bluuebunny/crossref_metadata_2025 huggingface dataset:
Electrophysiological Assessment (The Multiple Sleep Latency Test) of the Biphasic Effects of Ethanol in Humans
Authors: Papineau Kate L. , Roehrs Timothy A. , Petrucelli Nancie , Rosenthal Leon D. , Roth Thomas
Published: May 2006

The Multiple Sleep Latency Test (MSLT) was used to assess the effects of ethanol at the peak and descending phases of the breath ethanol curve. Ethanol (0.75 g/kg) was administered (at 0900 hr) to 8 healthy, normal‐sleeping men, aged 21 to 45 years old after 8 hr of sleep the previous night. MSLTs were conducted and breath ethanol concentrations (BrECs) were measured at 15, 45, 75, 105, 225, and 345 min after drinking was completed. Subjective measures were administered immediately before each sleep latency test. BrECs over the first 75 min (tests 1 to 3) peaked and differed from all subsequent tests (tests 4 to 6) over which BrECs declined. Sleep latency and subjective measures were averaged over tests 1 to 3 and 4 to 6. There was a significant increase in mean sleep latency relative to placebo for tests 1 to 3 and a significant reduction for tests 4 to 6. The subjective measure of stimulation sedation, the Biphasic Alcohol Effects Scale, showed lessened sedation after ethanol versus placebo on tests 1 to 3, compared with tests 4 to 6. This study confirmed the presence of a biphasic ethanol effect using an electrophysiological method (MSLT), showing increased physiological alertness on the peak phase of the BrEC curve and increased sedation on the descending phase. Relative to the effects observed on the MSLT with other low‐dose stimulant drugs, the stimulatory effect of ethanol was mild.
The Effects of Ethanol on Dopaminergic Neurons of the Ventral Tegmental Area Studied with Intracellular Recording in Brain Slices
Authors: Brodie Mark S. , Appel Sarah B.
Published: May 2006

Dopaminergic neurons in the ventral tegmental area of Tsai (VTA) have been implicated in the mediation of the rewarding effects of ethanol and many other drugs of abuse. Our previous extracellular studies in brain slices have demonstrated that ethanol increases the firing rate of dopaminergic neurons in the VTA. In the present intracellular study, ethanol (40–160 mM) increased the spontaneous firing rate of most (77%) VTA neurons. In addition, most (75%) VTA neurons were depolarized by ethanol. Ethanol also changed the shape of the spontaneous action potential in VTA neurons, reducing the amplitude of the spike after‐hyperpolarization (in 74% of neurons) and also reducing the amplitude of the depolarizing phase of the action potential (in 86% of neurons tested). Furthermore, analysis of Voltage/ Current curves in the presence and absence of ethanol showed that ethanol had little effect on the resistance of the cell membrane at membrane potentials near rest, but enhanced the time‐dependent inward rectification activated at more hyperpolarized membrane potentials (Ih). This intracellular study identifies several electrophysiological effects of ethanol that may underlie the ethanol‐induced excitation of VTA neurons and, therefore, may be important for the rewarding effects of ethanol.
Specificity of Neurobehavioral Outcomes Associated with Prenatal Alcohol Exposure
Authors: Jacobson Sandra W.
Published: May 2006

