bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of Ethanol on Plasma and Hepatic Insulin‐Like Growth Factor Regulation in Pregnant Rats
Authors: Breese Charles R. , Sonntag William E.
Published: April 2006

Alcohol consumption during pregnancy has been shown to have profound developmental and behavioral effects on the fetus; however, the specific cause of these abnormalities remains unknown. These studies examined the consequences of chronic ethanol exposure during pregnancy on the regulation of maternal plasma and hepatic insulin‐like growth factors (IGFs), and their associated plasma binding proteins (IGF‐BPs). Ad libitum, pair, and ethanol‐fed rats were fed a commercial liquid diet containing either ethanol or isocaloric maltose‐dextrin from day 2 of pregnancy through parturition and killed 6 hr postpartum. Maternal plasma IGF‐1 concentrations were reduced 51 % in ethanol, compared with pair‐fed mothers, with a corresponding 20% reduction in hepatic IGF‐1 mRNA levels. In contrast, plasma IGF‐2 concentrations were increased ∼100% in ethanol‐fed mothers. Whereas the smaller forms of the IGF‐binding protein subunits (24 kDa and 32–29 kDa) were not affected by ethanol treatment, a significant reduction was observed in the binding sub‐unit of IGF‐BP3 (640 kDa) in ethanol‐exposed mothers. These results suggest that alterations in plasma and hepatic IGF regulation may contribute to changes in maternal and placental metabolism and hormone regulation during pregnancy, which may in turn contribute to the intrauterine and postnatal growth retardation observed in prenatally ethanol‐exposed offspring.
Behavioral Effects and Pharmacokinetics of Propofol in Rats Selected for Differential Ethanol Sensitivity
Authors: Liu Yong , Fay Tina , Deitrich Richard A.
Published: April 2006

High‐ and low‐alcohol sensitivity (HAS and US) rats have been selected for their differences in ethanol‐induced sleep time. The rats also differ in sensitivity to pentobarbital, halothane, isoflurane, and enflurane. To determine if this sensitivity extended to propofol, the anesthetic requirements were measured. In this study, the sleep time and the tissue levels of propofol at awakening, as well as the pharmacokinetics, were evaluated. Propofol was administered intravenously. For one group of rats, sleep times were measured; blood and brain samples were taken at awakening. Blood samples were collected in another group of rats at frequent Intervals from 0 to 90 min after Injection. Propofol concentration of the samples was determined by gas chromatography. The pharmacokinetic analysis was performed using a nonlinear least‐squares regression program. Sleep time was not different; however, blood and brain propofol levels at awakening showed a small, but significant difference between HAS and IAS rats. Propofol blood concentration‐time curve data were fitted to a three‐compartment model. Pharmacokinetic parameters were also not different between the rat lines. However, sleep time was 50% longer in female rats than male rats in both strains (p < 0.0001). The rates of propofol clearance were slower in female rats, because of different rates of disappearance from the second compartment. The observations suggest that the genetic selection for ethanol sensitivity selection for propofol sensitivity was not nearly as intense and presumably involves some different genes. These two central nervous system dressings would seem to differ significantly in their mechanism of action. The differential sleep times produced by propofol in the male and female rats are caused by pharmacokinetic differences.
Chronic Ethanol Consumption Alters Effects of Ethanol In Vitro on Brain Membrane Structure of High Alcohol Sensitivity and Low Alcohol Sensitivity Rats
Authors: Avdulov Nicolai A. , Chochina Svetlana V. , Draski Laura J. , Deitrich Richard A. , Wood W. Gibson
Published: April 2006

In this study, we examined if differences in initial membrane sensitivity to ethanol were associated with development of membrane tolerance to ethanol. High Alcohol Sensitivity (HAS) and Low Alcohol Sensitivity (US) rats were administered a 15% ethanol solution in water as the sole source of fluid for 30 days. The amount of ethanol consumed per day did not significantly differ between the HAS and LAS rats. Development of membrane tolerance to in vitro effects of ethanol has been previously reported for bulk membrane fluidity and protein‐lipid interaction. Our data expands the understanding of “membrane tolerance” phenomenon to protein distribution and bi‐layer interdigitation. We also introduce genotype‐dependent and genotype‐independent properties of the membrane tolerance to ethanol. Chronic ethanol treatment produced genotype‐dependent and genotype‐independent membrane tolerance to ethanol. The in vitro effects of ethanol on synaptic plasma membrane (SPM) protein distribution and lipid bilayer interdigitation were abolished or decreased in the SPM of chronic ethanol‐treated HAS rats, as compared with the SPM of HAS control rats (genotype‐dependent tolerance). Protein distribution and bilayer interdigitation were not affected by ethanol in vitro in either chronic ethanol‐treated or control LAS rats. Genotype‐independent tolerance to ethanol in vitro was observed for SPM annular and bulk bilayer fluidity in chronic ethanol‐treated HAS and LAS rats. It is concluded that initial sensitivity to ethanol contributes to the development of membrane tolerance to ethanol in HAS and LAS rats.
Regional Differences in the Effects of Chronic Ethanol Administration on [3H]Zolpidem Binding in Rat Brain
Authors: Devaud Leslie L. , Morrow A. Leslie , Criswell Hugh E. , Breese George R. , Duncan Gary E.
Published: April 2006

