bluuebunny/crossref_metadata_2025_split huggingface dataset:
Examination of a CYP2E1 Repeat Polymorphism in a Monkey Model of Alcohol Abuse
Authors: Walker Stephen J. , Grant Kathleen A. , Vrana Kent E. 
Published: April 2006

Background: Cytochrome P‐450 2E1 (CYP2E1) is involved in alcohol metabolism, and the expression of this enzyme displays wide phenotypic variability in humans. It has been proposed that some of this variability in expression may be a consequence of the size of a repeat polymorphism in the 5″ regulatory region of the gene and that the polymorphism may segregate with alcoholism. This study examined whether the repeat polymorphism exists in macaque monkeys and whether it associates with excessive alcohol consumption in this animal model.Methods: Ten outbred cynomolgus monkeys (Macaca fascicularis) that displayed a voluntary alcohol consumption ranging from 1.0 to 3.6 g/kg/day were genotyped for a CYP2E1 repeat polymorphism. This polymorphism has been documented in the region from −2519 base pair (bp) to −1953 bp of the human CYP2E1 gene 5″ distal promoter.Results: Individual polymerase chain reaction amplification of genomic DNA from each of the 10 monkey samples revealed a single band of approximately 400 bp in the region corresponding to the human CYP2E1 polymorphism. Polymerase chain reaction amplicons from the 10 individuals were sequenced, and each one generated a 370 bp sequence that is 90% identical to the human gene sequence. However, unlike human alleles that contain five to eight repeats, the cynomolgus monkey is homozygous for a single copy of the repeat most closely resembling repeat 8 (88% identical) in the human gene.Conclusions: These data demonstrate that the CYP2E1 distal promoter region in monkeys is very similar to the human sequence yet lacks the extensive repeated DNA found in humans. This includes the rare repeats 3 and 4, which have been postulated to play a role in transcription regulation and to associate with alcohol abuse liability in humans. These data suggest that the CYP2E1 polymorphism arose late in evolution and that the regulation of the gene by this genetic region is not associated with a heavy alcohol drinking phenotype in the cynomolgus monkey.
The Role of Biomarkers in Alcoholism Medication Trials
Authors: Allen John P. , Litten Raye Z. , Strid Nuria , Sillanaukee Pekka 
Published: April 2006

Background: Increasingly, biomarkers are being incorporated into the research design of clinical trials on medications to reduce drinking in alcoholics. To date, however, there has been little analysis of the unique roles that biomarkers can play in such investigations or of the practical and conceptual considerations that surround their best use in this context.Methods: Clinical trials of alcoholism medications published between 1985 and the present were abstracted to determine how biomarkers were used and how changes in them related to self‐report measures of drinking.Results: Six uses of biomarkers were identified: determination of subjects to be included or excluded in the trial; description of baseline sample characteristics; primary and secondary outcome assessment; corroboration of self‐reports of drinking status; specification of patients likely to respond to the medication; and evaluation of drug safety.Conclusion: Use of biomarkers in such studies appears warranted, particularly as an objective source of information on treatment efficacy that can be considered with patient self‐report measures of drinking status. Biomarkers related to liver functioning also can assist in determination of drug safety for medications metabolized by the liver.
Confirmation That Offspring From Families With Alcohol‐Dependent Individuals Have Greater Hypothalamic‐Pituitary‐Adrenal Axis Activation Induced by Naloxone Compared With Offspring Without a Family History of Alcohol Dependence
Authors: Wand Gary , McCaul Mary E. , Gotjen Deidre , Reynolds Joanna , Lee Shing 
Published: April 2006

Background: This study was designed to confirm our previous findings that nonalcoholic offspring from families with alcohol‐dependent individuals have greater hypothalamic‐pituitary‐adrenal axis activation induced by opioid blockade compared with nonalcoholic subjects without a family history of alcohol dependence.Methods: Sixty‐four nonalcoholic subjects aged 18 to 25 years were enrolled in the protocol. Twenty‐seven subjects were offspring from families with alcohol dependence and were designated as family history–positive subjects (FHP). Thirty‐seven subjects were biological offspring of non–alcohol‐dependent parents and were designated as family history–negative subjects (FHN). Subjects received naloxone hydrochloride (0, 50, 125, 375, and 500 μg/kg) in double‐blind, randomized order; adrenocorticotropin (ACTH) and cortisol were monitored over 120 min.Results: No hormone differences at baseline or during placebo administration were identified between FHP and FHN subjects. FHP subjects had greater ACTH and cortisol response to opioid receptor blockade induced by naloxone hydrochloride compared with FHN subjects.Conclusions: These observations confirm previous findings that differences in ACTH and cortisol dynamics between FHP and FHN subjects can be unmasked by opioid receptor blockade.
Origins and Consequences of Age at First Drink. II. Familial Risk and Heritability
Authors: McGue Matt , Iacono William G. , Legrand Lisa N. , Elkins Irene 
Published: April 2006