A current issue in alcohol research is whether a “neurobehavioral profile” can be identified for prenatal alcohol exposure, even when dysmorphic features are not present, or whether comparable neurobehavioral deficits are detected when damage is incurred by numerous neurotoxicants to which the fetus is exposed during a common developmental period. Failure to detect such differences may, in part, be an artifact of the global developmental tests used to assess outcome. Cognitive effects of prenatal exposure to three different teratogens [polychlorinated biphenyls (PCBs), alcohol, and cocaine] are examined to determine whether exposure to each substance results in a common or different pattern of impairment on the same set of newer, more narrow band infant tests. Comparison of findings from three independent cohorts indicate that PCB exposure was related to poorer recognition memory on the Fagan Test of Infant Intelligence (FTII) in Michigan infants exposed prenatally to PCB‐contaminated fish, whereas prenatal alcohol exposure was unrelated to recognition memory but to slower processing speed on a new FTII measure and slower reaction time on Haith's Visual Expectancy Paradigm (VExP) in our Detroit alcohol‐exposed infants. Preliminary findings from a new study of infants recently born to Taiwanese women accidentally contaminated with sizable amounts of PCBs indicate recognition memory deficits, confirming our Michigan findings, but no processing speed effects on the FTII. Recent findings from our Detroit cohort suggest that heavy prenatal cocaine exposure is related to poorer recognition memory on the FTII, but faster reaction times on the VExP, a pattern different from that seen for either PCBs or alcohol.
Neuropsychological Disorders in Children Exposed to Alcohol during Pregnancy: A Follow‐Up Study of 24 Children to Alcoholic Mothers in Göteborg, Sweden
Authors: Aronson Marita , Hagberg Bibbi
Published: May 2006

This paper reports on a follow‐up study of 24 children to alcoholic mothers at 12 to 14 years of age. The mothers were offered support to help them stop drinking during pregnancy and was grouped to time point of instituted sobriety. Six of the 24 children attended a school for the mentally retarded, and 11 children had some kind of special education. The children have difficulties in mathematics, logical conclusions, visual perception, spatial relations, and short‐range memory/attention. Sixteen children were in fostercare. A clear correlation between the occurrence and severity of neuropsychological problems and the degree of alcohol exposure in utero was found.
Relation of Maternal Age and Pattern of Pregnancy Drinking to Functionally Significant Cognitive Deficit in Infancy
Authors: Jacobson Joseph L. , Jacobson Sandra W. , Sokol Robert J. , Ager Joel W.
Published: May 2006

Prospective studies of the effects of prenatal alcohol exposure on development have focused primarily on the detection of subtle deficits. This study was designed to extend those findings by evaluating dose‐response, functional significance, and pattern of drinking in greater detail. 480 African‐American infants, recruited to overrepre‐sent prenatal exposure at moderate‐to‐heavy levels, were assessed. For the five outcomes tested, nonparametric and hockey stick regression analyses both indicated essentially no relation between pregnancy drinking and developmental outcome below a median threshold of 0.5 oz absolute alcohol/day, with the impact of the exposure increasing gradually above threshold. Functional deficit was defined in terms of performance in the bottom 10th percentile of the distribution. For four of the five outcomes tested, there was no increased incidence of functionally significant deficit in infants born to moderate‐to‐heavy drinking mothers < 30 years old, whereas those born to older drinking mothers were 2 to 5 times more likely to be functionally impaired. Among the infants exposed above threshold, functionally significant deficits were seen primarily in those whose mothers averaged at least 5 drinks/occasion on an average of at least once/week. By contrast, a history of alcohol abuse was not related to functional deficit. These data suggest that efforts to reduce the incidence of alcohol‐related functional impairment should specifically target the older mother who engages in intermittent heavy drinking during pregnancy.
Comparison of Local and Systemic Ethanol Effects on Extracellular Dopamine Concentration in Rat Nucleus Accumbens by Microdialysis
Authors: Yim Hyeon Joo , Schallert Timothy , Randall Patrick K. , Gonzales Rueben A.
Published: May 2006

