bluuebunny/crossref_metadata_2025_split huggingface dataset:
NMDA Receptor Subunit Expression After Combined Prenatal and Postnatal Exposure to Ethanol
Authors: Nixon Kimberly , Hughes Peter D. , Amsel Abram , Leslie Steven W. 
Published: January 2004

Abstract: Background: The N‐methyl‐d‐aspartate receptor (NMDAR), a subtype of glutamate receptor, is essential for normal neurodevelopment. The brain growth spurt, which is both prenatal and postnatal in the rat, is a time when the brain is especially sensitive to the effects of a teratogen, such as alcohol. Changes in NMDAR function after early perinatal exposure to ethanol (EtOH) may be related to alterations in the expression of secondary subunits. Thus, we investigated the expression of the NR1, NR2A, and NR2B subunits after combined prenatal and postnatal exposure to EtOH.Methods: A binge model was used to administer EtOH (5 g/kg) or isocaloric vehicle to pregnant female rats followed by EtOH (6.2 g/kg) or isocaloric control diet from postnatal days 4 through 9 via an artificial rearing method. Proteins from crude membrane homogenates isolated from cortex and hippocampus at postnatal day 10, 14, or 21 were separated in a standard Western blot procedure.Results: The expression of the NR2A subunit of EtOH‐exposed pups showed a significant increase at postnatal day 10 in hippocampus compared with diet controls. No significant changes were seen for any other subunit in either region.Conclusions: The up‐regulation of NR2A during EtOH withdrawal is consistent with compensatory changes to prolonged inhibition of the NMDAR. These results indicate that postnatal exposure to ethanol produces distinct effects on the NMDAR, which may underlie deficits associated with alcohol‐related neurodevelopmental disorder.
Mismatch Negativity: No Difference Between Controls and Abstinent Alcoholics
Authors: Fein George , Whitlow Bridget , Finn Peter 
Published: January 2004

Abstract: Background: A number of studies have examined the amplitude of the mismatch negativity (MMN) evoked potential as a measure of a brain inhibitory deficit in alcoholics or those at risk for alcoholism. The current study examined MMN in alcoholics abstinent an average of 6.7 years (with a minimum of six months abstinence) compared to controls. This study examined the association of MMN with alcoholism family history density, with indices of the presence and severity of externalizing disorders (a risk‐factor for alcoholism), and with alcohol use variables.Methods: Electroencephalograms were gathered on 76 subjects (38 controls, 38 abstinent alcoholics) during a nonattending mismatch negativity experiment. Measures of alcoholism family history density, disinhibited personality traits, and antisocial symptoms served as measures of risk‐factors known to be associated with a genetic liability to alcoholism. Alcohol use variables were used as measures of alcoholism severity.Results: There were no differences in MMN amplitude or latency between controls and abstinent alcoholics. There also were no significant associations between MMN measures and the measures of risk for alcoholism or with the severity of alcohol use or duration of abstinence.Conclusions: The results suggest that MMN is neither affected in chronic alcoholics nor associated with alcoholism vulnerability, and thus does not reflect a trait marker of alcoholism or alcoholism risk. The current results do not address effects on MMN of acute alcohol ingestion or withdrawal from alcohol.
Effective Strategies for Recruiting Families Ascertained Through Alcoholic Probands
Authors: Seaton Kimberly L. , Cornell Jodi L. , Wilhelmsen Kirk C. , Vieten Cassandra 
Published: January 2004

Abstract: Background: Recruiting a large number of participants meeting strict inclusion criteria can be challenging, particularly when selecting for a condition associated with a social stigma such as alcoholism, when participation involves collection of medical specimens and sensitive information, and when the participation of family members or other collaterals is required. Developing and implementing a successful recruitment plan depends upon identifying the most effective recruitment strategies given the available resources.Methods: Several strategies for recruiting subjects for a large family study on the genetics of alcoholism were evaluated over a two‐year period with regard to participant yield, time and cost expenditure.Results: Overall effectiveness of a recruitment strategy was determined based on a composite of yield, cost and time expenditure. The most effective recruitment strategies were direct mail, press release, the Internet and treatment center collaborations.Conclusion:: Results provide insight into successful strategies for recruiting large numbers of participants and their family members selected for a condition associated with a social stigma.
Determination of an Estradiol Dose‐Response Relationship in the Modulation of Ethanol Intake
Authors: Ford Matthew M. , Eldridge J. C. , Samson Herman H. 
Published: January 2004

