanol in the prenatal human brain.

Methods: Prenatal human cephalic tissue homogenates were used as enzyme sources and were compared with analogous preparations of adult rat livers. Generated acetaldehyde was derivatized with cyclohexane‐1,3‐dione to yield fluorescent decahydroacrizine‐1,8‐dione, which was readily separated, detected, and quantitated with HPLC.

Results: Detected rates of accumulation were unexpectedly high, even in the absence of added NADPH, NAD+, or H2O2, which are cofactors/cosubstrates for cytochrome P‐450‐, alcohol dehydrogenase‐ and catalase/peroxidase‐catalyzed reactions, respectively. Without added cofactors/cosubstrates or other components and under linear reaction conditions, rates in human prenatal cephalic preparations were approximately 20% of those observed with analogous preparations of adult rat livers. Cofactor/cosubstrate‐independent reactions were localized in the cytosolic (soluble) fraction and were strongly dependent on molecular oxygen (O2). They were not inhibited substantially by carbon monoxide (CO:O2= 80:20 vs N2:O2= 80:20) or by pyrazole in concentrations up to 10 mM and were only weakly inhibited by azide. Preincubations with excess catalase did not result in decreased activity. Reactions exhibited substrate saturation and heat inactivation indicating enzymic catalysis.

Conclusions: Experiments indicated a relatively rapid accumulation of acetaldehyde from ethanol in human prenatal brain tissues and suggested that the observed cofactor/cosubstrate‐independent reactions were largely independent of P‐450 cytochromes, alcohol dehydrogenases, or catalase/peroxidases. Results were consistent with catalysis by an as yet unidentified cytosolic oxidase(s).
Levels of γ‐Aminobutyric Acid‐Benzodiazepine Receptors in Abstinent, Alcohol‐Dependent Women: Preliminary Findings From an 123I‐Iomazenil Single Photon Emission Tomography Study
Authors: Lingford‐Hughes A. R. , Acton P. D. , Gacinovic S. , Boddington S. J. A. , Costa D. C. , Pilowsky L. S. , Ell P. J. , Marshall E. J. , Kerwin R. W.
Published: April 2006

Background: Although alcohol dependence in women is an increasing problem, little is known about the effects of alcohol on the female brain. Evidence from a few structural and functional neuroimaging studies suggests that the female brain may be more susceptible than the male brain to the harmful effects of alcohol. However, no in vivo studies of the neuropharmacology of alcohol dependence in women have been carried out. The aim of this preliminary study was to test the hypothesis that alcohol dependence in women is associated with greater reduction in γ‐aminobutyric acid (GABA)‐benzodiazepine receptor levels than in men with an equivalent drinking history.

Methods: We used single photon emission tomography and 123I‐iomazenil to label the central GABA‐benzodiazepine receptor and to compare semiquantified levels in 9 abstinent alcohol‐dependent and 13 control women. These groups were further compared with equivalent male groups from a previous study.

Results: There was a trend toward a reduction in GABA‐benzodiazepine receptor levels in alcohol‐dependent women, but this did not reach significance. These lower levels were seen primarily in the cerebellum, occipital lobes, and parietal cortex (left > right). This was in marked contrast with the pattern of reduction seen in the previous study of male dependence, where significant reductions were seen primarily in the frontal cortex.

Conclusions: Due to the semiquantitative analysis performed and the relatively small number of subjects in this study, which resulted in a nonsignificant trend, we can only comment on the differences in the pattern of lower levels of GABA‐benzodiazepine receptors seen in alcohol dependence in men and women. Although we are not able to ascertain whether the female brain is more susceptible to the effects of alcohol, it appears that alcohol has a differential effect on the central GABA‐benzodiazepine receptors in men and women. Recent animal evidence supports this hypothesis. Future studies should explore whether other neuropharmacological differences exist between men and women in alcohol dependence that could have implications for pharmacotherapy.
Alcohol Inhibits the Progression as Well as the Initiation of Atherosclerotic Lesions in C57Bl/6 Hyperlipidemic Mice
Authors: Emeson Eugene E. , Manaves Vlasios , Emeson Brian S. , Chen Lu , Jovanovic Igor
Published: April 2006

Background: Evidence that a moderate consumption of alcohol is associated with a reduced incidence of and mortality due to coronary artery disease continues to accumulate. Despite recent evidence that substances in red wine confer resistance to coronary artery disease, it is clear that at least a substantial proportion of the protective effect is due to the alcohol content of the beverage. We have previously shown that the chronic ingestion of alcohol incorporated into a total liquid diet during a 24‐week period inhibits the development of fatty streak lesions in hyperlipidemic C57Bl/6 mice. We have now repeated this study and demonstrated that alcohol continues to markedly inhibit atherogenesis during a 48‐week period.

Methods: Mice were fed a high fat atherogenic liquid diet with 0% or 6% alcohol or a high fat atherogenic pelleted diet with 0% or 15% alcohol in their drinking water. After 24 and 48 weeks on these diets, subgroups of mice were euthanized and the aortas were studied for extent of atherosclerosis. Plasma lipid levels were also measured and flow cytometry studies performed to characterize their T and B lymphocyte populations. Additional groups of mice were given the high fat atherogenic diets for 24 weeks to allow lesions to develop and were then treated with alcohol diets to determine whether they inhibit the progression of the lesions.

