bluuebunny/crossref_metadata_2025 huggingface dataset:
Alcohol and Behavioral Control: Cognitive and Neural Mechanisms
Authors: Vogel‐Sprott M. , Easdon Craig , Fillmore Mark , Finn Peter , Justus Alicia
Published: April 2006

This article represents the proceedings of a symposium at the 2000 RSA Meeting in Denver, Colorado. The organizer/chair was Muriel Vogel‐Sprott. The presentations were (1) Alcohol‐induced impairment of inhibitory control: Some commonalities with attention deficit hyperactivity disorder, by Mark Fillmore; (2) Neural interactions that underlie response inhibition under alcohol: A functional magnetic resonance imaging investigation, by Craig Easdon; (3) Intentional control of behavior under alcohol, by Muriel Vogel‐Sprott; and (4) Working memory and the disinhibiting effects of alcohol on passive avoidance learning, by Alicia Justius and Peter Finn.
Improving Alcoholism Treatment Across the Spectrum of Services
Authors: Hilton Michael E. , Maisto Stephen A. , Conigliaro Joseph , McNiel Melissa , Kraemer Kevin , Kelley Mary E. , Conigliaro Rosemarie , Samet Jeffrey H. , Larson Mary Jo , Savetsky Jacqueline , Winter Michael , Sullivan Lisa M. , Saitz Richard , Weisner Constance , Mertens Jennifer , Parthasarathy Sujaya , Moore Charles , Hunkeler Enid , Hu Teh‐Wei , Selby Joe , Stout Robert L. , Zywiak William , Rubin Amy , Zwick William , Shepard Don
Published: April 2006

This article represents the proceedings of a symposium at the 2000 RSA Meeting in Denver, Colorado. The chair was Michael E. Hilton. The presentations were (1) The effects of brief advice and motivational enhancement on alcohol use and related variables in primary care, by Stephen A. Maisto, Joseph Conigliaro, Melissa McNiel, Kevin Kraemer, Mary E. Kelley, and Rosemarie Conigliaro; (2) Enhanced linkage of alcohol dependent persons to primary medical care: A randomized controlled trial of a multidisciplinary health evaluation in a detoxification unit, by Jeffrey H. Samet, Mary Jo Larson, Jacqueline Savetsky, Michael Winter, Lisa M. Sullivan, and Richard Saitz; (3) Cost‐effectiveness of day hospital versus traditional alcohol and drug outpatient treatment in a health maintenance organization: Randomized and self‐selected samples, by Constance Weisner, Jennifer Mertens, Sujaya Parthasarathy, Charles Moore, Enid Hunkeler, Teh‐Wei Hu, and Joe Selby; and (4) Case monitoring for alcoholics: One year clinical and health cost effects, by Robert L. Stout, William Zywiak, Amy Rubin, William Zwick, Mary Jo Larson, and Don Shepard.
Association of Neuropeptide Y Polymorphism With the Occurrence of Type 1 and Type 2 Alcoholism
Authors: Ilveskoski Erkki , Kajander Olli A. , Lehtimäki Terho , Kunnas Tarja , Karhunen Pekka J. , Heinälä Pekka , Virkkunen Matti , Alho Hannu
Published: April 2006

Background: The susceptibility to alcoholism can be explained partially by genetic factors. Neuropeptide Y (NPY) has emerged as one potential factor contributing the development of alcoholism. A recent study indicated that the NPY gene variant producing a leucine‐to‐proline substitution (T to C at position 1128) was associated with 34% higher average alcohol consumption.

Methods: The subjects consisted of 122 alcoholics classified as type 1 and type 2 subtypes by psychiatric evaluation. A random sample of 59 social drinkers was used as a control group to compare the distribution of NPY genotypes with those of alcoholics.

Results: In a logistical regression model, there was a significantly lower frequency of the leucine(7)/proline(7) heterozygotes among well characterized type 2 alcoholics, compared with the controls (10.8 vs. 24.1%, p= 0.028).

Conclusions: We speculate that the genetic polymorphism producing the proline(7) substitution of NPY might not predispose to alcoholism, but indeed retard the transition to alcoholism.
Effects of Raclopride in the Nucleus Accumbens on Ethanol Seeking and Consumption
Authors: Czachowski Cristine L. , Chappell Ann M. , Samson Herman H.
Published: April 2006

Background: Nucleus accumbens dopamine has been shown to play a role in the processing of behaviorally relevant stimuli and to mediate ethanol‐reinforced responding. Previous research that used a fixed‐ratio schedule of responding maintained by the presentation of small dippers (0.1 ml) of ethanol demonstrated that the dopamine D2 antagonist, raclopride, decreased total responding for ethanol by both delaying the onset of responding and causing the early termination of lever‐press behavior. Because these studies required animals to continuously respond to obtain access to small amounts of ethanol over a period of self‐administration, this procedure assessed a combination of appetitive (seeking) and consummatory (drinking) behavior. The paradigm used in the present study separated the appetitive or seeking response from the consummatory response to assess the effects of raclopride on both types of ethanol‐related behaviors.

Methods: Male Long‐Evans rats were trained to emit a fixed number of lever‐press responses that resulted in access to a drinking tube that contained 10% ethanol for 20 min, once each day. We measured the effects of microinjections of raclopride (1.0, 3.0, and 10.0 μg/subject) into the nucleus accumbens, before the sessions, on appetitive and consummatory responding.