To determine the site of action of systemic ethanol on dopaminergic function in the nucleus accumbens, we compared the effect of intraperitoneal (ip) and local administration of ethanol on interstitial dopamine concentration using microdialysis in freely moving rats. The ip administration of 1 g/kg of ethanol significantly increased the dialysate dopamine (DA) concentrations (∼40% above basal), compared with saline treatment. The concentration‐time profile of DA and ethanol in dialysates was similar after two ethanol injections 4 hr apart. Local perfusion with several ethanol concentrations showed that 510 and 860 mM of ethanol caused a significant concentration‐related increase in extracellular DA concentrations in the nucleus accumbens (510 mM, 28% increase; 860 mM, 62% increase). However, lower ethanol concentrations, 170 mM or below, failed to change basal DA concentrations. Stimulation with high potassium (50 mM) in artificial cerebrospinal fluid preceding local ethanol treatment increased dialysate DA concentrations to 523 ± 83% of basal levels, confirming that the DA terminals were responsive to pharmacological manipulation. Basal DA levels in dialysates were ∼70% calcium‐dependent when tested at the end of the local perfusion experiments. Stereological examination of the nucleus accumbens revealed probe‐induced damage, but did not detect additional damage by local perfusion of ethanol. When ethanol concentrations in the DA sampling area around the probe are taken into account in both systemic and local administration experiments, this study suggests that concentrations of ethanol associated with moderate intoxication do not directly affect the function of DA terminals in the nucleus accumbens. Therefore, the systemic effects of ethanol on nucleus accumbens DAergic function is more likely due to an interaction with sites other than the nucleus accumbens.
Alcohol‐Induced Upregulation of Plasminogen Activators and Fibrinolytic Activity in Cultured Human Endothelial Cells
Authors: Aikens Michael L , Grenett Hernan E. , Benza Raymond L , Tabengwa Edlue M. , Davis Glenda C. , Booyse Francois M.
Published: May 2006

Clinical studies suggest that moderate alcohol consumption may decrease the risk for coronary artery disease and myocardial infarction. This effect may be attributed, in part, to the alcohol‐mediated increase in endothelial cell (EC)‐mediated fibrinolytic activity mediated by the increase in synthesis and/or activity of tissue‐type plasminogen activators (t‐PAs) and/or urokinase‐type PA (u‐PAs). To determine whether low alcohol levels (0.01 to 0.1%, v/v) induced the expression of these proteins, cultured human saphenous vein ECs (HSVECs) were preincubated in the absence/presence of ethanol for 5 to 120 min at 37°C, washed, refed, and further incubated for 8 and 24 hr without alcohol. PA mRNA (reverse transcriptase‐polymerase chain reaction) and secreted antigen (ELISA) levels were analyzed after incubation for 8 and 24 hr and the net expression of (sustained) endogenous PA‐mediated surface‐localized HSVEC fibrinolytic activity (plasmin generation) quantitated by activation of125l‐Glu‐plas‐minogen after incubation for 24 hr. A brief 5 to 30 min preincubation (induction) of both t‐PA and u‐PA antigen increased ∼3‐fold (t‐PA control, 14.2 ± 1.7, plus alcohol, 25.4 ± 5 ng/ml; u‐PA control, 15 ± 0.8, plus alcohol, 46.4 ±1.3 ng/ml) and mRNA levels 2‐fold, as compared with controls. Increased PA expression was associated with a significant concomitant ∼ 2‐fold increase in surface‐localized fibrinolytic activity (control, 96 ± 2.8, plus alcohol, 255 ± 42 fmol/ well). These combined results indicate that a brief exposure (<30 min) to low levels of alcohol can induce synthesis of EC‐produced t‐PA and u‐PA resulting in an increased expression of HSVEC surface‐localized fibrinolytic activity and may account, in part, for the apparent cardioprotective benefit associated with moderate alcohol consumption.
Common Quantitative Trait Loci for Alcohol‐Related Behaviors and CNS Neurotensin Measures: Voluntary Ethanol Consumption
Authors: Gehle Vaughn M. , Erwin V. Gene
Published: May 2006