Results: The alcohol diets suppressed the development of atherosclerotic lesions at both 24 and 48 weeks in both the liquid and pelleted diet models. The addition of the alcohol diets after allowing lesions to form for 24 weeks halted the further progression of the lesions. The alcohol treatments also decreased the plasma levels of total cholesterol and high density lipoprotein (HDL) cholesterol at almost all time intervals.

Conclusions: We conclude that alcohol not only inhibits the initial development of atherosclerotic lesions but also inhibits the progression of existing atherosclerotic lesions. The alcohol‐mediated decrease in HDL cholesterol in these experiments suggests that HDL plays little or no role in amelioration of atherogenesis in this model.
Suppression of Ethanol Responding by Centrally Administered CTOP and Naltrindole in AA and Wistar Rats
Authors: Hyytiä Petri , Kiianmaa Kalervo
Published: April 2006

Background: Both μ‐ and δ‐opioid receptors have been implicated in the reinforcing actions of ethanol. However, selective opioid receptor antagonists have not altered ethanol intake in all rodent strains consistently, which suggests that genotype may modulate their suppressive effects. Therefore, we tested the effects of the selective μ‐antagonist D‐Pen‐Cys‐Tyr‐D‐Trp‐Orn‐Thr‐Pen‐Thr‐NH2(CTOP) and the selective δ‐antagonist naltrindole in both high‐drinking AA (Alko, Alcohol) and heterogeneous Wistar rats.

Methods: AA and Wistar rats were trained to respond for ethanol (10% w/v) in a two‐lever operant condition by using a saccharin fading procedure. After stable baseline responding was established, rats were implanted stereotaxically either with a guide cannula above the lateral ventricle or with bilateral cannulas above the nucleus accumbens, basolateral amygdala, or ventral tegmental area. After postoperative recovery, AA and Wistar animals were tested after intracerebroventricular microinjections of either CTOP (0–3 μg) or naltrindole (0–30 μg) or subcutaneous injections of naloxone (0–1 g/kg), which was used as a reference antagonist. Effects of intracerebral microinjections of CTOP and naltrindole (both 0–500 ng) were tested only in Wistar rats.

Results: Subcutaneous naloxone and intracerebroventricular CTOP and naltrindole suppressed ethanol self‐administration in a similar manner in AA and Wistar rats. Cumulative response patterns indicated that naloxone and naltrindole had no effect on the initiation of responding but suppressed it later during the session, whereas CTOP also affected initiation. In Wistar rats, naltrindole microinjections into both the nucleus accumbens and basolateral amygdala decreased ethanol responding, whereas CTOP was effective only in the amygdala. Injections of these antagonists into the ventral tegmental area had little effect on ethanol intake.

Conclusions: The results confirm previous results which showed that both μ‐ and δ‐opioid receptors are involved in the regulation of ethanol self‐administration and indicate that genetic differences between AA and Wistar rats produced by selection do not modify the effects of opioid antagonists. The nucleus accumbens and the basolateral amygdala may be important central sites for the mediation of their suppressive effects.
Possible Reasons Why Heavy Drinking Increases Carbohydrate‐Deficient Transferrin
Authors: Sillanaukee Pekka , Strid Nuria , Allen John P. , Litten Raye Z.
Published: April 2006

Background: Transferrin is a globular protein synthesized in the liver that is responsible for iron transport in plasma. The structure of the molecule consists of two carbohydrate residues to which six sialic acid moieties can be attached. After periods of chronic, heavy alcohol consumption, carbohydrate‐deficient transferrin (CDT) isoforms often increase, which makes CDT a useful marker in screening for alcohol abuse and monitoring progress of alcoholics in treatment. However, the precise mechanism behind CDT increase remains unknown.

Methods: A review of the most relevant literature on CDT was conducted with a computer‐assisted literature search.

Results: During the past several years, a number of studies have explored possible mechanisms that may account for the alcohol‐induced increase of CDT. An inhibition of protein synthesis and a general effect of alcohol on protein glycosylation have been reported. Although the exact mechanisms that underlie production of CDT are not yet fully understood, possible bases for the phenomenon are presented in this article.

Conclusions: Experimental findings indicate that the ethanol‐induced effect on glycoprotein metabolism is a multistep process in which protein transport and changes of enzyme activity may play an important role.
Genetic Influences on Craniofacial Outcome in an Avian Model of Prenatal Alcohol Exposure
Authors: Su Birong , Debelak Katherine A. , Tessmer Laura L. , Cartwright Martina M. , Smith Susan M.
Published: April 2006

Background: Understanding the basis for ethanol's teratogenic effects may inform the etiology of fetal alcohol syndrome. Here we investigate how genetic background and susceptibility to ethanol‐induced neural crest apoptosis contribute to the distinctive craniofacial phenotype observed after prenatal alcohol exposure.

Methods: Nine different chick strains were exposed to ethanol at gastrulation. The sensitivity of these embryos to ethanol‐induced neural crest apoptosis was reported elsewhere (Debelak and Smith, 2000). Here, these embryos were permitted to develop until embryonic day 10, when facial morphogenesis was largely complete, and cephalometric measurements were made on cleared skulls. Shifts in facial growth were correlated against the severity of ethanol‐induced apoptosis in facial precursors.

Results: The facial shape produced by ethanol exposure was a function of the embryos’ genetic strain. Three general responses were observed: apparent midfacial flattening (Babcock B300 x Hampshire Red, ISA‐Babcock, HyLine W98, and HyLine W36 strains), overall facial expansion (Spafas and Babcock B300 strains), or overall facial hypoplasia (DeKalb strains). When dose and timing of exposure were held constant, the embryo's genetic background predicted the facial outcome. For ethanol‐sensitive strains, apoptosis of facial precursor populations was required to produce the facial defects. That some strains had essentially normal faces despite extensive cell death indicated a capacity to recover from the earlier neural crest losses.