Results: Raclopride delayed the onset of ethanol‐seeking (appetitive responding) at all doses and decreased the number of responses made at the low and high doses. The rate of responding, however, was unaffected. Raclopride had no effect on the latency to begin consuming ethanol or on any of the characteristics of the initial bout of ethanol intake at all doses tested. Total ethanol intake was decreased, after an initially “normal” pattern of self‐administration, following only the highest dose of raclopride. Mean ethanol intake (g/kg) was 0.54 (±0.03) after no injection, 0.51 (±0.04) after sham treatment, and 0.38 (±0.05) after 10 μg of raclopride.

Conclusions: The procedural separation of the seeking and intake responses used in this experiment allowed us to assess the effects of dopamine receptor antagonism in the nucleus accumbens on these two different behaviors. Overall, appetitive responding that preceded the delivery of an ethanol solution was more sensitive to raclopride treatment than was consummatory responding. These findings are consistent with a stimulus‐processing function of the mesolimbic dopamine system.
Allopregnanolone and Pentobarbital Infused Into the Nucleus Accumbens Substitute for the Discriminative Stimulus Effects of Ethanol
Authors: Hodge Clyde W. , Nannini Michelle A. , Olive M. Foster , Kelley Stephen P. , Mehmert Kristin K.
Published: April 2006

Background: The discriminative stimulus effects of ethanol are mediated in part by the γ‐aminobutyric acid type A (GABAA) receptor system. We have previously shown that microinjections of the competitive GABAA agonist muscimol in the nucleus accumbens and amygdala fully substitute for the discriminative stimulus effects of systemic ethanol. However, it is not known whether allosteric binding sites on GABAA receptors located within specific limbic brain regions contribute to the discriminative stimulus effects of ethanol.

Methods: Male Long‐Evans rats were trained to discriminate between intraperitoneal injections of ethanol (1 g/kg) and saline under a fixed‐ratio 10 schedule of sucrose (10% w/v) reinforcement. Injector guide cannulae, aimed at both the nucleus accumbens core and the hippocampus area CA1, were then implanted to allow site‐specific infusion of GABAA‐positive modulators.

Results: Infusion of the neurosteroid 3α‐hydroxy‐5α‐pregnan‐20‐one (allopregnanolone, or 3α‐5α‐P) in the nucleus accumbens resulted in dose‐dependent full substitution for intraperitoneal ethanol (50% effective dose = 0.38 ng/μl per side). Likewise, injection of the barbiturate pentobarbital into the nucleus accumbens also substituted dose‐dependently for ethanol (50% effective dose = 1.55 μg/μl per side). However, infusions of either 3α‐5α‐P or pentobarbital in the hippocampus failed to substitute for ethanol and produced inverted U‐shaped dose‐response curves.

Conclusions: These results demonstrate that allosteric positive modulation of GABAA receptors in the nucleus accumbens produces full substitution for the stimulus effects of ethanol. This suggests that GABAA receptors in the nucleus accumbens may play a more influential role in the discriminative stimulus effects of ethanol than those in the hippocampus.
Haloperidol Reduces Stimulant and Reinforcing Effects of Ethanol in Social Drinkers
Authors: Enggasser Justin L. , de Wit Harriet
Published: April 2006

Background: Despite abundant preclinical support for a role of dopamine (DA) in the stimulant‐like and reinforcing effects of ethanol, there have been few studies directly investigating this mechanism in human subjects. This study examined the effect of a DA antagonist, haloperidol, on the subjective stimulant‐like effects of acute doses of ethanol and on ethanol reinforcement in healthy human volunteers. It was hypothesized that a low dose of the DA D2/D3 antagonist haloperidol (3 mg) would attenuate stimulant‐like subjective effects of ethanol (0.75 g/kg) and reduce the number of drinks chosen during a subsequent choice phase.

Methods: Seventeen healthy men and women, 21 to 35 years old, participated in four laboratory sessions conducted at 1‐week intervals. During the four sessions they received, in randomized order under double‐blind conditions, capsules containing haloperidol or placebo followed by three drinks containing ethanol (0.75 g/kg) or placebo, at 30‐min intervals. Subjective and behavioral responses were measured before and after the beverages. After the third beverage, subjects could choose up to five additional doses of the beverage they had ingested.

Results: Haloperidol reduced the number of ethanol beverages subjects chose without altering placebo beverage choices. Haloperidol also dampened some of the subjective effects of ethanol, especially in subjects who experienced stimulation after ethanol. Haloperidol reduced stimulant‐like and euphorigenic effects of ethanol in subjects who experienced stimulant effects (n= 8) but had no effect in subjects who did not experience stimulation from ethanol (n= 9).

Conclusions: These findings suggest that DA plays a role in the stimulant‐like, euphorigenic, and reinforcing qualities of ethanol in humans. However, the findings also raised new questions about the link between the subjective and reinforcing effects of ethanol.
P300, Disinhibited Personality, and Early‐Onset Alcohol Problems
Authors: Justus Alicia N. , Finn Peter R. , Steinmetz Joseph E.
Published: April 2006

Background: Recent research suggests that a reduced P300 amplitude of the event‐related potential is associated with a vulnerability to alcoholism. This study tested the hypothesis that reductions in the P300 amplitude would be associated with specific dimensions of disinhibited personality (social deviance proneness and impulsivity) and that these personality traits would mediate the association between P300 and alcohol problems in a young adult sample that varied widely in disinhibitory traits.

Methods: Alcohol problems, personality (impulsivity, social deviance, harm avoidance, and excitement seeking), and event‐related potentials were measured in a sample of 190 subjects (87 men, 103 women) with a mean age of 20.7 ± 1.9 years.