Background: The association of age at first drink (AFD) and alcoholism may reflect a common inherited vulnerability to disinhibitory behavior and psychopathology rather than a direct influence of the former on the latter. We tested the common‐inherited‐vulnerability hypothesis by determining whether AFD is familial and heritable.Methods: A sample of 1,232 14‐year‐old twins was classified according to their biological parents’ AFD.Results: Lifetime symptoms of externalizing disorders (i.e., conduct disorder and oppositional defiant disorder) were significantly higher in the sons but not the daughters of parents whose AFD came before age 15 years. Offspring symptoms of internalizing disorders (i.e., major depressive disorder, separation anxiety disorder, and overanxious disorder) were not significantly associated with parental early use of alcohol in either sons or daughters. Early use of alcohol in mothers but not fathers was associated with a significant increase in both sons’ and daughters’ risk of alcohol use by age 14. The contribution of genetic and environmental factors to risk of early alcohol use was investigated in a sample of 416 monozygotic (MZ) and 225 like‐sex dizygotic (DZ) 14‐year‐old twin pairs. Twin similarity for early alcohol use was substantially greater in MZ than DZ twins in boys but about equally similar in MZ and DZ twins in girls. Estimated heritability of early alcohol use was significantly greater in boys (55%) than girls (11%), in part because the genetic factors underlying symptoms of disinhibitory psychopathology contributed more to risk of early alcohol use in boys than girls.Conclusions: Early use of alcohol is familial and, at least in males, heritable. The familial transmission of early alcohol use is caused in part by genetic risk for disinhibitory psychopathology in males and to shared environmental factors in girls. These results provide some support for a common‐inherited‐vulnerability hypothesis, and suggest that the processes underlying early alcohol use may differ in boys and girls.
Magnetic Resonance Relaxometry Reveals Central Pontine Abnormalities in Clinically Asymptomatic Alcoholic Men
Authors: Sullivan Edith V. , Pfefferbaum Adolf 
Published: April 2006

Background: Central pontine myelinolysis (CPM) is a rare, debilitating, life‐threatening condition, associated with chronic alcoholism, rapid correction of hyponatremia, and advanced age. It is unknown, however, whether older alcoholic patients who by age and diagnosis are at risk for CPM have objectively determined neuroimaging evidence of preclinical CPM that could be valuable in understanding its development and in initiating appropriate treatment. Accordingly, we examined central pontine magnetic resonance (MR) transverse relaxation time (T2), which reflects myelin and axonal integrity when measured in white matter and is prolonged with pathology that causes increased free water content in tissue.Methods: The subjects were 46 alcoholic men who were abstinent from alcohol for about 1 month and were asymptomatic for CPM, 9 men and 1 woman with alcoholic Korsakoff's syndrome (KS), and 74 healthy control men. All subjects received coronally acquired dual‐echo MR imaging (MRI), from which T2 times were calculated in central pons. MRI films were read clinically and independently of relaxometry results. Hematological and neuropsychological data were also available for many subjects.Results: Only the KS group showed prolonged T2 times; however, pontine T2 prolongation increased significantly with older age in the asymptomatic alcoholics but not controls. Clinical radiological readings detected pontine signal hyperintensity in five KS subjects (two without dementia and three with dementia), one control, and no alcoholic patient. Hematologic indexes of macrocytic anemia and nutritional deficiency and neuropsychological measures of verbal and nonverbal fluency correlated with prolonged T2 times in alcoholic men.Conclusions: This CPM‐like condition, manifest as prolonged T2, may occur with higher incidence than previously thought in clinically asymptomatic alcoholism and may contribute to neuropsychological compromise of initiation and production. Preclinical detection of abnormal pontine signal properties with MR relaxometry may identify patients at high risk for developing CPM.
Association of the ADH2 Genotypes With Skin Responses After Ethanol Exposure in Japanese Male University Students
Authors: Takeshita Tatsuya , Yang Xing , Morimoto Kanehisa 
Published: April 2006

