Haughey, Heather M.; Kaiser, Alan L.; Johnson, Thomas E.; Bennett, Beth; Sikela, James M.; and Zahniser, Nancy R.  Norepinephrine transporter: A candidate gene for initial ethanol sensitivity in inbred Long-Sleep and Short-Sleep mice.  Alcoholism: Clinical & Experimental Research 29(10):1759-1768, October 2005.

Address correspondence to Heather M. Haughey, Department of Pharmacology, University of Colorado Health Sciences Center, Aurora, Colorado, USA. E-mail: heather.haughey@colorado.edu.

Summary: Molecular biological, neurochemical, and behavioral approaches were used to test the hypothesis that the norepinephrine transporter (NET) contributes to the differences in ethanol-induced loss of righting reflex (LORR) in inbred Long-Sleep (ILS) and inbred Short-Sleep (ISS) mice. The aim was to investigate the NET as a candidate gene contributing to this phenotype. The ILS and ISS mice carry different deoxyribonucleic acid haplotypes for NET, showing eight silent differences between allelic coding regions. Only the ILS haplotype is found in other mouse strains thus far sequenced. Brain regional analyses revealed that ILS mice have 30% to 50% lower [3H]NE uptake, NET binding, and NET messenger ribonucleic acid levels than ISS mice. Maximal [3H]NE uptake and NET number were reduced, with no change in affinity, in the ILS mice. These neurobiological changes were associated with significant influences on the behavioral phenotype of these mice, as demonstrated by (1) a differential response in the duration of ethanol-induced LORR in ILS and ISS mice pretreated with a NET inhibitor and (2) increased ethanol-induced LORR in LXS recombinant inbred (RI) strains, homozygous for ILS in the NET chromosomal region (44-47 cM), compared with ISS homozygous strains. This is the first report to suggest that the NET gene is one of many possible genetic factors influencing ethanol sensitivity in ILS, ISS, and LXS RI mouse strains. NIAAA Glossary Terms:  norepinephrine, transport proteins, ethanol, righting reflex, phenotype, genotype, gene expression, chromosome, selective breeding, animal strains, laboratory mice, DNA, haplotype, mRNA, chromosome, animal model

Alam, Imranul; Robling, Alexander G.; Weissing, Sarah; Carr, Lucinda G.; Lumeng, Lawrence; and Turner, Charles H.  Bone mass and strength: Phenotypic and genetic relationship to alcohol preference in P/NP and HAD/LAD rats.  Alcoholism: Clinical & Experimental Research 29(10):1769-1776, October 2005.

Address correspondence to Department of Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.

Summary: The purpose was to determine whether there is a relationship between alcohol preference and high bone mass or strength and whether bone mass-regulating genes segregate during selective breeding of alcohol preferring rats. Six different lines of male rats with high or low preference for alcohol consumption were studied. The high alcohol preference lines were alcohol-preferring (P), high-alcohol-drinking 1 (HAD1), and high-alcohol-drinking 2 (HAD2). Their corresponding low alcohol preference lines were alcohol-nonpreferring (NP), low-alcohol-drinking 1 (LAD1), and low-alcohol-drinking 2 (LAD2). Bone mass phenotypes were determined using dual energy x-ray absorptiometry, peripheral quantitative computed tomography, and biomechanics in long bones and lumbar vertebrae from rats at 3 and 6 months of age. Bone mass and strength were significantly higher in P rats than in NP rats, mainly due to higher cortical bone in long bones and lumbar vertebrae. HAD2 rats also had significantly higher bone mass compared with LAD2 rats, but mostly due to increased trabecular bone leading to increased strength only in lumbar vertebra. Conversely, HAD1 rats had significantly lower bone mass and strength compared with LAD1 rats in long bones. Vertebral bone mass and strength did not differ between HAD1 and LAD1 rats. Thus there was no consistent relationship between preference for alcohol consumption and high bone mass or strength, as each alcohol-preferring rat line had its unique bone mass phenotypes. However, genes regulating bone mass and strength appear to segregate with alcohol preference genes in P and HAD rat lines, suggesting that alcohol preferring rat lines may be useful for identifying genes that regulate bone mass and structure. NIAAA Glossary Terms:  animal selectively bred for alcohol preference, animal strains, laboratory rat, bone mass density, phenotype, computed x-ray tomography, spine, animal model

Cowmeadow, R B.; Krishnan, H R.; and Atkinson, N S.  The slowpoke gene is necessary for rapid ethanol tolerance in Drosophila.  Alcoholism: Clinical & Experimental Research 29(10):1777-1786, October 2005.

Address correspondence to Section of Neurobiology and The Waggoner Center for Alcohol and Addiction Research, University of Texas at Austin, Austin, Texas 78712-0248, USA.

Summary: The slowpoke BK-type calcium-activated potassium channel gene has recently been shown to be involved in ethanol sensitivity in Caenorhabditis elegans and in rapid tolerance to the anesthetic benzyl alcohol in Drosophila. Drosophila mutants were used in this study to investigate the role of the slowpoke gene in rapid tolerance to sedation with ethanol vapor. Rapid tolerance was defined as a reduction in the sedative phase caused by a single previous sedation. The ethanol and water contents of flies were measured to determine if pharmacodynamic changes could account for tolerance. A saturated ethanol air stream caused sedation in <20 minutes and resulted in rapid tolerance that was apparent 4 hours after sedation. Two independently isolated null mutations in the slowpoke gene eliminated the capacity for tolerance. In addition, a third mutation that blocked expression specifically in the nervous system also blocked rapid tolerance. Water measurements showed that both ethanol and mock sedation caused equivalent dehydration. Furthermore, a single prior exposure to ethanol did not cause a change in the ethanol clearance rate. It was concluded that rapid tolerance, measured as a reduction in the duration of sedation, is a pharmacokinetic response to ethanol that does not occur without slowpoke expression in the nervous system in Drosophila. The slowpoke channel must be involved in triggering or producing a homeostatic mechanism that opposes the sedative effects of ethanol. NIAAA Glossary Terms:  gene, potassium channel, AOD sensitivity, ethanol, Drosophila melanogaster, AOD tolerance, mutation, gene expression, pharmacokinetics, homeostasis, sedative-hypnotics, animal study

Tsai, Chien-Sung; Loh, Shih-Hurng; Jin, Jong-Shiaw; Hong, Guo-Jieng; Lin, Hei-Ting; Chiung, Cheng-Shian; and Chang, Chung-Yi.  Effects of alcohol on intracellular pH regulators and electromechanical parameters in human myocardium.  Alcoholism: Clinical & Experimental Research 29(10):1787-1795, October 2005.

Address correspondence to Division of Cardiovascular Surgery, Tri-Service General Hospital, National Defense Medical Center, Neihu, Taipei, Taiwan, Republic of China. E-mail: sung1500@ndmctsgh.edu.tw.

Summary: Ethanol affects blood pressure and heart contractility and sometimes causes cardiac arrhythmia. This study assessed the effects of ethanol on intracellular pH (pHi) regulators and electromechanical parameters by superfusing various concentrations of ethanol into human myocardium obtained from hearts of patients undergoing corrective cardiac surgery. pHi was measured by a microspectrofluorimetry technique, while electrophysiological experiments were performed by traditional micropipette. Na+/H+ exchange (NHE) and Na+/HCO3– symporter (NHS) activities were measured after pHi recovery from intracellular acidosis induced by NH4Cl prepulse, while monocarboxylic acid transporter (MCT) activity was measured by a lactate adding/removing technique. It was shown in pHi experiments that ethanol could induce a biphasic, concentration-dependent (30–1000 mM) pHi change (i.e., alkalosis after acidosis) in human atrium in HEPES-buffered Tyrode solution. To a smaller extent, similar results were found when the superfusate was replaced by HCO3– buffered Tyrode solution. NHE activity was increased by a moderate concentration of ethanol (30 mM), but was inhibited in a concentration-dependent manner by higher concentrations of ethanol (>100 mM). In contrast, 30–1000 mM alcohol increased the activity of NHS in a concentration-dependent manner. Surprisingly, MCT activity was not affected by ethanol. In electromechanical experiments, ethanol (30-1000 mM) had a notable concentration-dependent inhibitory effect on the contractile force, while higher concentrations (>100 mM) decreased the action potential amplitude, upstroke velocity, duration of repolarization, and force of contractions in a concentration-dependent way. All these ethanol-induced pHi changes and electromechanical inhibitions were reversible. The authors believe that this study provides the first evidence that ethanol can affect pHi in human myocardial tissue by changing the activity of acid extruders (i.e., NHE and NHS). NIAAA Glossary Terms:  ethanol, pH, myocardium, transport proteins, acidosis, lactate, disorder of fluid or electrolyte or acid-base balance, heart function, muscle contraction, human study

Doremus, Tamara L.; Brunell, Steven C.; Rajendran, Pottayil; and Spear, Linda P.  Factors influencing elevated ethanol consumption in adolescent relative to adult rats.  Alcoholism: Clinical & Experimental Research 29(10):1796-1808, October 2005.

Address correspondence to Center for Developmental Psychology, Department of Psychology, Binghamton University, Binghamton, New York 13902-6000, USA.

Summary: Using a 24-hour, free-access, two-bottle-choice procedure between water and a sweetened solution with or without ethanol in nondeprived rats, this study examined the contribution of a variety of contextual and experimental variables (i.e., isolate-housing versus pair-housing, type of sipper tube, caloric value of solution, prior experimental perturbations) on alcohol consumption in both adolescent and adult Sprague-Dawley rats. Ethanol consumption was particularly magnified among adolescent rats using ball bearing-containing ball-point (BP) sipper tubes, with this exacerbated intake not due to caloric content of the ethanol solution. Isolation housing for 12 days did not alter ethanol consumption of adolescents relative to their socially housed counterparts, but did suppress consumption of isolated adults. An examination of differences in the relative magnitude of adolescent ethanol consumption across experiments in this series revealed that ethanol intake among adolescents was elevated not only by the inclusion of BP sipper tubes but also by staggering the timing of isolate housing relative to the presentation of the novel ethanol solution. These experiments demonstrate that adolescent animals consume significantly more ethanol than adult animals under a variety of home cage continuous-access circumstances, with the relatively greater intake of adolescents further magnified by a number of test conditions. Subtle experimental details often thought to be innocuous can have a substantial impact on overall amount of voluntary ethanol consumption observed in both adolescent and adult animals. NIAAA Glossary Terms:  ethanol, AOD consumption, adolescent, adult, laboratory rat, age differences, animal behavior, research issue, variable, characteristic, factor, animal study

Ristuccia, Robert C. and Spear, Linda P.  Sensitivity and tolerance to autonomic effects of ethanol in adolescent and adult rats during repeated vapor inhalation sessions.  Alcoholism: Clinical & Experimental Research 29(10):1809-1820, October 2005.

Address correspondence to Center for Developmental Psychobiology, Department of Psychology, Binghamton University, Binghamton, New York 13902-6000, USA.

Summary: A possible contributor to the increased ethanol consumption often seen during adolescence in humans and in various animal models is age differences in ethanol sensitivity and tolerance. This study examined the impact of age on ethanol-related alterations in the autonomic nervous system. Sensitivity to the initial ethanol challenge and chronic tolerance as well as acute and protracted withdrawal-like phenomena were assessed in male adolescent and adult Sprague-Dawley rats, using implanted telemetry probes with ethanol delivered by vapor inhalation. Adolescents and adults showed similar ethanol-induced tachycardia and activity suppression, but adolescents were more sensitive to the hypothermic effect of ethanol, contrary to other results from the authors' laboratory and elsewhere using intragastric or intraperitoneal ethanol administration. Although little tolerance to ethanol's tachycardic or activity suppressant effects was seen after repeated ethanol inhalation sessions, chronic tolerance to ethanol's hypothermic effect developed faster in adults than in adolescents. A withdrawal-like syndrome, characterized by bradycardia and hypoactivity, typically emerged during the dark phase of the diurnal cycle after ethanol vapor exposure sessions. These effects were observed in rats of both ages, with the bradycardic effect more pronounced in adolescents. In contrast to results indicating that adolescents may be less sensitive than adults to ethanol's hypothermic effect when ethanol is administered via bolus injection/intubation, adolescents appear more sensitive and develop tolerance to ethanol's hypothermic effects more slowly than adults when ethanol is administered at a more moderate rate by vapor inhalation. NIAAA Glossary Terms:  ethanol, inhalation, AOD consumption, AOD sensitivity, AOD tolerance, age differences, adolescent, adult, laboratory rat, tachycardia, bradycardia, hypothermia, chronic AODE, intragastric administration, intraperitoneal administration, physical activity, AOD withdrawal syndrome, animal study

Marinelli, Peter W.; Bai, Li; Quirion, Remi; and Gianoulakis, Christina.  A microdialysis profile of met-enkephalin release in the rat nucleus accumbens following alcohol administration.  Alcoholism: Clinical & Experimental Research 29(10):1821-1828, October 2005.

Address correspondence to Biobehavioural Pharmacology Section, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.

Summary: The majority of studies of the role of the endogenous opioid system in mediating alcohol intake have concentrated on endorphinergic systems. Other opioid systems have received comparably less attention despite some compelling evidence that implicates enkephalinergic peptide systems, particularly met-enkephalin, in mediating alcohol preference. This study investigated the effect of alcohol administration on extracellular levels of met-enkephalin in the rat nucleus accumbens (NA), a brain region that plays a significant role in the processes underlying reinforcement and stress. Male Sprague-Dawley rats were implanted with a microdialysis probe aimed at the shell region of the NA. Artificial cerebrospinal fluid was pumped at a rate of 1.75 μl/min in awake and freely moving rats, and dialysates were collected at 30-minute intervals. After several baseline collections, rats were injected intraperitoneally with either physiological saline or one of four doses of ethanol: 0.8, 1.6, 2.4, or 3.2 g/kg body weight. Met-enkephalin levels in the dialysates were analyzed with solid-phase radioimmunoassay. Within the first 30 minutes of administration, an ethanol dose of 1.6 g/kg caused a significant and prolonged elevation in the extracellular levels of met-enkephalin. Ethanol did not have a major effect on the release of met-enkephalin at any other dose. Enkephalins may modulate local neurotransmitter release by binding to presynaptic δ-opioid receptors, or, they may inhibit effector cells by binding to postsynaptic δ- or μ-opioid receptors. This may be one of multiple neurological mechanisms that modulate alcohol-drinking behavior. NIAAA Glossary Terms:   endogenous opioids, ethanol, methionine enkephalin, neurotransmitters, nucleus accumbens, microdialysis, intraperitoneal administration, delta-opioid receptors, mu-opioid receptors, reinforcement, stress, AOD use behavior, animal behavior, controlled study, laboratory rat, animal study

Slawecki, Craig J. and Ehlers, Cindy L.  Enhanced prepulse inhibition following adolescent ethanol exposure in Sprague-Dawley rats.  Alcoholism: Clinical & Experimental Research 29(10):1829-1836, October 2005.

Address correspondence to Craig J. Slawecki, Scripps Research Institute, Department of Neuropharmacology, La Jolla, California 92037, USA. E-mail: cslawecki@scripps.edu.

Summary: Recent studies have demonstrated that ethanol differentially affects adolescents and adults. The objective of this study was to compare the effects of 2-week exposure to ethanol during adolescence or adulthood on the acoustic startle response (ASR) and prepulse inhibition (PPI). Male Sprague-Dawley rats were exposed to ethanol vapor 12 hours a day (from 6 pm to 6 am) for 14 days during adolescence or adulthood. The ASR and PPI were assessed 6 days after the cessation of ethanol vapor exposure. During ethanol treatment, overall blood alcohol levels averaged 230 to 250 mg/dl in the adolescent and adult treatment groups. Assessment of the ASR revealed that latency to startle was shorter in adolescents than in adults, but ASR latency was not altered by ethanol exposure. In addition, ASR magnitude was lower in adolescents and was decreased in ethanol-exposed rats on startle trials. Ethanol exposure significantly enhanced PPI, but only in adolescents. These results further demonstrate differential sensitivity of adolescents and adults to the effects of ethanol exposure. Specifically, a 2-week period of ethanol exposure during adolescence selectively enhanced PPI, a neurobehavioral index of sensorimotor gating. However, ASR magnitude was decreased by ethanol exposure regardless of age. On the basis of previous studies, the effects of ethanol exposure on PPI data could indicate that adolescent rats exposed to ethanol are more likely to exhibit behavioral inflexibility and that ethanol acts as a more potent physical stressor in adolescent rats. NIAAA Glossary Terms:  adolescent, adult, age differences, ethanol, inhalation, laboratory rat, animal behavior, comparative study, stressor, animal study

Rewal, Mridula; Wen, Yi; Wilson, Andrew; Simpkins, James W.; and Jung, Marianna E.  Role of parvalbumin in estrogen protection from ethanol withdrawal syndrome.  Alcoholism: Clinical & Experimental Research 29(10):1837-1844, October 2005.

Address correspondence to Mridula Rewal, Department of Pharmacology and Neuroscience, University of North Texas Health Science Center at Fort Worth, Fort Worth, Texas 76107-2699, USA. E-mail: mrewal@hsc.unt.edu.

Summary: Parvalbumin is a calcium-binding protein that has been implicated in protecting neurons from hyperexcitability by sequestering intracellular calcium. This study examined whether ethanol exposure or ethanol withdrawal (EW) alter the levels of parvalbumin in a manner that is protected by 17β-estradiol (E2). Ovariectomized rats implanted with E2 (EW/E2) or oil pellets (EW/Oil) received chronic ethanol (7.5% w/v, 5 weeks) or control dextrin (Dex/Oil and Dex/E2) diets. At 0 hours, 24 hours, and 2 weeks of ethanol withdrawal, three brain areas (cerebellum, hippocampus, and cortex) were prepared for immunoblotting and immunohistological assessment of parvalbumin. At 24 hours of EW, the EW/Oil group showed reduced levels of parvalbumin protein and parvalbumin-positive neurons in the cerebellum and hippocampus compared with the dextrin control and the EW/E2 groups. At 2 weeks of ethanol withdrawal, the reduced levels of parvalbumin persisted in the cerebellum but recovered toward the control levels in the hippocampus. The cortex showed no change in parvalbumin levels in any of the treatment groups. When tested at 24 hours of ethanol withdrawal, the magnitude of withdrawal signs inversely correlated with the levels of parvalbumin in the cerebellum and hippocampus. Ethanol exposure itself did not affect parvalbumin levels. These results suggest that ethanol withdrawal, rather than ethanol exposure, reduces parvalbumin levels in a manner that is brain region specific and is protected by estrogen. Disturbed parvalbumin homeostasis is hypothesized to play a role in the hyperexcitability of ethanol withdrawal signs. NIAAA Glossary Terms:   calcium binding protein, ethanol, AOD withdrawal syndrome, estradiol, estrogens, cerebellum, hippocampus, cerebral cortex, neuron, immunoblotting, histologic study, controlled study, laboratory rat, homeostasis, hyperexcitability, animal study

Allen, Gregg C.; West, James R.; Chen, Wei-Jung A.; and Earnest, David J.  Neonatal alcohol exposure permanently disrupts the circadian properties and photic entrainment of the activity rhythm in adult rats.  Alcoholism: Clinical & Experimental Research 29(10):1845-1852, October 2005.

Address correspondence to Texas A and M University System Health Science Center, College of Medicine, Department of Human Anatomy and Medical Neurobiology, College Station, Texas 77843-1114, USA.

Summary: The long-term effects of neonatal alcohol exposure on circadian behavioral activity were examined in adult rats. Artificially reared Sprague-Dawley rat pups were exposed to ethanol (4.5 g/kg/day) or isocaloric milk formula (gastrostomy control; GC) on postnatal days 4-9. At 2 months of age, rats from the ethanol, GC, and suckle control (SC) groups were housed individually, and properties of the circadian rhythm in wheel-running behavior were continuously analyzed during exposure to a 12-hour light:12-hour dark photoperiod (LD 12:12) or constant darkness (DD). Neonatal ethanol exposure had distinctive effects on the rhythmic properties and quantitative parameters of adult wheel-running behavior. Ethanol-treated rats were distinguished by unstable and altered entrainment to LD 12:12 such that their daily onsets of activity were highly variable and occurred at earlier times relative to control animals. In DD, circadian regulation of wheel-running behavior was altered by neonatal ethanol exposure such that the free-running period of the activity rhythm was shorter in ethanol-exposed rats than in control animals. Total amount of daily wheel-running activity in ethanol-treated rats was greater than that observed in the SC group. In addition, the circadian activity patterns of ethanol-exposed rats were fragmented such that the duration of the active phase and the number of activity bouts per day were increased. These results indicate that neonatal alcohol exposure produces permanent changes in the circadian regulation of the rat activity rhythm and its entrainment to LD cycles. These long-term alterations in circadian behavior, along with the developmental ethanol-induced changes in suprachiasmatic nucleus endogenous rhythmicity, may have important implications in clinical sleep-wake disturbances observed in neonates, children, and adults exposed to alcohol in utero. NIAAA Glossary Terms:   postnatal alcohol exposure, neonate, adulthood, circadian rhythm, animal behavior, laboratory rat, controlled study, sleep disorder, animal study

Javors, Martin A.; Ginsburg, Brett C.; Friesenhahn, Greg; Delallo, Leo; and Lamb, Richard J.  Rat breathalyzer.  Alcoholism: Clinical & Experimental Research 29(10):1853-1857, October 2005.

Address correspondence to Martin A. Javors, Department of Psychiatry, University of Texas Health Science Center, San Antonio, Texas 78229, USA. E-mail: javors@uthscsa.edu.

Summary: This article describes the estimation of blood alcohol concentration (BAC) in laboratory rats by measuring ethanol concentration in breath (BrAC) using a specialized apparatus in combination with a gas chromatography system. The apparatus consisted of a body chamber, a plastic cylinder, from which the head of the rat protruded, a head chamber, and a water-jacketed cylinder, in which the rat's head was placed while the breath sample was collected. The breath sample was withdrawn from the head chamber through a sample loop by a Minipuls pump and then injected directly into the gas chromatography system, which was equipped with a flame ionization detector for the quantification of ethanol. For these experiments, Lewis rats were catheterized 1 week before the commencement of the experiments so blood samples could be collected at exactly the same time as the breath samples. The results showed that Lewis rats can be trained to enter and be secured in the body chamber and that they appear to be comfortable for periods as long as 150 minutes. The pharmacokinetic curves for BrAC and BAC had essentially identical profiles. Cmax for BrAC and BAC at 8 minutes after the intraperitoneal injection of ethanol was directly proportional to the ethanol doses. The ratio of BrAC expressed as peak area to BAC (expressed as mM) was calculated to be 3282. This conversion factor can be used to directly estimate the BAC from the BrAC. It was concluded that the rat breathalyzer is an accurate and convenient laboratory method for noninvasive estimation of BAC. The procedure is expected to be particularly useful for studies requiring repeated assessment of alcohol levels. NIAAA Glossary Terms:  ethanol, BAC, BAC method, breath alcohol analysis, laboratory measurement, laboratory rat, gas chromatography, pharmacokinetics, intraperitoneal administration, correlation analysis, animal study

Moos, Rudolf H. and Moos, Bernice S.  Paths of entry into Alcoholics Anonymous: Consequences for participation and remission.  Alcoholism: Clinical & Experimental Research 29(10):1858-1868, October 2005.

Address correspondence to Rudolf H. Moos, Center for Health Care Evaluation, Department of Veterans Affairs and Stanford University, Palo Alto, California, USA. E-mail: rmoos@stanford.edu.

Summary: Three groups of individuals with alcohol use disorders who, in the first year after initiating help-seeking were compared: those who entered Alcoholics Anonymous (AA) only, those who entered professional treatment and AA together, and those who entered professional treatment only. A sample of initially untreated individuals (N = 362) was surveyed at baseline and 1 year, 3 years, 8 years, and 16 years later. At each contact point, participants described their participation in AA and treatment and their current alcohol-related functioning. They also described their reasons for entering AA and/or treatment and the perceived benefits of these sources of help. Compared with individuals who initially participated only in treatment but later entered AA, those who entered treatment and AA together participated in AA longer and more frequently and were more likely to achieve remission. Among individuals who initially participated only in AA, those who later entered treatment had poorer remission outcomes than those who did not enter treatment. Longer duration of participation in AA was associated with a higher likelihood of remission at all four follow-ups; individuals who dropped out of AA were more likely to relapse or remain nonremitted. In conclusion, compared with individuals who participated only in professional treatment in the first year after they initiated help-seeking, individuals who participated in both treatment and AA were more likely to achieve remission. Individuals who entered treatment but delayed participation in AA did not appear to obtain any additional benefit from AA. NIAAA Glossary Terms:  treatment method, AOD dependence, Alcoholics Anonymous, professional, combined modality therapy, treatment factors, treatment outcome, treatment research, comparative study, human study

Kuperman, Samuel; Chan, Grace; Kramer, John R; Bierut, Laura; Bucholz, Kathleen K.; Fox, Louis; Hesselbrock, Victor; Numberger, John I. Jr; Reich, Theodore; Reich, Wendy; and Schuckit, Marc A.  Relationship of age of first drink to child behavioral problems and family psychopathology.  Alcoholism: Clinical & Experimental Research 29(10):1869-1876, October 2005.

Address correspondence to Samuel Kuperman, Department of Psychiatry, University of Iowa Hospitals and Clinics, Iowa City, IA 52242-1057, USA. E-mail: samuel-kuperman@uiowa.edu.

Summary: The objective was to quantify the contributions of antecedent variables in four areas to prediction of early age of first drink (early AFD): child characteristics, family demographics, family psychopathology, and child behavior problems. Using data from a multicenter study on alcoholism, the authors first investigated the differences between two groups of children (ages 7–17 years), one from families heavily loaded for alcohol dependence and the other from population controls. Second, a multidomain, multistep regression model using child characteristics, family demographics, family psychopathology, and child behavior problems was performed to determine significant contributors to predicted AFD. Five variables initially contributed to the prediction of AFD. These included gender, age at interview, the number of adult sibs with alcohol dependence, being held back a year in school, and conduct scale score. However, the number of conduct symptoms appeared to contain the contributions of gender and being held back a grade in school, so these two variables were subsequently removed from the model. The remaining three variables explained 45% of the model variance; age at interview accounted for 38.3%, conduct scale score accounted for 6.2%, and the number of alcohol-dependent adult sibs accounted for 0.5%. No family history measures of alcohol dependence or antisocial personality disorder were contributory to the prediction model for AFD. Both the "number of conduct symptoms" and the "number of adult sibs with alcohol dependence" are inversely associated with predicted AFD. The latter variable appears marginally predictive of AFD and suggests a condition in which the child's household, regardless of strength of family history of alcoholism (or antisocial personality disorder), appears conducive to early drinking. Thus child and environmental factors are stronger predictors of AFD than family history. NIAAA Glossary Terms:   early AODU onset, underage drinking, predictive factor, risk factors, demographic characteristics, individual differences, family dysfunction, psychopathology, childhood behavioral problem, familial alcoholism, regression analysis, gender differences, age differences, family AODU history, conduct disorder, antisocial personality disorder, environmental factors, human study

Yokoyama, Akira; Yokoyama, Tetsuji; Kumagai, Yoshiya; Kato, Hoichi; Igaki, Hiroyasu; Tsujinaka, Toshimasa; Muto, Manabu; Omori, Tai; Yokoyama, Masako; and Watanabe, Hiroshi.  Mean corpuscular volume, alcohol flushing, and the predicted risk of squamous cell carcinoma of the esophagus in cancer-free Japanese men.  Alcoholism: Clinical & Experimental Research 29(10):1877-1883, October 2005.

Address correspondence to Akira Yokoyama, National Hospital Organization Kurihama Alcoholism Center, 5-3-1 Nobi, Yokosuka, Kanagawa, Japan. E-mail: a_yokoyama@kurihama1.hosp.go.jp.

Summary: Because some of the causes of increased mean corpuscular volume (MCV) and esophageal squamous cell carcinoma (ESCC), including alcoholism, acetaldehyde exposure, smoking, and poor nutrition are common to both, macrocytosis has been used as a predictor of early ESCC in Japanese alcoholics. This study examined whether this was also true in the Japanese general population by comparing the MCV of cancer-free Japanese men (N = 522) at high risk of ESCC as defined using drinking, smoking, dietary habits and aldehyde dehydrogenase-2 (ALDH2) genotype in a previous case-control study of ESCC involving them as control subjects. MCV was significantly correlated with ESCC risk predicted by drinking combined with ALDH2 genotype, smoking, or fruit intake. Men at higher risk of ESCC were more frequent in the groups with higher MCV (p < 0.0001 for trend). The replies to a questionnaire about facial flushing in response to alcohol showed that the trend was more prominent in men with current/former flushing, a surrogate marker for inactive ALDH2, than in men with no flushing (p < 0.0001). In comparison with the mean risk of men with MCV ≤ 93 fl (lowest quartile), that of current/former flushing men with MCV ≥ 99 fl (highest quartile) was 6.35-fold higher, whereas that of never-flushing men with MCV ≥ 99 fl was 2.50-fold higher. The sensitivity and specificity of the combination of moderate-to-heavy drinking and either MCV ≥ 99 fl or current/former flushing, either 30+ pack-years or MCV ≥ 99 fl or either 30+ pack-years or current/former flushing for detection of high-risk persons ranking in the top 10%, was 85% and 84%, 94% and 76%, or 98% and 77%, respectively. MCV and alcohol flushing may be useful for selecting candidates to screen for this high-mortality cancer in alcoholic and nonalcoholic Japanese men. NIAAA Glossary Terms:  cancer, esophageal disorder, squamous cell carcinoma, mean corpuscular volume, risk factors, risk analysis, AOD dependence, acetaldehyde, aldehyde dehydrogenases, genotype, smoking, diet, AOD consumption, alcohol flush reaction, biological markers, Japan, human study

McKee, Martin; Suzcs, Sandor; Sarvary, Attila; Adany, Roza; Kiryanov, Nikolay; Saburova, Ludmila; Tomkins, Susannah; Andreev, Evgeny; and Leon, David A.  The composition of surrogate alcohols consumed in Russia.  Alcoholism: Clinical & Experimental Research 29(10):1884-1888, October 2005.

Address correspondence to Martin McKee, European Centre on Health of Societies in Transition, London School of Hygiene and Tropical Medicine, London, United Kingdom. E-mail: martin.mckee@lshtm.ac.uk.

Summary: During a case-control study examining determinants of premature death among working age men in Russia, it became clear that a significant percentage of the population (7.3%) were drinking a variety of surrogate alcohol products (products not legally sold for consumption). In this population, where there is a high death rate from alcohol-related causes, including acute alcohol poisoning, it was important to know what these products contained. The identity of the products was identified from the survey of controls, and representative samples were obtained for composition analysis using gas chromatography and mass spectrometry. Three broad groups of products were identified: samogon (home-produced spirits); medicinal compounds; and other spirits (mainly sold as aftershave lotions). Commercially produced vodkas were used for comparison. Samogon contained lower quantities of ethanol than vodka (mean, 39 versus 44 volumetric percentage [v/v%]) but also contained certain toxic long-chain alcohols. Medicinal compounds contained only ethanol, at a higher concentration than vodka (mean, 66 v/v%), while the other spirits, which were also essentially pure ethanol, contained a mean of 94 v/v%. Thus a significant number of Russian men are drinking products that have either very high concentrations of ethanol or contaminants known to be toxic. These products are untaxed and thus much less expensive than vodka. The authors urge policy responses that target their production and consumption. NIAAA Glossary Terms:   alcohol product, nonbeverage alcohol, nonfood alcohol product, Russia, AODR mortality, AOD poisoning, acute AODE, survey, gas chromatography, spectrometry, distilled alcoholic beverage, product substitution, aliphatic alcohols, congeners, toxic substances, public policy on AOD, human study

Soardo, Giorgio; Donnini, Debora; Varutti, Rosanna; Moretti, Massimo; Milocco, Carla; Basan, Lorenza; Esposito, Walter; Casaccio, Daniele; Stel, Giuliana; Catena, Cristiana; Curcio, Francesco; and Sechi, Leonardo A.  Alcohol-induced endothelial changes are associated with oxidative stress and are rapidly reversed after withdrawal.  Alcoholism: Clinical & Experimental Research 29(10):1889-1898, October 2005.

Address correspondence to Giorgio Soardo, Department of Internal Medicine and Liver Unit, Institute of Clinical Pathology, University of Udine School of Medicine, Udine, Italy. E-mail: giorgio.soardo@med.uniud.it.

Summary: Although heavy alcohol drinkers are at increased risk of developing cardiovascular events, moderate alcohol intake is associated with reduced incidence of cardiovascular death. This paradox might reflect a dose-related effect of different alcohol intakes on endothelial function and this, in turn, might depend on changes in oxidative stress. This study tested the effects of alcohol withdrawal in heavy drinkers and compared the plasma levels of endothelin-1, nitric oxide, plasminogen activator inhibitor-1, von Willebrand factor, malondialdehyde, and intracellular glutathione with those of alcoholics who did not modify their alcohol intake and nondrinkers. The same parameters after withdrawal of ethanol exposure were assessed In human endothelial cells that had been cultured for 2 weeks in the presence of different concentrations of ethanol. Alcohol increased the levels of endothelin-1, nitric oxide, and plasminogen activator inhibitor-1 and decreased the levels of von Willebrand factor both in vivo and in vitro. These changes were dose dependent, rapidly reversed after withdrawal of exposure, and associated with the presence of increased oxidative stress as indicated by increased levels of both malondialdehyde and intracellular glutathione. Blockade of oxidative stress by incubation of endothelial cells in the presence of oxidant scavengers prevented the alcohol-induced functional modifications of the endothelium. In conclusion, alcohol affects endothelial function with an effect that is mediated by an activated oxidative stress and is rapidly reversed after withdrawal. Dose-related endothelial responses to different alcohol intakes might translate in either vascular protection or vascular damage. NIAAA Glossary Terms:  heavy AOD use, moderate AOD use, AOD dependence, cardiovascular disorder, risk factors, protective factors, protective drug effect, endothelium, endothelial cell, endothelin, nitric oxide, plasminogen activator, malondialdehyde, glutathione, oxidative stress, in vivo study, in vitro study, dose-response relationship, antioxidants, human study

Sumida, Ken D.; Cogger, Alma A.; Arimoto, Steven M.; and Matveyenko, Aleksey V.  Opposing effects of chronic alcohol consumption on hepatic gluconeogenesis for female versus male rats.  Alcoholism: Clinical & Experimental Research 29(10):1899-1905, October 2005.