A strong association has been observed between [3H]zolpidem binding and the presence of γ‐aminobutyric acid (GABAA) receptor mRNA for α1‐, β2‐, and γ2‐subunits in specific brain regions. This correlates with observed sensitivity of individual neurons to zolpidem and ethanol in these same regions. Previous studies using homogenate binding approaches showed small alterations in [3H] zolpidem binding levels after chronic ethanol exposure. This study was undertaken to ascertain if there is regional specificity of the effects of chronic ethanol administration on [3H] zolpidem binding levels. Chronic ethanol administration induced small, but significant alterations in [3H] zolpidem (5 nM) binding in the Inferior colliculus, substantia nigra, and the medial septum. [3H]Zolpidem binding was increased in the inferior colliculus and substantia nigra, and decreased in the medial septum. No significant differences in [3H] zolpidem binding were noted in any other brain area analyzed, including the cortex and cerebellum. These findings show that chronic ethanol administration has small effects on [3H] zolpidem binding, although they occur in a site‐specific and bidirectional manner. Moreover, there is no correlation between changes in [3H] zolpidem binding and alterations In GABAA receptor subunit expression.
Alcohol‐Metabolizing Enzyme Polymorphisms and Alcoholism in Japan
Authors: Maezawa Yoshihiko , Yamauchi Masayoshi , Toda Gotaro , Suzuki Hitoshi , Sakurai Susumu
Published: April 2006

The liver enzymes, alcohol dehydrogenase (ADH) and aldehyde de‐hydrogenase (ALDH), which are responsible for the oxidative metabolism of ethanol, are polymorphic in humans. Cytochrome P450IIE1, an ethanol‐inducible isozyme of liver microsomal P450, is also important in ethanol metabolism. Genetic polymorphisms in the 5′‐flanking region of the human cytochrome P450IIE1 gene have recently been reported. We hypothesized that the polymorphisms of ADH, ALDH, and P450IIE1 modify the susceptibility to development of alcoholism. We determined the genotypes of the ADH2, ALDH2, and P450IIE1 loci of 96 Japanese alcoholics and 60 healthy male subjects, using leukocyte DNA by the restriction fragment‐length polymorphism by polymerase chain reaction. The alcoholics had significantly higher frequencies of the ADH21 and ALDH21 alleles than did the healthy subjects. No significant difference in the frequency of the P45011E1 genotype was observed between the alcoholics and the healthy subjects. In conclusion, genetic polymorphisms of the ADH and ALDH genes, but not of the P45011E1 gene, influence the risk of developing alcoholism in Japanese.
Effects of Hostility on Alcohol Stress‐Response‐Dampening
Authors: Zeichner Amos , Giancola Peter R. , Allen Joseph D.
Published: April 2006

The purpose of this study was to compare the stress‐response‐dampening (SRD) effect of alcohol in hostile and nonhostile men based on a combined score of four subscales of the Cook‐Medley Hostility Scale. Subjects were 72 male social drinkers. Subjects' cardiac interbeat‐interval, and systolic and diastolic blood pressure reactivity to a situational stressor were measured following the consumption of either alcohol, no alcohol, or an active placebo beverage. Results demonstrated that hostile men evinced lower heart rate and systolic blood pressure (SBP) reactivity to the stressor when given alcohol, compared with intoxicated nonhostile subjects, and lower reactivity relative to all other groups, with the exception of SBP in the nonhostile controls. These results allow for speculation that hostile men may be more likely than controls to experience possible SRD effects of alcohol and thus, perhaps, be predisposed to increased alcohol consumption when under stress.
Effects of Cerebral Electrical Stimulation on Alcoholism: A Pilot Study
Authors: Padjen A. L. , Dongier M. , Malec T.
Published: April 2006

Cerebral electrical stimulation (CES), born from research on electroanesthesia in the seventies, consists of the application of a pulsating current of small intensity (usually less than 1 mA, and below the threshold of perception) through the skull, e.g., in daily 30‐min sessions.

Claims of biological effectiveness (neurochemical, hormonal and EEG changes, naloxone‐reversible analgesia in rats, etc.) and of clinical effectiveness (anxiety, depression, cognitive functions in alcoholics) have often relied on poorly controlled data. A recent controlled study in the treatment of opiate withdrawal has been positive. The present double‐blind controlled study compares active CES with sham stimulation in 64 alcohol‐dependent males. Over 4 weeks, both treatment groups improved significantly in most aspects. In the active treatment group additional significant improvement was observed in week‐end alcohol consumption, and in two psychological measures: depression and stress symptoms index, but not in general drinking behavior.
Alcohol Schema Acquisition in Preschoolers: Differences Between Children of Alcoholics and Children of Nonalcoholics
Authors: Zucker Robert A. , Kincaid Stephen B. , Fitzgerald Hiram E. , Bingham C. Raymond
Published: April 2006

Cognitive schemas provide the structure within which children organize their knowledge and beliefs about the use of alcohol. The development of schemas about alcohol should be affected both by age and parental patterns of alcohol use. We examined differences in alcohol schema development among 139 male children of alcoholics (COAs) and 82 controls [children of nonalcoholics (NCOAs)] utilizing the Appropriate Beverage Task as an indicator of these processes. Overall, the vast majority of the sample identified at least one alcoholic beverage from photographs, even at age 3. COAs were more likely to identify at least one alcoholic beverage. With age controlled, COAs were better able to identify specific alcoholic beverages and correctly identified a larger number of alcoholic beverages. There was a trend for these children of alcoholic men to attribute more alcoholic beverage use to male adults than NCOAs. Moreover, differences in these children's attributions of alcoholic consummatory behavior were predicted by their parents' current consumption levels. Results provide evidence that alcohol schemas are detectable in early childhood and are more common in children from alcoholic homes. Discussion focuses on the potential relevance of these risk attributes to the development of more fully formed alcohol expectancies and to the later emergence of alcohol‐related difficulty.
Hon v. Stroh Brewery Company: What Do We Mean by “Moderate” and “Heavy” Drinking?
Authors: Abel Ernest L. , Kruger Michael L.
Published: April 2006