The C57BL/6, DBA/2, and recombinant inbred (RI) strains derived from them (B × D RIs) are the most frequently studied mouse strains with regard to genetic regulation of voluntary ethanol consumption (VEC). We have studied VEC in an alternate genetic model provided by the LS × SS RIs. These RI strains exhibit phenotypic extremes in VEC comparable to the C57BL/6 and DBA/2 mice and genotype‐dependent sex differences in drinking behavior. A correlational analysis between various ethanol‐related behaviors suggests genetic independence of VEC from high‐dose neurosensitivity (sleep time), acute ethanol tolerance, hypothermia, and low‐dose locomotor activity. A search for quantitative trait loci identified a number of putative quantitative trait loci (QTL), three of which are identical to those previously reported for 10% ethanol drinking in the B × D RIs. We also find a significant correlation between low‐affinity neurotensin receptor densities (NTRJ in the frontal cortex and VEC, and more common QTL between these two phenotypes than expected by chance. This suggests a role for frontal cortex NTRLin regulating voluntary ethanol intake
Effect of Pentylenetetrazole on Ethanol Intake, Ethanol Kinetics, and Social Behavior in Male Wistar Rats
Authors: Buczek Y. , Lê A. D. , Sellers E. M. , Tomkins D. M.
Published: May 2006

Stress and anxiety are often implicated in excessive alcohol use. The nature of this interaction, however, is not understood. The aim of this study was to examine the effect of the anxiogenic agent, pentylenetetrazole (PTZ), on the acquisition and maintenance of ethanol drinking behavior in male Wistar rats. In rats maintained on a limited access procedure, with a choice between a 12% w/v ethanol (ETOH) solution and water available for 30 min each day, acute PTZ administration (1.5 to 15.0 mg/kg) did not modify ETOH intake. Chronic PTZ administration elicited a significant suppression in ETOH intake; however, this effect developed gradually over time. During the acquisition phase, chronic PTZ treatment also suppressed ETOH consumption. Chronic, but not acute, treatment with PTZ seemed to enhance water consumption. To assess whether the effect of PTZ on ETOH intake was due to either alterations in ETOH kinetics or behavior, blood ETOH levels and social interaction behaviour were examined. PTZ (15.0 mg/kg) produced a significant suppression in social interaction behavior, although tolerance developed to this effect on chronic PTZ administration. Both acute and chronic PTZ treatment (15 mg/kg) resulted in lower blood ETOH levels achieved after administration of 1.0 g/kg po of ETOH. Because the anxiogenic effect of PTZ was not maintained on repeated administration, yet the suppression of ETOH intake was only observed after chronic treatment, this suggests a dissociation between the processes regulating these behaviors.
Involvement of κ‐Opioids in the Mouse Cerebellar Adenosinergic Modulation of Ethanol‐induced Motor Incoordination
Authors: Dar M. Saeed
Published: May 2006

Using rotorod performance as the test response, possible modulation and co‐modulation of ethanol‐induced motor incoordination by the cerebellar κ‐opioid and adenosine A1 receptors was studied. A dose‐related accentuation of ethanol‐induced motor incoordination was observed after direct cerebellar microinfusion of three κ‐opioid receptor agonists: U‐50488, U‐62066, and bremazocine. On the contrary, significant and dose‐related attenuation of ethanol's motor impairment was produced by intracerebellar nor‐binaltorphimine, a κ‐opioid receptor antagonist. Furthermore, the accentuation by κ‐agonists was virtually abolished by κ‐antagonist nor‐binaltorphimine. Therefore, the accentuation and attenuation by κ‐opioid receptor agonists/antagonist, respectively, was through specific κ‐opioid receptors. Pretreatment with the intracerebellar adenosine A1‐selective agonist, N6‐cyclohexyladenosine, further enhanced the ethanol‐induced motor incoordination and its accentuation by intracerebellar κ‐opioid receptor agonists. Ethanol‐induced motor incoordination was markedly attenuated by intracerebellar pertussis toxin (PTX) pretreatment, suggesting an involvement of PTX‐sensi‐tive G protein in the expression of motor incoordinating effect of ethanol. Additionally, the intracerebellar PTX also markedly attenuated the accentuation by κ‐opioid agonists of ethanol‐induced motor impairment, suggesting participation of PTX‐sensitive GTP‐binding G protein (Gi, Go in the κ‐opioid modulation of ethanol's motor impairment. It also confirms that κ‐opioid receptors are linked to PTX‐sensitive G protein. The functional similarity between κ‐opioid and adenosine A1 receptors in increasing ethanol's motor incoordination, together with their anatomical co‐localization primarily on the axons and axonal terminals of the cerebellar granule cells, suggests a possible common catalytic unit of adenylate cyclase as the basis of modulation of ethanol‐induced motor incoordination by both receptor mechanisms.
Induction of Fos‐Like Proteins and Ultrasonic Vocalizations during Ethanol Withdrawal: Further Evidence for Withdrawal‐Induced Anxiety
Authors: Knapp Darin J. , Duncan Gary E. , Crews Fulton T. , Breese George R.
Published: May 2006