Address correspondence to Ken D. Sumida, Department of Biological Sciences, Chapman University, Orange, California 92866, USA. E-mail: sumida@chapman.edu.

Summary: The relative impact of chronic alcohol consumption on hepatic gluconeogenesis (HGN) males and females is unknown. To determine the effects of chronic alcohol consumption (8 weeks) on HGN, the isolated liver perfusion technique was used on male and female Wistar rats fasted for 24 hours. After surgical isolation, livers were perfused (single pass) for 30 minutes with Krebs-Henseleit bicarbonate buffer and fresh bovine erythrocytes with no added substrate (washout period). After the washout period, livers were perfused with lactate (10 mM) and [U-14C]lactate (15,000 dpm/ml) using the recirculation method. Males and females fed the control diet did not differ significantly in HGN. In contrast, the females chronically fed the ethanol diet (FE) had significantly lower HGN rates (2.73 ± 0.37 μmol/min x g liver protein-1), whereas males fed the ethanol diet (ME) had significantly higher HGN rates (4.99 ± 0.45 μmol/min x g liver protein-1) than controls (3.83 ± 0.34 μmol/min x g liver protein-1). Concomitant decreases were also observed for both 14C-lactate incorporation into 14C-glucose and rates of lactate uptake for FE, while corresponding increases were observed for 14C-lactate incorporation into 14C-glucose for ME. The livers from ME were able to convert a greater percentage of the lactate into glucose, resulting in the elevation in gluconeogenic capacity. In conclusion, chronic alcohol consumption lowers the hepatic gluconeogenic capacity from lactate in females and elevates HGN in males. NIAAA Glossary Terms:   gluconeogenesis, liver function, ethanol, chronic AODE, gender differences, laboratory rat, lactate, controlled study, comparative study, glucose, metabolism, animal study

Mukamal, Kenneth J.; Massaro, Joseph M.; Ault, Kenneth A.; Mittleman, Murray A.; Sutherland, Patrice A.; Lipinska, Izabella; Levy, Daniel; D'Agostino, Ralph B.; and Tofler, Geoffrey H.  Alcohol consumption and platelet activation and aggregation among women and men: The Framingham Offspring Study.  Alcoholism: Clinical & Experimental Research 29(10):1906-1912, October 2005.

Address correspondence to Kenneth J. Mukamal, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA. E-mail: kmukamal@bidmc.harvard.edu.

Summary: Alcohol intake has been associated with lower platelet activity; however, few large-scale studies have included women, and it appears that the relationship of alcohol intake with measures of platelet activation has not been studied. This study was a cross-sectional analysis of adults free of cardiovascular disease enrolled in the Framingham Offspring Study. Alcohol consumption was assessed with a standardized questionnaire. Platelet activation was measured in response to 1 and 5 μmol of adenosine diphosphate (ADP) with a P-selectin assay among 1,037 participants and platelet aggregability in response to ADP, epinephrine, and collagen among 2,013 participants. Alcohol consumption was inversely associated with P-selectin expression in response to 1 μmol ADP (p = 0.007) and 5 μmol ADP (p = 0.02) among men but not among women. Alcohol consumption was also inversely associated with platelet aggregation induced by ADP among both women (p = 0.04) and men (p for trend = 0.008) and by epinephrine among men (p = 0.03). Thus alcohol consumption is inversely associated with both platelet activation and aggregation, particularly in men. Additional research is needed to determine whether these findings contribute to the contrasting associations of alcohol consumption with risk of thrombotic and hemorrhagic cardiovascular events. NIAAA Glossary Terms:   ethanol, platelet aggregation, platelet-activating factor, gender differences, ADP, AOD consumption, epinephrine, collagen, longitudinal study, comparative study, human study

Hayashino, Yasuaki.  Is herbal "root" effective for reducing alcohol drinking?  Alcoholism: Clinical & Experimental Research 29(10):1913, October 2005.  Scott E. Lukas, Scott E. and Lee, David Y-W. Reply.  Alcoholism: Clinical & Experimental Research 29(10):1914, October 2005.

(Letters to the editor. No abstracts available.)

Zhang, Ting; Guo, Chang-Jiang; Douglas, Steven D.; Metzger, David S.; O'Brien, Charles P.; Li, Yuan; Wang, Yan-Jian; Wang, Xu; and Ho, Wen-Zhe.  Alcohol suppresses IL-2-induced CC chemokine production by natural killer cells.  Alcoholism: Clinical & Experimental Research 29(9):1559-1567, September 2005.

Summary: The authors investigated whether ethanol impairs the functioning of natural killer (NK) cells, particularly production of CC chemokines induced by interleukin (IL)-2, the natural ligands for CCR5 receptor. Primary NK cells and NK cell line (YTS) were cultured for 3 hours with or without ethanol (10 to 80 mM). Culture supernatants were then harvested and used to treat human peripheral blood monocyte-derived macrophages and a HeLa cell line, which expresses CD4, CCR5, and CXCR4 receptors (MAGI cells). CC chemokine expression by YTS and primary NK cells treated with or without alcohol was analyzed with real-time reverse transcriptase-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). [Ca2+]i and Western blot assays were used to determine calcium-mediated intracellular signaling pathway and nuclear factor κB (NF-κB) p65 expression. Human immunodeficiency virus (HIV) strains (Bal and UG024) were used to infect macrophages and MAGI cells. In addition, ADA (macrophage-tropic strain) and murine leukemia virus (MLV) envelope-pseudotyped HIV infection was carried out in macrophages. HIV infectivity was determined by HIV reverse transcriptase (RT) and β-galactosidase activity assays. Ethanol inhibited IL-2-induced CC chemokine (CCL3 and CCL4) expression by NK cells, an inhibition that was shown by functional tests to be associated with diminished anti-HIV ability of NK cells. Ethanol also reduced the ability of NK cells to respond to CCL3-mediated chemotaxis. Ethanol inhibited IL-2-induced NF-κB p65 protein expression and calcium mobilization by NK cells. Ethanol, through inhibition of IL-2-induced NF-κB p65 protein expression and intracellular calcium mobilization, suppressed NK cell production of CC chemokines. This suppression of CC chemokine production was associated with diminished anti-HIV activity of NK cells. Thus, by inhibiting NK cell-mediated innate immunity against HIV, ethanol consumption may have a cofactor role in the immunopathogenesis of HIV disease. NIAAA Glossary Terms:   natural killer cell, ethanol, cytokines, interleukin-2, cultured cell line, cell culture study, ligand, macrophage, reverse transcriptase polymerase chain reaction, immunoassay, enzymes, Western blotting, cell signaling, human immunodeficiency virus, HIV infection, chemotaxis, proteins, immune system, immune response, laboratory mice, animal study

MacLaren, Erik J. and Sikela, James M.  Cerebellar gene expression profiling and eQTL analysis in inbred mouse strains selected for ethanol sensitivity.  Alcoholism: Clinical & Experimental Research 29(9):1568-1579, September 2005.

Summary: The expression levels of over 39,000 transcripts in the cerebellum of Inbred Long-Sleep (ILS) and Inbred Short-Sleep (ISS) mice were examined to find differentially expressed (DE) candidate genes for these phenotypes. The cerebellum is a major target of ethanol's actions in the central nervous system. DE genes between the strains were identified using oligonucleotide arrays and complimentary deoxyribonucleic acid (DNA) arrays. DE genes in the mouse genome assembly were located using sequence alignment. In silico expression quantitative trait loci (eQTL) mapping was used to identify chromosomal regions likely to control the transcription level of DE genes, and overrepresented functional themes were identified by the EASE program. The genomic region immediately upstream of the cyclase associated protein homolog 1 (Cap1) gene was directly sequenced from polymerase chain reaction products. Nearly 300 genes were identified as differentially expressed in the cerebellums of ILS and ISS mice. These genes and their corresponding eQTLs map to genomic regions linked to several phenotypes that differ between the ILS and ISS strains, including ethanol preference and cocaine-induced locomotor activation on chromosomes 4 and 7. Eight genes were cross-platform validated, four of which are more highly expressed in ILS cerebellum. Three single nucleotide polymorphisms, one of which disrupts a predicted Sp1 binding site, were found in the upstream region of Cap1, a strong candidate for influencing ethanol phenotypes. Many of these DE genes are candidates for influencing ethanol- and drug-regulated phenotypes because they either map to ethanol related QTLs in the genome or are linked to them through eQTL mapping. Genes involved in calcium ion binding and transcriptional regulation are overrepresented and  therefore may influence ethanol behaviors in mice and humans. NIAAA Glossary Terms:  animal strains, laboratory mice, selective breeding, sleep, ethanol, cerebellum, central nervous system, phenotype, gene, gene expression, oligonucleotide, cDNA, gene transcription, quantitative trait loci, chromosome, genome, polymerase chain reaction, single nucleotide polymorphism, cocaine, animal selectively bred for AOD preference, locomotion, calcium, animal behavior, animal model

Radcliffe, Richard A.; Floyd, Kirsten L.; Drahnak, Joseph A.; and Deitrich, Richard A.  Genetic dissociation between ethanol sensitivity and rapid tolerance in mouse and rat strains selectively bred for differential ethanol sensitivity.  Alcoholism: Clinical & Experimental Research 29(9):1580-1589, September 2005.

Summary: A study was undertaken to determine whether acute sensitivity in Inbred Long- and Short-Sleep mice (ILS and ISS) and High- and Low-Alcohol-Senstive rats (IHAS and ILAS)  is genetically correlated to a rapid tolerance to alcohol. Separate groups of animals were administered a single pretreatment dose of alcohol (0-6 g/kg for the mice and 0-4 g/kg for the rats). Alcohol sensitivity was tested 24 hours later with the loss -of-righting-reflex (LORR) test, and blood ethanol concentration was tested at regain of righting (BECRR). Ethanol-induced hypothermia also was determined in the mice. Independently derived replicate rat strains were used for all experiments (IHAS1, ILAS1; IHAS2, ILAS2) (such replicates do not exist for ILS and ISS mice).  Alcohol pretreatment dose-dependently decreased LORR duration and increased BECRR in the IHAS1 and ILS strain, suggesting the development of functional rapid tolerance. In contrast, LORR duration increased in the ILAS1, ILAS2, and ISS groups, but BECRR either increased (ILAS1, ILAS2) or did not change (ISS). These observations suggest that central nervous system sensitivity was decreased in the ILAS1 and ILAS2 groups (i.e., rapid functional tolerance) or unchanged in the ISS strain, but that some pharmacokinetic property also was altered in these strains. The results do not support a genetic relation between alcohol sensitivity and the development of rapid tolerance. NIAAA Glossary Terms:  animal strains, selective breeding, laboratory mice, laboratory rat, sleep, ethanol, AOD sensitivity, AOD tolerance, genetic correlation analysis, righting reflex, BAC, hypothermia, central nervous system, pharmacokinetics, animal model

De Bellis, Michael D.; Narasimhan, Anandhi; Thatcher, Dawn L.; Keshavan, Matcheri S.; Soloff, Paul; and Clark, Duncan B.  Prefrontal cortex, thalamus, and cerebellar volumes in adolescents and young adults with adolescent-onset alcohol use disorders and comorbid mental disorders.  Alcoholism: Clinical & Experimental Research 29(9):1590-1600, September 2005.

Summary: Prefrontal, thalamic, and cerebellar brain injury is associated with excessive ethanol intake in adults. This study tested the hypothesis that subjects with adolescent-onset alcohol use disorders (AUD) would have smaller volumes in these brain areas than sociodemographically similar control subjects. Magnetic resonance imaging was used to measure prefrontal cortex, thalamic, and cerebellar volumes in subjects with an AUD (n = 14; 8 males and 6 females; mean age, 17.0 ± 2.1 years) and 28 control subjects (n = 28; 16 males and 12 females; 16.9 ± 2.3 years). All AUD subjects were recruited from substance abuse treatment programs and had comorbid mental disorders. Subjects with an AUD had smaller prefrontal cortex and prefrontal cortex white matter volumes compared with controls. The groups did not differ in right, left, and total thalamic, pons/brainstem, right and left cerebellar hemispheric, total cerebellar, and cerebellar vermis volumes. There was a significant sex-by-group effect, indicating that males with an adolescent-onset AUD compared with control males had smaller cerebellar volumes, whereas the two female groups did not differ in cerebellar volumes. Prefrontal cortex volume variables correlated significantly with measures of alcohol consumption. These findings suggest that a smaller prefrontal cortex is associated with early-onset drinking in individuals with comorbid mental disorders. The authors recommend further studies to examine whether a smaller prefrontal cortex volume represents a vulnerability to early-onset drinking or is a consequence of it. NIAAA Glossary Terms:  prefrontal cortex, thalamus, cerebellum, central nervous system, brain damage, hazardous drinking, hypothesis testing, adolescence, early AODU onset, underage drinking, alcohol use disorder classification, brain atrophy, magnetic resonance imaging, brain imaging, treatment program, case-control study, comorbidity, mentally ill, pons, brainstem, gender differences, correlation analysis, human study

Sharpe, Amanda L.; Coste, Sarah C.; Burkhart-Kasch, Sue; Li, Na; Stenzel-Poore, Mary P.; and Phillips, Tamara J.  Mice deficient in corticotropin-releasing factor receptor type 2 exhibit normal ethanol-associated behaviors.  Alcoholism: Clinical & Experimental Research 29(9):1601-1609, September 2005.

Summary: Stress is believed to influence alcohol use and relapse in alcoholics. Animal studies suggest an interaction between corticotropin-releasing factor (CRF) and its receptors and the behavioral effects and consumption of alcohol. This study examined the effect of CRF receptor type 2 (CRF2) on ethanol consumption, conditioned taste aversion, sedation, and hypothermia. CRF2-null mutant or knock-out (KO), and wild-type (WT) mice were used to assess consumption of increasing concentrations of ethanol in a two-bottle, 24-hour test and during daily limited-access sessions. Ethanol-induced conditioned taste aversion (CTA), loss of righting reflex (LORR), hypothermia, and ethanol metabolism kinetics were also examined in the two groups. CRF2 KO mice did not differ from WT mice in sensitivity to ethanol-induced CTA, LORR, hypothermia, or ethanol metabolism kinetics. There was no genotypic difference in ethanol intake or preference in the 24-hour, two-bottle choice procedure, and only modestly reduced consumption of the 7.5 and 10% ethanol solutions in KO versus WT mice in the limited-access procedure. The observation that CRF2 deficiency had little effect on several ethanol-associated behaviors in CRF2 KO mice suggests that this receptor does not have a primary role in modulating these behaviors. Evidence of a role for this receptor in neural circuits subserving stress-coping behaviors suggest that future studies should focus on the role of endogenous CRF2 in ethanol-associated behaviors in mice that are stressed or withdrawing from dependence on ethanol. NIAAA Glossary Terms:  AOD use, AODD relapse, AOD dependence, corticotropin RH, hormone receptors, behavior, AOD consumption, ethanol, aversion conditioning, taste conditioning, sedative-hypnotics, hypothermia, knockout gene technology, righting reflex, ethanol metabolish, pharmacokinetics, AOD sensitivity, genotype, AOD preference, laboratory mice, animal study

Weitemier, Adam Z. and Ryabinin, Andrey E.  Brain region-specific regulation of urocortin 1 innervation and corticotropin-releasing factor receptor type 2 binding by ethanol exposure.  Alcoholism: Clinical & Experimental Research 29(9):1610-1620, September 2005.

Summary: Ethanol administration and consumption selectively activates the urocortin 1 (Ucn1)-expressing neurons of the Edinger-Westphal nucleus. The authors of this study investigated whether repeated ethanol exposure affects Ucn1 and Ucn1-responsive corticotropin-releasing factor type-2 receptors (CRF2). Male C57BL/6J and DBA/2J mice were injected intraperitoneally with ethanol (2 g/kg) once a day for 14, 7, or 0 days. Ucn1 immunoreactivity was measured in the lateral septum, dorsal raphe, and Edinger-Westphal nucleus. In a separate experiment, C57BL/6J mice were exposed to ethanol for 7, 1, or 0 days, and CRF2 receptor binding was measured in the lateral septum and dorsal raphe by receptor autoradiography. Ethanol administration induced parallel changes in Ucn1 immunoreactive terminal fibers in the lateral septum and dorsal raphe of both strains. Seven ethanol exposures but not one ethanol exposure significantly increased CRF2 receptor binding in the dorsal raphe and slightly increased CRF2 receptor binding in the lateral septum. The results provide evidence that the Ucn1/CRF2 receptor system can be modified by ethanol and suggest that this system may be involved in behavioral changes during alcoholism. NIAAA Glossary Terms:  ethanol, AOD consumption, neuron, brain, corticotropin RH, hormone receptors, intraperitoneal administration, laboratory mice, immune response, radiography, AOD use behavior, AOD dependence, animal study

Ginsburg, Brett C. and Lamb, R J.  Alphaxalone and epiallopregnanolone in rats trained to discriminate ethanol.  Alcoholism: Clinical & Experimental Research 29(9):1621-1629, September 2005.

Summary: Neurosteroids with a 3α-hydroxy orientation share pharmacological effects with ethanol, increase in brain after ethanol administration, and may mediate ethanol effects. 3β-hydroxy neurosteroids antagonize in vitro and some in vivo effects of ethanol and 3α-hydroxy neurosteroids. This study assessed the discriminative stimulus and rate-altering effects of alphaxalone, a 3α-hydroxy neurosteroid, and epiallopregnanolone, a 3β-hydroxy neurosteroid, in rats trained to discriminate either 0.8 g/kg or 1.2 g/kg of ethanol. The ability of epiallopregnanolone to antagonize the discriminative stimulus or rate-altering effects of ethanol or alphaxalone was also assessed. Ethanol had a similar discriminative ED50 (0.5 g/kg) in both groups, but rats trained with the lower ethanol dose were more sensitive to ethanol's rate-decreasing effects. Alphaxalone produced ethanol-appropriate responding in both training groups, although less effectively in rats trained on the lower ethanol dose (maximum 65% versus 80% ethanol-appropriate responding). The groups did not differ in sensitivity to the rate-decreasing effects of alphaxalone. Epiallopregnanolone did not reliably produce ethanol-appropriate responding in either training group, and rats trained on the lower ethanol dose were slightly more sensitive to epiallopregnanolone's rate-decreasing effects. Epiallopregnanolone did not alter any effects of ethanol or alphaxalone. The results agree with previous reports that 3α-hydroxy neurosteroids produce ethanol-appropriate responding, while 3β-hydroxy neurosteroids do not; as well as reports showing no antagonism of the discriminative stimulus or rate-suppressant effects of ethanol or 3α-hydroxy neurosteroids by 3β-hydroxy neurosteroids. Although the results demonstrate that ethanol and 3α-hydroxy neurosteroids share discriminative stimulus effects, they are inconsistent with the hypothesis that such neurosteroids mediate ethanol's discriminative stimulus. NIAAA Glossary Terms:   neurosteroids, steroid hormones, ethanol, drug discrimination, CNS stimulants, antagonists, AOD sensitivity, dose-response relationship, hypothesis testing, laboratory rat, animal study

Ford, Matthew M.; Nickel, Jeffrey D.; Phillips, Tamara J.; and Finn, Deborah A.  Neurosteroid modulators of GABA_A receptors differentially modulate ethanol intake patterns in male C57BL/6J mice.  Alcoholism: Clinical & Experimental Research 29(9):1630-1640, September 2005.

Summary: Allopregnanolone (ALLO) and structurally-related endogenous neurosteroids are potent modulators of gamma-aminobutyric acid A (GABAA) receptor function at physiologically relevant concentrations. Growing evidence implicates a modulatory role for ALLO in behavioral processes underlying ethanol self-administration, discrimination, and reinstatement. This study evaluated the impact of exogenous neurosteroid challenges with the agonist ALLO and the partial agonist/antagonist epipregnanolone (EPI) on ethanol drinking patterns. Male C57BL/6J mice were initiated to consume an unsweetened 10% v/v ethanol solution (10E) by a saccharin fading procedure during daily 2-hour limited-access sessions beginning 1-hour after dark-phase onset. Cumulative lick responses were recorded for 10E and water by lickometer circuits. After establishing 10E intake baselines, mice were habituated to intraperitoneal vehicle injection (VEH; 20% w/v β-cyclodextrin), then were treated with either VEH or neurosteroid immediately before the drinking session. Each mouse received a series of ALLO doses (3.2, 10, 17, and 24 mg/kg) alone and EPI doses (0.15, 1, 3, and 10 mg/kg) alone in a counterbalanced within-group design. The GABAA receptor-positive modulator ALLO dose-dependently modulated overall ethanol intake throughout the 2-hour session with the 3.2 mg/kg dose eliciting a significant increase, whereas the 24 mg/kg dose produced a significant suppression of ethanol intake versus VEH pretreatment. ALLO-evoked intake alterations corresponded to significant, dose-dependent alterations in bout frequency and interbout interval. ALLO also elicited robust, dose-dependent elevations in 10E licks during the initial 5 minutes of access but subsequently produced in a dose-dependent suppression of 10E licks during session minutes 20-80. In contrast, the partial agonist/antagonist neurosteroid EPI exhibited no influence on any consumption parameter evaluated. The results suggest that GABAA receptor-active neurosteroids may modulate the regulatory processes that govern the onset, maintenance, and termination of drinking episodes. The differential influence of ALLO and EPI on ethanol intake patterns may reflect an alteration in GABAergic inhibitory tone that is likely due to each neurosteroid's pharmacological profile at GABAA receptors. Manipulation of endogenous ALLO may prove useful for reducing excessive intake and protecting against the loss of regulatory control over drinking. NIAAA Glossary Terms:   GABA A receptor, GABAergic neuron, allopregnanolone, ethanol, neurosteroids, steroid hormones, animal behavior, laboratory mice, intraperitoneal administration, agonists, antagonists, AOD consumption, AOD intake per occasion, dose-response relationship, animal study

Brunell, Steven C. and Spear, Linda P.  Effect of stress on the voluntary intake of a sweetened ethanol solution in pair-housed adolescent and adult rats.  Alcoholism: Clinical & Experimental Research 29(9):1641-1653, September 2005.

Summary: Previous studies reporting greater voluntary ethanol intake in adolescent than adult rats have examined intake in isolate-housed animals. Because the stress of isolate housing may differ ontogenetically as well as confound interpretation of other stressor effects, this study examined stressor/ethanol interactions among pair-housed adolescent and adult rats. Sprague-Dawley male rats were implanted with identification tags to allow individual monitoring of homecage intake of water and either a 10% (v/v) ethanol solution containing 0.1% (w/v) saccharin or saccharin alone over a 14-day access period. Animals were given 0, 1, or 8 daily 15-minute footshock sessions, with shock-induced freezing and pre-, post-, and recovery corticosterone levels determined on the first and last footshock exposure days. After the access period, withdrawal was assessed with a plus maze, and tolerance to ethanol-induced loss of righting reflex was examined. Nonstressed adolescents drank considerably more sweetened ethanol than did adults, with chronic stress suppressing this adolescent consumption. Ethanol access in adolescents disrupted within-session adaptation to footshock in terms of freezing behavior, although no such disruption was evident at either age when indexed hormonally. Despite relatively high ethanol intakes (up to 6 g/kg/day in the adolescents), there was no evidence of withdrawal-associated anxiogenesis. Evidence of tolerance was mixed and when present was metabolic in nature. It was concluded that previous reports of heightened voluntary ethanol intake among adolescent rats are not a function of isolate stress. Adolescents were more sensitive than adults to ethanol/stress interactions, with the elevated ethanol intake of pair-housed adolescents selectively disrupted by chronic stress, a disruption not evident in adults. Likewise, ethanol disrupted behavioral adaptation to the footshock stressor among adolescents but not adults. NIAAA Glossary Terms:  laboratory rat, age differences, adolescent, adult, ethanol, stress, stressor, AOD intake per occasion, social isolation, confounding variable, saccharin, anxiety, animal study

Martin-Garcia, Elena and Pallares, Marc.  Effects of intrahippocampal nicotine and neurosteroid administration on withdrawal in voluntary and chronic alcohol-drinking rats.  Alcoholism: Clinical & Experimental Research 29(9):1654-1663, September 2005.

Summary: It has been shown in previous studies that 4.6 μg of nicotine administered to the hippocampus can deteriorate learning acquisition in alcohol-drinking rats. This study investigated whether this nicotine dose can alter the alcohol withdrawal syndrome and whether these effects can be modulated by the neurosteroids allopregnanolone (AlloP) and pregnenolone sulfate (PregS), at doses previously reported as anxiolytic and promnesic respectively. A free-choice drinking procedure was used that involved providing the rats with an alcoholic solution (10% ethanol) at an early age. Alcohol and control rats were assigned randomly to six groups that received two consecutive intrahippocampal (dorsal CA1) injections once a week during three consecutive weeks after 1 hour of ethanol drinking. The first injection was nicotine (4.6 μg, 20 mM) or saline and the second injection was PregS (5 ng, 24 μM), AlloP (0.2 μg, 1.26 μM) or saline. Blood alcohol concentrations were assessed one week before the withdrawal testing. Locomotor activity and audiogenic seizures were tested during withdrawal after 110 days of voluntary ethanol consumption. Rats were injected immediately before the withdrawal testing. AlloP induced a decrease in horizontal and vertical activities, suggesting that the dose tested has sedative effects. AlloP reversed the seizures induced by ethanol withdrawal and also the spontaneous audiogenic seizures induced by the acoustic stimulation in control rats. Moreover, AlloP decreased other alcohol withdrawal signs, such as tail stiffening and body rigidity. Intrahippocampal administration of nicotine or PregS, at the doses tested, did not effectively modify the expression of audiogenic seizures induced by alcohol withdrawal. The results show that hippocampal GABAergic activity and AlloP have an important role in preventing convulsive behavior. The results also highlight the therapeutic potential of AlloP for reducing the alcohol withdrawal syndrome. NIAAA Glossary Terms:  nicotine, hippocampus, AOD withdrawal syndrome, laboratory rat, neurosteroids, steroid hormones, allopregnanolone, pregnenolone, BAC, locomotion, AODR seizure, sound, sedative-hypnotics, convulsion, animal study

Ilgen, Mark A.; Tiet, Quyen; Finney, John W.; and Harris, Alex H. S.  Recent suicide attempt and the effectiveness of inpatient and outpatient substance use disorder treatment.  Alcoholism: Clinical & Experimental Research 29(9):1664-1671, September 2005.

Summary: This study tested the hypothesis that treatment setting (inpatient or outpatient) would make no difference in treatment outcome for nonsuicidal participants in substance abuse treatment, but that inpatient treatment would be more closely associated with positive outcomes than outpatient treatment in suicidal participants. The participants were a national sample of patients (N = 1,289) presenting for treatment of substance use disorders in the Veterans Administration healthcare system who provided complete data on psychiatric and substance-related problems at baseline and 6-month follow-up. At baseline, 4% (n = 53) of the sample reported having made a suicide attempt within the past 30 days. Those who reported a suicide attempt were no more likely to have been treated in an inpatient setting than in an outpatient setting. A significant interaction was found between baseline suicide attempt and treatment setting, with nonsuicidal patients reporting similar patterns of substance use when treated in inpatient or outpatient settings, but suicidal patients were significantly more likely to have better substance-related outcomes at 6-month follow-up if they had received inpatient treatment. In conclusion, suicidal patients displayed substantial improvement after substance use disorders treatment and seemed particularly responsive to treatment in inpatient settings. NIAAA Glossary Terms:  hypothesis testing, comparative study, inpatient care, outpatient care, treatment factors, treatment outcome, treatment program, AOD dependence, veteran, follow-up study, suicidal behavior, human study

Kraus, Courtney L.; Salazar, Natasha C.; Mitchell, Jamie R.; Florin, Whitney D.; Guenther, Bob; Brady, David; Swartzwelder, Scott H.; and White, Aaron M.  Inconsistencies between actual and estimated blood alcohol concentrations in a field study of college students: Do students really know how much they drink?  Alcoholism: Clinical & Experimental Research 29(9):1672-1676, September 2005.

Summary: Surveys are commonly used to measure alcohol use by college students on the assumption that students are aware of how much alcohol they actually consume. However, recent studies indicate that students tend to overestimate the appropriate sizes of standard drinks, suggesting that they might underestimate how much alcohol they consume. If so, then students' actual blood alcohol concentrations (BACs) should be higher than BACs estimated based on self-report data. This field study examined the issue by collecting breath analyzer readings and self-reported drinking data from college students (N = 152), calculating estimated BACs by means of a standard formula, and examining the relation between actual and estimated BACs. Factors contributing to discrepancies between the two values were identified. Estimated BAC levels were found to be significantly higher, not lower, than breath BAC measures. The accuracy of estimated BACs decreased as the number of drinks and amount of time spent drinking increased. Being male and drinking only beer was associated with greater accuracy of estimated BACs. Although laboratory data suggest that students underestimate how much they drink, the hypothesis was not supported by data collected in the field. It appears that students might actually overestimate rather than underestimate their levels of consumption when surveyed during a night of drinking. The findings corroborate observations made by other researchers and suggest that the findings of laboratory studies on college drinking do not necessarily extend to real-world settings. NIAAA Glossary Terms:  AOD consumption, undergraduate student, self report, BAC, breath alcohol analysis, comparative study, gender differences, beer, AOD use behavior, hypothesis testing, human study

Sander, Michael; von Heymann, Christian; Neumann, Tim; Braun, Jan P.; Kastrup, Marc; Beholz, Sven; Konertz, Wolfgang; and Spies, Claudia D.  Increased interleukin-10 and cortisol in long-term alcoholics after cardiopulmonary bypass: A hint to the increased postoperative infection rate?  Alcoholism: Clinical & Experimental Research 29(9):1677-1684, September 2005.

Summary: Perioperative levels of tumor necrosis factor-alpha (TNF-α), interleukin-6, interleukin-10, and cortisol were investigated in long-term alcoholic and nonalcoholic patients undergoing cardiac surgery to elucidate a possible association with postoperative infections. Patients (N = 44) undergoing elective cardiac surgery were studied prospectively. Long-term alcoholic patients (n = 10) were defined as having an ethanol consumption of at least 60 g/day and fulfilling Diagnostic and Statistical Manual of Mental Disorders criteria for alcohol abuse. The nonalcoholic patients (n = 34) were defined as drinking less than 20 g ethanol/day. Blood samples were obtained for analysis of immune status upon admission to hospital, the morning before surgery, and on admission to the intensive care unit (ICU), the morning of days 1 and 3 after surgery. The two groups did not differ in basic characteristics. Long-term alcoholics had a fourfold increase in postsurgery infection rate and prolonged need for ICU treatment and mechanical ventilation. Postoperative levels of interleukin-10 and cortisol were significantly increased in long-term alcoholic patients compared with nonalcoholic patients. These observations were in line with postoperative interleukin-10 being predictive for postoperative infectious complications. The increased infection rate in long-term alcoholics emphasizes the urgent need for interventions to provide modulation of the perioperative immune and hypothalamic-pituitary-adrenocortical response in these high-risk patients to counteract their postoperative immune suppression. NIAAA Glossary Terms:   tumor necrosis factor-alpha, interleukin, interleukin-6, interleukin-10, cortisol, AOD dependence, nonproblematic AOD use, controlled study, comparative study, prospective study, operative surgery, heart, treatment complications, infection, immune function, intensive care, predictive factor, hypothalamic-pituitary-adrenal axis, adrenal cortex hormones, human study

Schneider, Mary L.; Moore, Colleen F.; Barnhart, Todd E.; Larson, Julie A.; DeJesus, Onofre T.; Mukherjee, Jogeshwar; Nickles, Robert J.; Converse, Alexander K.; Roberts, Andrew D.; and Kraemer, Gary W.  Moderate-level prenatal alcohol exposure alters striatal dopamine system function in rhesus monkeys.  Alcoholism: Clinical & Experimental Research 29(9):1685-1697, September 2005.