Abstract: Background: Estradiol (E2) potentiates the self‐administration of numerous psychoactive drugs in female rodents. An analogous modulatory role of E2 on ethanol consumption remains unresolved because of examination of limited doses. The purpose of this study was to delineate a dose‐response relationship for E2 on ethanol intake with an extended range and number of E2 doses.Methods: Female Long‐Evans rats had continuous access (22 hr/day) to both 10% ethanol (10E) solution and water. After the establishment of stable 10E intake baselines, rats were assigned to one of seven dose groups balanced for 10E intake [sham‐operated (Shm) or ovariectomized (Ovx) plus E2 (μg/kg)]: Shm + 0, Ovx + 0, Ovx + 0.05, Ovx + 0.15, Ovx + 0.5, Ovx + 1.5, and Ovx + 5. Ethanol preference drinking was evaluated during 25 consecutive days of E2 replacement treatment, and trunk blood was collected for the determination of plasma E2 and progesterone concentrations.Results: Chronic E2 replacement regimens (0.05–1.5 μg/kg) dose‐dependently augmented 10E intakes and ethanol preference ratios without concomitantly altering water consumption. Despite the maintenance of 2‐ to 3‐fold greater plasma E2 levels, a supraphysiologic E2 dose (5 μg/kg) failed to precipitate ethanol intakes in excess of levels observed after treatment with a high physiologic E2 dose (1.5 μg/kg). Plasma progesterone concentrations were significantly increased in treatment groups (1.5 and 5 μg/kg E2) that exhibited corresponding significant increases in ethanol consumption.Conclusions: A positive dose‐response relationship between E2 and ethanol intake (incremental increases in E2 dose corresponded to incremental increases in intake) was apparently limited to a physiologic concentration range, because a supraphysiologic dose failed to elicit an additional stepwise increase in ethanol intake. These findings stipulate a modulatory role for E2 in the regulation of moderate ethanol intake and suggest that endogenous fluctuations of E2 may alter the propensity toward consumption in women and in female animal models of ethanol self‐administration.
Postnatal Binge Ethanol Exposure Affects Habituation of the Cardiac Orienting Response to an Olfactory Stimulus in Preweanling Rats
Authors: Hunt Pamela S. , Phillips Jessicah S. 
Published: January 2004

Abstract:Background:Prenatal exposure to alcohol can result in intellectual impairments, reduced habituation and distractibility, visual‐spatial deficits, and problems in attention. Dysfunction in attention, including habituation of responses to nonsignal stimuli, can have devastating consequences for cognitive development. This research examined whether binge exposure to ethanol on postnatal days (PD) 4 to 9 would affect cardiac orienting or response habituation to an olfactory stimulus in preweanling rats.Methods:Ethanol‐exposed subjects were given ethanol 5.25 g/kg/day on PD4 to 9. Controls were either sham intubated or unhandled during this time. To assess baseline and phasic cardiac function, PD16 subjects were tested under differential pharmacological blockade of the sympathetic or parasympathetic nervous systems by administration of the peripherally acting antagonists atenolol or atropine methyl nitrate. In a second experiment, separate groups of subjects were tested for habituation of the cardiac orienting response to an olfactory stimulus.Results:Results indicate that postnatal ethanol had no observable effect on the functional development of autonomic control over heart rate. Similarly, ethanol exposure had no effect on the form or magnitude of the cardiac orienting response. However, neonatal ethanol exposure did result in a deficit in orienting response habituation; ethanol‐exposed subjects continued to respond to the stimulus with a large‐magnitude bradycardia after control subjects exhibited complete response habituation. In addition, ethanol‐exposed subjects had longer orienting response latencies than controls.Conclusions:The results indicate that this animal model has the potential to contribute to investigations designed to understand basic forms of memory impairments observed in humans with a history of prenatal alcohol exposure. The postnatal binge ethanol model of fetal alcohol effects produces deficits in nonassociative memory that are similar to those observed in human infants exposed prenatally to ethanol. Deficits in response habituation have important implications for cognitive development.
Improvement in Quality of Life After Treatment for Alcohol Dependence With Acamprosate and Psychosocial Support
Authors: Morgan Marsha Y. , Landron Frédéric , Lehert Philippe ,   for the New European Alcoholism Treatment Study Group
Published: January 2004