Results: Social deviance, impulsivity, and alcohol problems were associated with reductions in the P300, but only in male subjects. A structural model suggested that social deviance, impulsivity, and alcohol problems were all strongly related to P300 amplitude at Fz. Further analyses indicated that for male subjects, social deviance mediated the association between P300 at Fz and alcohol problems as well as the association between impulsivity and alcohol problems.

Conclusions: This study suggests that reduced P300s are strongly associated with a general tendency toward antisocial, defiant, and impulsive traits, which might, in turn, increase the risk for alcohol abuse. The lack of an association between reduced P300s and personality or alcohol problems in women was unexpected and deserves further study.
Alcohol Availability and Injury: The Role of Local Outlet Densities
Authors: Treno Andrew J. , Gruenewald Paul J. , Johnson Fred W.
Published: April 2006

Background: We analyzed the relationship between alcohol availability and injury that occurred during the 6 months before survey administration.

Method: The data examined were from a general population survey administered to 13,440 California respondents as part of a community‐based project to reduce alcohol‐involved injury and death. Two separate analyses were performed. The first considered individual local outlet densities (which included both on‐premise establishments such as bars and restaurants and off‐premise establishments such as liquor and grocery stores) as they affect individual phone survey respondents’ self‐reported injuries. To address potential spatially autocorrelated errors and geographically lagged effects, a second analysis considered aggregate outlet densities within geographic areas as they affect the proportion of survey respondents who reported injury. No spatial autocorrelation or significant lagged effects were found, which supported our individual‐level analyses.

Results: Our analyses indicated an association between both on‐premise and off‐premise individual‐level outlet densities and self‐reported injuries.

Conclusion: Alcohol availability seems to be related to self‐reported injury. The mechanisms behind this relationship, however, are not clear, and further study is indicated.
Alcohol Abuse or Dependence Among Mexican American Women Who Report Violence
Authors: Anne Lown E. , Vega William A.
Published: April 2006

Background: Violence against women has been linked to alcohol disorders in various populations. Few studies have assessed alcohol disorders among assaulted women in a general population of Mexican Americans. This study examined alcohol disorders among Mexican American women who reported physical or sexual assault.

Methods: Participants were women (n= 1516, ages 18–59) living in Fresno County, California, who were enrolled in a population‐based, randomized household survey of Mexican‐origin men and women. Crude and adjusted odds ratios (ORs) were calculated for alcohol dependence/abuse (ADA) and physical or sexual assault by a current partner or someone other than a current partner.

Results: Women who reported lifetime physical or sexual assault were significantly more likely to meet criteria for ADA (OR = 8.2; 95% confidence interval [CI], 4.4–15.4). After we adjusted for birthplace, age, income, and parental problem drinking, assaulted women were still 4.7 times more likely to meet criteria for ADA (CI, 2.1–10.4). Physical or sexual assault by someone other than a partner was more strongly associated with ADA (OR = 8.7; CI, 4.5–16.9) than assault by a current partner (OR = 3.2; CI, 1.3–7.6). Both physical (OR = 9.0; CI, 4.7–17.0) and sexual assault (OR = 4.7; CI, 2.2–10.0) by either type of perpetrator were associated with ADA.

Conclusion: There is a strong association between reporting violence and having a lifetime history of ADA. Although temporal order could not be established, these findings highlight the importance of screening for physical and sexual assault in settings that treat alcohol disorders as well as screening for alcohol disorders among women who seek services related to previous or current violence.
Evidence That the Lore‐1 Region Specifies Ethanol‐Induced Activation in Addition to Sedative/Hypnotic Sensitivity to Ethanol
Authors: Owens Jeremy C. , Bennett Beth , Johnson Thomas E.
Published: April 2006

Background: Low‐dose ethanol‐induced activation (LDA) and initial sensitivity to alcohol are both predictors of alcohol abuse in human populations. Our hypothesis is that one or more genes specifying hypnotic sensitivity also specify LDA. We tested this hypothesis by using congenic mice derived from the inbred long‐sleep (ILS) and inbred short‐sleep (ISS) strains, which carry an ILS region introgressed onto an ISS background.

Methods: LDA was assessed by assigning mice randomly to receive one of five doses of ethanol ranging from 1.2 to 2.4 g/kg. On day 1, animals were injected with saline and placed in a brightly lit activity monitor for 30 min, after which they were returned to their home cages. On day 2, mice were injected with ethanol (20% w/v), their activity was monitored for a 30‐min period, and LDA was determined by subtracting day 1 activity. The blood ethanol concentration of each animal was then assessed at 30 min by retro‐orbital collection of 25 μl of blood.

Results: Ethanol had a significant effect on the activity of ISS mice, but ILS mice showed no activation at any dose, similar to the activities of the outbred lines. All three congenic strains were activated at several doses. Lore‐2 and Lore‐5 were not ILS‐like (less active than ISS) at any dose. In contrast, ISS.ILS‐Lore‐1 congenics (carrying an ILS‐derived Lore‐1 allele on the ISS background) were significantly less activated than the ISS controls at 1.8 and 2.4 g/kg of ethanol.

Conclusions: The Lore‐2 and Lore‐5 congenic regions do not affect LDA. In contrast, the Lore‐1 congenic region carries one or more genes specifying both initial hypnotic sensitivity to ethanol and LDA.
Does Acetaldehyde Mediate Ethanol Action in the Central Nervous System?
Authors: Mascia Maria Paola , Maiya Rajani , Borghese Cecilia M. , Lobo Ingrid A. , Hara Koji , Yamakura Tomohiro , Gong Diane H. , Beckstead Michael J.
Published: April 2006

Background: Some of the effects of ethanol in the central nervous system are due to changes in function of ligand‐gated ion channels. Production of detectable amounts of acetaldehyde, a primary metabolite of ethanol, has been demonstrated in brain homogenates. The aim of this study was to determine whether central actions that are often attributed to ethanol may actually be mediated by acetaldehyde.