Summary: Moderate prenatal exposure to ethanol can cause impairments even in the absence of gross morphological defects associated with fetal alcohol syndrome. The basal ganglia, which include the dopamine-rich striatum, are sensitive to prenatal ethanol-induced injury. This study with rhesus monkeys examined the relationship between the timing of moderate-level ethanol exposure and the risk of adverse effects on striatal dopamine (DA) system function. Young adult rhesus monkeys (N = 35)) from four groups of females were assessed: an early ethanol-exposed group (n = 9), in which mothers voluntarily consumed 0.6 g/kg ethanol solution on gestational days 0 through 50; a middle-to-late gestation ethanol-exposed group (n = 7), in which mothers voluntarily consumed 0.6 g/kg ethanol solution on gestational days 50 through 135; a continuous-exposure group (n = 9), in which mothers voluntarily consumed 0.6 g/kg ethanol solution on days 0 through 135; and controls (n = 10), in which mothers voluntarily consumed an isocaloric control solution on gestational days 0 through 50, 50 through 135, or 0 through 135. Striatal DA system function, including DA D2 receptor (D2R) binding and DA synthesis, was studied by positron emission tomography. Moderate-level ethanol exposure during early gestation and continuous exposure throughout gestation reduced the striatal D2R binding/DA synthesis ratio, whereas middle-to-late gestation ethanol exposure increased the ratio. The largest effect was seen in the continuous-exposure group. Moreover, the D2R binding/DA synthesis ratio was related to neonatal neurobehavior measures in control monkeys, but these relationships were disrupted in the fetal ethanol-exposed monkeys. The findings suggest that the vulnerability of the DA system to the effects of moderate ethanol exposure during gestation depends on the timing of the exposure. Moderate ethanol exposure during early gestation resulted in a reduction or blunting of dopaminergic function in adulthood, whereas middle to late exposure (without early exposure) either induced the opposite pattern or heightened dopaminergic function. Continuously exposed monkeys showed the largest effect, suggesting that the sooner pregnant women stop drinking, the better it is for the fetus. NIAAA Glossary Terms:  prenatal alcohol exposure, moderate AOD use, fetal alcohol effects, basal ganglia, corpus striatum, dopamine, nonhuman primate, monkey, controlled study, dopaminergic receptors, biosynthesis, neurotransmitter metabolism, positron emission tomography, neuropsychological assessment, animal study

Lewohl, Joanne M.; Wixey, Julie; Harper, Clive G.; and Dodd, Peter R.  Expression of MBP, PLP, MAG, CNP, and GFAP in the human alcoholic brain.  Alcoholism: Clinical & Experimental Research 29(9):1698-1705, September 2005.

Summary: Chronic alcohol abuse results in altered expression of a number of genes, including selective reprogramming of myelin gene expression in the frontal cortex. This study assessed the expression of myelin basic protein (MBP), myelin proteolipid protein (PLP), myelin-associated glycoprotein (MAG), cyclic nucleotide phosphodiesterase (CNP), and glial fibrillary acidic protein (GFAP) in the superior frontal gyrus and the primary motor cortex of control subjects, uncomplicated alcoholism cases, and alcoholic cirrhosis cases. The expression of cyclic nucleotide phosphodiesterase, glial fibrillary acidic protein, myelin-associated glycoprotein, and myelin basic protein was significantly lower in the alcoholic cirrhosis cases compared with controls, with a similar tendency for myelin proteolipid protein. Expression of the proteins studied and the brain weight of individual cases were strongly correlated, but this interaction did not confound the overall analysis. There was no significant difference between controls and uncomplicated alcoholics. The loss of myelin proteins occurred without gross changes in brain pathology or brain weight and was not restricted to pathologically susceptible brain regions. It is not possible to determine whether the loss of myelin proteins in cirrhotic alcoholics is the result of cirrhosis alone or the combination of alcohol abuse and cirrhosis. Further clarification will require studies comparing cases with alcoholic and nonalcoholic liver cirrhosis. NIAAA Glossary Terms:  gene expression, chronic AODE, AOD dependence, alcoholic liver cirrhosis, myelin sheath, frontal cortex, cerebral cortex, proteins, glycoproteins, glial fibrillary acidic protein, correlation analysis, controlled study, comparative study, human study

Matthews, Douglas B.; Bhave, Sanjiv V.; Belknap, John K.; Brittingham, Cynthia; Chesler, Elissa J.; Hitzemann, Robert J.; Hoffmann, Paula L.; Lu, Lu; McWeeney, Shannon; Miles, Michael F.; Tabakoff, Boris; and Williams, Robert W.  Complex genetics of interactions of alcohol and CNS function and behavior.  Alcoholism: Clinical & Experimental Research 29(9):1706-1719, September 2005.

Summary: The proceedings of a symposium held at the 2004 meeting of the Research Society on Alcoholism in Vancouver, British Columbia, Canada, are summarized. The symposium was organized by R. W. Williams and D. B. Matthews and M. F. Miles was the chairman. The presentations were (1) "WebQTL: A resource for analysis of gene expression variation and the genetic dissection of alcohol related phenotypes," by E. J. Chesler, (2) "The marriage of microarray and QTL analyses: What's to gain," by J. K. Belknap, (3) "Use of WebQTL to identify QTLs associated with footshock stress and ethanol related behaviors," by D. B. Matthews, (4) "A high throughput strategy for the detection of quantitative trait genes," by R. J. Hitzemann, and (5) "The use of gene arrays in conjunction with transgenic and selected animals to understand anxiety in alcoholism," by B. Tabakoff. NIAAA Glossary Terms:  conference proceedings, ethanol, central nervous system, genetic trait, genotype, phenotype, quantitative trait loci, stress, stressor, AODR behavioral markers, AODR genetic markers, transgenic technology, animal study

Barron, Susan; White, Aaron; Swartzwelder, H Scott; Bell, Richard L.; Rodd, Zachary A.; Slawecki, Craig J.; Ehlers, Cindy L.; Levin, Edward D.; Rezvani, Amir H.; and Spear, Linda P.  Adolescent vulnerabilities to chronic alcohol or nicotine exposure: Findings from rodent models.  Alcoholism: Clinical & Experimental Research 29(9):1720-1725, September 2005.

Summary: This article summarizes the proceedings of a symposium held at the 2004 meeting of the Research Society on Alcoholism in Vancouver, British Columbia, Canada. The symposium, titled "Is adolescence special? Possible age-related vulnerabilities to chronic alcohol or nicotine exposure," was organized by Susan Barron and Linda Spear and cosponsored by the Fetal Alcohol Syndrome Study Group and the Neurobehavioral Teratology Society. The discussions focused on current knowledge about the long-term consequences of ethanol and/or nicotine exposure during adolescence with emphasis on data from rodent models. Adolescence represents a unique developmental stage for the effects of chronic drug exposure and also marks an age in which many risky behaviors including alcohol consumption and smoking typically begin. Aaron White presented data on the effects of adolescent ethanol exposure on subsequent motor or cognitive response to an ethanol challenge in adulthood. Richard Bell presented data suggesting that genetic differences could play a role in adolescent vulnerability to ethanol. Craig Slawecki presented data on the effects of chronic exposure to alcohol or nicotine on neurophysiologic and behavioral end points. Ed Levin presented data on acute and long-term consequences of adolescent nicotine exposure. Linda Spear provided summary points and recommendations on unresolved issues and future directions. NIAAA Glossary Terms:  conference proceedings, adolescence, underage AOD use, underage drinking, smoking, early AODU onset, age differences, chronic AODE, ethanol, nicotine, laboratory rat, laboratory mice, cognition, animal study

Lakshman, Raj; Cederbaum, Arthur I.; Hoek, Jan B.; Konishi, Masahiro; Koop, Dennis; and Donohu, Terrence M.  Use of CYP2E1-transfected human liver cell lines in elucidating the actions of ethanol.  Alcoholism: Clinical & Experimental Research 29(9):1726-1734, September 2005.

Summary: The proceedings of a symposium held at the 2004 meeting of the Research Society on Alcoholism in Vancouver, British Columbia, Canada, are summarized. The symposium chairmen were Arthur I. Cederbaum and Raj Lakshman. Presentations included (1) "Ethanol regulates 2,6-sialyltransferase (2,6-ST) gene expression posttranscriptionally by the interaction of a cytosolic binding protein with 2,6-ST [messenger ribonucleic acid] mRNA in [cytochrome P450 2E1] CYP2E1- and [alcohol dehydrogenase] ADH-transfected HepG2 cells," by Raj Lakshman; (2) "Nature versus nurture: HepG2-E47 cells as a tool to investigate mechanisms of ethanol-mediated potentiation of cell killing," by Jan B. Hoek; (3) "Ethanol up-regulates profibrogenic connective tissue growth factor gene expression in HepG2 cells via cytochrome P-450 2E1-mediated ethanol oxidation," by Masahiro Konishi; (4) "Role of calcium and calcium-activated enzymes in CYP2E1-dependent toxicity," by Arthur I. Cederbaum; (5) "The use of cell lines to characterize the role of CYP2E1 in the metabolism of farnesol," by Dennis Koop; and (6) "Studies with HepG2 cells that express the two major ethanol-metabolizing enzymes," by Terrence M. Donohue. NIAAA Glossary Terms:  conference proceedings, ethanol, gene expression, gene transcription, transferases, mRNA, cytochrome P450 2E1, calcium, enzymes, ethanol metabolism, transgenic technology, cultured cell line

Thiele, Geoffrey M.; Mandrekar, Pranoti; Zakhari, Sam; Hoek, Jan; Cook, Robert T.; Ray, Nancy B.; Happel, Kyle I.; Kolls, Jay K.; Kovacs, Elizabeth J.; and Szab, Gyongyi.  RSA 2004: Combined basic research satellite symposium-Mechanisms of alcohol-mediated organ and tissue damage: Inflammation and immunity and alcohol and mitochondrial metabolism: At the crossroads of life and death, session one: Alcohol, cellular and organ damage.  Alcoholism: Clinical & Experimental Research 29(9):1735-1743, September 2005.

Summary: Proceedings of a satellite conference at the 2004 meeting of the Research Society on Alcoholism in Vancouver, British Columbia, Canada, are summarized. The purpose of the conference was to facilitate interaction among scientists investigating mechanisms of alcohol-mediated organ or tissue damage. There were four sessions: (1) Alcohol, cellular and organ damage; (2) Toll-like receptors and organ damage; (3) Alcohol and mitochondrial metabolism: At the crossroads of life and death; and (4) Hepatitis virus and alcohol interactions in immunity and liver disease. Dr. Bruce Beutler of the Scripps Institute gave the keynote address on "Toll-like receptors in iInflammation and immunity." Presentations included: (1) "Innate Immune responses of alcohol-exposed mice and macrophage-like cells following infections with Listeria monocytogenes," by Robert T. Cook; (2) "Alcohol, cytokines, and host defense," by Kyle Happel; (3) "Decreased antigen presentation and anergy induced by alcohol in myeloid dendritic cells," by Pranoti Mandrekar; (4) "Transcriptional regulation of tumor necrosis factor-alpha in human monocytes by chronic ethanol: Role of the cellular redox state," by Jay Kolls; and (5) "Estrogen and gender differences in inflammatory responses after alcohol and burn injury," by Elizabeth Kovacs. This session highlighted growing information on the role of pattern recognition molecules in alcohol-mediated tissue damage or dysfunction. NIAAA Glossary Terms:  conference proceedings, ethanol, receptors, biochemical mechanism, mitochondria, inflammation, immune system function, immune response, laboratory mice, macrophage, monocyte, infection, bacterial disease, antigens, gene transcription, tumor necrosis factor-alpha, inflammation, animal study

Mandrekar, Pranoti; Pruett, Stephen; Arteel, Gavin; Thiele, Geoffrey; and Szabo, Gyongyi.  RSA 2004: Combined basic research satellite symposium - session two: Toll-like receptors and organ damage.  Alcoholism: Clinical & Experimental Research 29(9):1744-1748, September 2005.

Summary: Proceedings of the Combined Basic Research Satellite Meeting of the 2004 meeting of the Research Society on Alcoholism in Vancouver, British Columbia, Canada, are summarized. The satellite meeting was titled "Toll-like receptors and organ damage" and featured three speakers. The chairmen were Steve Nelson and Craig McClain. The presentations were: (1) "Toll-like receptor [TLR]-mediated macrophage activation-modulation by acute alcohol administration in mice," by Stephen Pruett; (2) "Alcoholic liver disease: Crossroads of TLRs and oxidative stress," by Gavin Arteel; and (3) "The role of TLR2- and TLR4-mediated signals in liver injury," by Gyongyi Szabo. NIAAA Glossary Terms:  conference proceedings, ethanol, receptors, AODR injury, AODR disorder, macrophage, acute AODE, laboratory mice, alcoholic liver disorder, animal study

Szabo, Gyongyi; Hoek, Jan B.; Darley-Usmar, Victor; Hajnoczky, Gyorgy; Knudsen, Thomas; Mochly-Rosen, Daria; and Zakhari, Sam.  RSA 2004: Combined basic research satellite symposium - session three: Alcohol and mitochondrial metabolism: At the crossroads of life and death.  Alcoholism: Clinical & Experimental Research 29(9):1749-1752, September 2005.

Summary: The proceedings of the Research Society on Alcoholism 2004 Combined Basic Research Satellite Meeting in Vancouver, British Columbia, Canada, are summarized. One of the sessions, "Alcohol and mitochondrial metabolism: At the crossroads of life and death," featured five speakers and was chaired by Jan Hoek and Sam Zakhari. The presentations were: (1) "Introduction: Alcohol and cellular energy metabolism," by Jan Hoek; (2) "Ethanol-dependent dysfunction of mitochondrial energy metabolism: The role of NO," by Victor Darley-Usmar; (3) "Ethanol and apoptosis in the heart," by Gyorgy Hajnoczky; (4) "Alcohol and mitochondrial biogenesis in development," by Thomas Knudsen; and (5) "Alcohol, mitochondrial function and cardiac preconditioning," by Daria Mochly-Rosen. NIAAA Glossary Terms:  conference proceedings, ethanol, mitochondria, energy, metabolism, apoptosis, heart disorder, nitric oxide

Szabo, Gyongyi; Weinman, Steve A.; Gao, Bin; Polyak, Steve J.; Mandrekar, Pranoti; and Thiele, Geoffrey M.  RSA 2004: Combined basic research satellite symposium - session four: Hepatitis virus and alcohol interactions in immunity and liver disease.  Alcoholism: Clinical & Experimental Research 29(9):1753-1757, September 2005.

Summary: Proceedings of the Research Society on Alcoholism 2004 Combined Basic Research Satellite Meeting in Vancouver, British Columbia, Canada, are summarized. The session titled "Hepatitis virus and alcohol interactions in immunity and liver disease" featured four speakers and was chaired by Diane Lucas and Samuel French. The presentations were: (1) "Mitochondrial effects of HCV proteins and alcohol," by Steve Weinman; (2) "Chronic alcohol consumption accelerates viral hepatitis and T-cell hepatitis via dysregulation of cytokine signaling," by Bin Gao; (3) "Interactions between alcohol, hepatitis C virus, and innate defense pathways," by Steve Polyak; and (4) "Scavenger receptor-mediated modulation of the innate and adaptive immune responses following chronic ethanol consumption," by Geoffrey Thiele. NIAAA Glossary Terms:  conference proceedings, ethanol, hepatitis, viral disease, liver disorder, immune system function, immune response, mitochondria, hepatitis C virus, chronic AODE, T lymphocyte, cytokines, cell signaling, receptors, AOD consumption

Rasmussen, Carmen.  Executive functioning and working memory in fetal alcohol spectrum disorder.  Alcoholism: Clinical & Experimental Research 29(8):1359-1367, August 2005.

Summary: This article review research on executive functioning (EF) and working memory in individuals with fetal alcohol spectrum disorder (FASD). These individuals show EF deficits in the areas of cognitive flexibility, planning and strategy use, verbal reasoning, some aspects of inhibition, set shifting, fluency, working memory, and on tests of emotion-related or hot EF. Some researchers have linked prenatal alcohol exposure to abnormalities in the development of the frontal cortex of affected individuals or animals. These EF deficits commonly persist regardless of whether the individual has facial dysmorphology and are not simply due to low intelligence. More research is needed in this area is needed to resolve some inconsistencies in the literature, using larger sample sizes, smaller age ranges, and consistent measurement tools. Researchers should also focus on studying the pattern of weak EF in individuals with FASD as well as relations among working memory and EF, which will help to identify specific areas of weakness, enhance diagnosis, and improve treatment. The development of EF in individuals with FASD can have important implications for understanding how these deficits unfold from childhood through adulthood, but research in this area is limited. NIAAA Glossary Terms:  prenatal alcohol exposure, fetal alcohol effects, fetal alcohol syndrome, memory, cognitive ability, verbal memory, inhibition, frontal cortex, congenital facial anomaly, congenital morphologic anomaly, intelligence level, literature review

Jankala, Heidi; Eriksson, Peter C. J.; Eklund, Kari; Sarviharju, Maija; Harkonen, Matti; and Maki, Tiina.  Effect of chronic ethanol ingestion and gender on heart left ventricular p53 gene expression.  Alcoholism: Clinical & Experimental Research 29(8):1368-1373, August 2005.

Summary: Mild to moderate ethanol consumption has been associated with beneficial effects on the heart.. In contrast, alcohol abuse is a major cause of nonischemic cardiomyopathy in Western society, but the biochemical and molecular mechanisms that mediate the pathologic cardiac effects of ethanol remain largely unknown. This study explored the effects of chronic ethanol exposure on cardiac apoptosis and expression of some of the genes associated with cardiac remodeling in vivo, using Alcohol-avoiding Alko Non Alcohol rats of both sexes. The ethanol-exposed rats (females, n = 6; males, n = 8) were given 12% (v/v) ethanol as the only available fluid from 3 months to 24 months of age. The control rats (females, n = 7; males, n = 5) had only water available. At the end of the experiment, free walls of left ventricles of hearts were immediately frozen. Cytosolic deoxyribonucleic acid (DNA) fragmentation, reflecting apoptosis, was measured using a commercial quantitative sandwich enzyme-linked immunosorbent assay kit, and messenger ribonucleic acid (mRNA) levels were analyzed using a quantitative reverse transcriptase-polymerase chain reaction method. Ethanol treatment for 2 years increased cardiac left ventricular p53 mRNA levels significantly (p = 0.014) compared with control rats. The gene expression was also dependent on the gender (p = 0.001), with male rats having higher left ventricular p53 mRNA levels than female rats. No significant differences in levels of DNA fragmentation were detected, however. It was concluded that chronic ethanol exposure in vivo induces rat cardiac left ventricular p53 gene expression. Expression of p53 is also gender-dependent, with males having higher p53 mRNA levels than females. This preliminary study suggests a role for the p53 gene in ethanol-induced cardiac remodeling. The results might also have some relevance for the known gender-dependent differences in propensity to cardiovascular disease. NIAAA Glossary Terms:  chronic AODE, light AOD use, moderate AOD use, AOD abuse, gene expression, alcoholic cardiomyopathy, apoptosis, cardiac tissue, heart ventricle, animal selectively bred for AOD preference, laboratory rat, controlled study, DNA, mRNA, immunoassay, reverse transcriptase polymerase chain reaction, gender differences, in vivo study, animal study

Saito, Mariko; Saito, Mitsuo; Cooper, Thomas B.; and Vadasz, Csaba.  Ethanol-induced changes in the content of triglycerides, ceramides, and glucosylceramides in cultured neurons.  Alcoholism: Clinical & Experimental Research 29(8):1374-1383, August 2005.

Summary: The involvement of sphingolipids and neutral lipids in the apoptosis was assessed by examining, ethanol-induced changes in lipid content and metabolism in primary cultured rat cerebellar granule neurons (CGNs), human neuroblastoma SK-N-SH cells, and mouse neuroblastoma Neuro2a cells. Ethanol treatment conditions were selected to induce apoptosis in CGNs and SK-N-SH cells but not in Neuro2a cells. Cultured neurons were treated with and without 100 mM ethanol for 1-3 days, and the amounts of cellular sphingolipids (ceramide, glucosylceramide [GlcCer], and sphingomyelin) and neutral lipids (cholesterol, triglyceride [TG], and cholesterol ester) were analyzed by high-performance thin-layer chromatography. [14C] acetate incorporation into each lipid fraction was measured in CGNs treated with and without ethanol. The effect of delipidated serum, sterols, myriocin (an inhibitor of serine-palmitoyltransferase), and desipramine (an inhibitor of acid sphingomyelinase) on ethanol-induced lipid changes was studied in Neuro2a cells. In all three neuron types the most prominent change was ethanol-induced TG accumulation. Higher incorporation of radioactivity into TG was also seen in ethanol-treated cultures when cellular lipids were metabolically labeled with [14C] acetate in CGNs. Ethanol also elevated ceramide levels in all these neurons. However, ethanol decreased GlcCer and reduced viability in SK-N-SH and CGN cells, but increased GlcCer in Neuro2a cells that remained viable. Myriocin, which reduced ceramide levels, diminished ethanol-induced cell death in SK-N-SH cells. Ethanol-induced accumulation of TG was sterol-independent, whereas changes in ceramide and GlcCer were affected in Neuro2a cells by the presence of sterols in the medium. Staurosporine, which induced cell death in SK-N-SH cells, increased levels of TG, cholesterol ester, and ceramides and reduced GlcCer level. The ethanol-induced accumulation of TG and ceramide suggests that ethanol enhances lipogenesis or reduces fatty acid degradation in neurons, as previously observed in other cell types. Ethanol-induced changes in ceramide and GlcCer metabolism may be related to ethanol-induced apoptosis. NIAAA Glossary Terms:   sphingolipids, lipids, ethanol, apoptosis, ceramide, glucoside, cholesterol, triglycerides, esters, high pressure liquid chromatography, acetate, radioactive chemical elements, cerebellum, neuron, laboratory mice, cell culture study, animal study, human study

Karahanian, Eduardo; Ocaranza, Paula; and Israel, Yedy.  Aldehyde dehydrogenase (ALDH2) activity in hepatoma cells is reduced by an adenoviral vector coding for an ALDH2 antisense mRNA.  Alcoholism: Clinical & Experimental Research 29(8):1384-1389, August 2005.

Summary: The Glu487Lys coding mutation in the gene for mitochondrial aldehyde dehydrogenase (ALDH2) results in diminished capacity to metabolize acetaldehyde, causing increased blood acetaldehyde levels when ethanol is consumed. This in turn results in aversion to alcohol and marked protection against alcoholism. This study mimicked the high-acetaldehyde low-ALDH2 activity phenotype in a rat hepatoma cell line by inhibiting Aldh2 gene expression by an Aldh2 antisense-coding gene carried by an adenoviral vector. Rat hepatoma cells were infected with adenoviral vectors (1013 virions/ml) carrying Aldh2 complementary deoxyrobonucleic acid (cDNA) cloned in the reverse orientation preceded by a cytomegalovirus (CMV) promoter and followed by a poly-adenylyl termination signal. The antisense gene was actively transcribed in the cells and high levels of antisense messenger ribonucleic acid (mRNA) were attained. The antisense gene reduced ALDH2 activity by 65%, and when incubated with 10 mM ethanol, acetaldehyde accumulation by cells increased 8-fold to 80-90 µM, levels known to be aversive to animals and humans. The results show that antialcohol drugs that inhibit Aldh2 gene expression can be generated endogenously in liver cells infected by an adenoviral vector carrying an antisense-coding gene, thus mimicking the high-acetaldehyde phenotype in humans carrying the Glu487Lys mutation, which protects them against alcoholism. NIAAA Glossary Terms:  aldehyde dehydrogenases, mitochondria, mutation,  adverse drug effect, ethanol, acetaldehyde, ethanol-to-acetaldehyde metabolism, protective drug affect, AOD dependence, laboratory rat, cell culture study, cultured cell line, cancer, gene, genetic code, cDNA, virus, gene transcription, genotype, phenotype, animal study

Cook, Jason B.; Foster, Katrina L.; Eiler, William J. A. II; McKay, Peter F.; Woods, James II; Harvey, Scott C.; Garcia, Marin; Grey, Collette; McCane, Shannan; Mason, Dynesha; Cummings, Rancia; Li, Xiaoyan; Cook, James M.; and June, Harry L.  Selective GABA_A [alpha]5 benzodiazepine inverse agonist antagonizes the neurobehavioral actions of alcohol.  Alcoholism: Clinical & Experimental Research 29(8):1390-1401, August 2005.

Summary: Hippocampal α5-containing GABAA receptors have been implicated in the reinforcing properties of alcohol in previous studies. This study used the selective GABAA α5 benzodiazepine inverse agonist RY 023 in a series of in vivo and in vitro studies to determine the significance of the α5-receptor in the neurobehavioral actions of alcohol. Three experiments were done. In experiment 1, intraperitoneal (IP) injections of RY 023 (1 to 10 mg/kg) dose-dependently reduced ethanol-maintained responding by 52-86% of controls, whereas bilateral hippocampal infusions (0.3 to 20 µg) reduced responding by 66-84% of controls. Saccharin responding was reduced only with the highest IP (e.g., 10 mg) and microinjected (e.g., 20 µg) doses. In experiment 2, RY 023 (3.0 to 15 mg/kg IP) reversed the motor-impairing effects of a moderate dose of alcohol (0.75 g/kg) on an oscillating bar task in the absence of intrinsic effects. In the open field, RY 023 (3.0 to 7.5 mg/kg) produced intrinsic effects alone but attenuated the suppression of the 1.25 g/kg ethanol dose. Because the diazepam-insensitive receptors (e.g., α4 and α6) have been suggested to play a role in alcohol motor impairing and sedative actions, experiment 3 compared the efficacy of RY 023 with Ro 15-4513 and two prototypical benzodiazepine antagonists (e.g., flumazenil and ZK 93426) across the α4ß3τ2-, α5ß3τ2-, and α6ß3τ2-receptor subtypes in Xenopus oocytes. RY 023 produced classic inverse agonism at all receptor subtypes, whereas Ro15-4513 and the two antagonists displayed a neutral or agonistic profile at the diazepam-insensitive receptors. The results extend the authors' previous findings by demonstrating that an α5-subtype ligand can reduce not only the rewarding effect of alcohol but also its motor-impairing and sedative effects. The authors propose that these actions are mediated in part by the hippocampal α5-receptors, which could represent novel targets in understanding the neuromechanisms regulating the neurobehavioral actions of alcohol in humans. NIAAA Glossary Terms:  hippocampus, GABA A receptor, GABAergic neuron, benzodiazepines, agonists, antagonists, flumazenil, diazepam, neurotransmitter receptors, in vivo study, in vitro study, ethanol, intraperitoneal administration, controlled study, saccharin, animal behavior, diazepam, locomotion, sedative-hypnotics, ligand, neurobehavioral theory of AODU, ovum, animal study

Sircar, Ratna and Sircar, Debashish.  Adolescent rats exposed to repeated ethanol treatment show lingering behavioral impairments.  Alcoholism: Clinical & Experimental Research 29(8):1402-1410, August 2005.

Summary: Repeated ethanol treatment has been reported to differentially affect water maze performance in adolescent and adult rats. This study investigated the age-specific reversal of ethanol-induced deficit in water maze performance. Adolescent and adult male rats were subjected to repeated ethanol or saline treatments. Experimental rats were given daily intraperitoneal injections of 2 g/kg ethanol for 5 consecutive days (Days 1-5) and tested in the hidden platform task of the Morris water maze 30 minutes after ethanol treatment; control rats received isovolumetric saline. On the last training day, all rats were tested in the probe trial and the cued visual task. After an ethanol-free period of 4-25 days, rats were retested in the water maze. Ethanol-treated adolescents had significantly higher latencies and swam greater distances to find the hidden platform, compared to age-matched controls. Ethanol-treated rats also spent significantly more time near the periphery of the pool (hug time) than controls. In the probe trial, ethanol-treated rats spent less time in the target quadrant than saline-treated controls. However, there was no difference between ethanol- and saline-treated rats in the swim speed or the visual task performance. Experimental and control rats were retested in the water maze 4 days (Day 9), 7 days (Day 12), and 25 days (Day 30) after the last ethanol/saline treatment; no injections were given on those days. Ethanol-treated rats continued to do poorly on all retest days. Ethanol treatment of adult males acutely increased latency and distance to find the hidden platform, but unlike ethanol-treated adolescents, their performance in the probe trial did not differ from adult controls. Additionally, swim speed and visual task performance of adult rats were significantly affected by ethanol exposure. During retesting, their performance did not differ from adult controls. In summary, adolescent rats exposed to ethanol showed water maze performance deficits, increased hug time, and failure to catch up with controls during the weeks following cessation of ethanol treatment. Adult ethanol-exposed rats showed some behavioral dysfunction (increased latency and distance to find the hidden platform) but had problems swimming, and performed as well as controls in the probe trial. Also, ethanol-induced impairments in adult rats were quickly reversed after the ethanol treatment was over, which suggests impaired motor coordination more than a true learning deficit. The findings in this study indicate that repeated ethanol treatment in adolescent rats, but not in adults, causes long-term impairments in maze performance. NIAAA Glossary Terms:  ethanol, chronic AODE, adolescent, adult, laboratory rat, animal behavior, controlled study, locomotion, motor coordination, age differences, animal study

Mueller, Timothy I.; Pagano, Maria E.; Rodriguez, Benjamin F.; Bruce, Steven E.; Stout, Robert L.; and Keller, Martin B.  Long-term use of benzodiazepines in participants with comorbid anxiety and alcohol use disorders.  Alcoholism: Clinical & Experimental Research29(8):1411-1418, August 2005.

Summary: This study extends earlier research from the Harvard Anxiety Research Program showing that use of benzodiazepines was not significantly associated with presence or absence of a history of an alcohol use disorder (AUD) over the first year of follow-up. Standard parametric analytic methods were used in a 12-year prospective examination of patterns of use (routinely prescribed medication and as-needed [PRN] use) among participants receiving benzodiazepine treatment. Benzodiazepine usage pattern differences were examined in each year of follow-up between participants who did (n = 120) and did not (n = 425) have a new episode of AUD. Proportional hazards regression analysis was used to examine benzodiazepine usage levels as predictors of recovery and recurrence of AUD, and random-effects regression analyses were used to examine the patterns of benzodiazepine use before and after the onset of a prospectively observed AUD episode. Benzodiazepine usage levels remained stable for the full sample over the course of the 12 years. Benzodiazepine use did not distinguish participants who had a new AUD from those who did not. Over the 12-year follow-up, participants who had an AUD used more PRN medication in years 5 to 8. Although this difference reached statistical significance, it was not clinically significant. Benzodiazepine usage levels did not predict recovery or recurrence in AUD subjects. Neither the total dose nor the PRN usage of benzodiazepines was significantly associated with AUD onset, but when combined into a measure of any benzodiazepine use, a relationship emerged between increased use and onset of AUD. Thus, for participants with comorbid alcohol dependence and anxiety disorders, there was little association between the use of benzodiazepines and the occurrence of a new AUD, nor was there a temporal relationship between use of benzodiazepines and onset of a new AUD. Further investigation is need to determine whether this finding extends to a broader patient population or a group of people who present to addictions treatment. NIAAA Glossary Terms:  alcohol use disorder classification, AOD abuse, AOD dependence, benzodiazepines, drug therapy, regression analysis, treatment outcome, predictive factor, prospective study, follow-up study, statistical estimation, comorbidity, anxiety, human study

Sharpe, Amanda L.; Tsivkovskaia, Natalia O.; and Ryabinin, Andrey E.  Ataxia and c-Fos expression in mice drinking ethanol in a limited access session.  Alcoholism: Clinical & Experimental Research 29(8):1419-1426, August 2005.

Summary: The objective was to demonstrate ataxia and examine changes in c-Fos expression in mice after self-administration of intoxicating doses of ethanol. Male C57BL/6J mice were trained to drink a 10% ethanol solution during daily 30-minute limited access sessions. Mice were exposed to increasing concentrations of ethanol until a 10% ethanol solution was reached. Blood ethanol concentration (BEC) and ataxia, measured as foot slips off of a balance beam, were examined after the self-administration session. In a separate experiment, various brain structures from mice drinking water or ethanol were examined for changes in c-Fos expression 2 hours after the limited access session. Mice drank between 1.5 and 2 g/kg of 10% ethanol during the daily 30-minute session. BECs for these mice 15 minutes after the limited access session ranged between 0.52 and 2.13 mg/ml, a range considered pharmacologically relevant and intoxicating. A significant increase in foot slips off a balance beam was seen immediately after ethanol ingestion during the limited access session. Among mice drinking ethanol, an increase in c-Fos expression was observed in the Edinger-Westphal nucleus, and a decrease in c-Fos expression was seen in the cingulate cortex, ventral tegmental area, lateral and medial septum, CA1 region of the hippocampus, and basolateral amygdala. Significant ataxia was observed after ethanol self-administration. Brain regions showing changes in c-Fos expression after voluntary intoxication were similar to those previously reported, suggesting that these regions are involved in regulating behavioral effects of alcohol intoxication. NIAAA Glossary Terms:  ataxia, ethanol, self-administration of drugs, gene expression, laboratory mice, BAC, controlled study, AOD intoxication, animal behavior, brain, cerebral cortex, ventral tegmental area, hippocampus, amygdala, animal study

Tavares, Hermano; Zilberman, Monica L.; Hodgins, David C.; and el-Guebaly, Nady.  Comparison of craving between pathological gamblers and alcoholics.  Alcoholism: Clinical & Experimental Research 29(8):1427-1431, August 2005.