The ethanol withdrawal syndrome includes anxiety as a prominent symptom. Because the extent that specific regions of brain are critical to the generation of this emotional state is unknown, Fos‐like immunoreactivity (Fos‐LI) was used to associate specific regions of the rat brain with the anxiety component of the ethanol withdrawal syndrome exacerbated by an air puff challenge in rats. Chronic ethanol liquid diet was administered intragastrically for 4 days or by having the rats consume the diet for 14 days. During withdrawal from either treatment protocol, Fos‐LI was induced most prominently in forebrain areas, although the midbrain and hindbrain were also represented. Included in these Fos‐LI positive regions were many cortical regions, septum, accumbens, claustrum, amygdala, paraventricular nucleus of the thalamus and hypothalamus, hippocampus, locus coeruleus, and central gray. Fos‐LI expression differed mostly in intensity between the two treatment and withdrawal protocols, with the gastric protocol producing the greatest Fos‐LI induction in most brain regions. The threshold for air puff‐induced ultrasonic vocalizations was decreased, and the number of vocalizations was increased and the period of vocalization was extended. These behavioral data indicate that aversively motivated responding in rats during ethanol withdrawal can be readily quantified with the ultrasonic vocalizations test without precipitating convulsive activity. Furthermore, a comparison of the effects of the air puff challenge versus withdrawal on Fos‐LI indicated that the behavioral state induced in these two situations share functional neuroanatomical features. Some regions–such as the accumbens core, medial septum, subregions of the amygdala, hippocampus, substantia nigra, and cerebellum–exhibited little Fos‐LI during withdrawal and also did not exhibit strong increases after the addition of the air puff challenge. However, other regions–such as the cerebral cortex (medial prefrontal, frontal, cingulate and ventrolateral orbital, claustrum, and tenia tecta), hypothalamus, and locus ceoruleus–exhibited Fos‐LI at levels higher than that seen after either the ethanol withdrawal or puff challenge alone. These overlapping patterns of Fos‐LI in specific regions of the brain, activated by both ethanol withdrawal and an anxiety provoking behavioral challenge, suggest that specific neuroanatomical sites in brain are associated with the symptom of anxiety observed during the “ethanol withdrawal syndrome.”
An Initial Study of the Relationship Between Platelet Adenylyl Cyclase Activity and Alcohol Use Disorder Criteria
Authors: Ikeda Hiroshi , Menninger John A. , Tabakoff Boris
Published: May 2006