Methods: The effects of acetaldehyde (1–1000 μM) were tested by two‐electrode voltage‐clamp electrophysiology in Xenopus laevis oocytes expressing 10 different ligand‐gated ion channel receptors [α1 glycine; α1β2γ2Sγ‐aminobutyric acid (GABA)A; ρ1 GABAc; 5‐hydroxytryptamine‐3A; NR1a/NR2A NMDA; GluR1/GluR2 AMPA; GluR6/KA2 kainate; and α4β2, α4β4, and α2β4 nicotinic‐acetylcholine] and the G‐protein–coupled inward rectifying potassium channel GIRK2. We also investigated the effect of acetaldehyde on the dopamine transporter (DAT), performing dopamine uptake assays in oocytes expressing DAT.

Results: Acetaldehyde (1 and 10 μM) significantly enhanced α1 glycine receptor–mediated currents. Acetaldehyde did not affect the function of any of the other receptors tested or the potassium currents measured in GIRK2 channels. Moreover, acetaldehyde did not alter the DAT‐mediated dopamine uptake.

Conclusions: Our results suggest a potential minor role for acetaldehyde in the glycine receptor–mediated effects of ethanol. Otherwise, acetaldehyde does not modulate function of the neuronal receptors tested in this study, in GIRK channels or DAT, when expressed recombinantly in Xenopus laevis oocytes.
Drinking or Abstaining at Age 14? A Genetic Epidemiological Study
Authors: Rose Richard J. , Dick Danielle M. , Viken Richard J. , Pulkkinen Lea , Kaprio Jaakko
Published: April 2006

Background: Regular drinking by age 14 years is a significant risk factor for alcoholism, and genetically informative data suggest that whether a young adolescent abstains or drinks is largely attributable to familial (or other shared) environmental factors.

Methods: Three consecutive birth cohorts of Finnish twins, enrolled into a longitudinal study at age 11 to 12 years, completed a follow‐up questionnaire within 3 months of their 14th birthdays. The sample included 1380 twin sisters and 1330 twin brothers at age 14, and at that age, 35.4% reported using alcohol. Genetic analyses (model‐fitting of twin pair data) and epidemiological analyses (logistical regressions of data from individual twins) were conducted to examine predictive factors of drinking versus abstinence at age 14.

Results: Polychoric correlations were substantial across all same‐sex twin pairs but were lower for brother‐sister twins, suggesting significant influences of common environments, with some sex‐specific effects. Common environmental effects were equivalent in male and female adolescents and accounted for 76% of the total variation in abstinence/drinking. Logistical regression analyses among 2206 individual twins with complete data on risk‐relevant measures at both baseline and follow‐up identified significant predictors of drinking or abstaining at age 14, including female sex, twin sibling of the opposite sex, accelerated pubertal development, and the twins’ assessments, made at age 12, of reduced parental monitoring and a less supportive home atmosphere; drinking at age 14 was also predicted by behaviors rated by the twins’ classroom teachers 2 years earlier, increasing with rated behavioral problems but decreasing with rated emotional problems.

Conclusions: Our results show that environmental factors shared by twin siblings account for most of the variance in abstaining or drinking at age 14. We identify predictors of drinking in the adolescent twins’ home environments and in their dispositional behaviors, sibling interactions, and pubertal timing.
Naltrexone and Cue Exposure With Coping and Communication Skills Training for Alcoholics: Treatment Process and 1‐Year Outcomes
Authors: Monti Peter M. , Rohsenow Damaris J. , Swift Robert M. , Gulliver Suzy B. , Colby Suzanne M. , Mueller Timothy I. , Brown Richard A. , Gordon Alan , Abrams David B. , Niaura Raymond S. , Asher Marilyn K.
Published: April 2006

Background: Promising treatments for alcoholics include naltrexone (NTX), cue exposure combined with urge‐specific coping skills training (CET), and communication skills training (CST). This study investigated the effects of combining these elements as treatment adjuncts.

Methods: A 2 × 2 design investigated the effects of CET combined with CST, as compared with an education and relaxation control treatment, during a 2‐week partial hospital program (n= 165) followed by 12 weeks of NTX (50 mg/day) or placebo during aftercare (n= 128). Drinking outcomes were assessed at 3, 6, and 12 months after discharge from the partial hospital. Process measures included urge, self‐efficacy (confidence about staying abstinent in risky situations), and self‐reported coping skills. Medically eligible alcohol‐dependent patients were recruited.

Results: Among those compliant with medication on at least 70% of days, those who received NTX had significantly fewer heavy drinking days and fewer drinks on days that they drank than those receiving placebo during the medication phase but not during the subsequent 9 months. CET/CST‐condition patients were significantly less likely to report a relapse day and reported fewer heavy drinking days at the 6‐ and 12‐month follow‐ups than patients in the control treatment. Interactions of medication with behavioral treatments were not significant. Process measures showed that NTX resulted in lower weekly urge ratings, and those in CET/CST used more of the prescribed coping skills after treatment, reported fewer cue‐elicited urges, and reported more self‐efficacy in a posttest role‐play test. Drinking reductions at 3, 6, and 12 months correlated with more use of coping skills, lower urge, and higher self‐efficacy.