Although widely used, drinking terms such as “light,”“moderate,” and “heavy” are unstandardized and, as a result, public health messages using these terms may convey confusing information. As an initial attempt in providing such standardization, the present study surveyed public definitions for these terms. “Light” drinking was operationally defined as 1.4–2.4 drink/day; “moderate” drinking was defined as 2.5–3.6 drink/day; and “heavy” drinking was defined as 3.7 drinks/day and above. These ranges, however, were dependent on the respondent's gender, age, socioeconomic status, and especially the respondent's self‐reported tolerance. Males had a higher threshold of consumption for “moderate” and “heavy” drinking than women. Older respondents likewise assigned a higher threshold for these terms than younger respondents. As respondent income increased, the threshold for “heavy” drinking decreased. The heaviest drinkers had a higher threshold for assigning the “heavy” label than did any other group. Ethnicity did not significantly affect these ranges, and religion only affected the threshold for “heavy” drinking.

Because researchers ultimately rely on terms such as “moderate” or “heavy” to communicate their findings to colleagues and the public, it would seem apposite for them to agree on operational definitions for such terms. It would also seem appropriate to consider the operational definitions the public uses when referring to these terms to promote credibility of research findings and appropriate changes in behavior.
A Test of Tiffany's Cognitive Model of Drug Urges and Drug‐Use Behavior
Authors: Bradiua Clara M. , Lisman Stephen A. , Payne David G.
Published: April 2006

Tiffany's (1990) cognitive model proposes that drug urges and drug use result from distinct (i.e., controlled versus automatic) cognitive processes. This study tested Tiffany's cognitive model utilizing innovative methods derived from the Multiple Resource Theory of cognitive psychology. Forty‐two male and 42 female heavy drinking college students were assigned to 1 of 6 groups in two separate 1 (task) × 3 (treatment) factorial experiments in which half the subjects performed a math task while the other half performed a tracking task. Subjects received 1 of 3 treatments Urge generation, “Drug” (Placebo) Consumption, or a Water control. The predictions were that urges would interfere with performance on the math task, and “drug” consumption would interfere with performance on the tracking task. The main dependent variables were measures of task performance. The results of this study do not clearly support the model; however, several suggestions for future tests of the cognitive model are discussed. Our findings highlight both the difficulty in testing the model, as well as opportunities for further integration of cognitive psychology and behavioral approaches to addictions.
Brain Proton Magnetic Resonance Spectroscopy Studies in Recently Abstinent Alcoholics*
Authors: Martin Peter R. , Gibbs S. Julian , Nimmerrichter Amanda A. , Riddle William R. , Welch Larry W. , Willcott M. Robert
Published: April 2006

Chronic alcohol‐dependent patients have reduced brain volumes and concomitant neurobehavioral deficits that may recover during abstinence. In 10 chronic alcoholic patients, using localized proton magnetic resonance spectroscopy, we found reliable increases during the first 3–4 weeks of abstinence in the concentrations within the superior cerebellar vermis of choline (Cho)‐containing compounds relative to the neuronal marker, N‐acetylaspartate (NAA). Lesser changes were observed following 1 month of abstinence, and in one of the patients studied longitudinally over 3 months, a marked reduction in the Cho/NAA ratio was associated with relapse. After detoxification, the Cho/NAA ratio correlated with a composite clinical impression of brain functions. The lowest Cho/NAA was observed in a patient with persisting alcoholic dementia, in striking contrast to reduced relative concentrations of NAA reported in dementia of the Alzheimer's type. Possible molecular explanations for these brain metabolic changes are discussed.
Use of Lymphocytes for Assessing Ethanol‐Mediated Alterations in the Expression of Hepatic Cytochrome P4502E1
Authors: Raucy Judy L. , Curley Gerald , Carpenter Susan P.
Published: April 2006