Conclusions: We propose that ethanol's effects on craniofacial development are multifactoral, and these influences may include susceptibility to apoptosis, regenerative capacity, and compensatory outgrowth of the facial primordia. The embryo's genetic background may modulate these events. The high and low responder chick strains are useful tools to dissect these contributions.
Effect of Repeated Exposure to Alcohol on the Response of the Hypothalamic‐Pituitary‐Adrenal Axis of the Rat: I. Role of Changes in Hypothalamic Neuronal Activity
Authors: Lee Soon , Schmidt E. Donné , Tilders Fred J. H. , Rivier Catherine
Published: April 2006

Background: Prior (3–12 days) injection of alcohol significantly blunts the response of the hypothalamic‐pituitary‐adrenal (HPA) axis to a second drug challenge without measurably altering responses to other stressors. We therefore determined whether adaptation in hypothalamic neurons underlies this decreased activity.

Methods: Adult male rats were administered alcohol (4.5 g/kg intragastrically) or vehicle daily for three consecutive days and then were challenged with the vehicle or alcohol 7 days later. Levels of adrenocorticotropin hormone (ACTH) in the circulation, corticotropin‐releasing factor (CRF), CRF receptors type 1 (CRFR1) and vasopressin (VP) transcripts in the paraventricular nucleus (PVN) of the hypothalamus, and CRF/VP peptide in the median eminence were measured.

Results: Resting PVN levels of CRF, CRFR1, and VP were comparable in all animals on day 7 of recovery, whereas CRF and VP stores in the external zone of the median eminence were decreased in animals previously exposed to alcohol. After the acute alcohol challenge on day 7, rats previously exposed to the drug exhibited a significant (p < 0.01) dampening of their PVN CRF and CRFR1, but not VP neuronal response, compared with vehicle‐pretreated rats.

Conclusion: Blunted neuronal activity of PVN CRF neurons may be responsible for the decreased ACTH response that we previously reported in rats that had been injected with alcohol several days earlier. In addition, and despite comparable PVN VP transcript levels, the lower levels of this peptide in the median eminence also may participate in the blunted ACTH response that we observed.
Differences in Services Utilization Between White and Mexican American DUI Arrestees
Authors: Cherpitel Cheryl J.
Published: April 2006

Background: Hispanics traditionally have been considered an underserved population in relation to medical care and related services utilization.

Methods: Selected health and social services utilization (both alcohol‐specific and non‐alcohol‐specific) during the last year was compared between a sample of 249 Mexican American (half of whom were born in Mexico) and 250 white participants interviewed in all five DUI (driving under the influence) treatment programs in one northern California county.

Results: Among those who met DSM‐IV criteria for alcohol dependence and/or alcohol abuse, 49% of the white subjects compared with 59% of the Mexican American subjects reported no utilization, 77% of whites and 82% of Mexican Americans reported no utilization in which drinking was a factor, and 70% of whites and 80% of Mexican Americans reported no contact with an alcohol program. Mexican Americans were also significantly less likely to report contact with more than one program, and among Mexican Americans, those born in Mexico were significantly less likely to report utilization than those born in the U.S.

Conclusions: The data suggest that despite the higher rates of heavy drinking found among Mexican American DUI arrestees (especially those born in Mexico) in this sample, Mexican Americans with an alcohol use disorder are less likely to use health and social services than whites, and this may be related to country of birth and related variables that include health insurance.

Significance: The data suggest that DUI programs may offer one of the few opportunities Me‐ican American problem drinkers have of establishing contact with the health and social service system and, as such, would be well positioned to also offer other types of alcohol‐related health and social services and referrals to this underserved population. These findings have implications for intervention efforts for problem drinking and prevention of DUI among Me‐ican Americans, which are a rapidly growing ethnic minority in California.
Genetic and Environmental Influences on Alcohol Metabolism in Humans
Authors: Li Ting‐Kai , Yin Shih‐Jiun , Crabb David W. , O'Connor Sean , Ramchandani Vijay A.
Published: April 2006

This manuscript represents the proceedings of a symposium at the 2000 RSA Meeting in Denver, Colorado. The organizer/chair was Ting‐Kai Li. The presentations were: (1) Introduction to the Symposium, by Ting‐Kai Li; (2) ALDH2 polymorphism and alcohol metabolism, by Shih‐Jiun Yin; (3) ALDH2 promoter polymorphism and alcohol metabolism, by David W. Crabb; (4) Use of BrAC clamping to estimate alcohol elimination rates: Application to studies of the influence of genetic and environmental determinants, by Sean O'Connor; and (5) Effect of food and food composition on alcohol elimination rates as determined by clamping, by Vijay A. Ramchandani.
Long‐Lasting Resistance to Extinction of Response Reinstatement Induced by Ethanol‐Related Stimuli: Role of Genetic Ethanol Preference
Authors: Ciccocioppo Roberto , Angeletti Stefania , Weiss Friedbert
Published: April 2006

Background: The conditioning of ethanol's reinforcing effects with specific environmental stimuli is thought to be a critical factor in long‐lasting relapse risk associated with alcoholism. To study the significance of such learning factors in the addictive potential of ethanol, this experiment was designed (1) to characterize the effects of stimuli associated with alcohol availability on the reinstatement of responding at a previously ethanol‐paired lever in rats with genetically determined ethanol preference versus nonpreference and (2) to examine the persistence of the motivating effects of these stimuli over time.