Summary: The objectives were to compare craving between pathologic gamblers (PG) and alcohol-dependent subjects (ADS) and to correlate craving with personality. Pathologic gamblers (n = 49) and alcoholics (n = 101) willing to start treatment were recruited. The participants were diagnosed by a trained psychiatrist according to  criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. For inclusion in the study, subjects had to be abstinent for at least 5 days and no longer than 21 days. Alcoholics could have no significant physical withdrawal symptoms by the time of craving assessment. Subjects with current comorbidity with other addictions, except nicotine, were excluded. Alcoholics rated craving for alcohol and pathologic gamblers rated craving for gambling on the same questions. Both completed a semistructured interview, the Temperament and Character Inventory, and the Beck Scales for anxiety and depression. Pathologic gamblers scored significantly higher than alcoholics on craving measures (p < 0.001) and novelty seeking (p = 0.01). Alcoholics scored higher in harm avoidance (p = 0.01). Alcohol craving correlated positively with anxiety and novelty seeking and negatively with length of abstinence and persistence. Gambling craving correlated positively with depression and negatively with length of abstinence and reward dependence. In summary, pathologic gamblers experienced stronger cravings than alcoholics. This may be a disturbing experience for pathologic gamblers and a potential cause of relapse. Their higher scores on novelty seeking concur with previous studies that associate pathologic gambling and impulsivity. Alcoholics' higher scores on harm avoidance suggest anxiety vulnerability. The positive relation between alcohol craving, anxiety, and harm avoidance suggests that alcoholics rely on alcohol to deal with a proclivity to negative emotions. The positive relation of gambling craving to depression and negative relation to reward dependence suggests that individuals who have less susceptibility to experience positive emotions are the ones who miss gambling most when abstaining. NIAAA Glossary Terms:   pathological gambling, AOD dependence, comparative study, personality trait, correlation analysis, AOD craving, psychiatric status rating scales, novelty-seeking behavior, AOD abstinence, reward dependence behavior, AODD relapse, harm-avoidance behavior, anxiety, emotional and psychiatric depression, impulsive behavior, emotion, human study

Kushner, Matt G.; Abrams, Kenneth; Thuras, Paul; Hanson, Karen L.; Brekke, Marjorie; and Sletten, Sandra.  Follow-up study of anxiety disorder and alcohol dependence in comorbid alcoholism treatment patients.  Alcoholism: Clinical & Experimental Research29(8):1432-1443, August 2005.

Summary: The objectives were to test the hypothesis that a comorbid anxiety disorder increases the risk for relapse to drinking after alcoholism treatment, and to explore the prospective associations of specific anxiety syndromes (and depression) with drinking and anxiety outcomes. The diagnostic status and daily drinking patterns of alcoholics (n = 82) were assessed about a week after they entered alcoholism treatment (baseline) and again approximately 120 days later (follow-up) (n = 53). As predicted, those with a baseline anxiety disorder (approximately 55%) were significantly more likely than others to meet various definitions of drinking relapse over the course of follow-up. Regression models showed that the single best predictor of return to any drinking after treatment was baseline social phobia, and that panic disorder was the single best predictor of post-treatment relapse to alcohol dependence. Having multiple anxiety disorders (versus any specific anxiety disorder) at baseline was the strongest predictor of having at least one active ("persistent") anxiety disorder at follow-up. Cross-sectional analysis at follow-up showed that anxiety disorder persisted in the absence of a relapse to alcohol dependence far more often than relapse to alcohol dependence in the absence of a persistent anxiety disorder. It was concluded that screening for comorbid anxiety disorder in alcoholism treatment patients is warranted and, where found, should be considered a marker of high relapse risk relative to that of noncomorbid patients. Whether specific anxiety treatment can mitigate relapse risk among comorbid patients remains unknown. NIAAA Glossary Terms:  AOD dependence, AODD relapse, risk analysis, comorbidity, anxiety, emotional and psychiatric depression, AOD use pattern, follow-up study, predictive factor, hypothesis testing, social phobia, panic disorder, regression analysis, cross-sectional study, medical screening and diagnostic method, human study

Alvik, Astrid; Haldorsen, Tor; and Lindemann, Rolf.  Consistency of reported alcohol use by pregnant women: Anonymous versus confidential questionnaires with item nonresponse differences.  Alcoholism: Clinical & Experimental Research 29(8):1444-1449, August 2005.

Summary: Self-reported alcohol consumption before and during pregnancy is sensitive to response bias. This study compared the responses of pregnant women to a drinking questionnaire completed confidentially versus anonymously. A representative sample of ethnically Scandinavian pregnant women (n = 1,707) were invited to join a confidential questionnaire study, and another group of pregnant women (n = 178), selected the same way, were asked to answer the same questionnaire anonymously. Measures were T-ACE (an alcohol screening measure derived from the CAGE questionnaire, with a tolerance question replacing the guilt question), reported frequency of alcohol use, standard units (SU) per occasion (po), SU per week, and binge drinking (>=5 SU po), before and during pregnancy. There were no significant differences between the confidential and anonymous groups in reported alcohol consumption. Any alcohol consumption during pregnancy weeks 7-12 and week 13+ was reported by 22.6% and 23.3% respectively by women in the confidential group versus 22.5% and 25.8% by women in the anonymous group. Group differences tended to be larger for SU per week (p = 0.07 both before pregnancy and after week 12 than for the indirect alcohol (T-ACE) and binge drinking questions. In the confidential group, the women with lower education had nearly twice as much item nonresponse on the direct alcohol questions during pregnancy compared with those with higher education. This difference was smaller in the anonymous group. In conclusion, there was no significant difference in self-reported alcohol consumption obtained by confidential or anonymous questionnaires. NIAAA Glossary Terms:  prenatal alcohol exposure, alcohol use test, pregnancy, AOD consumption, parental AOD use, self report, questionnaire, AOD tolerance, AOD use frequency, AOD intake per occasion, binge AOD use, AODU testing confidentiality, standard drink, educational level achieved, human study

Wan, Qiang; Liu, Yi; Guan, Qingbo; Gao, Ling; Lee, Kok Onn; and Zhao, Jiajun.  Ethanol feeding impairs insulin-stimulated glucose uptake in isolated rat skeletal muscle: Role of Gs [alpha] and cAMP.  Alcoholism: Clinical & Experimental Research 29(8):1450-1456, August 2005.

Summary: To clarify the mechanism by which chronic alcohol consumption impairs insulin sensitivity, this study investigated the role of the Gs alpha [α]-mediated pathway in decreasing insulin sensitivity in skeletal muscle after ethanol consumption. Male Wistar rats (N = 60) were divided into four groups. Group 1 (controls) received distilled water and groups 2, 3, and 4 received a daily intragastric ethanol dose of 5 g/kg, 2.5 g/kg, and 0,5 g/kg respectively. After 20 weeks, fasting plasma glucose and serum insulin levels were measured. The hyperinsulinemic-euglycemic clamp study was performed under anesthesia to estimate whole-body insulin sensitivity. Insulin-stimulated glucose uptake was measured in vitro in dissected gastrocnemius muscle. Expression of glut4, Gs α, and Gi α was quantified using real-time polymerase chain reaction analysis and western blotting. Cyclic adenosine monophosphate (cAMP) levels were measured by enzyme-linked immunosorbent assay (ELISA). All of the following observations are in comparison with controls: (1)The hyperinsulinemic-euglycemic clamp study revealed impaired insulin action at the whole-body level after ethanol treatment. (2) Chronic ethanol feeding at 5 g/kg and 2.5 g/kg significantly decreased both basal and insulin-stimulated glucose uptakes in isolated skeletal muscle (p < 0.05), which was accompanied by decreased expression of glut4 (p < 0.05). (3) Expression of Gs α (messenger ribonucleic acid [mRNA] and protein) in skeletal muscle was significantly increased in all three ethanol groups (p < 0.05). cAMP levels were also increased by ethanol treatment (p < 0.05). (4) There was no significant change in Gi α expression in any of the ethanol groups. In conclusion, chronic ethanol exposure decreased insulin-induced glucose uptake in rat skeletal muscle, which was associated with increased expression of Gs α. Because Gs α is a negative regulator of insulin sensitivity, the alteration of its expression may contribute to the ethanol-induced impairment of insulin signal transduction. NIAAA Glossary Terms:  ethanol, insulin, signal transduction, skeletal muscle, glucose, in vitro study, polymerase chain reaction, Western blotting, cAMP, immunoassay, chronic AODE, mRNA, gene expression, controlled study, laboratory rat, animal study

Kamat, Pradip P.; Slutsky, Arthur; Zhang, Haibo; Bechara, Rabih I.; Brown, Lou Ann S.; Garcia, Raena C.; Joshi, Pratibha C.; Kershaw, Corey D.; and Guidot, David M.  Mechanical ventilation exacerbates alveolar macrophage dysfunction in the lungs of ethanol-fed rats.  Alcoholism: Clinical & Experimental Research 29(8):1457-1465, August 2005.

Summary: This study investigated in an animal model whether mechanical lung ventilation in alcoholism promotes, on balance, a proinflammatory phenotype that favors ventilator-induced lung injury or an immunosuppressive phenotype that favors ventilator-associated pneumonia. Lungs from rats fed an isocaloric diet with or without ethanol for 6 weeks were isolated and ventilated ex vivo with a low-volume (protective) or high-volume (injurious) strategy for 2 hours with or without prior endotoxemia (2 hours). In other experiments, rats were subjected to high-volume ventilation in vivo. Airway levels of the proinflammatory cytokines tumor necrosis factor-alpha (TNF-α), macrophage inflammatory protein-2 (MIP-2), and interleukin-1beta (IL-1ß) were determined after ex vivo mechanical ventilation and compared with edematous lung injury after high-volume ventilation in vivo. In parallel, alveolar macrophage phagocytosis of bacteria and IL-12 secretion during ventilation ex vivo and endotoxin-stimulated alveolar macrophage phagocytosis and TNF-α secretion in vitro were determined. The proinflammatory response to injurious mechanical ventilation was suppressed by ethanol ingestion and experimental ventilator-induced lung injury was not increased by it. In parallel, ethanol ingestion blunted the innate immune response of alveolar macrophages during injurious ventilation ex vivo and after endotoxin stimulation in vitro. Thus ethanol ingestion dampens ventilator-induced inflammation but exacerbates macrophage immune dysfunction, which could explain at least in part why risk of ventilator-associated pneumonia is increased in alcoholic patients. NIAAA Glossary Terms:   respiratory inflammation or infection, respiratory function, pneumonia, ethanol, AOD dependence, endotoxemia, endotoxins, inflammation, macrophage, phagocytosis, in vivo study, in vitro study, laboratory rat, comparative study, edema, treatment factors, animal study

Wahl, Elizabeth C.; Perrien, Daniel S.; Aronson, James; Liu, Zhendong; Fletcher, Terry W.; Skinner, Robert A.; Feige, Ulrich; Suva, Larry J.; Badger, Thomas M.; and Lumpkin, Charles K. Jr.  Ethanol-induced inhibition of bone formation in a rat model of distraction osteogenesis: A role for the tumor necrosis factor signaling axis.  Alcoholism: Clinical & Experimental Research 29(8):1466-1472, August 2005.

Summary: The rapid bone formation demonstrated during limb lengthening is inhibited, through distraction osteogenesis (DO), by chronic ethanol exposure. The inhibition is diminished by simultaneous administration of antagonists to the cytokines interleukin-1beta (IL-1ß) and tumor necrosis factor-alpha (TNF-α). This study tested the individual effects on inhibition of osteogenesis by these cytokines. It was hypothesized that administration of individual antagonists to these cytokines ─ IL-1 receptor antagonist (IL-1ra) or polyethylene glycol-conjugated soluble TNF receptor type 1 (sTNFR1) ─ would enhance DO and that the individual administration of each cytokine (recombinant rat  IL-1 [rr IL-1] or recombinant rat TNF [rr TNF] would inhibit DO. For antagonist studies rats were infused with a liquid diet with or without ethanol. For recombinant studies they were fed rat chow. They then underwent tibial fractures stabilized with external fixators for DO. The bioactive substances were administered by systemic diffusion (antagonist studies) or local diffusion (recombinant studies). Comparison of histologic sections from the distracted tibias revealed (1) a protective effect on bone formation by sTNFR1 (p < 0.05), (2) an unexpected IL-1ra-related decrease in bone formation (p < 0.02), (3) significantly decreased bone formation with rrTNF compared with vehicle controls (p < 0.02), and (4) no significant changes in bone formation with rrIL-1. The cellular responses (fibroblastic and inflammatory cells) were unique for each recombinant cytokine administered. The results suggest that the osteoinhibitory effects of chronic ethanol exposure are mediated in part by the TNF signaling axis. NIAAA Glossary Terms:  ethanol, chronic AODE, cytokines, tumor necrosis factor-alpha, antagonists, bone, interleukin-1, hypothesis testing, bone ossification, bone fracture, laboratory rat, controlled study, histologic study, fibroblast, inflammation, animal study

Burden, Matthew J.; Jacobson, Sandra W.; and Jacobson, Joseph L.  Relation of prenatal alcohol exposure to cognitive processing speed and efficiency in childhood.  Alcoholism: Clinical & Experimental Research 29(8):1473-1483, August 2005.

Summary: Prenatal alcohol exposure has been linked to processing speed deficits in both infancy and later in childhood. This study examined prenatal alcohol-related deficits in both processing speed (PS) and processing efficiency (PE) in four domains of cognitive function. Black children (N = 337; age 7.5 years) were prospectively recruited to over-represent moderate-to-heavy prenatal alcohol exposure, and were assessed on four processing speed tasks using a Sternberg paradigm. Hierarchical linear modeling was used to contrast overall PS, indicated by reaction time (RT) differences at the intercept, with PE, indicated by the slope of RT changes across increasing levels of task difficulty. Performance on these tasks within an effortful cognitive framework was compared with RT on a task involving relatively more automatic processing. The degree to which the effect of prenatal alcohol exposure on working memory was mediated by slower RT was assessed by path analysis. Prenatal alcohol exposure was associated with slower PS on several Sternberg tasks, and the number comparison task showed a specific deficit in PE. These effects on tasks involving effortful processing contrasted with the lack of performance differences on the more automatic RT measure. The relation of prenatal alcohol exposure to working memory was partly mediated by an associated reduction in PS. These findings confirm previous reports linking prenatal alcohol exposure to slower PS and show that this RT deficit is found within the context of complex cognition but not where automatic processing is involved. The reduction in RT accounts, in part, for the previously reported alcohol-related effects on working memory. The number comparison slope was the only specific component of information processing affected, confirming previous reports of a distinctive prenatal alcohol effect on number processing. NIAAA Glossary Terms:  prenatal alcohol exposure, cognitive ability, childhood, Black, statistical modeling, reaction time, psychological performance test, cognitive and memory disorder, human study

Gazdzinski, S; Durazzo, T C.; Studholme, C; Song, E; Banys, P; and Meyerhoff, D J.  Quantitative brain MRI in alcohol dependence: Preliminary evidence for effects of concurrent chronic cigarette smoking on regional brain volumes.  Alcoholism: Clinical & Experimental Research 29(8):1484-1495, August 2005.

Summary: Previous research has not accounted for the potential effects of chronic smoking on regional brain volumes in alcoholics, although cigarette smoking is common among them and studies shown that alcohol-induced brain injury is exacerbated by chronic cigarette smoking, which is also associated with reduced gray matter volume in healthy adults, greater brain atrophy in aging, and poorer neurocognition. In this study, high-resolution T1-weighted magnetic resonance images from 1-week-abstinent alcoholics and light drinkers were automatically segmented into gray matter, white matter, and cerebral spinal fluid of lobes and subcortical structures. Cognition in alcohol-dependent subjects was assessed with a brief neuropsychological test battery. The alcoholic and nonalcoholic groups were divided retrospectively into chronic smokers and nonsmokers, and volumetric data were analyzed as a function of alcohol and smoking status. Alcohol dependence was associated with smaller volumes of frontal and parietal white matter, parietal and temporal gray matter, and thalami, accompanied by widespread sulcal but not ventricular enlargements. Chronic cigarette smoking was associated with less parietal and temporal gray matter and more temporal white matter. Among nonsmoking alcoholics, better visuospatial learning and memory and greater visuomotor scanning speed were correlated with larger lobar white matter volumes. These results are preliminary evidence that comorbid chronic cigarette smoking accounts for some of the variance associated with cortical gray matter loss and appears to alter relationships between brain structure and cognitive functions in alcoholics. NIAAA Glossary Terms:  AOD dependence, AODR disorder, brain atrophy, smoking, cigarette, multiple drug use, comorbidity, chronic AODE, light AOD use, magnetic resonance imaging, brain imaging, cerebrospinal fluid, cognitive ability, neuropsychological assessment, frontal cortex, cerebral cortex, thalamus, spatial memory, controlled study, human study

Ji, Cheng; Mehrian-Shai, Ruty; Chan, Christine; Hsu, Ya-Hsuan; and Kaplowitz, Neil.  Role of CHOP in hepatic apoptosis in the murine model of intragastric ethanol feeding.  Alcoholism: Clinical & Experimental Research 29(8):1496-1503, August 2005.

Summary: The transcriptional regulator CHOP (C/EBP homologous protein) is involved in apoptosis caused by endoplasmic reticulum (ER) stress. The authors previously reported that CHOP as well as other ER stress response genes is induced in the liver of a mouse model of intragastric ethanol feeding. The aim of their present  study was to determine the role of CHOP in hepatocellular apoptosis and liver injury in the same model. CHOP wild-type (+/+) mice and CHOP null (-/-) mice were fed alcohol for 4 weeks with glucose as control. Hematoxylin-eosin staining, TUNEL (terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling), and caspase 3 staining of liver tissues were performed for assessment of fatty liver, necroinflammation, and apoptosis. Total ribonucleic acid (RNA) was extracted for microarray and reverse transcription-polymerase chain reaction (PCR) analyses, and proteins were used for Western blotting. In both genotypes, liver/body ratio, steatosis, liver triglyceride levels, and plasma homocysteine concentrations were significantly increased in alcohol-fed mice relative to controls. CHOP+/+ and CHOP-/- mice did not differ significantly in the parameters related to fatty liver. Alcohol-induced increased serum alanine aminotransferase levels and necroinflammatory foci were not significantly reduced in CHOP-/- mice. However, apoptosis was present in alcohol-fed wild-type mice but virtually absent in alcohol-fed CHOP-/- mice. The ER stress response indicated by increased Grp78 messenger RNA was observed in both types of mice fed alcohol. Of 12,423 transcripts analyzed for ≥ two-fold changes, several related to apoptosis were influenced by CHOP: Gadd45 and cathepsin B were up-regulated in ethanol-fed +/+ mice but not in CHOP -/- mice, whereas Jun D and Bcl-xL were down-regulated in ethanol-fed CHOP+/+ mice but not in ethanol-fed CHOP-/- mice. It was concluded that CHOP null mice have remarkable absence of hepatocellular apoptosis in response to alcohol feeding but no protection against hyperhomocysteinemia, ER stress, and fatty liver. Thus CHOP up-regulation occurs downstream of and contributes to one manifestation of ER stress, namely, apoptosis. Microarray studies confirmed by PCR analysis and western blotting indicate that genes affected by CHOP are both proapoptotic and antiapoptotic and CHOP induction by ethanol may tip the balance of cell survival and death toward apoptosis. NIAAA Glossary Terms:  ethanol, apoptosis, stress, proteins, alcoholic liver disorder, fatty liver, gene knockout technology, controlled study, laboratory mice, endoplasmic reticulum, reverse transcriptase polymerase chain reaction, Western blotting, RNA, mRNA, homocysteine, animal study

Crews, Fulton T.; Buckley, Tracey; Dodd, Peter R.; Ende, Gabriele; Foley, Nina; Harper, Clive; He, Jun; Innes, David; Loh, El-Wui; Pfefferbaum, Adolf; Zou, Jian; and Sullivan, Edith V.  Alcoholic neurobiology: Changes in dependence and recovery.  Alcoholism: Clinical & Experimental Research 29(8):1504-1513, August 2005.

Summary: Proceedings of a symposium on alcoholic neurobiology held at the 2004 meeting of the International Society for Biomedical Research on Alcoholism in Mannheim, Germany are summarized. The fluctuating course of alcoholism provides a natural experiment in vulnerability, resilience, and recovery of human neural systems in response to the presence, absence, and history of alcoholism's neurotoxic effects. Alcohol dependence is characterized by a neuropsychological profile of mild to moderate impairment in executive functions, visuospatial abilities, and postural stability, together with relative sparing of declarative memory, language skills, and primary motor and perceptual abilities. The partial reversal of deficits during recovery from alcoholism indicates that brain structure is capable of repair and restructuring in response to insult in adulthood. Indirect support of this repair model derives from studies of selective neuropsychological processes, structural and functional neuroimaging studies, and preclinical studies on degeneration and regeneration during the development of and recovery from alcohol dependence. Genetics and brain regional specificity contribute to unique changes in neuropsychology and neuroanatomy in alcoholism and recovery. The symposium included state-of-the-art presentations on changes that occur during active alcoholism as well as those that may occur during recovery-abstinence from alcohol dependence. The presentations included human neuroimaging and neuropsychological assessments, changes in human brain gene expression, allelic combinations of genes associated with alcohol dependence and preclinical studies investigating mechanisms of alcohol induced neurotoxicity, and neuroprogenetor cell expansion during recovery from alcohol dependence. NIAAA Glossary Terms:  conference proceedings, neurobiology (field), AOD dependence, neurotoxicity, neuropsychological assessment, cognition, cognitive and memory disorder, ataxia, genetic trait, genetics and heredity, neuroimaging, AOD abstinence, gene expression, human study

Quertemont, Etienne; Eriksson, C J. Peter; Zimatkin, Sergey M.; Pronko, Pavel S.; Diana, Marco; Pisano, Milena; Rodd, Zachary A.; Bell, Richard R.; and Ward, Roberta J.  Is ethanol a pro-drug? Acetaldehyde contribution to brain ethanol effects.  Alcoholism: Clinical & Experimental Research 29(8):1514-1521, August 2005.

Summary: This article summarizes a symposium on the contribution of acetaldehyde to ethanol's effects on the brain, held at the 2004 meeting of the International Society for Biomedical Research on Alcoholism, in Mannheim, Germany. Etienne Quertemont organized the symposium and C.J. Peter Eriksson was the chairman. The presentations were (1) "Brain ethanol metabolism and its behavior consequences," by Sergey M. Zimatkin and P.S. Pronko; (2) "Acetaldehyde increases dopaminergic neuronal activity: A possible mechanism for acetaldehyde reinforcing effects," by Marco Diana and Milena Pisano; (3) "Contrasting the reinforcing actions of acetaldehyde and ethanol within the ventral tegmental area (VTA) of alcohol-preferring (P) rats," by Zachary A. Rodd and Richard R. Bell; (4) "Molecular and biochemical changes associated with acetaldehyde toxicity," by Roberta J. Ward; and (5) "Role of acetaldehyde in human alcoholism and alcohol abuse," by C.J. Peter Eriksson. NIAAA Glossary Terms:  conference proceedings, brain, acetaldehyde, ethanol-to-acetaldehyde metabolism, AODR behavioral problem, dopaminergic neuron, reinforcement, ventral tegmental area, animal selectively bred for alcohol preference, laboratory rat, neurotoxicity, AOD dependence, AOD abuse

Sanchis-Segura, Carles; Grisel, Judy E.; Olive, M Foster; Ghozland, Sandra; Koob, George F.; Roberts, Amanda J.; and Cowen, Michael S.  Role of the endogenous opioid system on the neuropsychopharmacological effects of ethanol: New insights about an old question.  Alcoholism: Clinical & Experimental Research 29(8):1522-1527, August 2005.

Summary: The proceedings of a symposium on the role of the endogenous opioid system on ethanol's neuropsychopharmacological effects are summarized. The symposium was presented at the 2004 meeting of the International Society for Biomedical Research on Alcoholism, held in Heidelberg/Mannheim, Germany. The organizers and co-chairmen were Michael S. Cowen and Carles Sanchis-Segura. The following presentations were made: (1) "Regulation of the opioid system by alcohol: Comparison of alcohol-preferring and -nonpreferring strains," by Michael S. Cowen; (2) "Endogenous opioids and alcohol: Lessons from microdialysis and knock-out mice," by M. Foster Olive; (3) "From neurochemistry to neuroanatomy: The hypothalamic arcuate nucleus as a main site for ethanol-opioids interaction." by Carles Sanchis-Segura; (4) "Sensitivity to ethanol is modulated by beta-endorphin in transgenic mice." by Judy E. Grisel, Amanda J. Roberts, and George F. Koob; and (5) "The mu-opioid receptor modulates acute ethanol sensitivity and ethanol withdrawal severity," by Sandra Ghozland. NIAAA Glossary Terms:  conference proceedings, endogenous opioids, neuropharmacology (field), ethanol, animal selectively bred for alcohol preference, laboratory rat, laboratory rat, microdialysis, gene knockout technology, hypothalamus, AOD sensitivity, mu-opioid receptors, AOD withdrawal syndrome, symptom severity

Johnson, Bankole A.; Mann, Karl; Willenbring, Mark L.; Litten, Raye Z.; Swift, Robert M.; Lesch, Otto M.; and Berglund, Mats.  Challenges and opportunities for medications development in alcoholism: An international perspective on collaborations between academia and industry.  Alcoholism: Clinical & Experimental Research 29(8):1528-1540, August 2005.

Summary: Proceedings of a symposium on academia-industry collaboration in developing medications for alcoholism are summarized. The symposium was presented at the 12th Congress of the International Society for Biomedical Research on Alcoholism, Heidelberg/Mannheim, Germany, September 2004. The organizers and co-chairmen were Bankole A. Johnson and Karl Mann and the presentations included: (1) "A Perspective from Academia," by Bankole A. Johnson; (2) "A Perspective from the National Institute on Alcohol Abuse and Alcoholism (NIAAA)," by Mark L. Willenbring; (3) "A Perspective from US Clinical Practice," by Robert M. Swift; (4) "A European Perspective on Medications Development," by Otto M. Lesch; and (5) "A Scandinavian Perspective on Evidence-Based Addiction Treatment," by Mats Berglund. NIAAA Glossary Terms:  conference proceedings, drug therapy, AOD dependence, educational institution, business and industry, collaboration, treatment methood, government agency, clinical aspects, addiction, Scandinavia

Ait-Daoud, Nassima; Wiesbeck, Gerhard A.; Bienkowski, Przemyslaw; Li, Ming D.; Pfutzer, Roland H.; Singer, Manfred V.; Lesch, Otto M.; and Johnson, Bankole A.  Comorbid alcohol and nicotine dependence: From the biomolecular basis to clinical consequences.  Alcoholism: Clinical & Experimental Research 29(8):1541-1549, August 2005.

Summary: Proceedings of a symposium on comorbid alcohol and nicotine dependence are summarized. The symposium was presented at the 12th Congress of the International Society for Biomedical Research on Alcoholism, Heidelberg/Mannheim, Germany, in October 2004. The organizers and co-chairmen were Nassima Ait-Daoud and Gerhard A. Wiesbeck. Presentations included (1) "The Role of Nicotinic Acetylcholine Receptors in Alcohol-Seeking Behavior," by Przemyslaw Bienkowski; (2) "Utilization of Linkage Analysis Combined with Microarray Technology to Identify Genes and Mechanisms Underlying Nicotine and Alcohol Use and Abuse in Humans and Rodents," by Ming D. Li; (3) "Smoking and Alcoholic Chronic Pancreatitis: The Underestimated Risk?", by Roland H. Pfutzer; (4) "Anticraving Medication in Alcohol and Nicotine Dependence," by Otto M. Lesch; and (5) "Pharmacotherapy for Promotion of Abstinence from Nicotine Among Alcohol-Dependent Individuals," by Bankole A. Johnson. NIAAA Glossary Terms:  conference proceedings, ethanol, nicotine, comorbidity, AOD dependence, nicotinic receptor, cholinergic receptors, AOD-seeking behavior, genetic linkage, gene, human study, animal study, laboratory rat, laboratory mice, chronic AODE, alcoholic pancreatitis, anti-AOD-craving agents, drug therapy, AOD abstinence

Spanagel, Rainer; Rosenwasser, Alan M.; Schumann, Gunter; and Sarkar, Dipak K.  Alcohol consumption and the body's biological clock (literature review). Alcoholism: Clinical & Experimental Research 29(8):1550-1557, August 2005.

Summary: New findings on the bidirectional interactions between ethanol and the clock genes underlying the generation of circadian rhythms are reviewed. At the behavioral level, both adult and perinatal ethanol treatments alter the free-running period and light response of the circadian clock in rodents. Ethanol preference in alcohol-preferring rat lines is also associated with altered circadian pacemaker function. At the neuronal level, it has been shown that ethanol consumption alters the circadian expression patterns of period (per) genes in various brain regions, including the suprachiasmatic nucleus. Notably, chronic ethanol intake disturbs circadian functions of beta (ß)-endorphin-containing neurons involved in the control of alcohol reinforcement. Conversely, per2 gene activity regulates ethanol intake by affecting the glutamatergic system through glutamate reuptake mechanisms, thereby possibly affecting various physiological processes that are governed by the internal clock. In summary, a new pathologic chain has been identified that contributes to the negative health consequences of chronic ethanol consumption. Altered expression of per genes by chronic ethanol consumption results in disturbance of a variety of neurochemical and neuroendocrine functions. Further steps in this pathologic chain are alterations in physiological and immune functions that are under circadian control. As a final consequence, addictive behavior might be triggered or sustained by this cascade. NIAAA Glossary Terms:  ethanol, circadian rhythm, animal study, laboratory rat, laboratory mice, animal selectively bred for alcohol preference, gene expression, beta-endorphin, neuron, glutamate receptors, chronic AODE, reinforcement, neurochemistry, neuroendocrinology (field),  pathogenesis, immune function, physiological AODE, addiction, literature review

Munro, Cynthia A.; Oswald, Lynn M.; Weerts, Elise M.;  McCaul, Mary E.; and Wand, Gary S.  Hormone responses to social stress in abstinent alcohol-dependent subjects and social drinkers with no history of alcohol dependence.  Alcoholism: Clinical & Experimental Research 29(7):1133-1138, July 2005.

Summary: Responses of adrenocorticotropic hormone (ACTH), cortisol, and prolactin to a psychological stressor were compared in abstinent alcohol-dependent subjects and healthy control subjects. The cases (n = 18; mean duration of abstinence ± SEM, 3.5 ± 5.7 years) were individuals who met standard diagnostic criteria for a history of alcohol dependence but not for other axis I disorders. The control subjects (n = 23) were social drinkers. The sober alcohol-dependent and control subjects were matched for demographic measures including levels of stress symptoms. The Trier Social Stress Test (TSST), a laboratory-based psychological stressor, was administered to all subjects. Pre-stress and post-stress plasma ACTH, cortisol, and prolactin levels, as well as a self-report measure of anxiety (State-Trait Anxiety Inventory), were obtained. Nondepressed abstinent alcoholics and controls did not differ in age, racial composition, or baseline or poststress ratings of anxiety. ACTH and cortisol levels increased in response to the TSST, but prolactin levels did not. Stress hormone response curves for the three hormones did not differ between the alcoholics and controls. In conclusion, a laboratory-based psychological stress test did not induce differential hormone response curves for abstinent alcoholics and controls matched for stress levels. NIAAA Glossary Terms : adrenocorticotropic hormone, cortisol, prolactin, psychological stress, stressor, AOD dependence, AOD abstinence, social AOD use, case-control study, controlled study, demographic characteristics, psychological performance test, anxiety, emotional and psychiatric depression, self report, human study

Siegmund, Soren; Vengeliene, Valentina; Singer, Manfred V.; and Spanagel, Rainer.  Influence of age at drinking onset on long-term ethanol self-administration with deprivation and stress phases.  Alcoholism: Clinical & Experimental Research 29(7):1139-1145, July 2005.

Summary: This study compared the drinking behavior of two groups of adult male Wistar rats: one that initiated ethanol consumption during adolescence (adolescent onset group) and the other that initiated their drinking during adulthood (adult onset group) in a long-term ethanol self-administration model. Heterogeneous Wistar rats aged 31 days (adolescents) and 71 days (adults) were given ad libitum access to water, as well as 5% and 20% ethanol solutions during a 30-week observation period. A 14-day deprivation phase was instituted after 8 weeks of ethanol access. All animals were subjected for 3 consecutive days to forced swimming (after 16 weeks of ethanol access) and to electric foot shocks (after 26 weeks of access). At drinking onset, the adolescent onset group consumed less ethanol and showed lower preference than adults. The deprivation phase was followed by increased intake of highly concentrated ethanol solution without appreciable differences between age groups. Repeated swim stress produced a slight increase in ethanol consumption in both groups, with no significant difference between the groups. The increase in ethanol intake induced by foot shock stress was significantly higher in the adolescent onset group. After swim stress, the drinking behavior of the adolescent onset group resembled that of the adult onset group. In particular, the adolescent onset group increased their preference for 20% ethanol solution for the rest of the experiment. Age of voluntary ethanol drinking onset did not appear to be a strong predictor for prospective ethanol intake and relapse-like drinking behavior in these experiments. However, the adolescent onset group seemed more susceptible to acute stressor-specific effects in terms of ethanol consumption. NIAAA Glossary Terms : early AODU onset, adolescence, late AODU onset, adulthood, laboratory rat, ethanol, stress, stressor, AOD consumption, age differences, comparative study, animal behavior, animal study

Czachowski, Cristine L.  Manipulations of serotonin fFunction in the nucleus accumbens core produce differential effects on ethanol and sucrose seeking and intake.  Alcoholism: Clinical & Experimental Research 29(7):1146-1155, July 2005.