The ethanol‐inducible cytochrome P4502E1 (2E1) is involved in the bioactivation of numerous hepatotoxins and hepatocarcinogens. Because high levels of expression may enhance the degree and severity of hepatotoxicity from exposure to chemicals metabolized by this enzyme, a relatively noninvasive method to phenotypically distinguish those individuals exhibiting elevated concentrations of 2E1 may be useful. With this in mind, we examined whether ethanol exposure could alter 2E1 in rabbit white blood cells and liver in a similar manner. Microsomes prepared from freshly isolated, rather than cultured cells, were used to immunochemically detect 2E1. The enzyme was found in lymphocytes and neutrophils. Lymphocytes, which comprise the majority of the white cell population in rabbits, were monitored for changes in 2E1 protein levels after ethanol exposure and compared with alterations of the hepatic enzyme. Results presented herein demonstrate that the degree of enhancement in 2E1 expression of lymphocytes and liver was dependent on the length and dose of alcohol exposure. Indeed, correlations were observed between blood alcohol concentrations and 2E1 content in lymphocytes (r= 0.65, p < 0.01) and liver (r= 0.60, p < 0.01). The greatest increase in 2E1 (6‐ to 10‐fold) occurred in both liver and lymphocytes at a dose of 15% ethanol for 12 days of treatment. This induction was evident regardless of whether blood was taken from treated and compared with untreated rabbits or if white cells were obtained from the same animal before and after ethanol exposure. The latter findings demonstrate that changes in lymphocyte 2E1 were caused by ethanol exposure and not to variability in enzyme expression among rabbits. Interestingly, at the 10% dose, elevation of 2E1 was noted as early as 3 days, declined at 6 days, and at 12 and 24 days returned to slightly higher levels than those seen at the 3‐day exposure period. This pattern of 2E1 elevation was observed in both the liver and lymphocytes, in fact, at all exposure periods and at the two doses of alcohol examined, a correlation (r= 0.70, p < 0.01) was observed between lymphocyte and liver 2E1 content. Collectively, these studies show that induction of 2E1 in lymphocytes and liver occurs in a parallel fashion. Furthermore, results suggest that blood 2E1 may be used in humans as a phenotypic marker for xenobiotic‐promoted alterations in the expression of the liver enzyme. These findings should have a significant impact on in vivo monitoring of this P450 enzyme.
The Class I Alcohol Dehydrogenase Gene Is Glucocorticoid‐Responsive in the Rat Hepatoma Microcell Hybrid Cell Line, 11–3
Authors: Majewski Jessica L. , Yang Vincent W.
Published: April 2006

Expression of the class I alcohol dehydrogenase (ADH) gene in the rat hepatoma microcell hybrid cell line, 11–3, was examined. The steady‐state level of ADH mRNA in 11–3 was ∼2‐fold higher than that of rat liver and Fao, the parental cell line of 11–3. Removal of steroid hormones by activated charcoal from the serum in which 11–3 cells were maintained resulted in a significant decrease in the level of ADH transcript. Dexamethasone at a concentration of 1 μM increased the ADH mRNA content in 11–3 in a time‐dependent fashion, up to 48 hr after its addition to cells that had first been deprived of steroid hormones. In addition, levels of ADH transcript in cells treated with dexamethasone increased in a dose‐dependent manner, and the concentration of dexamethasone required to achieve half‐maximal activation was 5 nM. By using the techniques of reverse transcription and polymerase chain reaction, and by taking advantage of a restriction polymorphism present between the rat and mouse ADH cDNA, we found that 11–3 contained both the rat and mouse class I ADH transcripts, although the rat sequence accounted for the great majority. Moreover, levels of both rat and mouse class I ADH transcripts increased in a similarly time‐dependent manner in cells treated with dexamethasone. These results indicate that expression of class I ADH gene in 11–3 is high and is regulated by glucocorticoids, making the cell line an excellent model for the in vitro study of ADH expression.
Selective Effects of Ethanol on the Generation of cAMP by Particular Members of the Adenylyl Cyclase Family
Authors: Yoshimura Masami , Tabakoff Boris
Published: April 2006

A selective action of ethanol on major signal transduction proteins, such as adenylyl cyclase, has been considered to be important for certain actions of ethanol, and alcoholics have been demonstrated to differ from controls in measures of platelet adenylyl cyclase activity. Recent advances in identification and characterization of isoforms of adenylyl cyclase have demonstrated that there exists at least eight different forms of this enzyme. To examine whether the effect of ethanol on generation of cAMP is modified by the presence of particular isoforms of adenylyl cyclase within a cell, we transiently expressed each of six adenylyl cyclases in human embryonic kidney (HEK293) cells and measured cAMP accumulation in whole cells in the presence and absence of ethanol. The treatment of cells expressing the various adenylyl cyclases with ethanol alone did not enhance cAMP generation. In the presence of prostaglandin E1, cAMP generation by type I and type III adenylyl cyclases was insensitive to ethanol cAMP accumulation generated by the other adenylyl cyclases was, however, increased by incubation of cells with ethanol in the presence of stimulatory agonists (e.g., prostaglandin E1). Stimulation by ethanol of cAMP generation by type VII adenylyl cyclase was 2‐ to 3‐fold greater than that seen with the other tested adenylyl cyclases. The noted stimulation of cAMP generation by ethanol was dose‐dependent and required concurrent activation of adenylyl cyclase through the stimulatory G protein. The effects of ethanol were reversible and mimicked by butanol but not by chloroform.
Effect of Ethanol on the Synthesis of Insulin‐Like Growth Factor 1 (IGF‐1) and the IGF‐1 Receptor in Late Prepubertal Female Rats: A Correlation with Serum IGF‐1
Authors: Srivastava Vinod , Hiney Jill K. , Nyberg Christopher L. , Dees W. Les
Published: April 2006