Low platelet adenylyl cyclase (AC) activity has been previously proposed to be a trait marker reflecting a genetic predisposition to alcohol dependence. To determine whether low platelet AC activity in alcohol‐dependent subjects may be related to specific diagnostic criteria of DSM‐IV and ICD‐10 alcohol use disorders, we analyzed responses obtained in structured clinical interviews of 36 subjects who were determined to be alcohol‐dependent. Platelet AC activity when stimulated by guanylyl‐imidodiphosphate [Gpp(NH)p] or fors‐kolin was significantly lower in alcohol‐dependent subjects as a group, compared with controls. When we analyzed the responses of the alcohol‐dependent subjects to questions used to establish the diagnosis of alcohol abuse/dependence and dichotomized the subjects by positive or negative responses, we found that Gpp(NH)p‐and forskolin‐stimulated platelet AC activities were significantly lower among those alcohol‐dependent subjects who had positive responses to questions related to drinking despite negative effects on mood (“Did you ever continue to drink even though you knew it was making you feel depressed, uninterested in things, or suspicious or distrustful of other people?”), drinking despite negative effects on health (“Did you ever continue to drink even though you knew it was causing you a health problem or making a health problem worse?”), or violence when drinking (“Did you get into physical fights while drinking or right after drinking?”). The alcohol‐dependent subjects who had negative responses to these questions exhibited Gpp(NH)p‐and forskolin‐stimulated platelet AC activity that did not differ significantly from values in control subjects. The DSM‐IV diagnosis of antisocial personality disorder did not distinguish alcohol‐dependent subjects with regard to platelet AC activity. Gpp(NH)p and forskolin‐stimulated AC activity may distinguish certain subtypes of alcoholics (i.e., those who develop negative mood in response to drinking, those who continue drinking despite health effects, and those who become violent while drinking).
Investigation into the Use of Alcohol at Thermal Spas: Can a Spa Represent a Place for Primary Prevention?
Authors: Caputo Fabio , Addolorato Giovanni , Gaddi Antonio , Gasbarrini Giovanni , Bernardi Mauro , Stefanini Giuseppe Francesco
Published: May 2006

Primary prevention is one of the most effective means used nowadays to make the general population aware of most of the problems connected with health, but information campaigns have not yet shown results of alcohol‐related problems at thermal spas. The aim of this study was to assess the mean daily alcohol intake (grams/day) in a thermal spa population. The sample was conducted over a 6 month period and consisted of 290 subjects. The mean age was 59.01 years (range 23–89, SD ± 14.20) (150 males and 140 females). All of the subjects underwent a medical examination free of charge and an alcohol case history report. The medical staff working at the spa included two doctors, a biologist, a cardiologist, and a dietician. In the final 176 subjects studied, the mean daily alcohol intake was 32.33 g/day, significantly higher in the males than the females (p < 0.001). The 176 subjects were subsequently divided into three subgroups according to their daily alcohol intake: group A, <40 g/day; group B, 40 to 79 g/day; group C, ≥80 g/day. The number of subjects in group A was significantly greater than in group B and group C (p < 0.001). It is important to emphasize that 33.5% of the subjects studied presented a mean daily alcohol intake of ≥40 g/day and therefore were more exposed to the risk of the onset of alcohol‐related problems. In view of these results, thermal spas should thus be considered an additional place in which to identify subjects at risk for problematic use of alcohol and represent an environment in which primary prevention campaigns could be started.
Ethanol Acutely Decreases Calcium Transients in Cultured Human Myotubes
Authors: Nicolás Josep M. , Antúnez Emilia , Thomas Andrew P. , Fernández‐Solá Joaquim , Tobías Ester , Estruch Ramón , Urbano‐Márquez Alvaro
Published: May 2006