Summary: It is hypothesized that serotonin (5-HT) affects ethanol-directed behaviors by interacting with the nucleus accumbens (NA) / ventral tegmental area (VTA) / prefrontal cortex circuit. This investigation used two different operant paradigms, one focusing on reinforcer seeking and the other on reinforcer self-administration (both with ethanol and sucrose solutions as the reinforcer) to elucidate 5-HT-specific regulation of these behaviors. The experiments assessed the effects of microinjections of a 5-HT 1B agonist and a 5-HT 1A agonist in the NA core on ethanol- and sucrose-reinforced seeking and intake. In four separate experiments, male rats were trained to complete a single response requirement that resulted in access to 10% ethanol or 2% sucrose for 20 minutes. Before microinjections, ethanol-reinforced subjects were consuming an average of 0.5-0.95 g/kg ethanol and making 50-100 responses during intermittent nonreinforced sham (no drug) sessions (sucrose groups had similar baseline response levels). The four experiments showed: (1) manipulations of 5-HT function that affected ethanol-reinforced responding had either no effect or less pronounced effects on sucrose-reinforced responding; (2) administration of the 5-HT 1B agonist decreased seeking behaviors more than drinking behaviors; and (3) administration of the 5-HT 1A agonist decreased ethanol intake but not seeking and had no impact at all on sucrose-reinforced behaviors. In conclusion, manipulations of 5-HT activity in the NA core had little effect on sucrose-reinforced behaviors and differential effects on ethanol seeking versus intake, suggesting that this area may play a complex but selective role in the stimulus processing of external and internal alcohol-associated cues. NIAAA Glossary Terms : serotonin, operant conditioning, nucleus accumbens, ethanol, sucrose, reinforcement, agonists, laboratory rat, animal behavior, animal study

Font, Laura; Miquel, Marta; and Aragon, Carlos M.G.  Prevention of ethanol-induced behavioral stimulation by d-penicillamine: A sequestration agent for acetaldehyde.  Alcoholism: Clinical & Experimental Research 29(7):1156-1164, July 2005.

Summary: A substantial amount of research supports the idea that brain acetaldehyde, produced by central ethanol metabolism, plays a key role in some behavioral effects of ethanol administration. This study (1) tested whether d-penicillamine, a highly selective sequestering agent of in vivo acetaldehyde, could modify the depressant effects of acetaldehyde on behavior, and (2) examined the effect of d-penicillamine on ethanol-induced behavioral stimulation. Mice were pretreated with 75.00 mg/kg of d-penicillamine and 30 minutes later were given an intraperitoneal injection of acetaldehyde (0, 100, 200, or 300 mg/kg). Different groups of mice were treated with 0.0, 37.5, 75, 150, or 300 mg/kg of d-penicillamine simultaneously 30, 90, 150, or 210 minutes before intraperitoneal administration of saline or 1.2, 1.8, 2.4, 3.0, or 3.6 g/kg of ethanol respectively. The specificity of d-penicillamine effects was addressed using two drugs: cocaine (4 mg/kg) and caffeine (15 mg/kg). The results showed that behavioral depression caused by acetaldehyde (200 and 300 mg/kg) could be attenuated by d-penicillamine treatment. In addition, d-penicillamine was also effective in lowering ethanol-induced (1.8 and 2.4 g/kg) behavioral locomotion without altering spontaneous locomotor activity. d-Penicillamine specifically modified the effect of ethanol on locomotion because cocaine- or caffeine-induced locomotion was unaffected. In addition, blood ethanol levels were not different between d-penicillamine- and saline-pretreated mice. The results suggest that some of the psychopharmacological effects long attributed to ethanol could be mediated by its first metabolite, acetaldehyde. NIAAA Glossary Terms : penicillamine, acetaldehyde, ethanol metabolism, laboratory mice, controlled study, animal behavior, cocaine, caffeine, locomotion, BAC, animal study

Yokoyama, Masako; Yokoyama, Akira; Yokoyama, Tetsuji; Funazu, Kazuo; Hamana, Genichi; Kondo, Shuji; Yamashita, Takeshi; and Nakamura, Haruo.  Hangover susceptibility in relation to aldehyde dehydrogenase-2 genotype, alcohol flushing, and mean corpuscular volume in Japanese workers.  Alcoholism: Clinical & Experimental Research 29(7):1165-1171, July 2005.

Summary: This study examined associations between hangover and aldehyde dehydrogenase-2 (ALDH2) genotype (resulting in inactive or active forms of the enzyme), alcohol flush reaction, and mean corpuscular volume (MCV) in Japanese workers (N = 251; 139 men, 112 women). Inactive ALDH2*1/2*2 heterozygotes drank less alcohol than active ALDH2*1/2*1 homozygotes (p < 0.0001), but hangover frequency in the two groups did not differ significantly for either sex. The amount of drinking reported to lead to hangover was significantly less for male and female ALDH2*1/2*2 heterozygotes than for their ALDH2*1/2*1 homozygous counterparts (p < 0.005). The proportion of men who had hangover ≥3 times during the past year increased significantly with increased daily alcohol consumption in men with the ALDH2*1/2*2 genotype (p = 0.0002) but not in those with the ALDH2*1/2*1 genotype. For men who usually consumed <44 g of ethanol/day, the median amount of drinking before hangover was significantly less for ALDH2*1/2*2 men than for ALDH2*1/2*1 men reporting the same level of consumption. Hangover occurred with consistently high frequency among ALDH2*1/2*1 men, regardless of their daily consumption. Similar findings were observed in a comparison of men who never flushed and those who reported current or former flushing, a surrogate marker of inactive ALDH2. Assessment of hangover risk by quartiles of MCV showed that men with MCV of ≥96 had a significantly higher risk of hangover than did men with MCV of <91 (odds ratio = 5.56; 95% confidence interval,1.69-18.25). These results suggest that acetaldehyde is etiologically linked to the development of hangover. NIAAA Glossary Terms : alcohyde dehydrogenases, genotype, genetic polymorphism, hangover (any AOD substance), AOD consumption, alcohol flush reaction, incidence, mean corpuscular volume, risk analysis, relative risk, etiology, human study

Gau, Susan S.F.; Liu, Chia-Yih; Lee, Chau-Shoun; Chang, Jung-Chen; Chang, Ching-Jui; Li, Chang-Fang; Chen, Chiao-Chicy; and Cheng, Andrew T.A.  Development of a Chinese version of the Yale-Brown Obsessive Compulsive Scale for heavy drinking.  Alcoholism: Clinical & Experimental Research 29(7):1172-1179, July 2005.

Summary: The Yale-Brown Obsessive Compulsive Scale for heavy drinking (YBOCS-hd) is used to assess the severity of alcohol craving. This article describes the validation of a Chinese version of the instrument (YBOCS-hd-C). Han Chinese (n = 420, 220 with alcohol use disorders) and Bunun aborigines (n = 218, 150 with alcohol use disorders) in Taiwan were interviewed by mental health professionals with the YBOCS-hd-C and a Chinese version of the World Health Organization Schedules for Clinical Assessment in Neuropsychiatry to establish the psychiatric diagnosis. The YBOCS-hd-C was found to have acceptable interrater reliability (intraclass correlation, 0.89-0.96), internal consistency (Cronbach's alpha = 0.99), construct validity, concurrent validity, and cross-cultural validity. The correlations between 10 items of the YBOCS-hd-C and 11 items of the Schedules for Clinical Assessment in Neuropsychiatry adjusted for age, gender, and ethnicity ranged from 0.39 to 1.00. The YBOCS-hd-C also discriminated effectively among individuals with alcohol dependence, alcohol abusers, and normal drinkers. It was concluded that the YBOCS-hd-C is a reliable and valid instrument for assessing alcohol craving in Taiwanese Han and Bunun individuals. NIAAA Glossary Terms : heavy AOD use, AOD craving, patient assessment, psychological assessment, psychiatric status rating scales, Chinese language, validation study, ethnic group, diagnosis, diagnostic criteria, construct validity, psychometric properties, correlation analysis, AOD dependence, AOD abuse, nonproblematic AOD use, human study

Kahler, Christopher W.; Strong, David R.; and Read, Jennifer P.  Toward efficient and comprehensive measurement of the alcohol problems continuum in college students: The brief Young Adult Alcohol Consequences Questionnaire.  Alcoholism: Clinical & Experimental Research 29(7):1180-1189, July 2005.

Summary: The psychometric development and validation of measures of alcohol problems in college students have been limited, for the most part, to methods based on classical test theory. This study used analyses based on item response theory to select a set of items for measuring the alcohol problem severity continuum in college students that balances comprehensiveness and efficiency and is free from significant gender bias. Rasch model analyses of responses were applied to the 48-item Young Adult Alcohol Consequences Questionnaire, which was completed by college students (164 males, 176 females) who drank on at least a weekly basis. An iterative process using item fit statistics, item severities, item discrimination parameters, model residuals, and analysis of differential item functioning by gender was used to reduce the items to those that best fit a Rasch model and were most efficient in discriminating among levels of alcohol problems in the sample. This resulted in a final 24-item scale with the data showing a good fit with the unidimensional Rasch model. The scale showed excellent distributional properties, had items adequately matched to alcohol problems severity, covered a full range of problem severity, and appeared highly efficient in retaining all the meaningful variance captured by the original 48-item set. The use of Rasch model analyses to inform item selection produced a final scale that, in both comprehensiveness and efficiency, should be useful for studying alcohol problems in college students. Examples of the types of alcohol problems that are likely to be experienced across a range of selected scores are provided to aid interpretation of raw scores. NIAAA Glossary Terms : questionnaire, psychometric properties, problematic AOD use, undergraduate student, problem severity, statistical estimation, statistical modeling, gender differences, human study

Braithwaite, R. Scott; McGinnis, Kathleen A.; Conigliaro, Joseph; Maisto, Stephen A.; Crystal, Stephen; Day, Nancy; Cook, Robert L.; Gordon, Adam; Bridges, Michael W.; Seiler, Jason F.S.; and Justice, Amy C.  A temporal and dose-response association between alcohol consumption and medication adherence among veterans in care.  Alcoholism: Clinical & Experimental Research 29(7):1190-1197, July 2005.

Summary: The reported association between alcohol consumption and decreased medication adherence may be confounded by characteristics common among those who drink heavily and those who fail to adhere (e.g., illicit drug use). This study sought to determine whether there are temporal and dose-response relationships between alcohol consumption and poor adherence.  Telephone interviews were administered to participants in the Veterans Aging Cohort Study, an eight-site observational study of human immunodeficiency virus-positive (HIV+ and matched HIV-negative (HIV-) veterans in care, to determine whether alcohol consumption on a particular day was associated with nonadherence to prescribed medications on that same day. Alcohol consumption was measured by timeline followback and adherence was measured by timeline followback modified for adherence. Of 2,702 respondents, 1,582 (56.6%) were abstainers, 931 (34.5%) were non-binge drinkers, and 239 (8.9%) were binge drinkers. Abstainers missed medication doses on 2.4% of surveyed days. Non-binge drinkers missed doses on 3.5% of drinking days, 3.1% of postdrinking days, and 2.1% of nondrinking days (p < 0.001 for trend). This trend was more pronounced among HIV+ individuals than HIV- individuals. Binge drinkers missed doses on 11.0% of drinking days, 7.0% of postdrinking days, and 4.1% of nondrinking days (p < 0.001 for trend). This trend was comparably strong for HIV+ and HIV- individuals. It was concluded self-reported alcohol consumption among veterans in care shows a temporal and dose-response relationship to poor adherence. HIV+ individuals may be particularly sensitive to alcohol consumption. NIAAA Glossary Terms : drug therapy, patient compliance, illicit drug, dose-response relationship, survey, interview, self report, veteran, human immunodeficiency virus, HIV infection, comparative study, alcoholic beverage, AOD consumption, AOD abstinence, binge AOD use, human study

Quinton, Lee J.; Nelson, Steve; Zhang, Ping; Happel, Kyle I.; Gamble, Lisa; and Bagby, Gregory J.  Effects of systemic and local CXC chemokine administration on the ethanol-induced suppression of pulmonary neutrophil recruitment.  Alcoholism: Clinical & Experimental Research 29(7):1198-1205, July 2005.

Summary: The objective was to test the hypothesis that exogenous chemokine administration would mitigate the suppressive effect of alcohol on neutrophil recruitment into the lung. Macrophage inflammatory protein-2 (MIP-2), a rat chemokine, or live Klebsiella pneumoniae was administered to induce alveolar neutrophil migration in the absence or presence of acute ethanol intoxication. Depending on the experimental protocol, rats received either intravenous cytokine-induced neutrophil chemoattractant (CINC) or intratracheal (IT) chemokines (CINC and MIP-2) 20 minutes after IT MIP-2 or K. pneumoniae. Rats were euthanized 90 minutes or 4 hours after the first IT injection for sample collection. Neutrophil counts were significantly elevated in bronchoalveolar lavage fluid (BALF) of rats receiving IT MIP-2 compared with vehicle-treated rats, and this response was significantly decreased in animals pretreated with ethanol. CINC enhanced the neutrophil response to IT MIP-2 in both the absence and presence of acute ethanol intoxication. In rats challenged with K. pneumoniae, ethanol pretreatment significantly reduced BALF levels of CINC and MIP-2, suppressed alveolar neutrophil recruitment, and decreased whole-lung myeloperoxidase activity. CINC did not alter BALF neutrophil counts in the absence or presence of ethanol administration 4 hours after IT K. pneumoniae. Alternatively, IT chemokine instillation partially restored BALF neutrophil recruitment but not whole-lung myeloperoxidase activity in ethanol-treated rats. Thus ethanol significantly inhibits the pulmonary inflammatory responses to both MIP-2 and K. pneumoniae. Exogenous chemokine administration may be useful for enhancing host defenses in the ethanol-intoxicated host, although the results also indicate that ethanol intoxication can impair neutrophil recruitment, independent of its effects on local chemotactic gradients. NIAAA Glossary Terms : chemokines, cytokines, neutrophilic cell, lung, pneumonia, bacterial disease, macrophage, inflammation, ethanol, AOD intoxication, peroxidases,; immune response, laboratory rat, animal study

Campos, Joaquin; Gonzalez-Quintela, Arturo; Quinteiro, Celsa; Gude, Francisco; Perez, Luis-Fernando; Torre, Jose-Antonio; and Vidal, Carmen.  The -159C/T polymorphism in the promoter region of the CD14 gene Is associated with advanced liver disease and higher serum levels of acute-phase proteins in heavy drinkers.  Alcoholism: Clinical & Experimental Research 29(7):1206-1213, July 2005.

Summary: Innate inflammatory responses to endotoxin (lipopolysaccharide) contribute to the development of alcoholic liver disease (ALD). A single-nucleotide polymorphism (-159C/T) in the promoter region of the gene coding for the lipopolysaccharide receptor CD14 could be associated with the development of ALD. This study therefore investigated the relationship between the CD14/-159C/T polymorphism and advanced ALD and acute-phase protein levels in heavy drinkers. Heavy drinkers (N = 138) consecutively admitted to an internal medicine department were genotyped for the CD14/-159C/T polymorphism. Serum samples were analyzed for lipopolysaccharide-binding protein (LBP), soluble CD14 (sCD14), C-reactive protein (CRP), and immunoglobulins (IgA, IgG, and IgM). Patients with ascites or liver encephalopathy (n = 35) were classified as having advanced ALD. After adjustment for potential confounding variables, the CD14/-159TT genotype was positively associated with advanced ALD (odds ratio = 2.99; 95% confidence interval, 1.09-8.24; p = 0.03) and serum LBP (p = 0.01), and sCD14 (p = 0.04) levels. The CD14/-159C/T polymorphism was not associated with serum levels of CRP, IgA, IgG, or IgM. These results support the view that heavy drinking homozygotes (CD14/-159TT) have higher levels of the LPS-binding acute-phase proteins (LBP and sCD14) than carriers of the CD14/-159C allele. The CD14/-159TT genotype may also be a risk factor for advanced ALD. NIAAA Glossary Terms : inflammation, alcoholic liver disorder, genetic polymorphism, genotype, receptors, lipopolysaccharide, endotoxins, immunoproteins, immunoglobulin A, immunoglobulin G, immunoglobulin M, acites,; hepatic encephalopathy, genetic correlation analysis, risk analysis, relative risk, risk factors, disease severity, human study

Ma, Xiangyang; Coles, Claire D.; Lynch, Mary Ellen; LaConte, Stephen M.  Zurkiya, Omar; Wang, Danli; and Hu, Xiaoping.  Evaluation of corpus callosum anisotropy in young adults with fetal alcohol syndrome according to diffusion tensor imaging.  Alcoholism: Clinical & Experimental Research 29(7):1214-1222, July 2005.

Summary: Although fetal alcohol syndrome (FAS) and associated disorders resulting from maternal alcohol use during gestation are among the most common developmental disorders, they are rarely diagnosed, their behavioral and neurocognitive phenotypes are not fully understood, and there are no established markers for the neurological effects of exposure.The purpose of this study was to examine the impact of prenatal alcohol exposure on white-matter integrity in the corpus callosum and to describe the relationship between such effects and observed physical and behavioral outcomes. Diffusion tensor imaging (DTI) was used to evaluate diffusion anisotropy in the genu and splenium of corpus callosum in a group of low-income, primarily African-American volunteers (N = 16) who were recruited from a cohort of young adults who had received neuropsychological evaluations during adolescence. Of the 16 volunteers, 9 had been prenatally exposed to alcohol and had characteristics of FAS, and 7 were nonexposed controls. Significant differences in the means for diffusion fractional anisotropy (t = 2.26, df = 9, p <0.002) and apparent diffusion coefficient (t =2.14, df =14, p = 0.008) were observed in the corpus callosum of alcohol-exposed subjects compared with nonexposed controls. The groups did not differ significantly in intracranial volume. The results show that DTI can be used in evaluating the integrity of corpus callosum in alcohol-exposed individuals. If these findings are supported in future studies, diffusion anisotropy, represented by fractional anisotropy, has the potential to be used as a clinical marker in the diagnosis of FAS. NIAAA Glossary Terms :; prenatal alcohol exposure, fetal alcohol syndrome, diagnostic problem, phenotype, neurodevelopmental anomaly, behavioral and mental disorder, corpus callosum, brain imaging, controlled study, comparative study, biological markers, human study

Grisel, Jedidiah J. and Chen, Wei-Jung A.  Antioxidant pretreatment does not ameliorate alcohol-induced Purkinje cell loss in the developing rat cerebellum.  Alcoholism: Clinical & Experimental Research 29(7):1223-1229, July 2005.

Summary: Recent research suggests that oxidative stress is a potential mechanism for alcohol-induced injury and that such injury can be ameliorated by supplementation with antioxidants. This study assessed the effectiveness of the antioxidants melatonin and U83836E in blocking the expected alcohol-induced cerebellar Purkinje cell loss in neonatal rats. Sprague-Dawley rat pups were artificially reared from postnatal days (PDs) 4-9 and were exposed to either alcohol or antioxidants (melatonin or U83836E) individually or in combination. A normal control group (raised by rat dams) was included in the study. On PD 9, the brain from each pup was removed and weighed, and the cerebellar vermis was processed for stereological cell counting. Alcohol exposure during the brain growth spurt produced microencephaly, in addition to significant decreases in the number and density of Purkinje cells in lobule I and the volume of lobule I. The antioxidants did not reduce any of the observed adverse effects of alcohol exposure and did not decrease the Purkinje cell number when administered alone. Furthermore, antioxidants did not change the only blood alcohol concentration measured on PD 6. The results confirm alcohol-induced microencephaly and cerebellar Purkinje cell loss from neonatal alcohol exposure and show that neither antioxidant could attenuate these adverse effects on the developing brain. The inability of antioxidants to reduce Purkinje cell loss from neonatal alcohol exposure suggests the existence of alternative mechanisms for developmental alcohol-induced Purkinje cell loss. NIAAA Glossary Terms : oxidative stress, antioxidants, melatonin, ethanol,; postnatal alcohol exposure, cerebellum, Purkinje cell, brain damage, neurodevelopmental anomaly, controlled study, laboratory rat, animal study

Tang, Wai Kwong; Lum, C.M.; Ungvari, Gabor S.; and Chiu, Helen F.K.  Alcohol consumption, lung function, and quality of life in pneumoconiosis.  Alcoholism: Clinical & Experimental Research 29(7):1230-1236, July 2005.

Summary: Drinking patterns and the impact of drinking on lung function and health-related quality of life (HRQOL) were examined in Chinese patients (N = 300) with pneumoconiosis who were recruited from a community-based case registry. HRQOL was measured with the St. George's Respiratory Questionnaire (SGRQ). Pulmonary function, comorbidity, and psychosocial variables were also assessed. Alcohol use was evaluated with the Alcohol Use Disorders Identification Test (AUDIT). Of the 300 patients, 72.3% (217) reported that they had not consumed any alcohol during the past year, and 83 patients (27.7%) did report drinking alcohol. Of the drinking group, 88.0% (73) consumed <7 standard drinks a week, and none exceeded the safety limit of 21 standard drinks a week. The drinking group (n = 83) was younger, had fewer concurrent medical diseases, and lower (i.e., better) unadjusted SGRQ symptom, activity, impact, and total scores than the nondrinking group (n = 217). The SGRQ scores, which were adjusted for age, duration of occupation, concurrent medical diseases, smoking status, and forced expiratory volume in 1 second predicted tests (FEV1%), were significantly lower in the drinking group. Although the drinking group had a higher unadjusted FEV1% predicted, the difference between the FEV1% of the two groups, after adjustment for covariates, had only borderline significance. In conclusion, most Chinese patients with pneumoconiosis in this study did not consume alcohol, and the level of consumption was low among those who did. Low level of alcohol consumption was associated with a better HRQOL and possibly with better lung function. NIAAA Glossary Terms : physical health, quality of life, lung disorder, respiratory system function, alcoholic beverage, AOD use pattern, AOD nonuse, light AOD use, AOD intake per occasion, standard drink, comorbidity, psychosocial environment, alcohol use test, self report, age differences, statistical association, human study

Garic-Stankovic, Ana; Hernandez, Marcos R.; Chiang, Po Jen; Debelak-Kragtorp, Katherine A.  Flentke, George R.; Armant, D. Randall; and Smith, Susan M.  Ethanol triggers neural crest apoptosis through the selective activation of a pertussis toxin-sensitive G protein and a phospholipase C[beta]-dependent Ca2+ transient.  Alcoholism: Clinical & Experimental Research 29(7):1237-1246, July 2005.

Summary: Clinically relevant ethanol levels (0.3%) rapidly elicit in neural crest cells a phospholipase C (PLC)-dependent intracellular Ca2+ transient sufficient to activate apoptosis. This study investigated the biochemical origins of this Ca2+ transient. Three somite chick embryos (stage 8-) were pretreated with agonists and antagonists of PLC signaling pathways before ethanol challenge. The resulting intracellular Ca2+ release was quantified and apoptosis was assessed using vital dyes. Pretreatment of embryos with PLC antagonists confirmed that a phosphoinositide-specific PLC was required for both the ethanol-dependent Ca2+ transient and subsequent cell death. Ethanol rapidly elevated intracellular inositol-1,4,5-trisphosphate [Ins(1,4,5)P3] levels in the rostral portion of the embryo that contains neural crest progenitors. The Ins(1,4,5)P3 receptor antagonist xestospongin C prevented the ethanol-dependent Ca2+ transient. Pretreatment with the pan-Gα protein antagonist GDPßS, but not with the tyrosine kinase antagonist genistein, suppressed ethanol's ability to elicit the Ca2+ transient, suggesting that a rise in PLC activity and Ins(1,4,5)P3 concentration originates from stimulation of heterotrimeric G proteins. Embryos were treated with G protein antagonists to identify this G protein. Pertussis toxin and NF023 suppressed the ethanol-induced Ca2+ transient and subsequent neural crest apoptosis, whereas suramin was weakly inhibitory. C3 exoenzyme was lethal over a wide concentration range, consistent with suggestions that Rho family GTPases participate in neural crest development. Gαi2 was identified by immunostaining in the neural crest cells. The authors propose a role for Gαi/o protein activation and subsequent interaction of Gßγ with PLCß in mediating the proapoptotic effects of ethanol on the developing neural crest. NIAAA Glossary Terms : ethanol, phospholipases, calcium, ion, apoptosis, embryo, agonists, antagonists, G-protein-coupled receptors, tyrosine kinase, enzymes, neurodevelopmental disorder, animal study

Frost, Robert A.; Nystrom, Gerald; Burrows, Patricia V.; and Lang, Charles H.  Temporal differences in the ability of ethanol to modulate endotoxin-induced increases in inflammatory cytokines in muscle inder in vivo conditions.  Alcoholism: Clinical & Experimental Research 29(7):1247-1256, July 2005.

Summary: The aim was to determine whether the interval between ethanol and lipopolysaccharide (LPS) administration differentially affects the messenger ribonucleic acid (mRNA) content for selected elements of the innate immune response in skeletal and cardiac muscle and to compare such changes with those occurring in liver and spleen. The content of mRNA for interleukin (IL)-6, IL-1ß, tumor necrosis factor-alpha (TNF-α), and high-mobility group box (HMGB)-1, as well as toll-like receptors (TLRs)-2 and -4, were measured in gastrocnemius, heart, liver, and spleen from rats orally gavaged with ethanol and then injected with LPS either 2 or 24 hours later. Under in vivo conditions, the interval between ethanol exposure and LPS differentially affected the synthesis of various cytokines. In this regard, ethanol administered within 2 hours of LPS generally suppressed IL-6, IL-1ß, and TNF-α mRNAs in muscle, heart, liver, and spleen. Delaying the exposure of animals to LPS for 24 hours after ethanol, however, accentuated the increase in IL-6 and HMGB1, and for IL-6, this increased sensitivity appeared localized to striated muscle. NIAAA Glossary Terms : ethanol, lipopolysaccharide, mRNA, cytokines, interleukin-1, interleukin-6, tumor necrosis factor-alpha, receptors, skeletal muscle, heart, liver, spleen, in vivo study, intragastric administration, laboratory rat, animal study

Alling, C; Chick, J.D.; Anton, R; Mayfield, R.D.; Salaspuro, M.; Helander, A.; and Harris, R.A.  Revealing alcohol abuse: To ask or to test?; Alcoholism: Clinical & Experimental Research 29(7):1257-1263, July 2005.

Summary: Proceedings of a symposium on testing for alcohol abuse, held at the 2004 meeting of the International Society for Biomedical Research on Alcoholism in Heidelberg, Germany, are summarized. The chairmen were C. Alling and R. A. Harris. The presentations were (1) "Advantage and disadvantage of tests for self-reported intake in different settings," by J. D. Chick; (2) "Update on the use of biological markers to monitor outcome in alcoholism clinical treatment trials," by R. Anton; (3) "Identification of alcohol biomarkers using genomic and proteomic approaches," by R. D. Mayfield; (4) "Use of biomarkers as secondary or primary outcome measures in alcoholism treatment trials," by M. Salaspuro; and (5) "Use of tests for drink-drive offenders: A European perspective," by A. Helander. NIAAA Glossary Terms : conference proceedings, AOD consumption, alcohol use test, self report, AODR biological markers, clinical trial, treatment outcome, patient monitoring, drinking and driving, DWI arrest, human study

Reynaud, M.; Karila, L.; Chinet, L.; Allen, J.P.; Streel, E.; and Pelc, I.  Original strategies of screening, evaluation, and care of adolescent substance abuse.  Alcoholism: Clinical & Experimental Research 29(7):1264-1267, July 2005.

Summary: Proceedings of a symposium on screening, evaluation, and care in adolescent substance abuse, held at the meeting of the International Society for Biomedical Research on Alcoholism in Mannheim, Germany, in October 2004, are summarized. The aim of the symposium was to discuss new and interesting strategies of screening, evaluation, and care of adolescent substance abusers developed in various countries. The speakers explained these strategies and detailed the more original tools of diagnosis or way of care used in their country. The symposium described two ways for screening and assessment, one developed in France (M. Reynaud and L. Karila) and the other in Switzerland (L. Chinet) and made the point about questionnaires and biomarkers for alcohol problems in adolescents (J.P. Allen). The symposium concluded with the presentation of a cannabis clinic (E. Streel and J.P. Allen). NIAAA Glossary Terms : conference proceedings, AOD abuse, underage AOD use, adolescent, alcohol use test, questionnaire, evaluation, patient assessment, treatment factors, diagnosis, AODR biological markers, international differences, marijuana in any form, human study

Wurst, Friedrich M.; Tabakoff, Boris; Alling, Christer; Aradottir, Steina; Wiesbeck, Gerhard A.; Muller-Spahn, Franz; Pragst, Fritz; Johnson, Bankole; Javors, Marty; Ait-Daoud, Nassima; Skipper, Gregory E.; Spies, Claudia; Nachbar, Yvonne; Lesch, Otto; Ramskogler, Katrin; Hartmann, Susanne; Wolfersdorf, Manfred; Dresen, Sebastian; Weinmann, Wolfgang; Hines, Lisa; Kaiser, Alan; Lu, Ru-Band; Ko, Huei-Chen; Huang, San-Yuan; Wang, Tso-Jen; Wu, Yi-Syuan; Whitfield, John; Snell, Larry D.; Wu, Christine; and Hoffman, Paula L.  World Health Organization/International Society for Biomedical Research on Alcoholism study on state and trait markers of alcohol use and dependence: Back to the future.  Alcoholism: Clinical & Experimental Research 29(7):1268-1275, July 2005.

Summary: Proceedings of a symposium on state and trait markers of alcohol use and dependence, held at the 2004 meeting of the International Society for Biomedical Research on Alcoholism in Mannheim, Germany, are summarized. The chairmen were Boris Tabakoff and Friedrich M. Wurst. The presentations were (1) "Genetic associations with alcoholism and affective disorders," by Paula Hoffman; (2) "Proteomic analysis of blood constituents in alcoholism," by Boris Tabakoff; (3) "Contrasts between the responses of GGT [gamma-glutamyltransferase] and CDT [carbohydrate-deficient transferrin] to high alcohol intake, and a test of their combined use," by John Whitfield; (4) "Direct ethanol metabolites such as ethyl glucuronide, fatty acid ethyl esters, phosphatidylethanol, and ethyl sulfate: A new line of sensitive and specific biomarkers," by Friedrich Martin Wurst; and (5) "Genetic studies of alcoholism subtypes in a Han Taiwanese population," by Ru-Band Lu. NIAAA Glossary Terms : conference proceedings, AODR biological markers, AOD dependence, genetic markers, genetic correlation analysis, mood and affect disturbance, gamma glutamyl transferase, carbohydrate-deficient transferrin, heavy AOD use, ethanol metabolism, ethyl glucuronide, fatty acid ethyl esters, phosphatidylethanol, sulfate, specificity and sensitivity of measurement, ethnic differences, Taiwan

Seitz, Helmut K.; Lieber, Charles S.; Stickel, Felix; Salaspuro, Mikko; Schlemmer, Hans-Peter; and Horie, Yoshimori.  Alcoholic liver disease: From pathophysiology to therapy.  Alcoholism: Clinical & Experimental Research 29(7):1276-1281, July 2005.

Summary: Proceedings of a symposium held at the 2004 meeting of the International Society for Biomedical Research on Alcoholism in Mannheim, Germany, are summarized. The purpose of the symposium was to demonstrate how advances in understanding the pathophysiology of alcoholic liver disease are raising prospects for better treatment. Genetic factors are being elucidated, and Felix Stickel summarized his own studies as well as those of others. Mikko Salaspuro updated the possible role of gut bacteria in the pathogenesis of alcoholic liver disease, bringing antibacterial therapy closer as part of the treatment of alcoholic liver disease. Specifically, the gut bacterial flora may be important via the in situ production of acetaldehyde and the associated intestinal injury, which may favor the translocation of toxins from the gut lumen to the systemic circulation and the liver. The analytical progress in the assessment of alterations of phospholipid composition in liver membranes described by Hans-Peter Schlemmer may eventually provide an objective method to recognize patients in whom phospholipid therapy might be indicated. Other novel treatment modalities for severe alcoholic hepatitis were described by Yoshimori Horie and Hiromasa Ishii, including plasma exchange. Finally, the pros and cons of nutraceutical therapy were analyzed by Charles S. Lieber, with a demonstration that although some nutraceuticals may have toxicity exacerbated by alcohol and must be administered very carefully within a narrow therapeutic window, the beneficial effects of others have been demonstrated under controlled conditions. NIAAA Glossary Terms : conference proceedings, alcoholic liver disorder, pathologic process, treatment factors, genetic trait, intestine, pathogenesis, enteric bacteria, acetaldehyde, toxins, phospholipids, cell membrane, alcoholic hepatitis, nutrient intake

Schmidt, L.G.; Bleich, S; Boening, J; Buehringer, G; Kornhuber, J; Weijers, H.G.; Wiesbeck, G.A.;  Wolfgramm, J; and Havemann-Reinecke, U.  Advances in alcoholism research in Germany.  Alcoholism: Clinical & Experimental Research 29(7):1282-1287, July 2005.

Summary: Proceedings of a symposium on advances in alcoholism research in Germany are summarized. The symposium was held at the 2004 meeting of the International Society for Biomedical Research on Alcoholism in Heidelberg, Germany. The aim was to give an overview on recent findings from animal to human studies that were conducted by several research groups engaged in the alcoholism field in Germany for longer periods. J. Wolfgramm presented results of his animal studies, G. Buehringer reported on epidemiologic and psychotherapeutic research advances on alcohol-related disorders in Germany, L. G. Schmidt summarized results of novel diagnostic and therapeutic approaches in alcohol dependence, J. Boening focused on biopsychological personality traits as predictors for relapse in alcoholism, and J. Kornhuber presented data relating hyperhomocysteinemia and brain shrinkage in patients with alcoholism. Four federally funded addiction research networks presented their results in a separate symposium and therefore were not included in this one. NIAAA Glossary Terms : conference proceedings, AOD dependence, AODR disorder, survey of research, research in practice, Germany, human study, animal study, epidemiology, psychotherapy, diagnosis, treatment method, personality trait, predictive factor, AODD relapse, homocysteine, brain atrophy

Salize, Hans Joachim; Mohler-Kuo, Meichun; Godfrey, Christine; and Holder, Harold D.  Health economics of addiction.  Alcoholism: Clinical & Experimental Research 29(7):1288-1291, July 2005.