Abstract: Background: The impact of disease on health‐related quality of life is now well recognized, as is the importance of this variable as a measure of treatment efficacy.Methods: Patients from five European countries were enrolled in an open, multicenter, prospective study designed to observe outcome in dependent drinkers treated for 6 months with acamprosate and psychosocial support. Version 1 of the 36‐item Short Form Health Profile (SF‐36v1) questionnaire was administered at inclusion and at 3 and 6 months. Responses were described as handicaps compared with an appropriately matched, healthy reference population. One‐way fixed ANOVA and simultaneous stepwise linear regression analysis were used to identify potential predictors of quality of life at baseline and after treatment.Results: Baseline SF‐36v1 data were obtained from 1216 patients (mean age, 43 ± 9 years; 77% male). Mean values for all SF‐36v1 dimensions were significantly lower in the patient population than in the normative reference population; the most important deficits were observed in physical and emotional role limitations and in social functioning. The most important predictors of baseline quality of life were severity of alcohol dependence, employment status, psychiatric history, quantity and frequency of alcohol consumption, attendance at Alcoholics Anonymous, global alcohol health status, age, gender, and education. SF‐36v1 data were obtained from 686 patients at 3 months and from 497 at 6 months. Significant improvements were observed in all SF‐36v1 dimensional and summary scores after 3 months of treatment (p < 0.001); further marginal improvements were observed between 3 and 6 months. The most important predictors of quality of life following treatment were the SF‐36v1 profile at baseline, followed by abstinence duration; patients who completed the trial and remained abstinent throughout showed the greatest improvement.Conclusions: Health‐related quality of life is severly impaired in dependent drinkers. Treatment with acamprosate and psychosocial support, by promoting abstinence, improves the quality of life profile to levels comparable to those observed in healthy individuals.
Abnormal Hepatic Methionine and Glutathione Metabolism in Patients With Alcoholic Hepatitis
Authors: Lee Taunia D. , Sadda Mamatha R. , Mendler Michel H. , Bottiglieri Teodoro , Kanel Gary , Mato José M. , Lu Shelly C. 
Published: January 2004

Abstract: Background: Abnormal methionine metabolism occurs in animals fed ethanol and in end‐stage cirrhotic patients. Expected consequences of these abnormalities include reduced hepatic S‐adenosylmethionine and glutathione (GSH) levels, impaired transmethylation, and reduced homocysteine catabolism, resulting in the often‐observed hyperhomocystinemia in cirrhotic patients. These parameters have not been examined simultaneously in patients with less advanced alcoholic liver disease.Methods: Six patients hospitalized for alcoholic hepatitis were studied. Plasma was analyzed for homocysteine, methionine, and GSH levels. Liver biopsies diagnosed acute alcoholic hepatitis and underlying fibrosis. Liver specimens were processed for messenger RNA (mRNA) levels and various metabolites and were compared with those of six normal controls.Results: Three patients had cirrhosis, and three had only portal fibrosis. Plasma levels of homocysteine and methionine were increased in two of the three patients with cirrhosis but not in the patients with fibrosis. All patients had markedly lower plasma GSH levels (mean ± SD: 0.27 ± 0.19 μM, which is at least 10‐fold lower than the normal range). Hepatic S‐adenosylmethionine levels were reduced by 50%, whereas methionine, GSH, and cysteine levels were reduced by 70–80%. The mRNA levels of most enzymes involved in methionine metabolism and GSH synthesis were decreased, whereas albumin expression was unchanged. Despite the well known induction of cytochrome P450 2E1 in chronic alcoholics, its mRNA levels were nearly 70% lower in these patients.Conclusions: In alcoholic hepatitis, abnormal hepatic gene expression in methionine and GSH metabolism occurs and often contributes to decreased hepatic methionine, S‐adenosylmethionine, cysteine, and GSH levels. It may be important to replenish these thiols in patients hospitalized with alcoholic hepatitis.
Acute Ethanol Withdrawal (Hangover) and Social Behavior in Adolescent and Adult Male and Female Sprague‐Dawley Rats
Authors: Varlinskaya Elena I. , Spear Linda P. 
Published: January 2004