Background: A contribution of the alcohol dehydrogenase‐2 (ADH2) polymorphism to alcohol sensitivity and alcohol drinking behavior is still controversial. In this study, we examined the effects of the ADH2 genotypes on skin reactions to ethanol and habitual alcohol intake among Japanese male university students, controlling for the effects of the low Km aldehyde dehydrogenase (ALDH2) genotype, as an extension of our previous study.Methods: The study subjects were 357 Japanese male students [average age (mean ± SD) was 23.7 ± 3.0 years] in a medical university. The subjects completed a questionnaire regarding self‐reported alcohol‐associated symptoms and alcohol‐drinking behavior. The ADH2 and ALDH2 genotypes were determined through digestion of polymerase chain reaction products by restriction enzymes. All subjects participated in the ethanol patch test. We observed skin responses at 0, 5, 15, and 20 min after removal of the tape.Results: Among the ALDH2*1/*1 genotypes, only some subjects with ADH2*1/*2 or ADH2*2/*2 exhibited a positive response, which increased with increasing time after the removal. However, none of comparisons between the different ADH2 genotypes reached statistical significance. Among the ALDH2*1/*2 genotypes, those with ADH2*1/*2 or ADH2*2/*2 showed a significant increase in response with increasing time after the removal and revealed a significantly higher positivity rate at 15 min than those with ADH2*1/*1. In those with the ALDH2*1/*2 genotype, the positive rate of facial flushing with one glass of beer was higher in those with ADH2*1/*2 and ADH2*2/*2 than those with ADH2*1/*1, although this was not significant. However, the ADH2 genotype did not seem to influence drinking frequency or amounts of alcohol intake in each ALDH2 genotype.Conclusions: This study finds further evidence for a contribution of the ADH2 polymorphism to skin reactions after either local or systemic ethanol exposure in Asian people. However, the effects of the ADH2 polymorphism may be mild because this polymorphism does not seem to influence alcohol drinking behavior in these study subjects.
Acamprosate Is Neuroprotective Against Glutamate‐Induced Excitotoxicity When Enhanced by Ethanol Withdrawal in Neocortical Cultures of Fetal Rat Brain
Authors: Al Qatari Mona , Khan Shabeena , Harris Barton , Littleton John 
Published: April 2006

Background: Acamprosate reduces relapse, and the drug may interact with glutamate transmission and with glutamate/NMDA receptors. Because these systems are implicated in excess calcium entry leading to alcohol withdrawal–induced neurotoxicity, we evaluated the effects of acamprosate on these parameters in neuronal cultures.Methods: Primary cultures of neocortical neurons from fetal Sprague‐Dawley rats were maintained either in normal medium or in medium containing 100 mM ethanol for 4 days. After this time, cultures were challenged with glutamate for 10 min and then returned to medium (all in the absence of ethanol). 45Ca2+ uptake was measured during the challenge, and glutamate‐induced toxicity was assessed after 20 hr. The effects of acamprosate present during the glutamate challenge were measured on both parameters.Results: In controls, acamprosate did not significantly affect glutamate‐induced neurotoxicity but produced a significant inhibition of calcium entry. The NMDA receptor antagonists dizocilpine and d‐amino‐phosphonovalerate (D‐APV) inhibited both glutamate neurotoxicity and calcium entry. In cultures previously exposed to ethanol, glutamate‐induced neurotoxicity and calcium entry were both significantly enhanced. Dizocilpine reduced both these parameters to unstimulated control values, and D‐APV reduced both calcium entry and neurotoxicity with the same relation that we obtained in control cultures. In the ethanol‐withdrawn cultures, acamprosate reduced both the enhanced glutamate‐induced calcium entry and the enhanced neurotoxicity in a concentration‐dependent manner. Acamprosate also significantly reduced calcium entry caused by 80 mM K+ in control and ethanol‐exposed cultures.Conclusions: Acamprosate had protective effects against glutamate‐induced neurotoxicity only in ethanol‐withdrawn cultures. The neuroprotective effects of the drug did not correlate with its effects on calcium entry, making it unlikely that acamprosate directly affects NMDA receptors via the glutamate binding site or the receptor‐operated calcium channel. The results are, however, compatible with other inhibitory effects on NMDA receptor function.
Alcohol‐Naïve Alcohol‐Preferring (P) Rats Exhibit Higher Local Cerebral Glucose Utilization Than Alcohol‐Nonpreferring (NP) and Wistar Rats
Authors: Smith D.G. , Learn J.E. , McBride W.J. , Lumeng L. , Li T.‐K. , Murphy J.M. 
Published: April 2006