Methods: Male alcohol‐preferring (P) and alcohol‐nonpreferring (NP) rats were trained to operantly self‐administer ethanol (10% w/v) or water on a fixed‐ratio 1 schedule in a 30‐min daily session. Ethanol and water sessions were scheduled in random sequence across training days. Ethanol availability was signaled by an olfactory discriminative stimulus (banana extract, S+), and each lever press was paired with brief presentation of the conditioning chamber's house light (CS+). The discriminative stimulus signaling water availability (i.e., nonreward) consisted of anise odor (S−), and lever‐responses during water sessions were paired with a brief white noise generation (CS−). The rats then were placed on extinction conditions during which ethanol and water, as well as the corresponding stimuli, were withheld. The effects of noncontingent exposure to the S+ versus S− paired with response‐contingent presentation of the CS+ versus CS− on responding at the previously active lever were then determined in 30‐min reinstatement sessions. To study the resistance to extinction of the effects of the ethanol‐associated stimuli, additional tests were conducted at 3‐day intervals for a total of 50 days.

Results: The number of ethanol‐reinforced responses during self‐administration training was significantly greater in P than in NP rats (p < 0.01). After extinction, a significant recovery of responding was observed in both groups of rats under the stimulus conditions associated with ethanol (S+/CS+) but not those associated with water (S−/CS−). However, the response reinstatement was significantly greater in P than NP rats (p < 0.01). In addition, the results revealed a considerable resistance to extinction to the effects of the ethanol‐associated stimuli. Throughout the 50‐day test period, responding remained significantly above extinction levels in both P and NP rats (p < 0.01), but with an overall greater number of responses in P than NP rats (p < 0.05).

Conclusions: The results support the hypothesis that conditioning factors contribute importantly to compulsive ethanol seeking and long‐lasting vulnerability to relapse. In addition, the results suggest that genetic predisposition toward heightened ethanol intake extends to greater susceptibility to the motivating effects of ethanol‐related environmental stimuli.
Alcohol Use and Sexual Risk Taking Among Hazardously Drinking Drug Injectors Who Attend Needle Exchange
Authors: Stein Michael D. , Anderson Bradley , Charuvastra Anthony , Friedmann Peter D.
Published: April 2006

Background: To determine if sex‐risk days are also alcohol use days for active injection drug users.

Methods: Cross‐sectional interview of 187 active injection drug users who scored positively (≥8) on the Alcohol Use Disorders Identification Test who were recruited between February 1998 and October 1999 from a needle exchange program in Providence, Rhode Island. A sex‐risk day was defined as “vaginal sex, anal sex or oral sex without a condom,” measured by using a 30 day timeline follow‐back procedure.

Results: The sample was 64% male and 87% white, and 85% met DSM‐IV criteria for alcohol abuse/dependence. Of the total days analyzed (n= 5610), 19% were sex‐risk days; on 52% of these days drinking also occurred. By using a generalized estimating equation model to cluster by subject, alcohol use was associated with sex‐risk days (odds ratio, 1.76; 95% confidence interval, 1.35–2.29;p < 0.001), when we controlled for gender, age, race, education, cocaine use, injection frequency, exchanging sex for money or drugs, number of sexual partners, and perceived sexual risk of acquiring human immunodeficiency virus from partners.

Conclusions: Alcohol use is associated with sex risk‐taking behavior among injection drug users. A substantial majority of participants reported using alcohol before or during sexual relations, which temporally links alcohol use with human immunodeficiency virus injection risk.
Non‐Transferrin‐Bound Iron in Alcohol Abusers
Authors: de Feo Tullia Maria , Fargion Silvia , Duca Lorena , Cesana Bruno Mario , Boncinelli Lodovico , Lozza Paola , Cappellini Maria Domenica , Fiorelli Gemino
Published: April 2006

Background: Non‐transferrin‐bound iron, a low‐molecular‐weight iron complex capable of initiating free radical formation and lipid peroxidation, has been detected in the serum of animals experimentally fed with alcohol, but no data have been reported in alcohol abusers. The purpose of this study was to evaluate whether non‐transferrin‐bound iron is present in chronic alcohol abusers with liver involvement and whether alcohol plays any part in its appearance.

Methods: We measured non‐transferrin‐bound iron in a cohort of chronic alcohol abusers with and without liver cirrhosis at presentation, when 43 were active abusers and 33 were abstainers, and in a smaller group during a follow‐up period.

Results: At presentation, non‐transferrin‐bound iron was detectable in 83.7% of active abusers but only in 21.2% of abstainers, and within the group of abusers, patients with cirrhosis had significantly higher non‐transferrin‐bound iron than patients without. Non‐transferrin‐bound iron was present not only in patients with transferrin saturation >45% but also in those with transferrin saturation ≤45%. Multiple regression analyses revealed that only alcohol intake and total bilirubin were associated independently with non‐transferrin‐bound iron values. Longitudinal study confirmed the data of the cross‐sectional study.