Abstract: Background: The extensive use of alcohol during adolescence may be facilitated by an age‐specific attenuation in sensitivity to adverse effects of ethanol. Adolescent rats are less sensitive than adults to some delayed effects of acute ethanol, including hangover‐related anxiety on an elevated plus maze. The purpose of this study was to determine whether adolescent rats are also less sensitive than adults to hangover‐related anxiogenesis when indexed in terms of social inhibition.Methods: Anxiety during ethanol hangover was indexed in adolescent and adult Sprague‐Dawley rats of both genders by assessing the suppression in social behavior during a social interaction test. Animals were tested 18 hr after intraperitoneal administration of 0 g/kg (saline) or 4 g/kg ethanol (experiment 1) or at test intervals chosen on the basis of assessments of ethanol clearance time (experiment 2) to equate clearance‐to‐test intervals across age and gender (experiments 3–5).Results: Adults showed more hangover‐related social suppression and slower postclearance recovery than adolescents. Sex differences were more pronounced in adults than adolescents, with males being more affected than females. Ethanol clearance time was considerably longer in adult males than in adolescent animals and adult females. In contrast to the modest decreases in social activity observed in adolescent animals shortly after ethanol clearance, adolescents showed a surprising increase in play fighting later in the recovery period— a hangover‐related social facilitation that was not evident in adults.Conclusions: The attenuated anxiety and increase in social interactions seen in adolescents during hangover are less likely to serve as deterrents for further drinking than the aversive increase in anxiety seen in adults. A facilitation of social interactions not only during a drinking episode, but also during the postalcohol recovery period, could help to establish a persisting cycle of drinking in at‐risk adolescents, leading to dependency and a lifelong history of alcohol‐related problems.
The Efficacy of Acamprosate in the Maintenance of Abstinence in Alcohol‐Dependent Individuals: Results of a Meta‐Analysis
Authors: Mann Karl , Lehert Philippe , Morgan Marsha Y. 
Published: January 2004

Abstract: Background: A number of clinical trials have been undertaken to determine the efficacy of acamprosate in the maintenance of abstinence in alcohol‐dependent individuals. However, the reported differences in patient populations, treatment duration, and study endpoints make comparisons difficult. An assessment of the efficacy of treatment with acamprosate was, therefore, undertaken using meta‐analytical techniques.Methods: All randomized, placebo‐controlled trials (RCTs) that fulfilled predetermined criteria were identified using (1) a language unrestricted search of 10 electronic databases; (2) a manual search of relevant journals, symposia, and conference proceedings; (3) cross‐referencing of all identified publications; (4) personal communications with investigators; and (5) scrutiny of Merck‐Santé's internal reports of all European trials. Study quality was assessed, independently, by three blinded workers. Key outcome data were identified; some outcome variables were recalculated to ensure consistency across trials. The primary outcome measure was continuous abstinence at 6 months; abstinence rates were determined by estimating Relative Benefit (RB).Results: A total of 19 published 1 unpublished RCTs were identified that fulfilled the selection criteria; 3 were excluded because the documentation available was insufficient to allow adequate assessment. The remaining 17 studies, which included 4087 individuals, 53% of whom received active drug, were of good quality and were otherwise reasonably comparable. There was no evidence of publication bias. Continuous abstinence rates at 6 months were significantly higher in the acamprosate‐treated patients (acamprosate, 36.1%; placebo, 23.4%; RB, 1.47; [95% confidence intervals (CI): 1.29–1.69]; p < 0.001). This effect was observed independently of the method used for assigning missing data. The effect sizes in abstinent rates at 3, 6, and 12 months were 1.33, 1.50, and 1.95, respectively. At 12 months, the overall pooled difference in success rates between acamprosate and placebo was 13.3% (95% CI, 7.8–18.7%; number needed to treat, 7.5). Acamprosate also had a modest but significant beneficial effect on retention (6.01%; [95% CI, 2.90–8.82]; p= 0.0106).Conclusion:: Acamprosate has a significant beneficial effect in enhancing abstinence in recently detoxified, alcohol‐dependent individuals.
Chronic Ethanol Consumption Reduces δ‐and μ‐Opioid Receptor–Stimulated G‐Protein Coupling in Rat Brain
Authors: Saland L. C. , Abeyta A. , Frausto S. , Raymond‐Stintz M. , Hastings C. M. , Carta M. , Valenzuela C. F. , Savage D. D. 
Published: January 2004