Ethanol consumption frequently leads to a number of skeletal muscle disorders, including acute and chronic alcoholic myopathy. Ethanol has been found to interfere with signal transduction mechanisms in cardiac and smooth muscle cells. We studied the effects of ethanol on the intracellular calcium ([Ca2+]) transients responsible for excitation‐contraction coupling in human myotubes from chronic alcoholic patients and healthy controls. Cultured myotubes were loaded with the fluorescent Ca2+ indicator fura‐2 and evaluated on a single‐cell basis. Following electrical stimulation, ethanol caused a significant reversible dose‐dependent reduction in [Ca2+], transient amplitude, achieving a mean decrease of 36 ± 5% at 300 mM ethanol (p < 0.01), without modifying the basal [Ca2+],. This acute effect of ethanol was similar in myotubes obtained from chronic alcoholics and controls. Similarly, ethanol caused a dose‐dependent reduction of [Ca2+], transient amplitude in control samples when depolarization was elicited by 100 mM KCl (p < 0.01). Several potential mechanisms of ethanol action were studied in control muscle samples. Sarcolemmal Ca2+ entry was measured indirectly by monitoring Mn2+‐quenching of intracellular fura‐2 via the nitrendipine‐sensitive Ca2+ channels during electrical pacing. Ethanol at doses of 100 mM and greater caused a dose‐dependent reduction in the rate of quench (p < 0.01). In addition, the intracellular pool of Ca2+ releasable by caffeine was found to be reduced at 300 mM ethanol (p < 0.05). We conclude that ethanol reduces the [Ca2+], transients underlying excitation‐contraction coupling in human myotubes, and that this occurs to a similar extent in cells obtained from chronic alcoholics and controls. This acute effect of ethanol was primarily due to an inhibitory effect of ethanol on sarcolemmal Ca2+ influx via voltage‐operated Ca2+ channels, although there may also be an effect on the Ca2+ sarcoplasmic reticulum loading state.
The Reinforcing Effects of Ethanol Are Altered by the Endogenous Neurosteroid, Allopregnanolone
Authors: Janak Patricia H. , Redfern Jane E. M. , Samson Herman H.
Published: May 2006

We examined the effect of systemic administration of the endog‐enously occurring progesterone metabolite, allopregnanolone, on oral self‐administration of ethanol by male rats. Rats were trained to perform an operant response for presentation of 0.1 ml of a solution of 10% ethanol in water using the sucrose fading technique. After acquisition of stable lever‐press responding on a fixed‐ratio 4 schedule, subjects received subcutaneous injections of 1,3, or 10 mg/kg of allopregnanolone, or vehicle, 20 min prior to the self‐administration session. Pretreatment with 3 mg/kg, but not 1 or 10 mg/kg, increased the mean total number of lever press responses made to obtain ethanol, and therefore increased the mean total number of ethanol presentations. The number of responses and response rate were examined as a function of the number of “runs” within the 30‐min session; a “run” was defined as a series of consecutive responses with an interresponse interval of <1 min. The increase in total responses after 3 mg/kg was due in part to an increased number of responses for the first run of the session, with no effect on response rates. However, the higher dose of 10 mg/kg decreased response rates within the first run. Thus, allopregnanolone alters ethanol‐reinforced responding at concentrations lower than those that depress rates of responding. The effects of administration of the ben‐zodiazepene, diazepam, were determined for comparison with those of the neurosteroid. The subcutaneous injection of 0.3, 1.0, or 3.0 mg/kg of diazepam did not produce any clear dose‐dependent changes in measures of ethanol‐reinforced operant responding, supporting the suggestion of differences in the contribution of the benzodiazepene and neurosteroid binding sites to GABAA receptor function. The results indicate that exogenous administration of allopregnanolone dose‐dependently alters ethanol‐reinforced operant responding, and suggest that this endogenously occurring neurosteroid could mediate some of the reinforcing effects of ethanol.
Taste Reactivity to Alcohol and Basic Tastes in Outbred Mice
Authors: Kiefer Stephen W. , Hill Katherine G. , Kaczmarek Helen J.
Published: May 2006