Summary: The proceedings of a symposium held at the 2004 meeting of the International Society for Biomedical Research on Alcoholism in Mannheim, Germany, are summarized. The symposium covered some crucial aspects of research on the health economics of alcoholism including cost of treatment studies, evolution of health economic research in past years, methodological problems of cost-effectiveness studies, and the effects of tax or price policies on alcohol consumption and alcohol-related problems. Studies from the United States, the United Kingdom, Switzerland, and Germany demonstrated that, even in these highly industrialized countries, health economic research is far from providing the essential evidence needed for adequate service planning or effective cost containment strategies in the field of alcoholism or addiction in general. NIAAA Glossary Terms : conference proceedings, AOD dependence, economic cost of AODU, treatment cost, cost-effectiveness of AOD health services, research issue, research quality, AOD consumption, taxes, AOD price, AOD effects and AODR problems, human study

Purdy, Robert H.; Valenzuela, C. Fernando; Janak, Patricia H.; Finn, Deborah A.; Biggio, Giovanni; and Backstrom, Torbjorn.  Neuroactive steroids and ethanol.  Alcoholism: Clinical & Experimental Research 29(7):1292-1298, July 2005.

Summary: This article summarizes the proceedings of a symposium on neuroactive steroids and ethanol, held at the 2004 meeting of the International Society for Biomedical Research on Alcoholism in Heidelberg, Germany. Robert H. Purdy was the organizer and chairman of the symposium. The presentations were (1) "Fetal ethanol-induced increase in brain levels of pregnenolone sulfate," by C. Fernando Valenzuela; (2) "GABAergic neuroactive steroids after ethanol self-administration and relapse," by Patricia H. Janak; (3) "Neuroactive steroid modulation of ethanol intake patterns in C57BL/6J mice," by Deborah A. Finn; (4) "Role of neurosteroids in ethanol dependence and GABAA receptor plasticity," by Giovanni Biggio; and (5) "Alcohol and neuroactive steroid interactions in the menstrual cycle," by Torbjorn Backstrom. NIAAA Glossary Terms : conference proceedings, neurosteroids, ethanol, prenatal alcohol exposure, pregnenolone, GABAergic neuron, self administration of drugs, AOD dependence, AODD relapse, AOD consumption, GABA A receptor, laboratory mice, menstrual cycle

Apte, Minoti V.; Zima, Toma; Dooley, Steven; Siegmund, Soren V.; Pandol, Stephen J.;  and Singer, Manfred V.  Signal transduction in alcohol-related diseases.  Alcoholism: Clinical & Experimental Research 29(7):1299-1309, July 2005.

Summary: Proceedings of a symposium on signal transduction in alcohol-related diseases, held at the 2004 meeting of the International Society for Biomedical Research on Alcoholism in Heidelberg, Germany, are summarized. The symposium's organizers and co-chairmen were Manfred V. Singer and Stephen J. Pandol. The presentations were (1) "Ethanol-induced acinar cell injury," by Minoti V. Apte; (2) "Oxidants and antioxidants: Signal transduction and alcohol," by Thoma Zima; (3) "Anti-TGF [transforming growth factor]-ß strategies for the treatment of chronic liver disease," by Steven Dooley; (4) "Immune mechanisms in alcohol-induced liver disease," by Soren V. Siegmund; and (5) "Alcoholic pancreatitis: Insights from animal models," by Steven J. Pandol. NIAAA Glossary Terms : conference proceedings, ethanol, AODR disorder, signal transduction, acinar cell, oxidants, antioxidants, transforming growth factors, chronic AODE, alcoholic liver disorder, treatment method, immune response, alcoholic pancreatitis, animal model

Freeman, Thomas L.; Tuma, Dean J.; Thiele, Geoffrey M.; Klassen, Lynell W.;  Worrall, Simon; Niemela, Onni; Parkkila, Seppo; Emery, Peter W.; and Preedy, Victor R.  Recent advances in alcohol-induced adduct formation.  Alcoholism: Clinical & Experimental Research 29(7):1310-1316, July 2005.

Summary: This article summarizes the proceedings of a symposium on recent developments in research on alcohol-induced adduct formation presented at the 2004 meeting of the International Society for Biomedical Research on Alcoholism in Heidelberg, Germany. The symposium was organized by Simon Worrall and Victor Preedy. Onni Niemela and Geoffrey Thiele were the co-chairmen. The presentations were (1) "Adduct chemistry and mechanisms of adduct formation," by Thomas L. Freeman; (2) "Malondialdehyde-acetaldehyde adducts: The 2004 update," by Geoffrey Thiele; (3) "Adduct formation in the liver," by Simon Worrall; (4) "Protein adducts in alcoholic cardiomyopathy," by Onni Niemela; and (5) "Alcoholic skeletal muscle myopathy: A role for protein adducts," by Victor R. Preedy. NIAAA Glossary Terms : conference proceedings, adduct, chemical bonding, chemistry, biochemical mechanism, proteins, malondialdehyde, acetaldehyde, alcoholic liver disorder, alcoholic cardiomyopathy, skeletal muscle, AODR myopathy

Homann, N.; Seitz, H.K.; Wang, X.D.; Yokoyama, A.; Singletary, K.W.;  and Ishii, H.  Mechanisms in alcohol-associated carcinogenesis.  Alcoholism: Clinical & Experimental Research 29(7):1317-1320, July 2005.

Summary: Some aspects of pathogenetic mechanisms in alcohol-associated carcinogenesis are reviewed, based on presentations to a symposium held at the 2004 meeting of the International Society for Biomedical Research on Alcoholism in Heidelberg, Germany. Nils Homann and Hiromasa Ishii were co-chairmen of the symposium. The presentations were (1) "Genetic polymorphisms of alcohol and aldehyde dehydrogenases, mean corpuscular volume, and cancer risk of the upper aerodigestive tract in Japanese," by Akira Yokoyama; (2) "Retinoids, alcohol, and carcinogenesis," by Xiang-Dong Wang; (3) "Bacterial ethanol metabolism and cancer," by Nils Homann; (4) "The role of ethanol metabolism in alcohol-associated carcinogenesis," by Helmut K. Seitz; and (5) "Alcohol and breast cancer: Potential mechanisms," by Keith W. Singletary. NIAAA Glossary Terms : conference proceedings, carcinogenesis, pathogenesis, genetic polymorphism, ethanol, metabolism, alcohol dehydrogenases, aldehyde dehydrogenases, mean corpuscular volume, retinoids, enteric bacteria, breast, cancer, risk factors

Hesselbrock, Victor; Higuchi, Susumu; and Soyka, Michael.  Recent developments in the genetics of alcohol-related phenotypes.  Alcoholism: Clinical & Experimental Research 29(7):1321-1324, July 2005.

Summary: Proceedings of a symposium on the genetics of alcohol-related phenotypes, held at the 2004 meeting of the International Society for Biomedical Research on Alcoholism in Mannheim, Germany, are summarized. There were three presentations. The first focused on the possible contribution of polymorphisms of alcohol dehydrogenase (ADH) and aldehyde dehydrogenase-2 (ALDH2) as contributors to alcohol-related organ damage. These polymorphisms may explain individual differences in the concentration and elimination of blood ethanol and blood acetaldehyde after heavy drinking and may also contribute to possible alcohol-related types of organ damage, including amnestic problems and polyneuropathy. The second presentation examined externalizing behavior phenotypes -- conduct disorder symptoms, aggression, and suicidal behavior -- all of which are prevalent among alcoholics. A genome screen was performed in multiplex alcohol-dependent families to identify chromosomal regions related to these externalizing behaviors. Both the quantitative and qualitative phenotypes were examined, and evidence of linkage was found for several chromosomal regions. An area of chromosome 2 demonstrated linkages for suicidal behavior, conduct problems, and alcohol dependence, suggesting a possible sharing of genes for different externalizing behavior phenotypes. The third presentation focused on serotonin as a key neurotransmitter in antisocial alcoholism and related phenotypes. A study of adult alcoholics found an association between a lower frequency of the serotonin 1B 861C allele, antisocial personality traits, and conduct disorder in alcoholism. NIAAA Glossary Terms : conference proceedings, genetic polymorphism, genotype, phenotype, alcohol dehydrogenases, aldehyde dehydrogenases, AODR disorder, AOD dependence, heavy AOD use, individual differences, ethanol metabolism, acetaldehyde, BAC, AODR amnestic syndrome, alcoholic polyneuropathy, behavioral problem, conduct disorder, aggressive behavior, suicidal behavior, genome, genetic screening method, chromosome, genetic linkage, serotonin, allele, antisocial personality disorder

Rodd, Zachary A.; Anstrom, Kristin K.; Knapp, Darin J.; Racz, Ildiko; Zimmer, Andreas; Serra, Salvatore; Bell, Richard L.; Woodward, Donald J.; Breese, George R.; and Colombo, Giancarlo.  Factors mediating alcohol craving and relapse: Stress, compulsivity, and genetics. Alcoholism: Clinical & Experimental Research 29(7):1325-1333, July 2005.

Summary: Proceedings of a symposium on mediating factors of alcohol craving and relapse, held at the 2004 annual meeting of the International Society for Biomedical Research on Alcoholism in Heidelberg, Germany, are summarized. The symposium was organized by Zachary A. Rodd and Giancarlo Colombo. The presentations were (1) "Pharmacological reversal of cycled withdrawal-sensitized or stress-sensitized withdrawal anxiety and enhanced ethanol drinking," by Darin J. Knapp and George R. Breese; (2) "Alcohol craving and relapse in rats genetically selected for high alcohol preference," by Zachary A. Rodd and Richard L. Bell; (3) "Exposure to stress increases dopaminergic burst firing in awake rats," by Kristin Anstrom and Donald J. Woodward; (4) "Involvement of cannabinoid CB1 and GABAB receptors in the control of relapse-like drinking in alcohol-preferring Sardinian alcohol-preferring rats," by Giancarlo Colombo and Salvatore Serra; and (5) "Stress-induced ethanol drinking in CB1-/-, pro-opiomelanocortin-deficient (Pomc-/-), and preproenkephalin-deficient (Penk-/-) knockout mice," by Idiko Racz and Andreas Zimmer. NIAAA Glossary Terms : conference proceedings, AOD dependence, AOD craving, AODD relapse, AOD withdrawal syndrome, anxiety, AOD consumption, stress, animal selectively bred for alcohol preference, laboratory rat, laboratory mice, dopaminergic neuron, neurotransmission, cannabinoid receptors, GABA receptors, GABAergic neuron, pro-opiomelanocortin, gene knockout technology, animal study

Meyerhoff, Dieter J.; Bode, Christiane; Nixon, Sara Jo; de Bruin, Eveline A.; Bode, J. Christian; and Seitz, Helmut K.  Health risks of chronic moderate and heavy alcohol consumption: How much is too much?; Alcoholism: Clinical & Experimental Research 29(7):1334-1340, July 2005.

Summary: Proceedings of a symposium on health risks of moderate and heavy drinking, held at the 2004 meeting of the International Society for Biomedical Research on Alcoholism in Mannheim, Germany, are summarized. Most of what is known about the deleterious effects of alcohol on organ function has come from studies of sober alcoholics recruited from treatment programs, and little is known about effects of chronic moderate-to-heavy drinking, which is much more common. Several recent studies suggest that moderate alcohol consumption has certain beneficial health effects, whereas heavy social drinking has recently been associated with organ abnormalities and cognitive deficits. The symposium brought together researchers from different disciplines who reviewed and presented new data on consequences of social drinking in the areas of clinical neuropsychology and behavior (Sara Nixon and Dieter Meyerhoff), neurophysiology (Sara Nixon and Eveline De Bruin), neuroimaging (Eveline de Bruin and Dieter Meyerhoff), hepatic disease (Christiane Bode), and cancer (Helmut Seitz). The symposium aimed to clarify both the potential health benefits of moderate alcohol consumption and risks of moderate and heavy drinking on proper organ function and to provide insights and new data to practicing physicians and public health authorities for education on problem drinking. NIAAA Glossary Terms : conference proceedings, moderate AOD use, heavy AOD use, chronic AODE,; beneficial vs adverse drug effect, social drinking, cognitive and memory disorder, neuropsychological assessment, behavioral problem, protective drug effect, problematic AOD use, neuroimaging

Seitz, Helmut K.; Salaspuro, Mikko; Savolainen, Markku; Haber, Paul; Ishii, Hiromasa; Teschke, Rolf; Moshage, Hans; and Lieber, Charles S.  From alcohol toxicity to treatment.  Alcoholism: Clinical & Experimental Research 29(7):1341-1350, July 2005.

Summary: Proceedings of a symposium held at the 2004 meeting of the International Society for Biomedical Research on Alcoholism in Mannheim, Germany, are summarized. The symposium was dedicated to Charles S. Lieber in recognition of his 50 years of contributions in alcohol research. Presentations focused on alcohol's effects on the gastrointestinal tract and the liver, and on recent discoveries on mechanisms of alcohol-associated carcinogenesis. Mikko Salaspuro discussed the role of acetaldehyde in saliva and large intestine with respect to its role in the pathogenesis of alcohol-associated cancer. Helmut K. Seitz presented new data showing that individuals homozygous for the ADH1C&1 allele are at high risk for alcohol-associated cancer in the upper aerodigestive tract. Markku Savolainen discussed the role of phosphatidylethanol as a bioactive lipid that can mediate beneficial and harmful effects of alcohol drinking. Paul Haber presented new data on hepatic transcriptome in alcoholic liver disease with the identification of new genes possibly involved in alcohol-initiated fibrogenesis of the liver. Hans Moshage described survival mechanisms of cholestatic hepatocytes with implications for therapy in cholestatic liver disease. Rolf Teschke summarized the role of the hepatic microsomal ethanol oxidizing system in alcohol metabolism in alcoholic liver disease. Hiromasa Ishii discussed the current status and treatment of alcoholic hepatitis in Japan. The symposium concluded with Charles S. Lieber's review of the development of understanding of the pathophysiology of alcoholic liver disease in the last 50 years. Dr. Lieber emphasized the role of pathophysiology as an important prerequisite for better treatment strategies. NIAAA Glossary Terms : conference proceedings, AOD consumption, gastrointestinal disorder, AODR disorder, alcoholic liver disorder, acetaldehyde, saliva, large intestine, cancer, genetic trait, allele, alcohol dehydrogenases, respiratory airway, phosphatidylethanol, beneficial vs adverse drug effect, gene transcription, hepatocyte, MEOS, alcoholic hepatitis, treatment method

Adinoff, Bryon; Junghanns, Klaus; Kiefer, Falk; and Krishnan-Sarin, Suchitra.  Suppression of the HPA axis stress-response: Implications for relapse.  Alcoholism: Clinical & Experimental Research 29(7):1351-1355, July 2005.

Summary: Proceedings of a symposium held at the 2004 meeting of the International Society for Biomedical Research on Alcoholism in Mannheim, Germany, are summarized. The topic was the role of dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis in alcoholic relapse. HPA axis stimulation induces release of cortisol, a glucocorticoid that profoundly affects behavior and emotion. Altered stress-responses of the HPA axis in abstinent alcoholics may influence their affective and behavioral regulation, and thus their relapse potential. Bryon Adinoff reviewed HPA axis dysfunction in alcoholics, including recent studies from his lab showing an attenuated glucocorticoid response to both endogenous and exogenous stimulation in 1-month abstinent men. Klaus Junghanns presented his work showing that a blunted adrenocorticotropic hormone (ACTH) or cortisol response to subjective stressors is predictive of an early return to drinking. Falk Kiefer discussed the relationship between basal HPA axis responsivity and clinical outcome following treatment with naltrexone or acamprosate. Plasma ACTH significantly decreased during the study in the medication groups, but not in the placebo group. Lower basal concentrations of ACTH and cortisol were associated with quicker relapse only in the placebo group. Suchitra Krishnan-Sarin described her preliminary work in which family history-positive (FH+) and -negative (FH-) subjects were given naltrexone, followed by an assessment of alcohol-induced craving. The cortisol response to alcohol was significantly and inversely related to craving in the FH+, but not the FH-, subjects. Alterations in HPA axis responsivity may therefore have a negative impact on clinical outcome in alcoholics, and disinhibition of the axis with medication may have therapeutic potential. NIAAA Glossary Terms : conference proceedings, hypothalamic-pituitary-adrenal axis, AOD dependence, AOD abstinence, AODD relapse, predictive factor, cortisol, stress, stressor, endocrine disorder, endocrine function, glucocorticoids, adrenocorticotropic hormone, naltrexone, calcium acetylhomotaurinate, controlled study, family AODU history, familial alcoholism, AOD craving, drug therapy, human study

Spear, Norman E. and Molina, Juan C.  Fetal or infantile exposure to ethanol promotes ethanol ingestion in adolescence and adulthood: A theoretical review.  Alcoholism: Clinical & Experimental Research 29(6):909-929, June 2005.

Summary: There is good evidence that the earlier the onset of drinking in human adolescence the more likely ethanol abuse in adulthood becomes. It is not clear, however, why early onset of drinking occurs in the first place. This review of animal studies and human clinical, epidemiologic, and experimental studies supports the view that precipitating conditions for ethanol abuse occur well before adolescence, in very early exposure to ethanol as a fetus or infant. Two broad theoretical frameworks are suggested to explain the increase in affinity for ethanol that follows very early exposure to ethanol, one based on effects of mere exposure and the other on associative conditioning. "Effects of mere exposure" refers to enhanced preference for flavors, or just about any stimuli, that are relatively familiar. The associative conditioning framework is guided by the hypothesis that during ethanol exposure the fetus or infant acquires an association between ethanol's orosensory (odor/taste) and pharmacological consequences, causing subsequent seeking of ethanol's odor and taste. The implication that ethanol has rewarding consequences for the fetus or young infant is supported by recent evidence with perinatal rats. Paradoxically, several studies have shown that such early exposure to ethanol may in some circumstances make the infant treat ethanol-related events as aversive, yet, paradoxically, enhanced intake of ethanol in adolescence is nevertheless a consequence. Alternative interpretations of this paradox are considered among the varied circumstances of early ethanol exposure that lead subsequently to increased affinity for ethanol. NIAAA Glossary Terms:  early AODU onset, adolescence, underage drinking, AOD abuse, adulthood, prenatal alcohol exposure, infancy, postnatal alcohol exposure, taste perception, olfactory perception, conditioning theory of AODU, reward dependence behavior, literature review, human study

Luedemann, Corinne; Bord, Evelyn; Qin, Gangjian; Zhu, Yan; Goukassian, David; Losordo, Douglas W.; and Kishore, Raj.  Ethanol modulation of TNF-alpha biosynthesis and signaling in endothelial cells: Synergistic augmentation of TNF-alpha mediated endothelial cell dysfunctions by chronic ethanol.  Alcoholism: Clinical & Experimental Research 29(6):930-938, June 2005.

Summary: Dose-related bimodal effects of ethanol on the cardiovascular system (cardioprotective at low levels, a risk factor for coronary artery disease in alcoholism) might reflect contrasting influences of light versus heavy ethanol consumption on the vascular endothelium. Chronic ethanol-induced damage to various organs has been linked to the increased release of tumor necrosis factor-alpha (TNF-α). The authors of this article showed previously that TNF-α, expressed at the sites of arterial injury, suppresses re-endothelialization of denuded arteries and inhibits endothelial cell (EC) proliferation in vitro. In the current article they report that in vitro chronic ethanol exposure enhances agonist-induced TNF-α messenger ribonucleic acid (mRNA) and TNF-α protein expression in EC. Ethanol-mediated increment in TNF-α expression involves increased de novo transcription without affecting mRNA stability. Deoxyribonucleic acid (DNA) binding assays revealed that ethanol-induced TNF-α up regulation was AP1 dependent. Functionally, TNF-α induced EC dysfunction (reduced proliferation, migration, and cyclin A expression) was markedly enhanced in the presence of ethanol. Additionally, cyclin D1 expression was significantly attenuated in cells co-treated with TNF-α and ethanol whereas each treatment alone had little effect on that expression. Furthermore, ethanol exposure potentiated and prolonged agonist-induced activation of c-Jun N-terminal kinase (JNK). Inhibition of JNK by over-expression of dominant negative JNK1 substantially reversed ethanol/TNF-α-mediated inhibition of cyclin A expression and EC proliferation, suggesting modulation of JNK1 signaling as the mechanism for ethanol/TNF-α-induced EC dysfunctions. Overall, these findings indicate that chronic ethanol consumption may have a negative influence on post angioplasty re-endothelialization, thereby contributing to the development of restenosis. NIAAA Glossary Terms:  tumor necrosis factor-alpha, ethanol, moderate AOD use, heavy AOD use, protective factors, risk factors, chronic AODE, cardiovascular system, endothelium, endothelial cell, kinases, vascular stenosis, cell signaling, gene transcription, in vitro study

Gorin, Rebecca E.; Crabbe, John C.; Tanchuck, Michelle A.; Long, Season L.; Finn, Deborah A.  Effects of finasteride on chronic and acute ethanol withdrawal severity in the WSP and WSR selected lines.  Alcoholism: Clinical & Experimental Research 29(6):939-948, June 2005.

Summary: The neurosteroid allopregnanolone (ALLO) is a potent positive modulator of gamma-aminobutyric acidA (GABAA) receptors that can modulate ethanol withdrawal. The 5-alpha-reductase inhibitor finasteride blocks the formation of ALLO from progesterone and was recently found to reduce certain effects of ethanol. The authors of this article used the Withdrawal Seizure-Prone (WSP) and Withdrawal Seizure-Resistant (WSR) selected mouse lines to examine the effect of finasteride on acute and chronic ethanol withdrawal severity. In the first two studies, male WSP and WSR mice were exposed to ethanol vapor or air in an inhalation chamber for 72 hours and received four intraperitoneal (ip) injections of finasteride (50 mg/kg) or vehicle 24 hours before and each day of vapor exposure. After removal from the chamber, mice were scored for handling-induced convulsions (HICs) hourly for 12 hours and again at 24 hours (study 1) or were tested on the elevated plus maze at 24 hours after removal from the chamber (study 2). In the third experiment, mice were pretreated with finasteride or vehicle 24 hours before an acute dose of ethanol (4 g/kg ip) or saline, then tested for HICs as in the chronic study. In both chronic ethanol studies, finasteride pretreatment reduced ethanol withdrawal severity, as measured by HICs, and anxiety-related behavior, but only in the WSP selected line. However, finasteride pretreatment also significantly decreased blood ethanol concentration on the initiation of withdrawal in both chronic ethanol studies in both mouse lines. In contrast, finasteride pretreatment slightly enhanced acute ethanol withdrawal severity in WSP mice whereas finasteride or ethanol injection had no effect on HICs in WSR mice. The results indicate that the WSP line is more sensitive than the WSR line to the modulatory effects of finasteride on both chronic and acute ethanol withdrawal severity. The differential effect of finasteride on acute versus chronic ethanol withdrawal severity may result from an indirect effect of finasteride on ethanol pharmacokinetics in the chronic paradigm. NIAAA Glossary Terms:  GABA A receptor, enzyme inhibitors, ethanol, allopregnanolone, neurosteroids, selective breeding, animal behavior, laboratory mice, AOD withdrawal syndrome, AODR seizure, convulsion, symptom severity, acute AODE, chronic AODE, animal study

Navarro, Montserrat; Cubero, Inmaculada; Chen, Airu S.; Chen, Howard Y.; Knapp, Darin J.; Breese, George R.; Marsh, Donald J.; and Thiele, Todd E.  Effects of melanocortin receptor activation and blockade on ethanol intake: A possible role for the melanocortin-4 receptor.  Alcoholism: Clinical & Experimental Research 29(6):949-957, June 2005.

Summary There is growing evidence suggesting that the melanocortin (MC) system modulates neurobiological responses to drugs of abuse. It is possible that MC neuropeptides participate in the control of voluntary ethanol consumption, because ethanol has direct effects on central pro-opiomelanocortin activity. This study assessed the possibility that MC receptor (MCR) agonists modulate ethanol intake via the MC3 receptor (MC3R) and/or the MC4 receptor (MC4R) and whether the MCR antagonist AgRP-(83-132) controls ethanol consumption. Mc3r-deficient (Mc3r -/-) and wild-type (Mc3r +/+) littermate mice were given intraperitoneal (10 mg/kg) and intracerebroventricular (ICV; 1.0 µg) doses of melanotan II (MTII), a nonselective MCR agonist. To assess the role of MC4R, C57BL/6J mice were given an ICV infusion of cyclo(NH-CH2-CH2-CO-His-d-Phe-Arg-Trp-Glu)-NH2 (1.0 or 3.0 µg), a highly selective MC4R agonist. Finally, naive C57BL/6J mice were given an ICV infusion of AgRP-(83-132) (0.05 and 1.0 µg). MTII was similarly effective at reducing ethanol drinking in Mc3r-deficient (Mc3r -/-) and wild-type (Mc3r +/+) littermate mice. Furthermore, ICV infusion of the MC4R agonist significantly reduced ethanol drinking, whereas ICV infusion of AgRP-(83-132) significantly increased ethanol drinking in C57BL/6J mice. Neither MTII nor AgRP-(83-132) altered blood ethanol levels at doses that modulated ethanol drinking. The results suggest that MC4R, and not MC3R, modulates MCR agonist-induced reduction of ethanol consumption and that ethanol intake is increased by the antagonistic actions of AgRP-(83-132). These findings strengthen the argument that MCR signaling controls ethanol consumption and that compounds directed at MCR may be promising targets for treating alcohol abuse disorders in addition to obesity. NIAAA Glossary Terms:  melanocortin, pro-opiomelanocortin, receptors, agonists, antagonists, ethanol, AOD consumption, gene knockout technology, laboratory mice, cell signaling, AOD abuse, obesity, animal study, intraperitoneal administration, intracerebroventricular administration, animal study

Duncan, Elizabeth A.; Proulx, Karine; and Woods, Stephen C.  Central administration of melanin-concentrating hormone increases alcohol and sucrose/quinine intake in rats.  Alcoholism: Clinical & Experimental Research 29(6):958-964, June 2005.

Summary: Because ethanol calories can contribute to energy intake, it is likely that peptides that regulate energy balance modify the motivation to drink alcohol. Melanin-concentrating hormone (MCH) regulates energy homeostasis and has been implicated in other behaviors that affect alcohol consumption, including anxiety, fluid balance, and reward. This study tested the hypothesis that MCH would decrease the motivation to consume alcohol secondarily to reducing anxiety. Rats were trained to drink 10% ethanol or an isocaloric concentration of sucrose with use of a sucrose-fading technique. MCH (1, 5, or 10 µg) or its saline vehicle was administered into the third cerebral ventricle (i3vt), and intake of ethanol or sucrose and chow was assessed for 2 hours. Alcohol-naive rats were evaluated in an elevated plus maze after i3vt MCH (10 µg), neuropeptide Y (NPY), or saline administration. Contrary to the hypothesis, MCH dose-dependently increased alcohol intake: saline, 0.7 ± 0.1 g/kg; 1 µg MCH, 1.0 ± 0.1 g/kg; 5 µg MCH, 1.2 ± 0.1 g/kg; and 10 µg MCH, 1.8 ± 0.3 g/kg (p < 0.01). This was true whether water was simultaneously available or not. MCH also significantly increased sucrose intake (saline = 1.0 ± 0.3 g/kg; 10 µg MCH, 1.4 ± 0.5 g/kg; p < 0.05). MCH had no effect on time spent in the open arms (54.3 ± 11.5 seconds) relative to saline (58.2 ± 23.8 seconds), whereas NPY, a known anxiolytic, increased time spent on the open arms (119.2 ± 22 sec, p < 0.05). It was concluded that MCH nonspecifically increases ingestive behavior. Furthermore, MCH had no apparent effect on anxiety. The ability of MCH to increase alcohol or sucrose intake may be explained by the effect of MCH on energy balance or reward processes. NIAAA Glossary Terms:  ethanol, sucrose, melanin, energy, homeostasis, hormones, anxiety, brain reward pathway, hypothesis testing, motivation, laboratory rat, intracerebroventricular administration, dose-response relationship, controlled study, animal study

Yoder, Karmen K.; Kareken, David A.; Seyoum, Regat A.; O'Connor, Sean J.; Wang, Chunzhi; Zheng, Qi-Huang; Mock, Bruce; and Morris, Evan D.  Dopamine D2 receptor availability is associated with subjective responses to alcohol.  Alcoholism: Clinical & Experimental Research 29(6):965-970, June 2005.

Summary: Alcohol abuse and dependence are thought to be mediated by the mesolimbic dopaminergic system. Determining the relationship between in vivo dopamine and the subjective response to alcohol could improve understanding of the mechanisms that lead to alcohol abuse and dependence. The authors of this study examined the relationship between dopamine D2 receptors in the nucleus accumbens (NA) and numerical ratings of perceived "high" and "intoxication" during an intravenous (IV) ethanol infusion. Nine healthy control subjects received [11C]raclopride positron emission tomography (PET) scanning at baseline. Eight subjects received a second PET scan during a pharmacodynamically modeled and controlled rise of IV ethanol, followed by steady state (60 mg% ± 5 mg%) alcohol infusion. Numerical ratings of "high" and "intoxication" were tested for correlations with measures of dopaminergic function. Baseline D2 receptor availability in the left NA was significantly correlated with peak perceived "intoxication" (p = 0.02) and marginally correlated with peak perceived "high" (p = 0.07). The results suggest that resting D2 receptor availability may predict responses to alcohol exposure in healthy subjects. NIAAA Glossary Terms:  AOD abuse, AOD dependence, mesolimbic system, dopaminergic neuron, dopaminergic receptors, dopamine, nucleus accumbens, brain reward pathway, AOD intoxication, euphoria, subjective variables, intravenous administration, ethanol, correlation analysis, brain imaging, positron emission tomography, controlled study, human study

Farr, Susan A.; Scherrer, Jeffrey F.; Banks, William A.; Flood, James F.; and Morley, John E.  Chronic ethanol consumption impairs learning and memory after cessation of ethanol.  Alcoholism: Clinical & Experimental Research 29(6):971-982, June 2005.

Summary: Acute ethanol consumption causes reversible changes in learning and memory whereas chronic ethanol consumption of 6 or more months produces permanent deficits and neural damage in rodents. The objective of this study was to determine whether shorter durations of chronic ethanol ingestion in mice would produce long-term deficits in learning and memory after the cessation of ethanol. The authors first examined the effects of 4 and 8 weeks of 20% ethanol followed by a 3-week withdrawal period on learning and memory in mice. They found that 3 weeks after 8 weeks, but not 4 weeks, of 20% ethanol consumption produced learning and long-term memory deficits (7 days) in T-maze footshock avoidance and Greek Cross brightness discrimination, step-down passive avoidance, and shuttlebox active avoidance. Short-term memory (1 hour) was not affected. The deficit was not related to changes in thiamine status, caloric intake, or nonmnemonic factors such as activity or footshock sensitivity. Lastly, the authors examined whether the mice recovered after longer durations of withdrawal. After 8 weeks of ethanol, mice were compared after 3 and 12 weeks of withdrawal. Mice that had been ethanol-free for both 3 and 12 weeks were impaired in T-maze footshock avoidance compared to control mice. These results indicate ethanol consumption for as little as 8 weeks produces deficits in learning and memory that are present 12 weeks after withdrawal. NIAAA Glossary Terms:  chronic AODE, ethanol, learning ability, memory, harm-avoidance behavior, short-term memory, long-term memory, laboratory mice, animal study

Feinn, Richard and Kranzler, Henry R.  Does effect size in naltrexone trials for alcohol dependence differ for single-site vs. multi-center studies?  Alcoholism: Clinical & Experimental Research 29(6):983-988, June 2005.

Summary: The opioid antagonist naltrexone was first shown in single-site trials to be efficacious in the treatment of alcohol dependence. Recent clinical trials of the medication have used multi-center designs, which permit greater generalization and increased statistical power. In this study, the effect sizes for these two kinds of trial design were compared on the hypothesis that multi-center trials introduce sources of variation that reduce the observed effect size. A meta-analysis was performed using data from 19 placebo-controlled trials of the efficacy of naltrexone (7 multi-center and 12 single-site studies). Effect size estimates for these two study designs were compared using percentage of days drinking and percentage of subjects relapsing to heavy drinking as outcomes. Compared with single-site studies, multi-center studies were estimated to yield a nonsignificantly smaller effect on the percentage of days drinking (Cohen's d = 0.20 vs. 0.33 respectively) and a significantly smaller effect on the percentage of subjects relapsing to heavy drinking (Cohen's d = 0.17 vs. 0.41 respectively; p = 0.014). Earlier studies showed a larger effect size than later studies. The smaller effect size seen with multi-center studies may reflect random error due to heterogeneity among the sites. However, because multi-center studies generally were more recent than single-site studies, it was not possible conclusively to disentangle the moderating impact of study type and year of publication on effect size. Further research on factors that moderate effect size can contribute to the development of medications to treat alcohol dependence. NIAAA Glossary Terms:  naltrexone, opioid receptors, antagonists, AOD dependence, heavy AOD use, AOD use pattern, AOD use frequency, drug therapy, meta-analysis, clinical trial, therapeutic drug effect, study design, treatment outcome, human study

Mertens, Jennifer R; Weisner, Constance; Ray, G Thomas; Fireman, Bruce; and Walsh, Kevin.  Hazardous drinkers and drug users in HMO primary care: Prevalence, medical conditions, and costs.  Alcoholism: Clinical & Experimental Research 29(6):989-998, June 2005.