Conclusions: The results suggest the probable value of keeping alcoholics on NTX for longer periods of time and the importance of increasing compliance with NTX. They also support the earlier promising effects of CET and CST as adjuncts to treatment programs for alcoholics by maintaining treatment gains over at least a year. The value of the urge‐specific and general coping skills and of self‐efficacy and urge constructs was demonstrated in their association with drinking outcomes.
Assays for Acetaldehyde‐Derived Adducts in Blood Proteins Based on Antibodies Against Acetaldehyde/Lipoprotein Condensates
Authors: Latvala Jaana , Melkko Jukka , Parkkila Seppo , Järvi Kimmo , Makkonen Kati , Niemelä Onni
Published: April 2006

Background: Acetaldehyde‐derived protein condensates (adducts) have been suggested as promising biological markers of alcohol abuse because they represent actual metabolites of ethanol. However, the detection of such condensates in vivo has been hampered by a lack of sensitive and specific methods.

Methods: To develop new approaches for the detection of acetaldehyde adducts, we have raised antibodies against condensates with acetaldehyde and lipoproteins, which have previously been shown to be readily modified by acetaldehyde in vitro. The characteristics of these antibodies were compared with those raised against bovine serum albumin/acetaldehyde adduct and against other types of lipoprotein modifications, as induced by malondialdehyde, oxidation, and acetylation.

Results: The antibodies raised against low‐density lipoprotein (LDL)/acetaldehyde, very low density lipoprotein (VLDL)/acetaldehyde, and bovine serum albumin/acetaldehyde all reacted with protein adducts generated at physiologically relevant concentrations of acetaldehyde in vitro, whereas the antibodies raised against malondialdehyde/LDL, oxidized LDL, or acetylated LDL were not found to cross‐react with the acetaldehyde‐derived adducts. In assays for acetaldehyde adducts from erythrocyte and serum proteins of patients with excessive ethanol consumption (n= 32) and healthy control individuals (n= 22), the antibody prepared against the acetaldehyde/VLDL condensate was found to provide the most effective detection of acetaldehyde adducts in vivo.

Conclusions: Current data indicate that acetaldehyde generates immunogenic adducts with lipoproteins in vivo. Antibodies raised against the VLDL/acetaldehyde may provide a basis for new diagnostic assays to examine excessive alcohol consumption.
Regional Specificity Of Ethanol and NMDA Action in Brain Revealed With FOS‐Like Immunohistochemistry and Differential Routes of Drug Administration
Authors: Knapp Darin J. , Braun Christopher J. , Duncan Gary E. , Qian Ying , Fernandes Alda , Crews Fulton T. , Breese George R.
Published: April 2006

Background: Inhibition of NMDA receptor function in brain is believed to be an important action of ethanol (EtOH). To investigate EtOH inhibition of NMDA receptor responses in vivo, the interaction of these agents in brain after different routes of administration were investigated by using transcription factor Fos protein expression to follow NMDA receptor activation and EtOH inhibition of this response.

Methods: The induction of Fos‐like immunoreactivity (Fos‐LI) in 38 regions of the rat brain was measured 2 hr after treatment with NMDA, EtOH, or both. To determine the relative contribution of abdominal drug effects on Fos induction, rats received either intraperitoneal (ip) or intragastric (ig) EtOH and ip or intravenous (iv) NMDA. Rats received EtOH (2.5 g/kg ip or 4 g/kg ig) or vehicle 15 min before NMDA (125 mg/kg ip or 60 mg/kg iv) or vehicle.

Results: For the 38 forebrain regions examined, ip and iv NMDA significantly induced Fos‐LI in 13 and 32 regions, respectively. These effects occurred without elicitation of tonic‐clonic seizure activity and were strong after iv NMDA in the frontal, prefrontal, and cingulate cortices, supraoptic nucleus, anterior lateral septum, and dentate gyrus. For EtOH, prominent Fos‐LI induction was found in the central amygdala, dorsolateral bed nucleus of the stria terminalis, Edinger‐Westphal nucleus, and paraventricular hypothalamus. Despite ip and ig EtOH induction of Fos‐LI in these regions, the major effect of EtOH was to block NMDA‐induced Fos‐LI in 8 of 13 (ip) and 27 of 32 (ig) of the NMDA‐positive regions, respectively, including retrosplenial, cingulate, and medial prefrontal cortices, central amygdala, and taenia tecta.

Conclusions: These results provide new evidence for the regionally specific functional interactions of EtOH on NMDA receptors in vivo. Moreover, these results support efforts to identify brain region–specific targets for EtOH and EtOH‐induced changes in gene expression.
Effects of Abstinence on the Brain: Quantitative Magnetic Resonance Imaging and Magnetic Resonance Spectroscopic Imaging in Chronic Alcohol Abuse
Authors: O'Neill Joseph , Cardenas Valerie A. , Meyerhoff Dieter J.
Published: April 2006

Background: Structural brain damage, especially to white matter, is well documented in chronic alcohol abuse. There is also evidence for brain metabolic abnormalities in this condition. It is unknown, however, to what extent these structural and metabolic changes are present in treated alcohol abusers who achieve long‐term abstinence versus treatment‐naïve, heavily drinking individuals.

Methods: This study compared 12 recovering alcoholics with 8 actively heavily drinking subjects. Participants underwent magnetic resonance (MR) imaging and proton MR spectroscopic imaging of the brain. Semiautomated image segmentation techniques yielded volumes for gray matter, white matter, white matter lesions, and cerebral spinal fluid in multiple brain regions defined by Talairach stereotaxic coordinates. Automated spectral processing methods yielded gray and white matter concentrations of the metabolites N‐acetylaspartate, creatine, and choline for the same regions.