For several years, it has been well accepted that insulin‐like growth factor 1 (IGF‐1) plays a critical role in peripubertal growth. Recently, we have provided evidence to suggest that this peptide may also be involved in the sexual maturation process, via an action to stimulate hypothalamic luteinizing hormone releasing hormone release. Because ethanol (ETOH) delays puberty, an event that is associated with depressed growth rates and decreased growth hormone and luteinizing hormone (LH) secretion via actions at the hypothalamic level, we investigated whether this drug is capable of altering the expression of genes encoding IGF‐1 in liver and brain, as well as the expression of the type 1 IGF receptor (IGF‐1R) within the median eminence (ME). Also, we wanted to determine if any regional changes in the expression of these genes were associated with concomitant alterations in the serum levels of IGF‐1 and LH. Rats were implanted with gastric cannulae on day 24 and began receiving specific control or ETOH diets on day 29. Rats were killed on day 34, determined to be in the late juvenile stage of development, and their tissues and blood were collected. Results indicate that the ETOH‐fed rats showed a decrease (p < 0.01) in the expression of hepatic IGF‐1 mRNA when compared with the controls, and this paralleled depressions in both serum IGF‐1 (p < 0.01) and LH (p < 0.01). In contrast, no changes were detected in IGF‐1 mRNA expression in the preoptic area and hypothalamus, as well as in IGF‐1 R mRNA expression within the ME. These results suggest that the well‐known detrimental effects of ETOH on growth rates and the progression of the female pubertal process in the rat may be associated with the drug's ability to depress the hepatic synthesis of IGF‐1 and the subsequent prepubertal circulating levels of the protein.
Adult Male Rats Exposed to an Alcohol Diet Exhibit a Blunted Adrenocorticotropic Hormone Response to Immune or Physical Stress: Possible Role of Nitric Oxide
Authors: Rivier Catherine
Published: April 2006

Intact adult male rats fed an alcohol [ethanol (EtOH)] diet for 10 days show blunted adrenocorticotropic hormone (ACTH) release in response to immune signals such as the cytokine interleukin‐1β (IL‐1β) and endotoxin [lipopolysaccharide (LPS)], as well as to physical stress (mild electroshocks). The mechanisms responsible for this effect remain poorly understood, but we have recently reported that decreased pituitary responsiveness to vasopressin (VP) might play a role. In naive rats, nitric oxide (NO) exerts a restraining influence on the response of the hypothalamic‐pituitary (H‐P) axis to cytokines and VP. The ability of long‐term EtOH treatment to increase glutamate receptors, and thus NO formation, prompted us to test the hypothesis that abnormally high NO concentrations might modulate the influence of the drug. Blockade of the activity of NO synthase (NOS), the enzyme responsible for NO formation, with the arginine derivative l‐Nωnitro‐l‐arginine‐methylester (l‐NAME), augmented the ACTH response to IL‐1β or LPS in both control (C) and EtOH‐fed (E) rats. Indeed, after l‐NAME treatment, ACTH concentrations were statistically comparable in C and E animals injected with endotoxin or a large dose of IL‐1β. VP‐induced ACTH secretion also became comparable in both experimental groups after blockade of NOS activity. In contrast, the decreased response of the H‐P axis of E animals to shocks was only slightly ameliorated, compared with that of C rats. It is therefore possible that changes in the NOergic tone induced by alcohol play a role in the decreased response of the H‐P axis to cytokines, possibly in part by altering the stimulatory action of VP on the corticotrophs. On the other hand, in E rats NO seems to exert only a minimal influence on the central nervous system circuits activated by shocks.
Age‐Dependent Inhibition of Long‐Term Potentiation by Ethanol in Immature Versus Mature Hippocampus
Authors: Swartzwelder H. Scott , Wilson W. A. , Tayyeb M. I.
Published: April 2006

The goal of this study was to assess the effects of ethanol on the induction of long‐term potentiation (LTP) in hippocampal slices from immature versus mature rats. Population excitatory postsynaptic potentials (pEPSPs) were recorded from stratum radiatum of area CA1 of hippocampal slices using electrical stimulation of the Schaffer collateral/commissural fiber pathway. The slices were prepared from rats aged 15 to 25 or from 70 to 100 days. Long‐term potentiation (LTP) of the pEPSP slope was induced using a single, θ‐burst stimulus train in the presence or absence of 60 mM ethanol. Under control conditions, the stimulus train induced LTP in slices from both immature and mature animals. However, the magnitude of LTP was greater in slices from immature rats. When ethanol was present during the stimulus train, the magnitude of LTP in slices from mature animals did not differ significantly from the magnitude of LTP in control slices. However, ethanol virtually blocked the induction of LTP in slices from immature animals. These results indicate that memory‐related synaptic plasticity in the hippocampus is attenuated by ethanol to a greater degree in immature versus mature animals.
Generation of Neurons in the Rat Dentate Gyrus and Hippocampus: Effects of Prenatal and Postnatal Treatment with Ethanol
Authors: Miller Michael W.
Published: April 2006

Neurons in the rat hippocampal formation (the dentate gyrus and the hippocampus) are born over a protracted period, from gestational day (G) 15 into adulthood. Dentate gyral neurons born prenatally are generated from the ventricular zone, whereas those born postnatally are derived from a secondary proliferative zone, the intrahilar zone. In contrast, hippocampal pyramidal neurons are generated only prenatally from the ventricular zone. In the neocortex, ethanol depresses the proliferation of cells in the ventricular zone and stimulates the proliferation of cells in the secondary proliferative zone. The present study tests the hypotheses that prenatal treatment with ethanol has a different effect on the generation of dentate gyral neurons than does postnatal ethanol treatment, and that these differences are determined by the timing of the ethanol exposure relative to the period and site of neuronal generation.