Background: The present study determined local cerebral glucose utilization (LCGU) rates in alcohol‐naïve alcohol‐preferring (P), alcohol nonpreferring (NP), and outbred Wistar rats to test the hypothesis that innate differences in functional neuronal activity are present in limbic regions as a result of selective breeding for high‐alcohol drinking behavior.Methods: All procedures were conducted during the dark cycle. 2‐[14C]deoxyglucose ([14C]2‐DG; 125 μCi/kg) was injected intravenously and timed arterial blood samples were collected during the following 45 min and assayed for glucose and [14C]2‐DG content. Rats were then decapitated, the brains removed and frozen to −70°C, and 20 μm coronal sections were prepared for quantitative autoradiographic analysis.Results: Rates of LCGU were determined in 55 regions and subregions, including limbic, cortical, and subcortical structures. LCGU rates were significantly (p < 0.01) higher in several limbic (e.g., ventral tegmental area, nucleus accumbens shell, olfactory tubercle, medial prefrontal cortex, and lateral hypothalamus), cortical (e.g., parietal, temporal, occipital, cingulate, piriform, and entorhinal), and subcortical (e.g., thalamus, habenula, preoptic area, and striatum) regions in P rats, compared with NP and Wistar rats, whereas rates in Wistar rats were higher in a few regions (e.g., CA1 and CA3 regions of the posterior hippocampus) than NP rats.Conclusions: The data suggest that selective breeding for high‐alcohol drinking produces intrinsically higher functional neuronal activity in the central nervous system regions of the high‐alcohol consuming P line compared with low‐alcohol drinking NP or Wistar rats, although these differences may not generalize to other rat lines selectively bred for divergent alcohol drinking.
Effects of CB1 Cannabinoid Receptor Blockade on Ethanol Preference After Chronic Ethanol Administration
Authors: Lallemand F. , Soubrié P. H. , de Witte P. H. 
Published: April 2006

Background: Chronic ethanol administration results in neurobiological alterations similar to those observed after chronic cannabinoid exposure. The purpose of this study was to investigate alcohol drinking and the withdrawal responses after pulmonary chronic alcoholization with intraperitoneal or oral administration of a cannabinoid CB1 receptor antagonist.Methods: The cannabinoid receptor antagonist SR141716A, 1, 3 or 10 mg/kg/day intraperitoneally or orally, was administered to Wistar rats either during a 30‐day chronic ethanol exposure or at the cessation of this procedure. Motility was recorded during 18 hr after the cessation of chronic alcoholization just before the beginning of the free‐choice paradigm (water versus alcohol 10% v/v).Results: A significant increase in ethanol preference was observed during the free‐choice paradigm after chronic alcoholization with concurrent SR141716A administration (3 or 10 mg/kg/day). A significant decrease in withdrawal motility after administration of SR141716A was observed with only the highest dose (10 mg/kg/day). The administration of SR141716A, 3 or 10 mg/kg/day, after chronic pulmonary alcoholization significantly decreased the preference for alcohol. Finally, a significant decrease in ethanol preference was seen during the free‐choice paradigm of nonalcoholized rats treated with SR141716A, 3 or 10 mg/kg/day, during 30 days before the free‐choice paradigm.Conclusions: The concurrent administration of the CB1 antagonist together with the chronic alcoholization increases the preference for ethanol. Also, the administration of the CB1 antagonist after the chronic alcoholization or at the time of withdrawal drastically diminishes the ethanol preference.
Efficacy of Naltrexone and Acamprosate for Alcoholism Treatment: A Meta‐Analysis
Authors: Kranzler Henry R. , Van Kirk Jeffrey 
Published: April 2006