Summary: There is substantial evidence that alcohol and drug disorders are associated with higher comorbidities and health care costs, but little is known about the larger population of "hazardous" drinkers and drug users -- those whose consumption increases their risk of physical and psychological harm. In this study, a sample of patients (N = 1,419) from HMO primary care clinics was screened for hazardous drinking and drug use. Health plan databases were used to examine medical conditions and health care costs of hazardous drinkers and drug users in the year prior to screening, in comparison to 13,347 patients from the same clinics, excluding those screened. A prevalence of 7.5% was found for hazardous drinking and 3.2% for hazardous drug use in primary care; 10% had at least one of those two problems. Hazardous drinkers and drug users had higher prevalences for eight medical conditions, including costly conditions such as injury, hypertension, and psychiatric conditions. Medical costs for the year examined were not higher, except for those who also had psychiatric conditions. The prevalence of hazardous drinking and drug use was similar to those of hypertension and diabetes. Higher prevalence of medical conditions in hazardous drinkers and drug users, especially those related to alcohol and drug abuse, indicate that screening and brief intervention at this lower threshold of hazardous drinking and drug use allows earlier detection of individuals with health risks. Optimal treatment and prevention of some medical disorders may require identification and intervention of underlying hazardous alcohol or drug use. NIAAA Glossary Terms:  AOD abuse, hazardous AOD use, hazardous drinking, risk-taking behavior, database, health care costs, prevalence, comorbidity, injury, hypertensive disorder, psychopathology, diabetes, human study

Haorah, James; Heilman, David; Knipe, Bryan; Chrastil, Jesse; Leibhart, Jessica; Ghorpade, Anuja; Miller, Donald W.; and Persidsky, Yuri.  Ethanol-induced activation of myosin light chain kinase leads to dysfunction of tight junctions and blood-brain barrier compromise.  Alcoholism: Clinical & Experimental Research 29(6):999-1009, June 2005.

Summary: This study tested the hypothesis that alcohol abuse may impair blood-brain barrier (BBB) permeability by modifying tight junctions (TJ) in the brain endothelium. Primary cultured bovine brain microvascular endothelial cells (BBMEC) were treated with 50 mM ethanol, and monolayer tightness was assessed by measuring transendothelial electrical resistance (TEER). Changes in TEER were correlated with alterations in TJ protein distribution using immunofluorescence (IF). Expression of myosin light chain (MLC) kinase (MLCK), zonula occludens-1 (ZO-1), claudin-5, and phosphorylated myosin light chain (MLC) kinase, occludin and claudin-5 were determined by immunoprecipitation and Western blot. Ethanol-induced changes in monocyte migration across in vitro BBB constructs were also examined. Ethanol induced a decrease in TEER of BBMEC monolayers that was reversed by ethanol withdrawal. Treatment of BBMEC with ethanol or its metabolite, acetaldehyde, prior to monocyte application resulted in a 2-fold increase in monocyte migration across the BBB. IF showed decreased claudin-5 staining, occludin translocation from cell borders to cytoplasm, and gap formation in ethanol-treated BBMEC monolayer. These changes paralleled significant increase in phosphorylation of MLC, occludin, and claudin-5. Ethanol-treated BBMEC showed reduction of total occludin and claudin-5 without changes in ZO-1 or MLC. TEER decrease; changes in occludin/claudin staining; increase in MLC, occludin, and claudin-5 phosphorylation; and enhanced monocyte migration across the BBB were all reversed by inhibition of MLCK. Inhibition of ethanol metabolism in BBMEC also reversed these events. These results suggest that ethanol activates MLCK leading to phosphorylation of MLC, occludin, and claudin-5. Cytoskeletal alterations (MLC) and TJ changes (occludin and claudin-5 phosphorylation) result in BBB impairment (decrease in TEER). TJ compromise is associated with increased monocyte migration across the BBB. NIAAA Glossary Terms:  AOD abuse, blood-brain barrier, endothelium, endothelial cell, cytoplasm, Western blotting, cytoskeleton, monocyte, ethanol, acetaldehyde, phosphorylation, kinases, myosin, cell migration, in vitro study

Hill, Martin; Popov, Petr; Havlikova, Helena; Kancheva, Lyudmila; Vrbikova, Jana; Meloun, Milan; Kancheva, Radmila; Cibula, David; Pouzar, Vladimir; Cerny, Ivan; and Starka, Luboslav.  Reinstatement of serum pregnanolone isomers and progesterone during alcohol detoxification therapy in premenopausal women.  Alcoholism: Clinical & Experimental Research 29(6):1010-1017, June 2005.

Summary: Alcohol abuse is associated with menstrual irregularities related to the inhibition of progesterone secretion involved in regulation of the menstrual cycle. Reduced progesterone metabolites, including pregnanolone isomers (PIs), are efficient neuromodulators. The authors evaluated whether levels of PIs reflect impaired progesterone biosynthesis in premenopausal women treated for alcohol dependence and whether alcohol detoxification contributes to restoration of reproductive functions and psychosomatic stability by influencing steroid biosynthesis. Serum allopregnanolone, pregnanolone, isopregnanolone, epipregnanolone, progesterone, pregnanolone sulfate, and estradiol were measured in 20 women during therapy (at start, 3 days, 14 days, 1 month, and 4 months). Results were evaluated by a linear mixed model for longitudinal data. During detoxification, progesterone increased in the luteal phase. Allopregnanolone, isopregnanolone, and epipregnanolone rose in both phases of the menstrual cycle. Given the similar mechanism in the effects of alcohol and steroids in activating gamma-aminobutyric acid A (GABAA) receptors, the restoration of progesterone and PIs during therapy could be explained as an adaptation to increasing requests for GABAA-receptor activating substances due to cessation of alcohol intake or by regeneration of progesterone formation. In conclusion, the reinstatement of serum progesterone, allopregnanolone, and epipregnanolone levels shows the favorable effect of detoxification on both reproductive functions and the psychosomatic stability of premenopausal women treated for alcohol dependence. NIAAA Glossary Terms:  reproductive effects of AODU, menstrual cycle, AOD dependence, AOD abuse, progesterone, hormone metabolism, allopregnanolone, estradiol, steroid hormones, sex hormones, detoxification, GABA A receptor, pre menopause, reproductive function, human study

Romics, Laszlo Jr; Mandrekar, Pranoti; Kodys, Karen; Velayudham, Arumugam; Drechsler, Yvonne; Dolganiuc, Angela; and Szabo, Gyongyi.  Increased lipopolysaccharide sensitivity in alcoholic fatty livers is independent of leptin deficiency and toll-like receptor 4 (tlr4) or tlr2 mrna expression.  Alcoholism: Clinical & Experimental Research 29(6):1018-1026, June 2005.

Summary: Both alcoholic and nonalcoholic fatty livers (AFL and NAFL) show increased sensitivity to endotoxin-induced injury. Lipopolysaccharide (LPS) is recognized by toll-like receptor 4 (TLR4), whereas lipopeptide triggers TLR2 to induce common downstream activation of nuclear factor-kappa B (NF-κB) and pro-inflammatory pathways that are activated in AFL and NAFL. Serum alanine aminotransferase (ALT), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6) levels; hepatic NF-κB activity; and expression of TLR2, TLR4, inducible nitric oxide synthase (iNOS), and heme oxygenase (HO)-1 messenger ribonucleic acids (mRNAs) were investigated in lean and leptin-deficient ob/ob mice after LPS challenge in combination with acute or chronic ethanol feeding. Increased LPS sensitivity in AFL and NAFL was characterized by elevated serum TNF-α and IL-6 induction, but there was no difference in TLR2 and TLR4 mRNA levels between lean and ob/ob livers at baseline and after acute or chronic ethanol treatment. LPS increased TLR2, but not TLR4, mRNA levels in all groups. Chronic ethanol feeding and LPS increased serum ALT and TNF-α levels in lean but not in ob/ob mice compared with pair-fed controls. Hepatic NF-κB activation was increased in both ob/ob and lean mice after chronic ethanol feeding compared with pair-fed controls. Expression of iNOS, an inducer of oxidative stress, and HO-1, a cytoprotective protein, were higher in ob/ob compared with lean mice after chronic ethanol. However, LPS-induced HO-1, but not iNOS, expression was attenuated in ob/ob compared with lean mice. The results imply that the increased sensitivity of AFL to LPS occurs without up-regulation of TLR2 or TLR4 genes and may be related to an imbalance of pro-inflammatory/oxidative and cytoprotective mechanisms. NIAAA Glossary Terms:  alcoholic fatty liver, chronic AODE, fatty liver, endotoxins, nuclear factor-kappa B, lipopolysaccharide, alanine aminotransferase, tumor necrosis factor-alpha, interleukin-6, cytokines, receptors, mRNA, laboratory mice, obesity, controlled study, nitric oxide, synthetases, oxidative stress, gene expression, inflammation, oxidation, protective factors, animal study

Alele, P.E. and Devaud, L.L.  Differential adaptations in GABAergic and glutamatergic systems during ethanol withdrawal in male and female rats.  Alcoholism: Clinical & Experimental Research 29(6):1027-1034, June 2005.

Summary: In previous work, the authors found significant and consistent sex differences in recovery from ethanol withdrawal in an animal model of ethanol dependence. They have also observed significant and varied sex differences in subunit protein levels of gamma-aminobutyric acid A (GABAA) and the N-methyl-D-aspartate subtype of glutamate receptors occurring with ethanol dependence and withdrawal. In their present study they explored additional possible mechanisms underlying changes in GABAergic and glutamatergic responses after chronic ethanol exposure. The objective was to examine GABAergic- and glutamatergic-associated proteins at 3 days of ethanol withdrawal, when female rats appear to have largely recovered but male rats still display robust signs of withdrawal. Male and female rats were fed 6% ethanol in a nutritionally complete liquid diet for 14 days in a pair-fed design; withdrawal was initiated by replacement of the diet with chow. At 3 days of withdrawal, the cerebral cortex and hippocampus were dissected for Western blot analysis. The paired design was maintained throughout all experimental procedures. At 3 days of ethanol withdrawal, there were region-specific and sex-selective alterations in levels of GAD (glutamic acid decarboxylase, GABA synthetic enzyme), GABA and glutamate transporters, and the synapse-associated proteins HSP70, PSD-95, and synaptophysin. There were also several significant differences in transporter function at this time that varied between males and females. The findings show differential adaptations of GABAergic and glutamatergic neurotransmission between female and male rats that are associated with withdrawal recovery. This suggests that selective withdrawal-induced neuroadaptations in regulation of these systems' activities underlie, at least in part, sex differences in withdrawal recovery between male and female rats. NIAAA Glossary Terms:  GABA A receptor, NMDA receptors, glutamate receptors, ethanol, AOD dependence, AOD withdrawal syndrome, cerebral cortex, hippocampus, Western blotting, laboratory rat, gender differences, neurotransmission, animal study

Gauthier, Theresa W.; Drews-Botsch, Carolyn; Falek, Arthur; Coles, Claire; and Brown, Lou Ann S.  Maternal alcohol abuse and neonatal infection.  Alcoholism: Clinical & Experimental Research 29(6):1035-1043, June 2005.

Summary: Chronic alcohol use suppresses the adult immune system. This study tested the hypothesis that maternal alcohol ingestion increases the risk of infection in term newborns. Analysis of a large case-control study of birth weight for gestational age focused on maternal alcohol ingestion and the development of infection in term newborns with 36 or more weeks of gestation. After delivery, mothers were asked about alcohol and tobacco use in the 3 months prior to conception and each trimester of pregnancy. Of 872 singleton newborns, 51 (5.8%) had neonatal infections. Gestational age, sex, and small for gestational age (SGA) were not significantly different in the newborns with and without infection. Infants whose mothers reported alcohol use, excessive drinking, or smoking in pregnancy were more likely to have a newborn diagnosed with an infection than were mothers who reported abstaining from alcohol or cigarettes (p < 0.05). When controlling for race and smoking, SGA infants whose mothers used any alcohol had a 2.5-fold increase risk of infection, while excessive alcohol use increased the risk 3-4-fold. In a multivariable logistic regression analysis controlling for low maternal income, smoking, and SGA, excessive alcohol use during the 2nd trimester increased the risk of newborn infection (odds ratio = 3.7; confidence interval,1.1-12.8; p < 0.05). Excessive maternal alcohol use was associated with an increased risk of newborn infection in this patient sample. Increased awareness and further clinical investigations are warranted to address the detrimental effects of alcohol exposure on the developing immune system. NIAAA Glossary Terms:  prenatal alcohol exposure, prenatal chemical exposure, prenatally AOD-exposed child, immune system, immune function, infection, neonate, tobacco in any form, first trimester, second trimester, third trimester, risk analysis, relative risk, human study

Blasco, Carmen; Caballeria, Juan; Deulofeu, Ramon; Lligona, Anna; Pares, Albert; Lluis, Josep M; Gual, Antoni; and Rodes, Juan.  Prevalence and mechanisms of hyperhomocysteinemia in chronic alcoholics.  Alcoholism: Clinical & Experimental Research 29(6):1044-1048, June 2005.

Summary: Homocysteine (Hcy) is formed as an intermediary in methionine metabolism. Impairment of Hcy remethylation or transulfuration leads to hyperhomocysteinemia, which is considered a risk factor for atherosclerotic vascular disease and stroke in alcoholics. This study investigated the prevalence of hyperhomocysteinemia in alcoholics and the influence of alcohol consumption, vitamin deficiencies and liver damage on the plasma levels of Hcy. Alcoholic patients (N = 228) consecutively admitted for detoxication, classified according to clinical and biochemical data in normal liver (n = 117), and in mild to moderate liver disease (n = 111) were compared with healthy controls (N = 49). Blood levels of Hcy, vitamin B6, vitamin B12, and folate were measured. Plasma Hcy was significantly higher in alcoholics than in controls (9.66 ± 8.1 vs. 6.93 ± 2.33 µmol/liter, p < 0.025). Furthermore, plasma Hcy levels were significantly higher in alcoholics with liver injury (12.17 ± 10.14 µmol/liter) than in those with normal liver and in controls (p < 0.001). The prevalence of hyperhomocysteinemia was also significantly higher in alcoholics with liver damage than in those with normal liver and in controls (29.7%, 5.1%, and 2% respectively, p < 0.001). Serum folate values were lower in alcoholics than in controls (4.7 ± 2.6 vs. 7.6 ± 2.4 nmol/liter, p < 0.001). The lowest values of folate were found in alcoholics with liver disease, especially in those with hyperhomocysteinemia, with a negative correlation between the two parameters. In conclusion, moderate hyperhomocysteinemia is common in alcoholics, mainly those with liver damage, suggesting that, though folate deficiencies may have a contributory role, liver impairment through changes in methionine metabolism, is the most important mechanism for the elevated plasma Hcy found in these patients. NIAAA Glossary Terms:  homocysteine, risk factors, atherosclerosis, stroke, alcoholic liver disorder, AOD dependence, pyridoxine, vitamin B12, folates, prevalence, vitamin deficiency syndrome, clinical study, controlled study, human study

Clements, Koreen M.; Girard, Todd A.; Ellard, Colin G.; and Wainwright, Patricia E.  Short-term memory impairment and reduced hippocampal c-Fos expression in an animal model of fetal alcohol syndrome.  Alcoholism: Clinical & Experimental Research 29(6):1049-1059, June 2005.

Summary: Previous work in the authors' laboratory showed that exposure to ethanol during the brain growth spurt impairs spatial short-term memory in rats on the delayed matching-to-place (DMP) version of the Morris water maze. In their present study they sought to determine whether this impairment could be prevented by increasing the length of encoding time and whether it could be related to hippocampal c-Fos expression. In an artificial rearing model, male Long-Evans rats were fed ethanol (6.5g/kg/day) from postnatal days 6-9. Controls were fed an isocaloric amount of maltose dextrin. As adults, rats in each treatment condition were trained and subsequently tested on either the DMP version of the Morris water maze, or on a random platform version (RAN) that incorporated the same performance requirements, but disallowed spatial learning. Brains were processed for c-Fos expression. Ethanol-exposed rats showed longer search trials during training and took longer to learn the DMP task. When the delay between search and recall trials was increased from 60 seconds to 120 minutes, the performance of ethanol-exposed rats was impaired compared with that of controls after a 10-second, but not after a 45-second, encoding time. Brain c-Fos expression was increased in hippocampus, prefrontal cortex, and visual cortex in rats trained on the DMP compared to the RAN task. Furthermore, in the DMP-trained rats, hippocampal c-Fos expression was lower in ethanol-exposed rats. The results suggest that the short-term memory impairment of ethanol-exposed rats can be improved slightly by an increase in encoding time and is related to decreased hippocampal c-Fos expression. NIAAA Glossary Terms:  short-term memory, hippocampus, ethanol, controlled study, laboratory rat, learning, spatial memory, prefrontal cortex, visual cortex, gene expression, animal study

Zima, Tomas; Albano, Emanuele; Ingelman-Sundberg, Magnus; Arteel, Gavin E.; Thiele, Geoffrey M.; Klassen, Lynell W.; and Sun, Albert Y.  Modulation of oxidative stress by alcohol.  Alcoholism: Clinical & Experimental Research 29(6):1060-1065, June 2005.

Summary: This article summarizes the proceedings of a symposium on modulation of oxidative stress by alcohol at the 2004 International Society for Biomedical Research on Alcoholism in Mannheim, Germany. It is well established that reactive oxygen species (ROS) and reactive nitrogen species (RNS) have a causative role in acute and chronic ethanol toxicity. Biochemical signs of oxidative damage can be detected in experimental animals exposed to ethanol as well as in alcoholic patients. Ethanol-induced oxidative stress is the consequence of the combined effect of increased production of ROS by the mitochondria and the alcohol-inducible cytochrome P450 2E1 (CYP2E1) and impairment of antioxidant defenses. Furthermore, by promoting the activation of Kuppfer cells, ethanol causes the release of cytokines, ROS, and RNS. The mechanisms by which oxidative damage contributes to alcohol toxicity include direct hepatocellular damage, induction of apoptosis, and stimulation of collagen deposition by hepatic stellate cells. In addition, lipid peroxidation products, particularly acetaldehyde and malondialdehyde adducts, along with immune reactions triggered by oxidative stress, might also contribute to perpetuate hepatic inflammation. The implication of oxidative stress in alcohol liver damage gives a rationale to the clinical application of antioxidant therapies aimed at preventing or reducing ethanol-induced oxidative damage. NIAAA Glossary Terms:  conference proceedings, oxidative stress, free radicals, acute AODE, chronic AODE, ethanol, mitochondria, cytochrome P450 2E1, inducible enzymes, antioxidants, Kuppfer cell, cytokines, apoptosis, collagen, hepatic stellate cell, lipids, peroxidation, acetaldehyde, malondialdehyde, adduct, inflammation, literature review

Bergeson, Susan E.; Berman, Ari E.; Dodd, Peter R.; Edenberg, Howard J.; Hitzemann, Robert J.; Lewohl, Joanne M.; Lodowski, Kerrie H.; and Sommer, Wolfgang H.  Expression profiling in alcoholism research.  Alcoholism: Clinical & Experimental Research 29(6):1066-1073, June 2005.

Summary: This article summarizes the proceedings of a symposium on expression profiling in alcohol research at the 2004 International Society for Biomedical Research on Alcoholism in Mannheim, Germany. The organizers and co-chairmen of the symposium were Susan E. Bergeson and Wolfgang Sommer. The presentations and presenters were (1) Gene expression in brains of alcohol-preferring and non-preferring rats, by Howard J. Edenberg; (2) Candidate treatment targets for alcoholism: Leads from functional genomics approaches, by Wolfgang Sommer; (3) Microarray analysis of acute and chronic alcohol response in brain, by Susan E. Bergeson; (4) On the integration of QTL [quantitative trait locus] and gene expression analysis, by Robert J. Hitzemann; and (5) Microarray and proteomic analysis of the human alcoholic brain, by Peter R. Dodd. NIAAA Glossary Terms:  conference proceedings, gene expression, animal selectively bred for alcohol preference, laboratory rat, genome, acute AODE, chronic AODE, brain, quantitative trait locus, AOD dependence, human study

Guerri, Consuelo; Pascual, M; Garcia-Minguillan, M C.; Charness, Michael E.; Wilkemeyer, Michael F.; Klintsova, Anna Y.; Goodlett, Charles R.; Greenough, William T.; Sakata-Haga, Hiromi; Dominguez, Hector D.; and Thomas, Jennifer D.  Fetal alcohol effects: Potential treatments from basic science.  Alcoholism: Clinical & Experimental Research 29(6):1074-1079, June 2005.

Summary: This article summarizes the proceedings of a symposium on potential treatments for fetal alcohol effects presented at the 2004 annual meeting of the International Society for Biomedical Research on Alcoholism, in Mannheim, Germany. The presentations were: (1) Antioxidants prevent ethanol-induced cell death in developing brain and in cultured neural cells, by M. Pascual, M. C. Garcia-Minguillan, and Consuelo Guerri; (2) Rational development of ethanol antagonists, by Michael E. Charness and Michael F. Wilkemeyer; (3) Choline supplementation as a treatment for fetal alcohol effects, by Jennifer D. Thomas and Hector D. Dominguez; (4) Cerebellar and cortical plasticity after neonatal alcohol exposure: Model of intervention, by Anna Y. Klintsova, Charles R. Goodlett, and William T. Greenough; and (5) Circadian rhythms in prenatally ethanol-exposed rats, by Hiromi Sakata-Haga. NIAAA Glossary Terms:  conference proceedings, fetal alcohol effects, ethanol, antioxidants, neuron, cell culture study, cultured cell line, antagonists, choline, AODR neonatal disorder, postnatal alcohol exposure, circadian rhythm, laboratory rat, animal study

Syapin, Peter J.; Hickey, William F.; and Kane, Cynthia J.M.  Alcohol brain damage and neuroinflammation: Is there a connection?  Alcoholism: Clinical & Experimental Research 29(6):1080-1089, June 2005.

Summary: The question of whether neuroinflammation plays a role in alcohol-induced brain damage has received little attention. This symposium at the 2004 World Congress on Biomedical Alcohol Research in Mannheim, Germany, considered for the first time the relationship between alcohol neuropathology and neuroinflammation. The organizers and co-chairmen were Peter J. Syapin and Cynthia J. M. Kane. Neuroinflammatory responses including glial activation, demyelination, neuronal damage and neurodegeneration may contribute to the neurological deficits associated with alcoholism, alcohol abuse, fetal alcohol syndrome, or alcohol-related neurodevelopmental disorder. A substantial literature indicates that alcohol directly affects astroglial cell function, including inflammation-related activity. In addition, emerging data indicate that alcohol affects microglial cell development and function in specific ways that interfere with microglial interactions with the immune system and with neurons. The symposium provided alcohol researchers with background information on central nervous system (CNS) immunity and inflammatory processes and examined emerging experimental evidence that neuroinflammatory processes might be involved in alcohol-induced brain damage. A brief introduction was followed by four presentations: (1) Initiation of inflammation in the nervous system, by William Hickey; (2) Microglia - Interface between immune system and brain, by Helmut Kettenmann; (3) Ethanol and neuroinflammatory response in brain astroglia, by Peter Syapin; and (4) Microglia are targets of alcohol pathogenesis in the developing CNS, by Cynthia Kane. NIAAA Glossary Terms:  conference proceedings, neuron, inflammation, neuropathy, AOD dependence, myelin sheath, astrocyte, central nervous system,  neuroglia, immune system, pathogenesis,  AODR structural brain damage

Sisson, Joseph H.; Wyatt, Todd A.; Guidot, David M.; Bagby, Gregory J.; Helander, Anders; Tonnesen, Hanne; and Spies, Claudia D.  Bench to bedside: Mechanisms and consequences of alcohol-altered host defenses.  Alcoholism: Clinical & Experimental Research 29(6):1090-1097, June 2005.

Summary: This article summarizes the proceedings of a symposium on mechanisms and consequences of alcohol-altered host defenses presented at the 2004 World Congress on Biomedical Alcohol Research in Mannheim, Germany. The organizers and chairmen were Joseph H. Sisson and Claudia Spies. The presentations were: (1) Alcohol: Impact on mucociliary clearance; (2) Alcohol and alveolar epithelial dysfunction; (3) The reluctant neutrophil in lung bacterial host defense during alcohol abuse; (4) Prevalence, diagnosis, and relevance of alcohol use disorders in surgical patients; and (5) Intervention in alcohol-use disorders: How can we meet the challenge to reduce postoperative complications? Alcohol alters pulmonary host defenses, thus creating risk of severe lung infection. Alcohol is also recognized as a major risk factor for acute respiratory distress syndrome. These pulmonary complications pose especially difficult management challenges during surgery and after trauma, because the prevalence of alcohol abuse is very high in these settings. Particularly common in this perioperative context is pneumonia, which, despite advances in antimicrobial therapy, remains a major cause of morbidity and mortality in alcoholics. The symposium approached the topic from a "bench-to-bedside" perspective by linking the mechanisms by which alcohol impairs lung defenses to the perioperative consequences of lung impairment. The speakers highlighted recent advances from the "bench" in understanding the mechanisms of alcohol-mediated lung impairment and from the "bedside," where understanding the consequences of these impairments affects patient outcomes. The symposium also examined ways to detect and monitor patients at risk for alcohol-related complications and how clinical systems are being developed to minimize risk. Better clinical outcomes in alcohol-consuming patients depend on heightened awareness of patients at risk, understanding of the mechanisms that put them at risk, and application of appropriate prevention and treatment strategies. NIAAA Glossary Terms:  conference proceedings, infection, immune function, ethanol, AOD dependence, pneumonia, diagnosis, patient monitoring, risk factors, laboratory study, clinical study, prevention strategy, treatment method, human study

Pandey, Subhash C.; Chandler, L J.; Nixon, Kim; Crews, Fulton T.; Hensler, Julie G.; Ukai, Wataru; and Saito, Toshikazu.  Neurotrophic factor signaling in alcoholism.  Alcoholism: Clinical & Experimental Research 29(6):1098-1105, June 2005.

Summary: This article summarizes the proceedings of a symposium on neutrophilic factor signaling in alcoholism presented at the 2004 World Congress on Biomedical Alcohol Research in Mannheim, Germany. The organizers and chairmen were Subhash C. Pandey and Toshikazu Saito. The presentations were (1) Ethanol and NMDA receptor coupling to ERK signaling, by L.J. Chandler; (2) Ethanol modulation of CREB [Cyclic-AMP Response Element Binding]: Role in neurogenesis, by Fulton Crews; (3) Serotonin dysfunction and alcohol preference in mice deficient in brain-derived neurotrophic factor (BDNF), by Julie G. Hensler; (4) BDNF gene and related signaling: Role in anxiety and alcohol dependence and preference, by Subhash C. Pandey; and (5) BDNF and CREB: Role in ethanol induced neuronal damage, by Wataru Ukai. NIAAA Glossary Terms:  conference proceedings, ethanol, cell signaling, AOD dependence, NMDA receptors, N methyl D aspartate, serotonin, gene, anxiety, AOD dependence, neuropathy

Harper, Clive; Matsumoto, Izuru; Pfefferbaum, Adolf; Adalsteinsson, Elfar; Sullivan, Edith V.; Lewohl, Joanne; Dodd, Peter; Taylor, Michael; Fein, George; and Landman, Bennett.  The pathophysiology of 'brain shrinkage' in alcoholics - structural and molecular changes and clinical implications.  Alcoholism: Clinical & Experimental Research 29(6):1106-1115, June 2005.

Summary: This article summarizes a symposium on the pathophysiology of brain atrophy presented at 2004 World Congress on Biomedical Alcohol Research in Mannheim, Germany. The presentations were: (1) Review of the neuropathological and neurochemical changes seen in alcohol-related "brain shrinkage," by Clive Harper; (2) In vivo detection of macrostructural and microstructural markers of brain iIntegrity in human alcoholism and a rodent model of alcoholism, by Adolf Pfefferbaum, Elfar Adalsteinsson, and Edith Sullivan; (3) Gene and protein changes in the brains of alcoholics with "brain shrinkage," by Joanne Lewohl and Peter Dodd; (4) Cross sectional and longitudinal MR [magnetic resonance] spectroscopy studies of chronic adult alcoholics, by Michael Taylor; and (5) Brain atrophy associated with impairment on a simulated gambling task in long-term abstinent alcoholics, by George Fein and Bennett Landman. NIAAA Glossary Terms:  conference proceedings, AOD dependence, brain atrophy, animal study, human study, gene, proteins, magnetic resonance spectroscopy, chronic AODE, AOD abstinence, gambling

Takei, Yoshiyuki; Arteel, Gavin E.; Bergheim, Ina; Lambert, Jason C.; McMullen, M R.; Nagy, Laura E.; Enomoto, Nobuyuki; and Sato, Nobuhiro.  Roles of Kupffer cells in alcoholic liver disease.  Alcoholism: Clinical & Experimental Research 29(6):1116-1120, June 2005.

Summary: This article summarizes a symposium on the roles of Kupffer cells in alcoholic liver disease presented at the 2004 World Congress on Biomedical Alcohol Research in Mannheim, Germany. The organizers and chairmen were Yoshiyuki Takei and Gavin E Arteel. The presentations were: (1) Kupffer cell-derived mediators involved in alcoholic liver disease: Reactive oxygen and nitrogen species, by Gavin E. Arteel; (2) Kupffer cell-derived mediators in alcoholic liver disease: Tumor necrosis factor-alpha, by Laura E. Nagy; (3) Metformin [an oral hypoglycemic drug] prevents acute alcohol-induced fat accumulation in mouse liver, by Ina Bergheim; (4) Gender difference in alcoholic liver disease, by Nobuyuki Enomoto; and (5) Kupffer cells as a therapeutic target of alcoholic liver disease, by Yoshiyuki Takei. NIAAA Glossary Terms:  conference proceedings, Kupffer cell, alcoholic liver disorder, free radicals, oxidative stress, tumor necrosis factor-alpha, fatty liver, animal study, laboratory mice, gender differences, treatment method, hypoglycemia

Stromland, Kerstin; Mattson, Sarah N.; Adnams, Colleen M.; Autti-Ramo, Ilona; Riley, Edward P.; and Warren, Kenneth R.  Fetal alcohol spectrum disorders: An international perspective.  Alcoholism: Clinical & Experimental Research 29(6):1121-1126, June 2005.

Summary: This article summarizes the proceedings of a symposium on fetal alcohol spectrum disorders (FASD) presented at the 2004 annual meeting of the International Society for Biomedical Research on Alcoholism, in Mannheim, Germany. The organizers and chairmen were Kerstin Stromland and Kenneth R. Warren. The presentations were: (1) Comparison of FASD in Moscow, Russia, and San Diego, California, by Sarah N. Mattson; (2) Neurobehavior and interventions in FASD in South Africa, by Colleen M. Adnams; (3) Ophthalmologic involvement in fetal alcohol syndrome, by Kerstin Stromland; and (4) Brain imaging in children with fetal alcohol spectrum disorders, by Ilona Autti-Ramo. NIAAA Glossary Terms:  conference proceedings, fetal alcohol effects, fetal alcohol syndrome, prenatal alcohol exposure, comparative study, regional differences, Russia, United States, South Africa, psychobehavioral AODE, visual system disorder, brain imaging,

Rist, Fred; Randall, Carrie L.; Heather, Nick; and Mann, Karl.  New developments in alcoholism treatment research in Europe.  Alcoholism: Clinical & Experimental Research 29(6):1127-1132, June 2005.

Summary: This article summarizes the proceedings of a symposium held at the meeting of the International Society for Biomedical Research on Alcoholism (ISBRA) in Mannheim, Germany, in October 2004. The organizers and chairs were Karl F. Mann, Fred Rist and Carrie L. Randall. The presentations were: (1) Searching for the acamprosate and naltrexone responders, by Karl Mann on behalf of the Project Predict Research team (K. Mann, R. Bruck, H. Gann, U. Zimmermann, A. Heinz, M. Smolka et al.); (2) Treatment outcomes from the United Kingdom Alcohol Treatment Trial (UKATT), by Nick Heather on behalf of the UKATT research team (N. Heather, A. Copello, Ch. Godfrey, R. Hodgson, J. Orford, D. Raistrick, I. Russell, and G. Tober); and (3) Conjoint screening and Brief intervention for Alcohol and Nicotine misuse in primary health care (BrIAN), by Fred Rist on behalf of the BrIAN research team (Ralf Demmel, Ines Aulhorn, Jutta Hagen, Barbara Scheuren, and Fred Rist). NIAAA Glossary Terms:  conference proceedings, calcium acetylhomotaurinate, AOD dependence, drug therapy, naltrexone, treatment method, treatment outcome, Europe, United Kingdom, brief intervention, AOD abuse, nicotine, primary health care, medical screening and diagnostic method

Hajnoczky, Gyorgy; Buzas, Christopher J; Pacher, Pal; Hoek, Jan B; and Rubin, Emanuel.  Alcohol and mitochondria in cardiac apoptosis: Mechanisms and visualization.   (Literature review.) Alcoholism: Clinical & Experimental Research 29(5):693-701, May 2005.