Rats were treated with ethanol between G6 and G21 or between postnatal day (P) 4 and P12. They were given an injection of [3H]thymidine on G15, G18, G21, P6, P9, or P12. Rats were killed on P30–P35. The tissue was processed by standard autoradiographic methods and assessed using rigorous stereological procedures. The total number of neurons and the density of radiolabeled neurons in both the dentate gyrus and the CA1 region of the hippocampus were determined.

Prenatal ethanol treatment decreased the total number of neurons in the CA1 segment of the hippocampus and had little impact on neuronal number in the dentate gyrus. Likewise, the number of hippocampal and dentate gyral neurons generated daily was significantly lower in ethanol‐treated rats than in controls. Postnatal treatment to ethanol, however, significantly increased the total number of dentate gyral neurons and the density of neurons generated postnatally. These postnatal changes depended on the blood ethanol concentration (BEC). At moderate BECs, the total number of neurons in the dentate gyrus and the number of neurons generated was increased. At high BECs, however, neuronal number and neuronal generation were decreased. Postnatal ethanol treatment had no effect on the number of (total or radiolabeled) CA1 neurons.

Thus, pre‐ and postnatal exposure to ethanol have opposite effects both on the number of neurons in the dentate gyrus and on the generation of neurons. These paradoxical effects likely result from three causes: the differential effects of ethanol on the two proliferative zones, the critical period of neuronal development, and the potentially opposite effects of moderate and high BEC.
Preadolescent Conduct Disorder Behaviors Predict Relapse and Progression of Addiction for Adolescent Alcohol and Drug Abusers
Authors: Myers Mark G. , Brown Sandra A. , Mott Mariam A.
Published: April 2006

Increased awareness of the heterogeneity among alcohol and drug abusers has led to examination of the influence of concomitant psychopathology on the course of addiction and addictive relapse. Research among adult alcohol and drug abusers has found a detrimental influence of comorbid psychopathology on treatment outcome. Evidence exists for prevalent comorbidity, in particular conduct disorder (CD), among clinical samples of teen alcohol and drug abusers. However, little information is currently available on the relation and influence of psychopathology on outcome after treatment for adolescent alcohol and drug abuse. The current study examines the relation between CD, as assessed by the extent of preadolescent CD behaviors occurring before the initiation of drug use, and outcome for 131 adolescents over 2 years after inpatient treatment for alcohol and drug abuse. Drawing on recent conceptualizations of the process of relapse and progression of addictive behavior, CD is hypothesized to influence the process of relapse by altering coping efforts and intentions and increasing exposure to potential relapse situations. Results reveal that the extent of preadolescent CD behaviors is positively related to alcohol involvement in the 2 years after treatment, and that much of this relation is accounted for by posttreatment cognitive coping, motivation for alcohol abstinence, interpersonal problems, and exposure to alcohol use. Contrary to expectations, preadolescent CD behaviors did not predict posttreatment drug use. These findings provide evidence for the influence of psychopathology on the process of relapse and progression of addiction after treatment for adolescent alcohol and drug abuse, and suggest that teens with early life CD behaviors may be at greater risk for continued alcohol abuse.
Lack of Plasma Complement Activation in Severe Acute Alcoholic Hepatitis
Authors: Bird G. L. A. , Lau J. Y. N. , Davies E. T. , Williams R. S.
Published: April 2006

To investigate whether complement pathway activation contributes to the clinical and histological features of acute alcoholic hepatitis, we studied the activation of the classical and alternative pathways in patients with alcoholic hepatitis (n= 20), inactive alcoholic cirrhosis (n= 8), heavy drinkers without alcoholic liver disease (n= 10), patients with liver disease of nonalcoholic etiology (n= 11), and healthy control subjects (n= 18). Complement activation was evaluated in the alcoholic hepatitis patients by its correlation with a number of clinical and laboratory features indicative of the severity of liver injury, as well as by comparison of the patient groups. There was no significant difference in circulating C3 [1.02 g/liter, confidence interval (CI) = 0.76–1.28] or C4 (0.25 g/liter, CI = 0.17–0.33) in patients with alcoholic hepatitis when compared with the four control groups. Factor B levels (0.24 g/liter, Cl = 0.21–0.27) were higher in the alcoholic hepatitis patients than the control groups (p < 0.01). However, activation of complement (given by the ratios C3d/C3, C4d/C4, and Ba/factor B) was not different in alcoholic hepatitis patients when compared with the control groups. Univariate analysis of a wide range of clinical and laboratory features in the alcoholic hepatitis subjects showed a positive correlation between plasma C3 and serum alkaline phosphatase (r= 0.68, p= 0.0014), AST (r= 0.55, p= 0.015), and γ‐glutamyltranspeptidase (r= 0.47, p= 0.035), but no correlation with clinical or laboratory features associated with high morbidity or mortality. There is no relationship between clinical or laboratory indicators of disease severity and complement activation, and it is unlikely that complement activation contributes to the clinical and histological features of alcoholic liver disease.
A Fetal Alcohol Syndrome Screening Tool
Authors: Astley Susan J. , Clarren Sterling K.
Published: April 2006