Results: Recovering alcoholics had greater volumes of frontal white matter, but the opposite was true for white matter in a “remainder” region encompassing the basal frontal and temporal lobes, the cerebellum, and the brainstem. Recovering alcoholics also had smaller volumes of white matter lesions in whole brain, in occipital and mesial parietal regions, and in the remainder region. Recovering alcoholics had greater gray matter volumes in the orbital frontal pole and postcentral gyrus, but smaller gray matter volumes in the anterior cingulate. Whole‐brain and regional metabolite concentrations did not differ significantly between the two groups.

Conclusions: White and gray matter volumes in different regions of the brain were greater or smaller in recovering, treated alcoholics. The findings suggest region‐specific structural recovery from chronic alcohol–induced brain injury, but also region‐specific long‐term structural damage in abstinent alcoholics. White matter lesions were widespread in active drinkers and may partly resolve during long‐term abstinence. Proton MR spectroscopic measures, as applied in this cross‐sectional study, were largely ineffective in revealing metabolic effects of abstinence on the alcohol‐damaged brain.
Sex Differences in Rats in the Development of and Recovery From Ethanol Dependence Assessed by Changes in Seizure Susceptibility
Authors: Devaud Leslie L. , Chadda Ritu
Published: April 2006

Background: Previous investigations have found sex differences in rats in response to chronic ethanol exposure. The most dramatic differences were observed with anticonvulsant treatment during ethanol withdrawal, when seizure susceptibility is significantly increased. Sex differences in this response were found for both GABAergic and glutamatergic compounds. This study was aimed at exploring whether sex also influences the timing for the development of and recovery from ethanol dependence.

Methods: Ethanol was administered in a liquid diet, with pair‐fed animals receiving dextrose, substituted isocalorically for the ethanol. Ethanol dependence and withdrawal were assessed by measurement of seizure thresholds after abrupt removal of the ethanol diet. Seizure thresholds were determined by slow, tail vein infusion of the γ‐aminobutyric acidA–receptor antagonist bicuculline.

Results: Male and female rats displayed differences in timing for both onset and recovery from ethanol dependence, as determined by changes in ethanol withdrawal seizure susceptibility. Female rats were slower to develop dependence and quicker to recover compared with male rats. Furthermore, acute ethanol administration did not alter seizure susceptibility in pair‐fed control animals, but it was anticonvulsant in ethanol‐withdrawn rats. Ethanol‐withdrawn female rats showed a greater response to acute ethanol administration than did male rats.

Conclusions: This set of experiments uncovered additional sex differences in one measure of ethanol dependence and withdrawal. Proposed mechanisms for the development of ethanol dependence involve alterations in subunit assembly of γ‐aminobutyric acidA and NMDA receptors or various posttranslational modifications. In consideration of these findings, whatever mechanisms underlie the development of ethanol dependence, there is a different sequence of events in male compared with female rats. Studies are ongoing to determine associations between behavioral measures of ethanol dependence/withdrawal and selective neuronal adaptations.
GABAA‐Receptor δ Subunit Knockout Mice Have Multiple Defects in Behavioral Responses to Ethanol
Authors: Mihalek Robert M. , Bowers Barbara J. , Wehner Jeanne M. , Kralic Jason E. , VanDoren Margaret J. , Morrow A. Leslie , Homanics Gregg E.
Published: April 2006

Background: The γ‐aminobutyric acid type A receptors (GABARs) are involved in mediating some of the behavioral effects of beverage alcohol (ethanol). However, the unique pharmacological and behavioral responses conferred by each of the various receptor subunits are not well understood.

Methods: To address the role of the GABAR δ subunit in mediating ethanol responses, gene knockout mice that lack this subunit were tested for a variety of ethanol‐induced behavioral responses.

Results: Our results indicate that, compared with controls, δ‐deficient mice (δ−/−) have (1) reduced ethanol consumption, (2) attenuated withdrawal from chronic ethanol exposure, and (3) reduced anticonvulsant (seizure‐protective) effects of ethanol. These mice demonstrate a normal anxiolytic response to ethanol and a normal hypothermic response to ethanol, and they develop both chronic and acute tolerance.

Conclusions: These results further establish the link between GABARs and specific behavioral responses to ethanol and begin to reveal the role of the δ subunit in these responses.
Dose‐Related Impact of Alcohol Consumption on Cognitive Function in Advanced Age: Results of a Multicenter Survey
Authors: Zuccalà Giuseppe , Onder Graziano , Pedone Claudio , Cesari Matteo , Landi Francesco , Bernabei Roberto , Cocchi Alberto
Published: April 2006

Background: Moderate alcohol consumption has been associated in several studies with decreased risk of cardiovascular and cerebrovascular events; however, available data on the effects of alcohol intake on cognitive functioning are conflicting. We assessed the association between alcohol consumption and cognitive impairment in a series of older subjects enrolled in a multicenter pharmacoepidemiology survey.

Methods: The association between average alcoholic intake and cognitive performance was assessed in 15,807 patients admitted to participating centers during the survey periods. Demographic variables, comorbid conditions, medications, and objective tests that were associated with cognitive impairment (as indicated by a Hodkinson Abbreviated Mental Test score <7) in separate logistical regression models were examined as potential confounders in a summary model.

Results: Cognitive impairment was detected in 1693 (19%) of 8755 drinkers and 2008 (29%) of 7052 nondrinkers (Fisher's exact test, p < 0.0001). After adjusting for potential confounders, alcohol consumption was associated with decreased probability of cognitive impairment (odds ratio, 0.75; 95% confidence interval, 0.66–0.85). The relationship between drinking level and cognitive dysfunction was nonlinear, because the probability of cognitive impairment was decreased for moderate alcohol use as compared with abstinence, but it was increased for daily consumption exceeding one wine‐equivalent liter among men and 0.5 liter among women. This nonlinear association persisted when cerebrovascular and Alzheimer's disease were considered separately.