Conclusions: Non‐transferrin‐bound iron could have a role in initiating or promoting alcohol‐induced liver damage.
Selective Vulnerability of Embryonic Cell Populations to Ethanol‐Induced Apoptosis: Implications for Alcohol‐Related Birth Defects and Neurodevelopmental Disorder
Authors: Dunty William C. , Chen Shao‐yu , Zucker Robert M. , Dehart Deborah B. , Sulik Kathleen K.
Published: April 2006

Background: Ethanol‐induced cell death has been characterized in very few stages of embryogenesis. This investigation comprehensively maps patterns of both programmed and ethanol‐induced cell death in the central nervous system and craniofacial region at 0.5‐day intervals from gestational day (GD) 6.5 to 11 in mice.

Methods: A teratogenic dosage of ethanol (2.9 g/kg) or vehicle was administered via two intraperitoneal injections to pregnant C57BL/6J mice at various stages of gestation. Cell death patterns were characterized using Nile blue sulfate vital staining and histological analysis of plastic sections. Confocal laser scanning microscopy of LysoTracker Red–stained specimens allowed for three‐dimensional visualization of areas of apoptosis and precise sectional imaging of mouse embryos. Apoptosis was also documented using a TUNEL technique on histological sections.

Results: Normal programmed cell death in control embryos was noted in the prechordal plate region at GD 8, the neuroepithelium of the fourth ventricle and anterior neuropore at GD 9, and within the ganglia of cranial nerves V, VII–VIII, IX, and X at GD 10. Acute maternal ethanol administration 12 hr before examination resulted in a dramatic increase in apoptosis within sites of programmed cell death in the embryo. Moreover, ethanol‐exposed specimens exhibited stage‐dependent excessive cell death in other distinct cell populations, particularly within the developing central nervous system. Ethanol‐induced apoptosis was notable as follows: GD 7.5‐neuroectoderm; GD 8‐neural plate and primitive streak; GD 9‐alar plate and presumptive neural crest of the rostral hindbrain, especially at the mesencephalon/rhombencephalon junction; GD 9.5–10‐branchial arches and rhombomeres; and GD 11‐diencephalon, basal ganglia, pons, and developing cerebellum.

Conclusions: The results of this study revealed developmental stage‐specific cell populations of the developing brain and craniofacial region that are vulnerable to ethanol‐induced apoptosis and provide new insight relative to the genesis of alcohol‐related birth defects.
Ionotropic Glutamate Receptor Subunit Expression in the Rat Hippocampus: Lack of an Effect of a Long‐Term Ethanol Exposure Paradigm
Authors: Ferreira Vania M. , Frausto Shanti , Browning Michael D. , Savage Daniel D. , Morato Gina S. , Valenzuela C. Fernando
Published: April 2006

Background: Studies have shown that acute ethanol exposure inhibits ionotropic glutamate receptor function and that long‐term ethanol exposure results in maladaptive increases in the expression of some of these receptors in neurons. It has been postulated that these changes, when unopposed by ethanol, contribute, in part, to the hyperexcitability associated with ethanol withdrawal. In this study, we compared the effect of long‐term ethanol exposure on the hippocampal expression levels of subunits belonging to the three families of ionotropic glutamate receptors.

Methods: Adult male Sprague‐Dawley rats were fed an ethanol‐containing diet for 16 days. This diet contained 0% ethanol on days 1 and 2, 3% on days 3 and 4, 5% on days 5 to 7, and 6.7% on days 8 to 16. Control rats received an equivalent amount of an isocaloric diet without ethanol. Rats were killed on day 16 at the peak of ethanol consumption. Hippocampal homogenates were prepared by sonication and analyzed by Western immunoblotting techniques. On a separate group of rats, we measured withdrawal scores and audiogenic seizures on day 17.

Results: Ethanol‐exposed rats had significantly higher withdrawal scores, and a significantly higher percentage of them developed audiogenic seizures; this indicates that the 16‐day ethanol diet induces ethanol dependence. Unexpectedly, we found that expression of NR1 (including the expression of NR1 subunits containing the N1, C1, and C2 inserts), NR2A, NR2B, NR2C, GluR1, GluR2/3, GluR5, GluR6/7, and KA2 subunits was not altered in hippocampal homogenates from ethanol‐exposed rats.

Conclusions: These results indicate that maladaptive changes in the hippocampal expression levels of ionotropic glutamate receptor subunits do not always occur in ethanol‐dependent rats. Consequently, other mechanisms must mediate the hyperexcitability state associated with ethanol withdrawal in these animals.
Prolonged Hya‐Disparate Skin Graft Survival in Ethanol‐Consuming Mice: Correlation With Impaired Delayed Hypersensitivity
Authors: Wang Kegiang , Busker‐Mannie Ann E. , Hoeft Jennifer , Vasquez Kristine , Miller Stephen D. , Melvold Roger W. , Waltenbaugh Carl
Published: April 2006

Background: Ethanol consumption impairs cell‐mediated immunity and enhances humoral immunity. Among cell‐mediated immune reactions, little is known of the effect of ethanol on chronic graft rejection. Allograft responses against the male‐specific minor histocompatibility antigen, Hya, are widely used to study chronic graft rejection.

Methods: Female C57BL/6 (B6) mice were fed ethanol‐containing liquid diets, were pair‐fed an isocaloric liquid control diet, or were fed solid diet and water ad libitum. One week after diet initiation, the mice were grafted with split thickness, orthotopic male tail skin grafts, and the integrity of the grafts was monitored as the diet continued. Delayed hypersensitivity (DTH) was also determined in these same mice. In addition, Hya‐cytolytic T‐cell–deficient syngeneic major histocompatibility complex mutant B6.C‐H2bm13 (bm13) and B6.C‐H2bm14 (bm14) mice were assessed for skin graft rejection, DTH, and cytotoxic T‐lymphocyte (CTL) activity.