The purpose of this study was to derive a multivariate, quantitative case definition of the fetal alcohol syndrome (FAS) facial phenotype from a dysmorphologist‐derived gold standard and use it to develop an effective screening tool for identification of children at risk for FAS. The facial and physical features of a racially mixed group of children (0.2–10.0 years of age), evaluated by a single dysmorphologist in the University of Washington FAS Clinic, were used to determine which feature or set of features best differentiated between children with and without a diagnosis of FAS. The study population was divided into two groups balanced on gender, age at examination, race, diagnosis, and date of examination. Group 1 was used to identify the most differentiating feature(s), and group 2 was used to validate the differentiating capability of the feature(s). Group 1 included 97 children (20 with FAS and 77 without FAS). Group 2 included 97 children (19 with FAS and 78 without FAS). Discriminant analysis identified smooth philtrum, thin upper lip, and short palpebral fissures as the cluster of features that best differentiated children with and without FAS based on the discriminant function [D = 1.7953086 + 0.8116083 (thin upper lip) + 2.6411562 (smooth philtrum) ‐ 3.4073780 (% predicted right palpebral fissure length)]. Patients with a D‐score ± 1.5 were classified as at‐risk for FAS (screen positive). Using this cut‐off value for the D‐score, children in group 1 were classified with 100% sensitivity (20 of 20 true positives) and 90.0% specificity (70 of 77 true negatives). The children in group 2 were classified with 100% sensitivity (19 of 19 true positives) and 87.3% specificity (68 of 78 true negatives). Across all 194 patients, sensitivity was 100% [95% confidence interval (97–100)] and specificity was 89% [95% confidence interval (85 to 93)]. Seventy‐one percent (n= 12) of the 17 false‐positives had a true classification of possible fetal alcohol effects. Sensitivity and specificity were unaffected by race, gender, and age through 10 years. This screening tool is effective at differentiating children with and without FAS as diagnosed by a single dysmorphologist (S.K.C.) at the University of Washington FAS Clinic. Assessment of diagnostic interrater agreement between trained dysmorphologists and testing in other clinic populations will be needed to assess the tool's external validity.
Trends in Alcohol‐Related Mortality among New Mexico's American Indians, Hispanics, and Non‐Hispanic Whites
Authors: Gilliland Frank D. , Becker Thomas M. , Samet Jonathan M. , Key Charles R.
Published: April 2006

Reduction of alcohol‐related mortality is a national goal for health promotion and disease prevention. We conducted this analysis to determine whether trends in New Mexico's Hispanics, non‐Hispanic Whites, and American Indians were consistent with national trends in alcohol‐related mortality, and whether differences in drinking patterns could account for racial and ethnic differences in rates. Age‐adjusted, race‐specific, and ethnic‐specific alcohol‐related mortality rates and 95% confidence intervals were calculated for 5‐year periods for 1958–1991 using New Mexico vital statistics data. We estimated the prevalence of acute and chronic at‐risk drinking behaviors and abstinence from data collected by the Behavioral Risk Factor Surveillance System (BRFSS) for the period 1986–1992. We found that alcohol‐related mortality rates varied substantially by race, ethnicity, sex, age, and calendar period. American Indians had the highest rates for both sexes. Rates increased sharply from the period 1958–1962 until the late 1970s and the early 1980s, and then began to decrease rapidly. However, during the most recent decade, the rates have followed contrasting trends in the three ethnic and racial groups. Although rates have continued to decline among non‐Hispanic Whites, rates for Hispanics and American Indians have not declined, and still remain substantially higher than rates during the 1958–1962 period. Differences in at‐risk drinking behaviors reported to the BRFSS do not explain the contrast in race‐specific and ethnic‐specific mortality rates. Although progress has been made in reducing national per capita alcohol consumption and alcohol‐related mortality, certain high‐risk racial and ethnic groups may not be sharing in the progress.
D‐Fenfluramine‐Induced Prolactin Responses in Postwithdrawal Alcoholics and Controls
Authors: Farren Conor K. , Ziedonis Douglas , Clare Anthony W. , Hammeedi Faiq A. , Dinan Timothy G.
Published: April 2006

Serum prolactin response to the serotonin agonist d‐fenfluramine were measured in 19 DSM‐111‐R male alcoholics, 2.5 or more weeks postalcohol withdrawal. Prolactin responses were compared with nine healthy nonalcoholic male controls. After an overnight fast, each subject received 30 mg of d‐fenfluramine orally, and serial samples of serum prolactin were taken over a 4‐hr period. d‐fenfluramine caused a significantly attenuated peak δ‐prolactin response in the alcoholics relative to the controls (p= 0.05). A repeated‐measures ANOVA of δ‐prolactin yielded a significant within‐subjects effect of time (p < 0.05), a within‐subjects effect of group that reached significance (p= 0.05), and a nonsignificant group by time interaction. The δ‐prolactin value at time points 60 and 240 min postadministration of the probe was significantly attenuated in the alcoholic group, with p < 0.05. There was also some evidence for a diminished serotonergic response in those alcoholics with a negative family history. The δ‐prolactin response did not correlate with subjects'age, duration of alcohol use, duration of abstinence from alcohol, severity of alcohol dependence, or age of onset. Results imply a relative sub‐sensitivity of the serotonin system in postwithdrawal alcoholics, and this may be primarily of the 5‐HT2 receptor.
Beverage Effects on Patterns of Alcohol Consumption
Authors: Rio Carmen Del , Prada Carlos , Alvarez F. Javier
Published: April 2006