Background: Renewed interest in medications to prevent relapse in alcoholics (i.e., antidipsotropics) resulted in approval by the Food and Drug Administration of naltrexone to treat alcohol dependence. Acamprosate, although not approved in the United States, is used in alcoholism treatment in many other parts of the world. In the absence of studies that compare the effects of these medications, we used a meta‐analytic approach to the literature to compare their efficacy in alcoholism treatment.Methods: All published placebo‐controlled trials of naltrexone or acamprosate for alcohol dependence were examined, and, when suitable, data were extracted for calculation of a mean effect size. A sample of studies of selective serotonin reuptake inhibitors for treatment of major depression conducted over the last two decades served as a comparator for the antidipsotropics.Results: Both antidipsotropics exerted significant, but modest, effects on treatment retention and/or drinking outcomes. There was significant variability among the studies for the measure on which the largest effect was exerted by each of these medications. Based on limited comparisons of the two medications, there appears to be no statistical difference in their efficacy in the treatment of alcohol dependence. In contrast, there was a consistent effect of selective serotonin reuptake inhibitors on depressive symptoms in major depression, which was significantly greater than the effects observed for the antidipsotropics.Conclusions: Both naltrexone and acamprosate are efficacious in reducing alcohol consumption in alcoholics. However, their specific role in alcoholism treatment remains to be more clearly defined. New approaches to the use of these medications and development of new medications are needed if pharmacotherapy is to play a substantial role in the treatment of alcoholism.
Screening for High‐ and Moderate‐Risk Drinking During Pregnancy: A Comparison of Several TWEAK‐Based Screeners
Authors: Dawson Deborah A. , Das Abhik , Faden Vivian B. , Bhaskar Brinda , Krulewitch Cara J. , Wesley Barbara 
Published: April 2006

Purpose: This study investigated the use of the TWEAK and nine alternative screeners for predicting high‐risk and moderate‐risk drinking during pregnancy.Method: The analysis was based on self‐reports from 404 lifetime drinkers who presented for an initial visit at nine prenatal clinics in Washington, DC. Data were collected anonymously by having women directly enter their responses onto an audio, computer‐assisted interview that was programmed onto a laptop computer. Pregnancy risk drinking status was based on both average daily volume of intake and frequency of drinking 3+ drinks in a day. Each of the alternative screeners was constructed by adding one additional risk indicator to the TWEAK, and three different scoring options were explored.Results: Using thresholds of 2 points for high‐risk drinking and 1 point for moderate‐risk drinking, the TWEAK demonstrated a sensitivity and specificity of 70.6% and 73.2% for high‐risk drinking and a sensitivity and specificity of 65.6% and 63.7% for any (high‐ or moderate‐) risk drinking during pregnancy. None of the alternative screeners resulted in significant improvement, but the addition of current smoking status showed enough promise to warrant further testing in larger samples.Conclusions: Despite some loss in sensitivity and specificity, the TWEAK, in its original or a modified form, can be extended to measures of high‐risk drinking that incorporate infrequent heavy intake and can be used to test for moderate‐ as well as high‐risk drinking. Because identification of moderate‐risk drinkers substantially increases the pool of women targeted for intervention, cost implications must be considered in designing appropriate interventions.
Effect of β‐Carotene on Hepatic Cytochrome P‐450 in Ethanol‐Fed Rats
Authors: Kessova Irina G. , Leo Maria A. , Lieber Charles S. 
Published: April 2006

Background: Hepatotoxicity of ethanol is increased by β‐carotene in both rodents and nonhuman primates. Furthermore, in smokers who are also drinkers, β‐carotene increases the incidence of pulmonary cancer. The hepatotoxicity was associated with proliferation of the membranes of the smooth endoplasmic reticulum, suggesting the involvement of cytochromes P‐450. Therefore, the aim of the present study was to assess the effect of β‐carotene and ethanol treatment on rodent hepatic cytochromes P‐450.Methods and Results: Weanling male Sprague‐Dawley rats were pair‐fed β‐carotene (56.5 mg/l of diet) for 8 weeks, with and without ethanol (Lieber‐DeCarli, 1994 liquid diet). As expected, ethanol increased CYP2E1 (measured by Western blots) from 67 ± 8 to 317 ± 27 densitometric units (p < 0.001). Furthermore, β‐carotene potentiated the ethanol induction to 442 ± 38 densitometric units (p < 0.01) with a significant interaction (p= 0.012). The rise was confirmed by a corresponding increase in the hydroxylation of p‐nitrophenol, a specific substrate for CYP2E1, and by the inhibition with diethyl dithiocarbamate (50 μM). β‐Carotene alone also significantly induced CYP4A1 protein (328 ± 49 vs. 158 ± 17 densitometric units, p < 0.05). The corresponding CYP4A1 mRNA (measured by Northern blots) was also increased (p < 0.05) and there was a significant interaction of the two treatments (p= 0.015). The combination of ethanol and β‐carotene had no significant effect on either total cytochrome P‐450 or CYP1A1/2, CYP2B, CYP3A, and CYP4A2/3 contents.Conclusions: β‐Carotene potentiates the CYP2E1 induction by ethanol in rat liver and also increases CYP4A1, which may, at least in part, explain the associated hepatotoxicity.