Results: Ethanol‐consuming female B6 mice are impaired in their ability to reject syngeneic male skin grafts and to develop Hya‐specific DTH responses. To address the underlying mechanism, we show that Hya graft rejection correlates with DTH and not with CTL activity. Female B6 mice clearly differ from female bm13 and bm14 mice in their ability to generate CTLs against Hya antigen. Despite their inability to make Hya‐specific CTL responses, bm13 and bm14 female mice, nevertheless, make Hya‐specific DTH responses and ultimately reject Hya‐disparate skin grafts, indicating that Hya‐specific graft rejection results from DTH. Ethanol, by impairing Hya‐specific DTH, inhibits Hya‐specific skin graft rejection.

Conclusions: We demonstrate that ethanol consumption impairs Hya‐specific graft rejection. In addition, experiments with mice unable to generate anti‐Hya CTLs support previous observations suggesting that DTH responses are sufficient to cause rejection of Hya‐incompatible grafts.
Effects of Naltrexone and Ro 15‐4513 on a Multiple Schedule of Ethanol and Tang Self‐Administration
Authors: Shelton Keith L. , Grant Kathleen A.
Published: April 2006

Background: Both the opioid antagonist, naltrexone, and GABAA/benzodiazepine‐site negative modulator, Ro 15‐4513, decrease ethanol self‐administration in rodents and nonhuman primates. However, the selectivity of these drugs for decreasing ethanol self‐administration relative to reducing responding maintained by other reinforcers in primates is not clear. The present study used a multiple schedule self‐administration procedure in cynomolgus monkeys to examine the selectivity of naltrexone and Ro 15‐4513 for reducing ethanol self‐administration relative to an orange flavored sugar‐free sweetened solution (Sugar‐free Tang).

Methods: Six adult cynomolgus monkeys were trained to self‐administer 4% (w/v) ethanol and 4% or 6% (w/v) Tang under a multiple schedule of liquid access. The effect of acute administration of naltrexone (0.1, 0.3, 1, 3 mg/kg) was examined. The effect of 15 days of chronic, 1 mg/kg naltrexone on ethanol and Tang self‐administration was then examined in four monkeys. Acute administration of Ro 15‐4513 (0.01, 0.03, 0.1, 0.3 mg/kg) as well as 15 days of chronic administration of 0.1 mg/kg Ro 15‐4513 was also examined in four monkeys.

Results: Ethanol and Tang were self‐administered at similar volumes and patterns under baseline conditions. Acute naltrexone administration significantly decreased total session ethanol and Tang intake as well as the number and volume of ethanol and Tang drinks. Chronic naltrexone also significantly decreased ethanol and Tang intake. Ethanol, but not Tang, drink volume was significantly decreased by chronic 1 mg/kg naltrexone pretreatment. The number of ethanol and Tang drinks and drink duration were not significantly decreased by chronic naltrexone. Acute Ro 15‐4513 pretreatment significantly decreased ethanol and Tang intake, mean drinks and median drink duration. Chronic 0.1 mg/kg Ro 15‐4513 pretreatment significantly decreased total ethanol intake only during the first week of pretreatment, but it significantly decreased Tang intake for all 3 pretreatment weeks.

Conclusions: Similar to rodent studies, acute and chronic naltrexone and Ro 15‐4513 reduced ethanol and Tang intake in cynomolgus monkeys. However, unlike rodent studies, neither drug showed selectivity for reducing ethanol intake compared with a comparison reinforcer. These differences highlight the need for testing putative ethanol abuse treatment drugs under diverse conditions and multiple species before undertaking human clinical trials.
A 2‐Year Follow‐Up of 120 Swedish Female Alcoholics Treated Early in Their Drinking Career: Prediction of Drinking Outcome
Authors: Haver Brit , Dahlgren Lena , Willander Anders
Published: April 2006

Background: One hundred twenty women alcoholics recruited to a treatment program called EWA (Early Treatment for Women With Alcohol Addiction) were studied. The selected women were not previously treated for alcohol abuse.

Methods: The women were followed up by use of a structured personal interview, biomarkers sensitive for alcohol abuse (i.e., glutamyl transpeptidase), and questionnaires, by using defined criteria for abstinence, social drinking, satisfactory drinking outcome, and unsatisfactory drinking outcome.

Results: Drinking outcome was good (i.e., total abstinence, social drinking, or satisfactory drinking outcome) for 67% of the women during the total follow‐up time, by use of strict criteria for relapse. The results were corroborated by the biomarkers. Similar results were reported from two previously studied groups of women from the same department. However, the frequency of abstinence was higher and social drinking was significantly lower among this sample of women. Daily drinking, the use of sedatives, and a long duration of pretreatment alcohol abuse predicted an unfavorable outcome. However, a long duration of outpatient treatment predicted a good outcome, whereas treatment dropout was related to an unsatisfactory drinking outcome. A majority of the women (96%) rated the treatment experience and the treatment program favorably. The overall good results might reflect the selection of the subjects studied.