Summary: The authors discusse potential mechanisms of the effect of alcohol on mitochondrial membrane permeabilization and visualization of mitochondria-dependent apoptosis in cardiac muscle. Apoptosis of myocytes probably contributes to a variety of heart conditions and could also be important in the development of alcoholic heart disease. A fundamental pathway to apoptosis is through activation of mitochondrial membrane permeability and release of proapoptotic factors from the mitochondrial intermembrane space into the cytosol. The authors have shown that prolonged exposure of cultured cardiac cells to ethanol (35 mM for 48 hours) promotes Ca2+-induced activation of the mitochondrial permeability transition pore (PTP). PTP-dependent mitochondrial membrane permeabilization is followed by release of cytochrome c and execution of apoptosis. They propose that chronic ethanol exposure, combined with other stress signals, may allow physiological calcium oscillations to activate the PTP, providing a trigger for cardiac apoptosis during chronic alcohol abuse. Coincidence of apoptosis-promoting factors occurs in only a small fraction of myocytes, but because regeneration is absent, even a modest increase in the rate of cell death may contribute to decreased cardiac contractility. Detection of apoptotic changes that are present in only a few myocytes at a certain time in the heart is not feasible with most of the apoptotic assays. Fluorescence imaging is a powerful technology to visualize changes that are confined to a minor fraction of cells in a tissue, and the use of multiphoton excitation permits imaging in situ deep in the wall of the intact heart. NIAAA Glossary Terms:  apoptosis, mitochondria, cell culture study, ethanol, cardiomyocyte, calcium, cell function, membrane permeability, cytochromes, chronic AODE, diagnostic imaging, laboratory study

Mottagui-Tabar, Salim; Prince, Jonathan A; Wahlestedt, Claes; Zhu, Guanshan; Goldman, David; and Heilig, Markus.  A novel single nucleotide polymorphism of the neuropeptide Y (NPY) gene associated with alcohol dependence.  Alcoholism: Clinical & Experimental Research 29(5):702-707, May 2005.

Summary: Neuropeptide Y (NPY) is a major endogenous regulator of anxiety-related behaviors and emotionality. NPY has been implicated in the control of alcohol consumption through transgenic work and null-mutant mice studies, suggesting that genetic variation of the prepro-NPY gene may also contribute to the heritability of alcoholism. This study examined whether polymorphic variants of the NPY gene are associated with the diagnosis of alcohol dependence. The authors compared allele frequencies of five NPY polymorphisms (-883-ins/del, -602, -399, -84, and +1128) in a Nordic population of alcohol-dependent individuals (n = 428 males; n = 149 females) and ethnically matched controls (n = 84 males; n = 93 females) for whom alcohol dependence or any diagnosis of substance disorder was excluded. Alcoholic patients were further subtyped into type I (late-onset) and type II (early-onset). The -602 marker was significantly associated with alcohol dependence (p = 0.0035; odds ratio [OR] = 2.3; 95% confidence interval [CI], 1.3-4.0). A trend-level association was also observed for the -399 marker (p = 0.058; OR = 1.3; 95% CI, 0.99-1.7) and the +1128 marker (p = 0.053; OR = 1.8; 95% CI, 0.99-3.1). The association for the -602 marker remained and was strengthened when analyzed in type I subjects only, although this association was not seen in type II patients, and there also was a significant association in the female subjects but not in males. The -602 single nucleotide polymorphism was in strong linkage disequilibrium (r2 = 0.7; p < 0.0001) with the +1128 single nucleotide polymorphism, which has previously been reported to be associated with a diagnosis of alcoholism. These results were confirmed by haplotype-based association. In conclusion, a novel polymorphism was identified at position -602 in the 5' region of the NPY gene that is significantly associated with alcohol dependence. The haplotype frequencies and linkage disequilibrium pattern of four variations in that region are also described. NIAAA Glossary Terms:  neuropeptide Y, AOD dependence, anxiety, genetic polymorphism, gene, allele, genetic markers, gene frequency, risk analysis, genetic correlation analysis, early AOD onset, late AOD onset, gender differences, relative risk, nucleotides, haplotype, human study

Fehr, Christoph; Shirley, Renee L; Crabbe, John C; Belknap, John K; Buck, Kari J; and Phillips, Tamara J.  The syntaxin binding protein 1 gene (Stxbp1) is a candidate for an ethanol preference drinking locus on mouse chromosome 2.  Alcoholism: Clinical & Experimental Research 29(5):708-720, May 2005.

Summary: The authors previously mapped a quantitative trait locus (QTL) for ethanol preference drinking to mouse chromosome 2 (mapped with high confidence, LOD = 15.5, p = 3 x 10-16). The specific gene(s) in the QTL interval responsible for phenotypic variation in ethanol preference drinking has not been identified. In the current study, the authors investigated the association of the syntaxin binding protein 1 gene (Stxbp1) with ethanol preference drinking and other ethanol traits using a panel of B6 x D2 (BXD) recombinant inbred (RI) strains derived from the C57BL/6J (B6) and DBA/2J (D2) inbred mouse strains. Confirmation analyses for ethanol consumption and withdrawal were performed using a large B6D2 F2 cross, short-term selected lines derived from the B6 and D2 progenitor strains, and standard inbred strains. BXD RI strain analysis detected provisional associations between Stxbp1 molecular variants and ethanol consumption, as well as severity of acute ethanol withdrawal, ethanol-conditioned taste aversion, and ethanol-induced hypothermia. The involvement of Stxbp1 in ethanol preference drinking, but not in ethanol withdrawal, was supported by confirmation analyses using three independent genetic models. Stxbp1 encodes a Sec1/Munc18-type protein essential for vesicular neurotransmitter release. This study provides supporting evidence for the involvement of Stxbp1 in ethanol preference drinking. NIAAA Glossary Terms:  quantitative trait locus, gene, binding proteins, gene, laboratory mice, animal strains, comparative study, ethanol, AOD consumption, AOD withdrawal syndrome, taste, hypothermia, neurotransmission, neurotransmitters, animal study

Hayes, Dayna M.; Knapp, Darin J.; Breese, George R.; and Thiele, Todd E.  Comparison of basal neuropeptide Y and corticotropin releasing factor levels between the high ethanol drinking C57BL/6J and low ethanol drinking DBA/2J inbred mouse strains.  Alcoholism: Clinical & Experimental Research 29(5):721-729, May 2005.

Summary: Recent genetic and pharmacological evidence indicates that ethanol consumption is increased by low neuropeptide Y (NPY) levels in brain regions involved with neurobiological responses to ethanol. It has been suggested that NPY and corticotropin releasing factor (CRF), because of their opposing actions, exert a reciprocal regulation on drug self-administration. It has been widely reported that inbred C57BL/6 mice consume significantly larger amounts of ethanol than DBA/2 mice. This study therefore examined whether basal NPY and/or CRF levels differed in predicted directions between C57BL/6J and DBA/2J mice. Ethanol-naive C57BL/6J and DBA/2J mice were deeply anesthetized with sodium pentobarbital (100 mg/kg) and perfused transcardially with 0.1 mM of phosphate-buffered saline followed by 4% paraformaldehyde in buffered saline. Brains were collected and postfixed for 4 hours at 4°C and then were cut into 35-µm sections. Tissues containing the nucleus accumbens (NAc), hypothalamus, and amygdala were processed for NPY or CRF immunoreactivity using immunofluorescent or 3,3'-diaminobenzidine (DAB) techniques. Immunoreactivity was quantified from digital images using Image J software. The C57BL/6J mice showed reduced NPY expression in the NAc shell, the basolateral amygdala, and the central nucleus of the amygdala when compared with DBA/2J mice. However, these strains did not differ in CRF expression in any of the brain regions analyzed. The findings suggest that low NPY levels in the amygdala or the shell of the NAc, which are not compensated for by similar changes in CRF levels, may contribute to the high ethanol consumption characteristic of C57BL/6J mice. NIAAA Glossary Terms:  neuropeptide Y, corticotropin RH, self administration of drugs, ethanol, AOD consumption, laboratory mice, animal strains, comparative study, nucleus accumbens, hypothalamus, amygdala, immunoassay, animal study

Kovacs, Krisztina M.; Szakall, Istvan; O'Brien, Danielle; Wang, Ray; Vinod, K Yaragudri; Saito, Mariko; Simonin, Frederic; Kieffer, Brigitte L.; and Vadasz, Csaba.  Decreased oral self-administration of alcohol in [kappa]-opioid receptor knock-out mice.  Alcoholism: Clinical & Experimental Research 29(5):730-738, May 2005.

Summary: Although a role for the opioid system in alcoholism is suggested by a large body of evidence, the precise role of µ-, δ-, κ-, and ORL1 (opioid receptor-like1)-opioid receptors and the physiological significance of their natural genetic variation have not been identified. This study examined the effects of targeted disruption of κ-opioid receptor (KOR) on oral ethanol self-administration and other behaviors in mice. Oral ethanol, saccharin, and quinine self-administration was assessed in a two-bottle choice paradigm using escalating concentrations of ethanol, or tastant solutions. In preference tests 12% ethanol, 0.033% and 0.066% saccharin, and 0.03 mM and 0.1 mM quinine solutions were used. Open-field activity was determined in an arena equipped with a computer-controlled activity-detection system. Subjects were tested for 3 consecutive days. Locomotor activity was assessed on days 1 and 2 (after intraperitoneal saline injection) and on day 3 (after ethanol injection). Alcohol-induced locomotor activity was determined as the difference in activity between day 3 and day 2. Male KOR knock-out (KO) mice in preference tests with 12% ethanol consumed about half as much ethanol as wild-type (WT) or heterozygous (HET) mice, showed lower preference for saccharin (0.033% and 0.066%), and higher preference to quinine (0.1 mM) than WT mice. Female KOR KO mice showed similar reduction in ethanol consumption in comparison to WT and HET mice. Partial deletion of KOR in HET mice did not change ethanol consumption in comparison to WT mice. In all genotype-groups females drank significantly more ethanol than males. Multivariate analysis of variance (MANOVA) of locomotor activity among KO, WT, and HET mice indicated that strain and sex effects were not significant for ethanol-induced activation (p > 0.05), while strain x sex interaction effects on ethanol-induced activation could be detected (F1,55 = 6.07, p < 0.05). These results indicating decreased alcohol consumption, lower saccharin preference, and higher quinine preference in KOR KO mice are consistent with previous observations of opioid involvement in maintenance of food intake and raise the possibility that the deficient dynorphin/KOR system affects orosensory reward through central mechanisms that reduce ethanol intake and disrupt tastant responses, either as direct effects of absence of κ-opioid receptors, or as effects of indirect developmental compensatory changes. NIAAA Glossary Terms:  endogenous opioids, opioid receptors, mu-opioid receptors, kappa-opioid receptors, delta-opioid receptors, ethanol, saccharin, quinine, laboratory mice, gene knockout technology, AOD consumption, dynorphin, animal study

Beulens, Joline W J; Sierksma, Aafje; Schaafsma, Gertjan; Kok, Frans J; Struys, Eduard A; Jakobs, C; and Hendriks, Henk FJ.  Kinetics of homocysteine metabolism after moderate alcohol consumption.  Alcoholism: Clinical & Experimental Research 29(5):739-745, May 2005.

Summary: Moderate alcohol consumption is associated with decreased risk of cardiovascular disease. Because plasma homocysteine (tHcy) is considered an independent risk factor for cardiovascular disease and is associated with alcohol consumption, the authors investigated the effect of moderate ethanol consumption on kinetics of plasma tHcy concentration, vitamin B status, and other parameters involved in tHcy metabolism. The subjects (10 healthy men and 9 healthy postmenopausal women; aged 45-65 years) participated in a randomized, diet-controlled, crossover trial in which they consumed beer or alcohol-free beer (men: 4 units/day; women: 3 units/day) during 3 weeks, separated by a 1-week washout. Fasting blood samples were taken on days 5, 10, 15, and 20 of each period. Plasma tHcy (µM) and S-adenosyl methionine/S-adenosyl homocysteine ratio were not affected by consumption of beer (p = 0.33) or alcohol-free beer (p = 0.14). Plasma pyridoxal-5-phosphate (µg/liter) increased during consumption of beer (+11.0%) but decreased during consumption of alcohol-free beer (-34.0%; p = 0.042). Changes over time of plasma vitamin B6 (µg/liter) were similar to changes in plasma pyridoxal-5-phosphate (p = 0.10). Serum vitamin B12 was higher (p < 0.001) after 3 weeks consumption of alcohol-free beer (382.8 ± 23.7 pg/liter) as compared with beer consumption (327.5 ± 22.2 pg/liter). Changes in serum methionine, cysteine, cystathionine, and plasma folate were not different between beer-drinking and alcohol-free beer-drinking periods. This study shows that moderate alcohol consumption does not affect plasma tHcy concentrations or S-adenosyl methionine/S-adenosyl homocysteine ratio. However, it does increase plasma vitamin B6 and decrease serum vitamin B12. NIAAA Glossary Terms:  homocysteine, vitamin B complex, moderate AOD use,  beer, nonalcoholic beverage, alcoholic beverage, comparative study, amino acid metabolism, randomized controlled trial, S-adenosylmethionine, S-adenosylhomocysteine, pyridoxal phosphate, pyridoxine, vitamin B12, methionine, cysteine, cystathionine, folates, human study

Robinson, Donita L.; Volz, Trent J.; Schenk, James O.; and Wightman, R Mark.  Acute ethanol decreases dopamine transporter velocity in rat striatum: In vivo and in vitro electrochemical measurements.  Alcoholism: Clinical & Experimental Research 29(5):746-755, May 2005.

Summary: Ethanol increases dopamine transporter (DAT) velocity when measured in cell expression systems, but its effects in vivo are mixed. This study examined the effect of acute ethanol on dopamine transmission, particularly DAT velocity, in anesthetized animals as well as rat striatal suspensions. To determine the effect of acute ethanol on DAT function in vivo, dopamine uptake was measured in real time using fast-scan cyclic voltammetry and constant potential amperometry in the olfactory tubercle of anesthetized rats. Dopamine fibers were electrically stimulated, and the resulting transient dopamine signals were analyzed to describe the release and uptake kinetics. The effect of ethanol on DAT velocity was also measured in vitro in striatal tissue suspensions using rotating disk electrode voltammetry. Ethanol (2.5 and 4 g/kg, intraperitoneally) decreased the electrically stimulated dopamine signal in the olfactory tubercle by 35%-55%. The slope of the clearance curve of dopamine was 40% shallower after both doses of ethanol, indicating slower uptake. Modeling the data using Michaelis-Menten uptake kinetics showed that the slower uptake was due to a decrease in DAT Vmax. These results were confirmed in vitro, because ethanol decreased the velocity of dopamine uptake by 35% in striatal tissue suspensions. These findings indicate that acute ethanol decreases DAT function in rat dorsal and ventral striatum in anesthetized rats and tissue suspensions, in contrast to its effects on human DAT expressed in single cells. Given the variety of molecular targets of ethanol in the brain, including the DAT itself, it is likely that several mechanisms converge to produce a net effect on DAT regulation and function that could very well be different in intact tissue versus single cells. NIAAA Glossary Terms:  dopamine, transport proteins, dopaminergic neuron, neurotransmission,  ethanol, acute AODE, corpus striatum, electrical life processes, in vitro study, in vivo study, cell culture study, laboratory rat, animal study

Lukas, Scott E.; Penetar, David; Berko, Jeff; Vicens, Luke; Palmer, Christopher; Mallya, Gopinath; Macklin, Eric A.; and Lee, David Y.-W.  An extract of the Chinese herbal root kudzu reduces alcohol drinking by heavy drinkers in a naturalistic setting.  Alcoholism: Clinical & Experimental Research 29(5):756-762, May 2005.

Summary: Extracts of kudzu containing a variety of isoflavones have been shown to reduce ethanol drinking in rats and hamsters. This study tested the efficacy of a kudzu extract in a clinical population. Male and female "heavy" alcohol drinkers were treated with either placebo or a kudzu extract for 7 days, then were given an opportunity to drink their preferred brand of beer while in a naturalistic laboratory setting. Participants served as their own controls, and order of treatment exposure was counterbalanced. Drinking behavior was monitored by a digital scale that was located in the top of an end table. Kudzu treatment resulted in significant reduction in the number of beers consumed, an increase in the number of sips and the time to consume each beer, and a decrease in the volume of each sip. These changes occurred in the absence of a significant effect on the urge to drink alcohol. There were no reported side effects of kudzu treatment. These data suggest that an extract of this leguminous plant may be a useful adjunct in reducing alcohol intake in a naturalistic setting. NIAAA Glossary Terms:  herbal therapy, alternative medicine, ethanol, AOD consumption, heavy AOD use, AOD use behavior, beer, clinical trial, controlled study, human study

Bonsch, Dominikus; Greifenberg, Verena; Bayerlein, Kristina; Biermann, Teresa; Reulbach, Udo; Hillemacher, Thomas; Kornhuber, Johannes; and Bleich, Stefan.  alpha-Synuclein protein levels are increased in alcoholic patients and are linked to craving.  Alcoholism: Clinical & Experimental Research 29(5):763-765, May 2005.

Summary: α-Synuclein has been found to be increased in dopamine neurons of cocaine abusers and in rats with inbred preference for alcohol. Furthermore, increased α-synuclein messenger ribonucleic acid (mRNA) expression has been linked to craving in alcoholics. This study investigated whether α-synuclein protein levels are changed in alcoholics and influence alcohol craving. The α-synuclein protein expression level was measured by enzyme-linked immunosorbent assay in the serum of male alcoholics (n = 49) and nondrinking healthy controls (n = 50). Alcohol craving was assessed by the Obsessive-Compulsive Drinking Scale (OCDS) total score, including subscales for obsessive and compulsive craving. α-Synuclein protein expression in patients with alcoholism (14.33 ng/mL; SD, 13.01 ng/mL) was significantly higher (t test, T = 3.66, p < 0.0001) compared to healthy controls (5.92 ng/ml; SD, 9.72 ng/mL). In multivariate analysis, all craving scores (OCDS total score and obsessive and compulsive subscale scores) in alcoholics were significantly associated with their α-synuclein protein levels (multiple linear regression, p < 0.014). This study, which the authors believe is the first to evaluate α-synuclein protein expression in alcoholics, provides further evidence of altered α-synuclein levels in alcoholic patients and their linkage to alcohol craving. Because α-synuclein is involved in the modulation of dopaminergic neurotransmission, these results provide further pathophysiological explanations of craving mechanisms. NIAAA Glossary Terms:  proteins, brain, mRNA, AOD dependence, AOD craving, immunoassay, obsessive-compulsive disorder, regression analysis, dopaminergic neuron, neurotransmission, controlled study, human study

Miguel-Hidalgo, Jose Javier.  Lower packing density of glial fibrillary acidic protein-immunoreactive astrocytes in the prelimbic cortex of alcohol-naive and alcohol-drinking alcohol-preferring rats as compared with alcohol-nonpreferring and Wistar rats.  Alcoholism: Clinical & Experimental Research 29(5):766-772, May 2005.

Summary: Low packing density of glial cells, possibly astrocytes, has been described in the prefrontal cortex and hippocampus of "uncomplicated" alcoholics. Astrocytes perform crucial support functions in the processing of neurotransmitters and transfer of energy substrates from blood to cortical neurons. It is still unknown whether attrition in the numbers of astrocytes is only a consequence of prolonged alcohol abuse or also predates exposure to alcohol in subjects at risk for alcohol dependence. In this study, alcohol-preferring (P) rats were exposed ad libitum for 2 or 6 months to either water only or 10% ethanol, and alcohol-nonpreferring (NP) rats and nonselected Wistar rats were exposed only to water for 2 months. Sections through the frontal cortex were immunostained for glial fibrillary acidic protein (GFAP), a specific marker of astrocytes. The packing density of GFAP-immunoreactive (IR) astrocytes and the area fraction of GFAP immunoreactivity were measured in the prelimbic cortex (PLC) using the dissector probe and analysis of binary images of GFAP immunostaining respectively. The packing density of GFAP-IR astrocytes was significantly lower in both alcohol-naive and alcohol-exposed P rats than in NP rats or Wistar rats. The area fraction of GFAP immunoreactivity was significantly lower in the alcohol-exposed P rats than in NP rats, Wistar rats, and alcohol-naive P rats. These results suggest that low density of GFAP-IR astrocytes in the PLC of P rats predates the exposure to alcohol and might be a factor contributing to the increased risk for alcohol dependence. In addition, prolonged free-choice alcohol drinking may reduce the extent of GFAP-IR processes in the PLC of P rats. NIAAA Glossary Terms:  astrocyte, neuroglia, animal selectively bred for alcohol preference, laboratory rat, animal strains, comparative study, controlled study, glial fibrillary acidic protein, immunoassay, AOD dependence, risk factors, animal study

Gabbay, Frances H.  Family history of alcoholism and response to amphetamine: Sex differences in the effect of risk.  Alcoholism: Clinical & Experimental Research 29(5):773-780, May 2005.

Summary: Persons at risk for alcoholism show an enhanced stimulant response to alcohol. This study examined whether persons at risk also exhibit heightened sensitivity to other drugs with stimulant properties. Healthy young men and women each received, in separate sessions, placebo and 10 mg of d-amphetamine in counterbalanced order. Stimulant and sedative subjective effects were recorded before and three times after capsule administration using the Biphasic Alcohol Effects Scale. The sample comprised 19 family-history-positive (FHP; 58% women) and 53 family-history-negative (FHN; 51% women) participants. Compared with placebo, amphetamine increased ratings of stimulation in the sample as a whole. The ratings also revealed an enhanced, and protracted, stimulant response to amphetamine among FHP men compared with FHN men: for FHP men, ratings of stimulation made 3 and 6 hours after amphetamine administration were greater than baseline ratings. Moreover, in FHP men, the effect of amphetamine, compared with placebo, was most evident 6 hours after capsule administration. In contrast, despite a dose x hour interaction in FHN men, post hoc comparisons revealed no differences between the baseline and any of the post-amphetamine measurements or between amphetamine and placebo ratings at any of the time points. Among women, the drug effect did not differentiate the family-history groups. Consistent with previous research on alcohol, high-risk men in this study showed a heightened stimulant response to amphetamine. Thus, for men, sensitivity to the stimulant properties of drugs may be an endophenotype for alcoholism. The present results suggest that women at risk do not exhibit an enhanced stimulant response to amphetamine, but further study is needed, including evaluation at various points in the menstrual cycle. NIAAA Glossary Terms:  AOD sensitivity, CNS stimulant, CNS depressants, dextroamphetamine, familial alcoholism, family background, controlled study, comparative study, gender differences, phenotype, risk factors, human study

Borucki, K; Schreiner, R; Dierkes, J; Jachau, K; Krause, D; Westphal, S; Wurst, F M.; Luley, C; and Schmidt-Gayk, H.  Detection of recent ethanol intake with new markers: Comparison of fatty acid ethyl esters in serum and of ethyl glucuronide and the ratio of 5-hydroxytryptophol to 5-hydroxyindole acetic acid in urine.  Alcoholism: Clinical & Experimental Research 29(5):781-787, May 2005.

Summary: At present, routine detection of recent ethanol consumption can be done with certainty only by directly measuring ethanol concentration in blood or urine, but the time window is in the range of hours because of ethanol's rapid elimination. The authors of this study investigated three new markers and compared their kinetics and sensitivities: (1) fatty acid ethyl esters (FAEEs) in serum, (2) ethyl glucuronide (EtG) in urine, and (3) the ratio of 5-hydroxytryptophol to 5-hydroxyindole acetic acid (5-HTOL:5-HIAA) in urine. The subjects were 17 healthy males who participated in a drinking experiment. Blood and urine samples were collected twice daily on 3 consecutive days and once daily on days 4 and 5. Ethanol concentrations were determined by gas chromatography, FAEE levels by gas chromatography with mass spectrometry, EtG concentrations by liquid chromatography-tandem mass spectrometry, and 5-HTOL:5-HIAA by high-performance liquid chromatography. The peak serum ethanol concentrations of the subjects ranged from 5.4 to 44.7 mmol/L (mean ± SD, 30.1 ± 9.1 mmol/L). In the case of the serum ethanol determination 100% sensitivity was reached only immediately after the end of the drinking experiment, and in the case of FAEE levels and 5-HTOL:5-HIAA it tested for 6.7 hours after the end of ethanol intake. These latter parameters then declined until 15.3 hours (FAEEs) and 29.4 hours (5-HTOL:5-HIAA), subsequently remaining in a stable range until 78.5 hours without further decrease. In contrast, EtG concentration showed 100% sensitivity until 39.3 hours and thereafter decreased, falling to below the limit of quantification of 0.1 mg/L at 102.5 hours. EtG in the urine proved to be a superior marker of recent moderate ethanol intake in healthy subjects because it is a direct ethanol metabolite, occurs in the urine only when ethanol has been consumed, and retains 100% sensitivity for 39.3 hours. NIAAA Glossary Terms:  AOD use, AODR biochemical markers, moderate AOD use, BAC, fatty acid ethyl esters, ethyl glucuronide, hydroxytryptophol, hydroxyindoleacetic acid, comparative study, laboratory measurement, gas chromatography, spectrometry, high pressure liquid chromatography, serum, urine, sensitivity of measurement, ethanol metabolism, ethanol metabolite, laboratory study

Sun, Leimin; Konig, Inke R.; Jacobs, Arne; Seitz, Helmut K.; Junghanns, Klaus; Wagner, Thomas; Ludwig, Diether; Jacrobs, Arne; and Homann, Nils.  Mean corpuscular volume and ADH1C genotype in white patients with alcohol-associated diseases.  Alcoholism: Clinical & Experimental Research 29(5):788-793, May 2005.

Summary: It has been demonstrated that increased MCV could be an independent biomarker for esophageal cancer in Asians. The present study investigated possible associations of MCV with polymorphisms of alcohol dehydrogenase (ADH)1C in white patients with alcohol-associated gastrointestinal (GI) diseases as well as in heavy drinkers without organ damage. Enrolled alcoholic patients (N = 510) included patients with esophageal carcinoma (n = 98), chronic alcoholic pancreatitis (n = 98), alcoholic cirrhosis (n = 151), and alcohol abuse without GI disease (n = 163). ADH1C genotyping was performed by polymerase chain reaction (PCR)-based restriction fragment length polymorphism (PCR-RFLP) analysis from whole blood. The relation between MCV and ADH1C gene polymorphisms (ADH1C*1 and 1C*2), controlled for the amount of drinking, smoking, and age, were investigated using both univariate and multivariate analysis. In univariate analysis, higher alcohol consumption was associated with increased MCV. Other variables were not associated with macrocytosis. In multiple linear regression analysis, after adjustment for age and smoking, higher alcohol consumption and female sex were independently associated with higher MCVs. No other variables, including type of alcohol-associated disease, had an independent effect. Adding ADH genotype provided no independent significant effect on MCV. Thus MCVs were not associated with ADH1C polymorphisms in a white population. In contrast to findings in Asians, macrocytosis does not seem to be an independent biomarker for esophageal cancer. The role of ADH1C polymorphism in increasing MCV and the potential use of MCV as a marker for esophageal carcinoma remain unclear. NIAAA Glossary Terms:  AODR biological markers, biological markers, mean corpuscular volume, macrocytosis, alcohol dehydrogenases, gene, genetic polymorphism, genotype, restriction fragment length polymorphism, polymerase chain reaction, White, Asian, gastrointestinal disorder, chronic AODE, esophageal disorder, carcinoma, alcoholic pancreatitis, multivariate analysis, univariate analysis, regression analysis, human study

Schade, Annemiek; Marquenie, Loes A.; van Balkom, Anton J.L.M.; Koeter, Maarten W.J.; de Beurs, Edwin; van den Brink, Wim; and van Dyck, Richard.  The effectiveness of anxiety treatment on alcohol-dependent patients with a comorbid phobic disorder: A randomized controlled trial.  Alcoholism: Clinical & Experimental Research 29(5):794-800, May 2005.

Summary: Recent evidence indicates that  alcohol-dependent patients with a comorbid anxiety disorder have a higher post-treatment relapse rate than alcohol-dependent patients without a comorbid anxiety disorder. This raises the question whether the relapse rate in these dually diagnosed patients could be reduced if they were given additional treatment for the comorbid anxiety disorder. The authors sought to answer this question by conducting a 32-week randomized controlled trial with abstinent patients (N = 96) with a primary diagnosis of alcohol dependence and a comorbid anxiety disorder involving agoraphobia or social phobia. The patients were randomly assigned to an intensive psychosocial relapse-prevention program alone (n = 49) or in combination with an anxiety treatment program comprising cognitive behavioral therapy and optional pharmacotherapy consisting of a selective serotonin reuptake inhibitor (SSRI; n = 47). The primary outcome measure was the percentage of patients who suffered an alcohol relapse during the 32-week period. The secondary outcome measures were total abstinence, a reduction in the days of heavy drinking, and less severe anxiety symptoms. The results indicated that the additional therapy clearly reduced anxiety symptoms but had no significant effect on alcohol relapse rates. NIAAA Glossary Terms:  AOD dependence, anxiety, comorbidity, dual diagnosis, treatment method, combined modality therapy, treatment outcome, agoraphobia, social phobia, relapse prevention, psychosocial treatment method, cognitive therapy, behavior therapy, drug therapy, serotonin uptake inhibitors, AOD abstinence, AOD use pattern, heavy AOD use, symptom severity, human study

Sterling, Stacy and Weisner, Constance.  Chemical dependency and psychiatric services for adolescents in private managed care: Implications for outcomes.  Alcoholism: Clinical & Experimental Research 29(5):801-809, May 2005.

Summary: The literature suggests that patients entering chemical dependency (CD) treatment with comorbid mental health problems have less successful outcomes. This study examined the impact of psychiatric services on treatment initiation, retention, and alcohol and drug abstinence outcomes for adolescents in CD treatment. The adolescents (N = 419) were aged 12-18 years who were seeking treatment at four CD programs of a nonprofit, managed care, group model health system and a parent or guardian for each adolescent. The participants were surveyed at intake and 6 months and clinical and administrative data on diagnoses and use of CD and psychiatric services were examined. Of the patients with treatment intakes, 55% had at least one psychiatric diagnosis in addition to a CD disorder. Compared with matched controls, patients with CD intakes had higher rates of depression, anxiety, eating disorders, attention deficit hyperactivity disorder, conduct disorder, and conduct disorder including oppositional defiant disorder. Of the full sample, 31% had psychiatric visits in the 6 months after intake; among those with a psychiatric diagnosis, 54% had a psychiatric visit. Girls and those with higher Youth Self-Report internalizing scores were more likely to have a psychiatric visit (odds ratio [OR] = 2.27, p < 0.001 and OR = 1.05, p < 0.0001 respectively). Adolescents receiving psychiatric services were more likely to be abstinent from both alcohol and drugs than those not receiving these services (OR = 1.57, 95% confidence interval [CI], 0.98-2.5) and more likely to be alcohol abstinent (OR = 1.68, 95% CI, 1.00-2.85). The adolescents at colocated clinics had higher odds of abstinence from both alcohol and drugs (OR = 1.57, 95% CI, 1.03-2.39) and drugs (OR = 1.84, 95% CI, 1.87-2.85) and of returning after intake to initiate CD treatment (OR = 2.28, 95% CI, 1.44-3.61, p < 0.001) than others. The results show the need for psychiatric treatment of adolescents in CD treatment and emphasize the importance of their receiving such services. NIAAA Glossary Terms:  AOD dependence, adolescent, comorbidity, mentally ill, psychiatric care, health care utilization, treatment outcome, controlled study, comparative study, emotional and psychiatric depression, anxiety, eating disorder, attention deficit disorder with hyperactivity, conduct disorder, gender differences, AOD abstinence, alcoholic beverage, illicit drug, human study

Harford, Thomas C; Grant, Bridget F; Yi, Hsiao-ye; and Chen, Chiung M.  Patterns of DSM-IV alcohol abuse and dependence criteria among adolescents and adults: Results from the 2001 National Household Survey on Drug Abuse.  Alcoholism: Clinical & Experimental Research 29(5):810-828, May 2005.

Summary: The validity of studies comparing the prevalence of alcohol abuse and dependence in adolescent surveys with the prevalence in adult general population surveys is diminished by differences in survey design and measurement. This study examined the effects of age, sex, race/ethnicity, and drinking status on the prevalence of alcohol abuse and dependence (including diagnostic orphans) and associated diagnostic criteria among adolescents and adults aged 12-65 years in a single representative sample of the US population. The study was based on data from the 2001 National Household Survey on Drug Abuse. Of the 55,561 subjects in the survey, 33,576 (60.5%) reported alcohol use in the past year and provided information on Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) alcohol use disorder (AUD) criteria. These criteria were assessed by questions related to specific symptoms occurring during the past 12 months. Overall, the most prevalent criteria of DSM-IV alcohol dependence were "tolerance" and "time spent obtaining alcohol, drinking, or getting over its effects." The most prevalent criterion of DSM-IV alcohol abuse was "hazardous use." The prevalence of alcohol abuse only and of dependence with and without abuse was highest among respondents aged 18-23 years, followed by respondents aged 12-17 years, and lowest among respondents aged 50 years and older. Among subgroups of current and heavier drinkers, differences between adolescents and young adults were less pronounced, especially among females. For each age group, the prevalence of alcohol abuse only was greater than the prevalence of dependence (with or without abuse). The abuse-to-dependence ratios also were generally consistent across age groups and slightly higher among males (2.1:1.0) than females (1.6:1.0). The higher prevalence for some dependence criteria among adolescents and young adults as measured in the present study may blur the distinction between symptom reports associated with the normative development of drinking patterns and clinically relev