Conclusions: Alcohol abuse is associated with increased prevalence of cognitive dysfunction among older subjects; however, a daily alcohol consumption of less than 40 g for women and 80 g or less for men might be associated with a decreased probability of cognitive impairment. This possible protective effect of alcohol consumption should be further assessed by prospective studies.
Expression and Cytoskeletal Association of Integrin Subunits Is Selectively Increased in Rat Perivenous Hepatocytes After Chronic Ethanol Administration
Authors: Schaffert Courtney S. , Sorrell Michael F. , Tuma Dean J.
Published: April 2006

Background: For normal function and survival, hepatocytes require proper cell–extracellular matrix (ECM) contacts mediated by integrin receptors and focal adhesions. Previous studies have shown that chronic ethanol consumption selectively impairs perivenous (PV) hepatocyte attachment and spreading on various ECM substrates but increases expression of the β1 integrin subunit, the common β subunit for two major hepatocyte‐ECM receptors, α1β1 and α5β1 integrins. This study examined the effects of ethanol treatment on the expression and cytoskeletal distribution of α1, α5, and β1 integrin subunits, the epidermal growth factor receptor (EGF‐R), and the cytoskeletal proteins focal adhesion kinase, paxillin, vinculin, and actin in periportal and PV hepatocytes.

Methods: Periportal and PV hepatocytes were isolated from control and ethanol‐fed rats. For expression analysis, lysates were examined by SDS‐PAGE and immunoblotting procedures. For cytoskeletal distribution studies, Triton‐soluble and ‐insoluble (cytoskeletal) fractions from hepatocytes cultured on collagen IV were analyzed by SDS‐PAGE and immunoblotting.

Results: Chronic ethanol administration caused PV‐specific increases in expression and cytoskeletal association of the integrin subunits. Although ethanol treatment did not affect expression of the EGF‐R in either cell type, it did increase the association of the EGF‐R with the cytoskeleton selectively in PV hepatocytes. Ethanol treatment had no significant effect on either the expression or the cytoskeletal distribution of focal adhesion kinase, paxillin, vinculin, or actin in either cell type.

Conclusions: The increases in integrin expression and cytoskeletal association observed after chronic ethanol administration suggest that a process downstream of integrin‐ECM interactions is impaired selectively in PV hepatocytes, possibly involving altered focal adhesion assembly or turnover, processes essential for efficient cell‐ECM adhesion. Alterations in these processes could contribute to the impaired hepatocyte function and structure observed after chronic ethanol administration.
Ethanol Consumption Alters Electroretinograms and Depletes Neural Tissues of Docosahexaenoic Acid in Rhesus Monkeys: Nutritional Consequences of a Low n‐3 Fatty Acid Diet
Authors: Pawlosky Robert J. , Bacher John , Salem Norman
Published: April 2006

Background: Alcohol amblyopia is a rare neuropathy characterized by the development of blurred vision and a reduction in visual acuity. Further diagnostic details of this condition have shown abnormalities in the electroretinogram (ERG) that include an increase in implicit times in the a‐ and b‐waves and a depression of b‐wave amplitude.

Methods: Periodically, the ERGs and the fatty acyl composition of nervous tissue were analyzed from alcohol‐consuming rhesus monkeys (Macaca mulatta) (mean consumption 2.6 g kg/day over a 5‐year period) and controls that were maintained on a nutritionally sufficient diet that had low, yet adequate, amounts of linoleic acid but very low α‐linolenic acid.

Results: Animals consuming alcohol had increased a‐ and b‐wave implicit times and decreased b‐wave amplitudes in their electroretinograms compared with those of the dietary control group at 2.5 and 5 years. The fatty acyl composition of brain specimens obtained by surgical biopsy at baseline, 2.5 years, and 5 years demonstrated that docosahexaenoic acid (DHA) had decreased in both groups of animals compared with baseline values. In the brains of the alcohol‐treated animals, DHA was even further decreased (2.5 years: −20%; 5 years: −33%) compared with the diet controls. In the retinas of the alcohol‐consuming animals at 5 years, there was a similar decrease in DHA (‐35%) compared with controls. Generally, the n‐6 fatty acid, docosapentaenoic acid (DPAn‐6) increased in these tissues, apparently compensating for the loss of DHA.

Conclusions: A reciprocal change in the DHA/DPAn‐6 ratio is known to be associated with abnormal electroretinograms in a number of species. Thus, a marginal intake of n‐3 fatty acids in some alcohol abusers may, in part, be responsible for the biochemical changes that underlie the diminished retinal function associated with the visual abnormalities observed in alcohol‐amblyopic patients.
Ethanol‐Induced Up‐Regulation of the Urokinase Receptor In Cultured Human Endothelial Cells
Authors: Tabengwa Edlue M. , Grenett Hernan E. , Benza Raymond L. , Abou‐Agag Laila H. , Tresnak Jennifer K. , Wheeler Crystal G. , Booyse Francois M.
Published: April 2006

Background: Moderate alcohol consumption has been correlated to reduced coronary artery disease (CAD) risk and mortality. This alcohol effect may be mediated in part by an increased endothelial cell (EC) fibrinolysis. ECs synthesize fibrinolytic proteins, tissue plasminogen activator (t‐PA), urokinase type plasminogen activator (u‐PA), and plasminogen activator inhibitor type‐1(PAI‐1). In addition, they synthesize and regulate receptors for fibrinolytic proteins, namely (t‐PA and plasminogen receptor) Annexin II and u‐PA receptor (u‐PAR). These receptors play an important role in the regulated expression of receptor‐bound plasminogen activator conversion of receptor‐bound plasminogen to receptor‐bound plasmin on the EC surface (surface‐localized fibrinolytic activity). Therefore, systemic factors, such as ethanol, that affect the level, or activity or interaction of one or more of these components, resulting in the increased expression of surface‐localized EC fibrinolytic activity, will be expected to reduce the risk for thrombosis, CAD, and myocardial infarction (MI). We have previously shown that low ethanol up‐regulates t‐PA and u‐PA gene transcription, while it down‐regulates PAI‐1, hence resulting in increased (sustained, 24 hr) surface‐localized EC fibrinolytic activity. The current studies were carried out to determine whether low ethanol increased u‐PAR expression in cultured human umbilical cord vein ECs (HUVECs).