Conclusions: Improving treatment program adherence would probably improve outcome for the women with an unsatisfactory drinking outcome.
Naltrexone Suppresses Ethanol Intake in 6‐Hydroxydopamine–Treated Rats
Authors: Koistinen Meri , Tuomainen Päivi , Hyytiä Petri , Kiianmaa Kalervo
Published: April 2006

Background: The suppressive effect of opioid antagonists, such as naltrexone, on ethanol intake has been suggested to be based on the interference with ethanol‐induced stimulation of dopamine release in the nucleus accumbens. The aim of this study was to determine whether reduction of dopamine innervation to the nucleus accumbens with the neurotoxin 6‐hydroxydopamine (6‐OHDA) alters naltrexone‐induced suppression of ethanol consumption. Because the mesolimbic dopaminergic neurons have also been implicated in ethanol reinforcement, the effects of 6‐OHDA on the maintenance and acquisition of ethanol intake were also studied.

Methods: To damage accumbal terminals of the mesolimbic dopamine neurons, alcohol‐preferring Alko Alcohol (AA) rats were given bilateral injections of 6‐OHDA or vehicle into the nucleus accumbens after pretreatment with desipramine and pargyline. The effect of the lesion on the acquisition or maintenance of ethanol self‐administration was studied in animals having continual access to ethanol solution (10% v/v) and water. Subsequently the effect of naltrexone on ethanol consumption was determined.

Results: Naltrexone (0.03–3.0 mg/kg subcutaneously) suppressed ethanol consumption in a dose‐dependent manner both in 6‐OHDA–treated and control animals given a daily 90‐min access to ethanol solution. When the rats had continual access to ethanol, there was a clear day‐to‐day decline in ethanol intake during the first 5 days of the 7‐day naltrexone treatment (10 mg/kg subcutaneously). 6‐OHDA treatment had no effect on either the acquisition or maintenance of ethanol self‐administration. Postmortem analysis of the brain dopamine content revealed approximately 92% depletion of dopamine in the nucleus accumbens of the 6‐OHDA–treated rats.

Conclusions: The suppressive effect of naltrexone does not depend on naltrexone's interaction with dopaminergic terminals in the nucleus accumbens. Furthermore, the role of the mesolimbic dopamine pathway is probably not central either in the acquisition or maintenance of ethanol self‐administration in alcohol‐preferring AA rats.
Genetic Selection for High and Low Alcohol Consumption in a Limited‐Access Paradigm
Authors: Lê A. D. , Israel Y. , Juzytsch W. , Quan B. , Harding S.
Published: April 2006

Background: Several rat lines have been bred for their differences in alcohol consumption based on a continuous‐access paradigm in which alcohol solution is available 24 hr/day. The limited‐access paradigm (LAP), in which access to alcohol solution is restricted to a short period per day, however, has been used extensively to investigate the neurochemical mechanisms underlying alcohol consumption. There is evidence of possible differences in genetic determination of alcohol drinking in a continuous‐ versus limited‐access condition. For these reasons, selective breeding for high‐ and low‐alcohol consumption (HARF and LARF, respectively) based on a LAP was conducted.

Methods: N/Nih rats were used as the breeding stock. A within‐family breeding procedure was used to develop HARF and LARF lines with 10 families per line. Access to alcohol solution was restricted to 20 min/day. Alcohol was provided as 3%, 6% and 12% w/v solutions. Average intake of alcohol during the 12% phase was used as the selection criterion. Inbreeding began in the seventh generation.

Results: After the sixth generation of selection, rats from the HARF line consumed an average of 1.2 g/kg, whereas rats from the LARF line consumed an average of 0.6 g/kg of alcohol during the 20‐min access period. Alcohol consumption remained stable over the next eight generations of inbreeding. In the continuous‐access‐drinking paradigm, the HARF and LARF rats consumed an average of 5.5 to 7.0 g/kg and 1.0 to 2.0 g/kg of alcohol per day respectively. An estimated heritability of 0.25 was obtained.

Conclusions: These findings indicate that alcohol drinking in the LAP is influenced by genetic factors. Differences in alcohol drinking in the LAP also generalize to continuous access drinking. These rat lines will be very useful for investigations into the genetic and neurochemical mechanisms underlying alcohol drinking.
The Role of Alcohol in Accident and Violent Deaths in Finland
Authors: Lunetta Philippe , Penttilä Antti , Sarna Seppa
Published: April 2006

Background: In Finland, the high rates of forensic autopsy and postmortem toxicology furnish a reliable base for nation‐wide studies on alcohol‐related violent deaths.

Material and Methods: National mortality and population data within Finland, from 1987 to 1996, were used to analyze sex‐ and age‐specific rates, proportions, and trends of violent deaths associated with alcohol. Deaths were defined as alcohol‐related when alcohol was certified as a contributing factor to death.

Results: During the study period, 10,360 (23.3%) of the 45,544 violent deaths that occurred were alcohol‐related. Among 15‐ to 64‐year‐olds, 28.6% of accidents, 30.5% of suicides, and 55.3% of homicides were associated with alcohol (alcohol‐positive). Differences in epidemiologic patterns and trends for different types of violent death were observed between sexes and age groups. For instance, alcohol‐positive accidents significantly decreased in males (−2.3%/year; CL95: −3.3, −1.2;p < 0.001), but not in females (+0.5%/year; CL95: −2.7, +3.7;p= 0.772), and alcohol‐positive suicides increased slightly in females (+3.9%/year; CL95: +0.0, +7.9;p= 0.047), but not in males (−0.2%/year, CL95: −1.4, +1.0;p= 0.704).