Abstract: Background: Ethanol consumption is thought to enhance the release of endogenous opioids acting at opioid receptors (ORs) in the central nervous system. Prior studies have shown that chronic ethanol consumption in alcohol‐preferring rats uncouples μ‐ORs from Gi proteins. The purpose of this study was to investigate the potential for uncoupling of the δ‐ and the μ‐OR after chronic ethanol consumption in a nonpreferring rat strain.Methods: We used radiohistochemical methods to study μ‐ and δ‐OR‐stimulated G‐protein coupling in brain tissue of rats ingesting liquid diets containing 6.7% ethanol (v/v) for 16 days, as compared with 0% ethanol pair‐fed control rats. Sections of brain from pair‐fed and ethanol‐treated rats were incubated with guanylyl 5′‐[gamma‐[35S]‐thio]‐triphosphate ([35S]‐GTPγS) in the absence and presence of d‐Pen2,d‐Pen5 enkephalin (DPDPE), a δ‐OR agonist, or Tyr‐d‐Ala‐Gly‐N (me)Phe‐Gly‐ol‐enkephalin (DAMGO), a μ‐OR agonist.Results: DPDPE significantly stimulated [35S]‐GTPγS binding in the hippocampal dentate gyrus (DG), CA1, cerebellum, and inferior colliculus of untreated pair‐fed controls. By contrast, DPDPE‐stimulated [35S]‐GTPγS binding was reduced significantly in those brain regions in the ethanol‐consuming group. DAMGO stimulated [35S]‐GTPγS binding in cortex, caudate, nucleus accumbens, DG, CA1, and superior and inferior colliculi, whereas the DG, CA1, and colliculi showed a significant reduction of binding after chronic ethanol. Basal [35S]‐GTPγS binding was not different between the two diet groups.Conclusions: These data are the first to demonstrate functional uncoupling of δ‐ORs from G proteins after chronic ethanol consumption. Uncoupling may result from modulation of receptors, possibly by internalization or phosphorylation. Alterations in functional coupling of both δ‐ and μ‐ORs and subsequent effects may contribute to continued ethanol consumption.
The Effects of Binge Alcohol Exposure on Bone Resorption and Biomechanical and Structural Properties are Offset by Concurrent Bisphosphonate Treatment
Authors: Callaci John J. , Juknelis Dainius , Patwardhan Avinash , Sartori Mark , Frost Nathan , Wezeman Frederick H. 
Published: January 2004

Abstract: Background: Chronic alcohol consumption reduces bone mass and strength, increasing fracture risk for alcohol abusers. Mechanisms underlying this vulnerability involve modulation of bone remodeling. Direct effects of alcohol on bone formation have been documented; those on bone resorption are less well studied. Skeletal effects of exposure to high blood alcohol concentrations (BAC's) attained during binge drinking have not been studied. We examined the effects of repeated binge‐like alcohol treatment on bone resorption, bone mineral density and vertebral compressive strength in adult male rats treated with the aminobisphosphonate, risedronate.Methods: A binge alcohol exposure model was developed using intraperitoneal (IP) injection to administer a 20% (vol/vol) alcohol/saline solution (3 g/kg, 1X/day) on four consecutive days for 1, 2 or 3 weeks in 400 g rats, with and without weekly risedronate treatment (0.5 mg/kg, 1X/week). Total serum deoxypyridinoline (Dpd) a crosslink of bone type collagen released during resorption was measured by ELISA. Bone mineral density (BMD) was measured using peripheral quantitative computed tomography (pQCT). Vertebral compressive strength was determined using an Instron materials testing machine. Trabecular integrity was analyzed by computer‐aided trabecular analysis system (TAS).Results: Peak BAC's averaged 308.5 ± 12 mg/dL; average BAC was 258.6 ± 28.7 mg/dL at time of euthanasia. No significant effects of treatment were observed after 1 or 2 weeks of binge alcohol exposure. At 3 weeks of alcohol treatment serum Dpd was significantly increased (205%, p < 0.05) over controls. Bone mineral density (BMD) in cancellous bone of distal femur and lumbar spine were significantly decreased (34% and 21% respectively, p < 0.01) after 3 weeks of binge treatment. Vertebral (L4) compressive strength (maximum load sustained before failure) also decreased (27%, p < 0.05) after 3 binge alcohol cycles. Risedronate maintained the Dpd level (p < 0.01), BMD (p < 0.001) and vertebral structural biomechanical properties (p < 0.01) of binge‐treated rats at control levels (E vs ER). Indices of trabecular architectural integrity [Trabecular bone volume/tissue volume (BV/TV), bone area (BAR) and trabecular separation (Tb.Sp)] analyzed at week 3 showed (BV/TV) and (BAR) were significantly reduced in alcohol‐binged rats (p < 0.01), while (Tb.Sp) was significantly increased (p < 0.01). Risedronate also maintained the trabecular architectural indices of binge‐treated rats at control levels (E versus ER, p < 0.01).Conclusions: In adult male rats, BAC's reflective of those attained during alcoholic binge drinking may affect the skeleton in part by stimulating bone resorption, an effect mitigated by risedronate.