Methods: Cultured HUVECs were preincubated (1 hr) in the absence/presence of ethanol (0.025–0.2%, v/v); u‐PAR mRNA (RT‐PCR), antigen (western blot), and activity (125I‐u‐PA ligand binding/Scatchard analysis) levels were then measured after 0–24 hr. To determine whether the ethanol‐induced changes in the u‐PAR expression were transcriptional, transient transfection studies were carried out using a u‐PAR/luciferase promoter construct (pu‐PAR120/luc [1.2‐kb u‐PAR promoter fragment ligated to a promoterless luciferase vector]).

Results: uPAR mRNA levels increased 2‐ to 3‐fold and antigen levels (western blot) increased 2‐ to 4‐fold while u‐PA binding activity increased 36% (1.25 vs. 1.7 − 105 sites/cell, Bmax) without significantly affecting the Kd (1–2 nM). Transient transfection of cultured HUVECs with a pu‐PAR120/luc construct resulted in a 2‐ to 3‐fold increase in promoter activity in ethanol‐induced cultures, compared with controls.

Conclusion: These combined results demonstrate that low ethanol (≤0.1%, v/v) induces the up‐regulation of u‐PAR gene transcription, resulting in increased u‐PAR ligand binding activity. These results also further identify/define the contribution and role of another fibrinolytic protein in the overall ethanol‐induced increase in surface‐localized EC fibrinolysis that may underlie and contribute, in part, to the cardioprotection attributed to moderate alcohol consumption.
No Effect of Albinism on Sedative‐Hypnotic Sensitivity to Ethanol and Anesthetics
Authors: Rikke Brad A. , Simpson Victoria J. , Montoliu Lluis , Johnson Thomas E.
Published: April 2006

Background: Studies using the long‐sleep (LS) X short‐sleep (SS) (LSXSS) recombinant inbred mice and inbred long‐sleep (ILS) by inbred short‐sleep (ISS) intercrosses have found genetic linkage between Tyr albinism (c/c) and differential sensitivity to sedative‐hypnotic doses of ethanol and general anesthetics. This linkage could be due to a gene or genes near Tyr or Tyr itself. With regard to the latter possibility, the absence of tyrosinase activity (encoded by Tyr) in albinos could alter tyrosine availability and thus the rate‐limiting step in catecholamine synthesis. In addition, albinism is associated with altered brain development that could have pleiotropic effects on behavior. Therefore, in this study, we asked whether albinism affects sedative‐hypnotic sensitivity.

Methods: Loss of righting reflex (LORR) duration was measured using doses of ethanol (4.1 g/kg), pentobarbital (70 mg/kg), isoflurane (2 g/kg), and etomidate (20 mg/kg) that were previously associated with differential sensitivity of albino versus nonalbino mice. Tyr transgenics (c/c, TgTyr+) were backcrossed to ISS (c/c) to compare pigmented (c/c, TgTyr+) and albino (c/c) mice in the context of an ISS‐like background. ISS was also crossed with C57BL/6 (B6) mice heterozygous for a spontaneous albino mutation (c2j) to compare pigmented (c/+) and albino (c/c2j) mice. Pigmented B6 (c2j/+ and +/+) and albino B6 (c2j/c2j) mice were also compared (pentobarbital).

Results: For each sedative hypnotic, albinism had no effect on LORR duration. Each expected difference was ruled out at the 95% or 99% confidence level. For each sedative hypnotic, males were more sensitive than females even though the effect size was usually smaller than the expected albino effect size, arguing empirically that the inability to detect an albino effect was not due to systematic error or an insufficient number of mice.

Conclusion: We conclude that the differential sensitivity associated with albinism is most likely due to a gene or genes near Tyr rather than Tyr itself.
Dopamine D2 Receptor Gene (DRD2) Is Associated With Alcoholism With Conduct Disorder
Authors: Lu Ru‐Band , Lee Jia‐Fu , Ko Huei‐Chen , Lin Wei‐Wen
Published: April 2006

This study examined whether there is evidence for an association between alcoholism with conduct disorder and alleles of the Taq I A and Taq I B polymorphisms, both individually and as haplotypes, at the dopamine D2 receptor gene (DRD2). We studied 182 Han Chinese subjects, including 34 alcoholics with conduct disorder, 63 alcoholics without conduct disorder, and 85 nonalcoholics. Alcohol dependence and conduct disorder were defined according to DSM‐III‐R criteria. Significant associations were observed between Taq I A and Taq I B at the DRD2 locus, tested individually and as haplotypes, and alcoholism with conduct disorder. Our results suggested that DRD2 might be associated with conduct disorder or a predisposition to both conduct disorder and alcoholism. However, this needs to be further investigated by examining the differences among conduct disorder with alcoholism, conduct disorder only, and controls for the Taq I A and B system at DRD2.