Conclusions: The victims of violent deaths have often consumed or abused alcohol before the fatal events. Especially in young adults, consumption of alcohol is likely one of the most serious risk factors in accidents and may decrease the threshold for suicide ideation and impulsive behaviors. Studies that explore the effects of sociodemographic and health factors on random populations with relevant control data will increase the understanding of the causal connection between alcohol and violent deaths.
Confirmation of Correlations and Common Quantitative Trait Loci Between Neurotensin Receptor Density and Hypnotic Sensitivity to Ethanol
Authors: Erwin V. Gene , Gehle Vaughn M. , Davidson Kirsten , Radcliffe Richard A.
Published: April 2006

Background: In previous studies, genetic correlations were observed between hypnotic sensitivity to ethanol and high‐affinity neurotensin receptor (NTS1) binding. Provisional quantitative trait loci (QTLs) were identified for these traits, and some of these QTLs were found on common chromosomal regions. In continued efforts to examine the relationship between NTS1 binding capacity and hypnotic sensitivity to ethanol, studies were designed to confirm correlations between NTS1 densities in the brain, duration of ethanol‐induced loss of righting reflex (LORR), and blood ethanol concentrations at regain of righting reflex (BECRR). Another purpose of the study was to confirm QTLs for these traits.

Methods: ILS X ISS F 2 mice and HAS X LAS F 2 rats as well as the progenitors were tested for LORR, BECRR, and NTS1 densities. Phenotypic correlations were calculated between LORR and BECRR and between these measures and NTS1 densities in striatum from both mice and rats. The F 2 mice were genotyped by using polymorphic markers for five previously reported QTLs for LORR to confirm QTLs for BECRR and NTS1 densities in striatum, ventral midbrain, and frontal cortex.

Results: Phenotypic correlations were found between LORR and BECRR (r=−0.66 to −0.74, p < 10−9) and between these measures and NTS1 densities in striatum (r= 0.28–0.38, p < 10−2) from both mice and rats. QTLs for LORR and BECRR (lod score = 2–6) were found in common regions of chromosomes 1, 2, and 15. By using the combined results from a previous LSXSS RI study and the current results, a suggestive QTL (lod score = 3.1) for striatal NTS1 receptor densities was found on chromosome 15 at approximately 60 cM, in the same region as the chromosome 15 LORR/BECRR QTL.

Conclusions: The results are in agreement with previously reported correlations and QTLs for NTS1 receptor densities and measures of hypnotic sensitivity to ethanol in mice and extend those correlations to another species, the rat. These findings support a role for NTS1 in genetically mediated differences in hypnotic sensitivity to ethanol.
Classification and Course of Alcohol Problems Among Adolescents in Addictions Treatment Programs
Authors: Chung Tammy , Martin Christopher S.
Published: April 2006

Background: This study tested whether adolescents in addictions treatment programs could be reliably classified into milder and more severe alcohol problem categories using latent class analysis, and examined the relation of latent class structure to DSM‐IV alcohol diagnoses. Transition probabilities among the latent classes at 1‐year follow‐up and their predictors were used to characterize the short‐term course of alcohol problems.

Methods: Adolescents recruited from addictions treatment were administered a modified section of the Structured Clinical Interview for the DSM (SCID) alcohol use disorders (AUD) during or shortly after addictions treatment and at 1‐year follow‐up. DSM‐IV lifetime conduct disorder diagnosis was assessed at baseline using a modified version of the Schedule for Affective Disorders and Schizophrenia for School‐Age Children (K‐SADS).

Results: A 3‐class solution that represented increasing severity of alcohol problems (i.e., asymptomatic, mild, and severe) provided the best fit to the alcohol symptom data, and was consistent across gender, ethnicity, and presence of conduct disorder. Cross‐classification of latent class membership with DSM‐IV alcohol diagnosis indicated only a fair level of agreement. There was an overall decrease in alcohol problem severity from baseline to follow‐up. Conditional transition probabilities indicated that males and those with conduct disorder, particularly for those in the severe class at baseline, had a lower likelihood of transitioning to the asymptomatic class at 1‐year follow‐up.

Conclusions: The latent class structure of alcohol problems in an adolescent clinical sample was best represented by a 3‐class severity‐based model. Cross‐classification of latent class membership with DSM‐IV alcohol diagnosis suggests the potential utility of re‐organizing diagnostic criteria to better distinguish the relative severity of abuse and dependence diagnoses. Transitions between latent classes were fairly common at 1‐year follow‐up, and characterized by a general reduction in alcohol symptoms.
Summary Report of a Symposium: Genes and Gene Delivery for Diseases of Alcoholism
Authors: Crews Fulton T.
Published: April 2006

Abstract: This article represents a summary of a symposium on genes and gene delivery for diseases of alcoholism that was held at the University of North Carolina, Chapel Hill, on May 7–10, 2001. The purpose of the meeting was to examine two key technologies: gene chip‐microarrays and gene delivery. Three main pathologies associated with alcoholism—addiction, liver disease, and birth defects—were discussed. This summary of the meeting is grouped into sections on the brain, liver, and fetus.
The Research Community and the Private Sector: A Hands‐On or Hands‐Off Relationship?
Authors: Martinic Marjana
Published: April 2006

Abstract: This article summarizes a symposium held at the 2001 Annual Meeting of the Research Society on Alcoholism (RSA) in Montreal, Canada, and was prepared on behalf of the symposium participants. The discussion focused the relationship between research and the private sector, addressing whether such a relationship is possible or even desirable and how concerns regarding the implementation of any such arrangement can be met. Although participants represented a range of views, there was general agreement on two issues—the need to keep the source of funding separate from the research itself, and the requirement for disclosure and complete transparency.