In this paper an analysis is made of beverage preferences and their effect on alcohol consumption patterns. For this purpose we have used the 1993 Spanish National Household Health Survey conducted on members of the population aged 16 or over. Beer and spirits are consumed more frequently by young people and wine by older people. The most consumed daily drink is wine and beer on a weekly basis. Men always drank more frequently and consumed a greater number of drinks per occasion than women for the three types of drink analyzed. The study shows that beverage preference is an important factor in the characterization of alcohol use patterns.
Computational Modeling of a Putative Fetal Alcohol Syndrome Mechanism
Authors: Whitmire David , Bowen J. Phillip , Shim Joong‐Youn , Whitmire Paula S.
Published: April 2006

Fetal alcohol syndrome (FAS) refers to a pattern of birth defects occurring in a subpopulation of children born to women who consume alcohol during pregnancy. The significant medical, social, and economic impact of FAS is increasing. Particularly hard‐hit are African‐American and native‐American women and children. Over the past two decades, basic and clinical research produced voluminous data on ethanol effects on developing organisms. In 1991, Duester and Pullarkat proposed that competition of ethanol with retinol at the alcohol dehydrogenase (ADH) binding site formed the basis of the FAS mechanism. This competition adversely affects the developing fetus caused by deregulation of retinoic acid (RA) homeostasis essential for proper fetal tissue development. Stated concisely, the FAS hypothesis is:

Class I ADH catalyzes the rate‐limiting step in oxidation of retinol (ROH) to RA, and ethanol (ETOH) to acetic acid, thus establishing competition for ADH between ROH and ETOH.

RA is required as a signal molecule for cell differentiation critical for normal fetal morphogenisis.

ADH binds ingested ETOH, thus deregulating RA homeostasis leading to improper RA signal transduction.

Preliminary results from molecular modeling studies of ROH‐ADH and ETOH‐ADH structures, and physiologic pharmacokinetic modeling confirm the hypothesis with remarkable fidelity.
Voice of the Victims
Authors: Erickson Carlton K.
Published: April 2006

Over the past 10 years, I have been privileged to conduct educational forums for audiences containing many recovering alcoholics or otherwise chemically dependent persons. In these forums about the addictive diseases and their treatment and research possibilities, significant interaction with the audience members occurs. During these interactions, certain anecdotal phenomena seem to predominate. The repetitive nature of these reports suggests the need for systematic investigation. As with editorial comments in major medical journals, observed phenomena and unanswered questions from the victims can be valuable in the generation of testable hypotheses. Perhaps the ideas presented herein will be useful in the development of future research on alcohol abuse and alcohol dependence.
Tuberculosis in the 1990s
Authors: Bass John B.
Published: April 2006

The steady decline in tuberculosis case rate reversed in the mid‐1980s, and tuberculosis cases have increased dramatically since that time. Important factors contributing to this increase are the human immunodeficiency virus (HIV) epidemic and tuberculosis occurring in foreign‐born persons. Tuberculosis outbreaks have occurred in HIV clinics and wards, prisons, homeless shelters, nursing homes, and health care facilities. Some of the outbreaks have involved strains of tuberculosis resistant to multiple antituberculosis drugs. Recent recommendations for initial therapy of tuberculosis include the use of four drugs and directly observed therapy in an effort to prevent the emergence of further drug resistance.
Pulmonary Host Defenses
Authors: Reynolds Herbert Y.
Published: April 2006

Well functioning host defenses in the respiratory tract effectively remove microbes and other debris that reach the conducting airways and alveoli, and this usually prevents infections. People with acute and chronic illnesses can experience failure of any number of these defense mechanisms that allow pneumonia (and bacteremia) to occur, often with considerable morbidity and mortality. People with alcohol‐related illnesses are a susceptible group for infections, and many strategies are needed to help them such as moderating alcohol abuse and dependence, providing timely immunizations to create antibody against encapsulated bacteria, anticipating microbial colonization of mucosal areas that can promote infection, giving excellent supporting medical care in crisis situations, and prescribing appropriate antibiotics. New approaches to boosting inflammatory reactions to control lung infections better with cytokines and new immunomodulator therapies must be investigated now.
Antisocial Tendencies and Cortical Sensory‐Evoked Responses in Alcoholism
Authors: Hegerl U. , Lipperheide K. , Juckel G. , Schmidt L G. , Rommelspacher H.
Published: April 2006

Alcohol‐dependent patients with antisocial, aggressive, and impulsive behaviors form a subgroup, in which a dysfunction of the brain serotonin system is discussed as a pathogenetic factor. Early onset and a transmission from fathers to sons (type II alcoholism; Clon‐inger, 1987) are supposedly further characteristics of this subgroup. The response pattern of primary auditory cortices to auditory stimuli with different intensities is discussed as a noninvasive indicator of the level of central serotonergic neurotransmission. A strong intensity dependence of these responses is supposed to indicate low serotonergic neurotransmission and vice versa. A strong intensity dependence is therefore expected to characterize patients with antisocial tendencies. Auditory‐evoked potentials (N1/P2 component) to stimuli in five different intensities were recorded in 53 hospitalized patients after 1 week of withdrawal. Dipole source analysis was performed to separate responses of primary and secondary auditory cortices. Patients with antisocial tendencies showed a significantly stronger intensity dependence of their evoked responses of primary auditory cortices (tangential dipoles). Age at onset and family history were not related to the intensity dependence of the evoked responses. The results support the notion that alcohol‐dependent patients with strong intensity dependence and antisocial tendencies form a subgroup with a serotonergic hypofunction. These patients may respond favorably to a relapse prevention with serotonergic drugs.