The taste reactivity test was used to determine the response of out‐bred mice to orally infused taste solutions. For the initial measures, mice (n= 10) were tested with 3%, 6%, 9%, and 12% (v/v) alcohol and four taste solutions: sucrose, sodium chloride, hydrochloric acid, and quinine hydrochloride (a single concentration of each). A second group of naive mice (n= 16) was tested with 5%, 10%, 20%, 30%, and 40% alcohol. The final set of measures with naive mice (n= 26) was taken with a range of sucrose concentrations: 0.01 M, 0.05 M, 0.1 M, 0.5 M, and 1.0 M. In general, mice made similar reactivity responses to all solutions tested. A predominant component of the mouse response to all infused fluids was forelimb flailing; gaping was also a common response to all solutions. Despite the large number of aversive‐type responses, mice rejected very little fluid via passive drip or fluid expulsion. The single, significant difference in responding to the four taste stimuli was that mice made fewer aversive responses to sucrose. Differential responding to the 5 to 40% alcohol concentrations and sucrose concentrations was observed. Mice increased ingestive responding as the concentration of alcohol and sucrose increased. Aversive responding decreased reliably only with increases in the sucrose concentration. Data provide the first reported taste reactivity responses of mice to orally infused taste solutions. These results can be compared with the extant data available in rats and can also be used as a basis for exploring taste factors in genetically defined mouse populations.
Studies on the Enzymology of Aldehyde Dehydrogenase‐2 in Genetically Modified HeLa Cells
Authors: Crabb David , Xiao Qing
Published: May 2006

The Asian flush reaction is known to result from a lysine for glutamine substitution in the aldehyde dehydrogenase 2 (ALDH2) gene. This mutation was studied in HeLa cells transduced with retroviruses carrying the ALDH2E (wild‐type) and ALDH2K (variant) cDNAs. The cells expressed high levels of the enzyme protein that had the same pl and enzymatic characteristics as the corresponding liver enzyme. When cells expressing ALDH2E were transduced with ALDH2K expressing retrovirus, the ALDH2 activity was reduced roughly in proportion to the amount of ALDH2K mRNA expressed, indicating a dominant suppression of activity. The half‐life of the wild‐type enzyme was 22 hr, while that of variant enzyme was 14 hr. The half‐lie of the enzyme in cells expressing both cDNAs was 13 hr, indicating that the shorter half‐life of the variant was also dominant. These data are consistent with a model in which the wild‐type homodimers have normal activity and turnover, while the heterodimers have reduced to virtually no activity and increased turnover. The model predicts residual ALDH2 activity in heterozygotes of about 13% of that in individuals homozygous for ALDH2*1, in good agreement with experimentally determined values.
Use of Transfected Liver Cells to Evaluate Potential Mechanisms of Alcohol‐Induced Liver Injury
Authors: Hill Daniell B. , McClain Craig J. , Clair Daret St. , Barve Shirish
Published: May 2006

There is increased activity of the proinflammatory cytokine, tumor necrosis factor (TNF) in alcoholic liver disease (ALD). Hepatic neutrophil infiltration is a principal injurious manifestation of ALD. TNF can induce cellular oxidative injury directly, and indirectly by inducing neutrophil chemotactic factor (IL‐8) production by hepatocytes. IL‐8 activates and chemotactically attracts neutrophils to the liver where they release oxidizing substances. Patients with ALD also have decreased protective factors for cellular oxidative injury. Manganous superoxide dismutase (MnSOD) is an antioxidant protective factor. The objectives of these studies were to investigate mechanisms for induction of an injurious factor (IL‐8) and a protective factor (MnSOD) in the HepGP human hepatoma cell line. In the first set of experiments, IL‐8 gene reporter constructs were used to transiently transfect a derivative (MVh2E1‐9) of the HepG2 cell line which expresses P‐4502E1 and metabolizes ethanol. Inactivation of the NF‐κB and 3′NF‐IL‐6 DNA binding sites decreased IL‐8 gene transcriptional activation in response to TNF while inactivation of the 5′NF‐IL‐6 binding site increased IL‐8 gene transcriptional activity in response to TNF. This system may be useful to assess the effects of ethanol on TNF‐induced hepatocyte IL‐8 production. In the second set of experiments, HepGP cells were cultured in 25 to 100 mmol concentrations of ethanol. Both TNF and ethanol increased HepGP cell MnSOD activity in short‐term (72 hr) cultures with ethanol. However, after long‐term (10 weeks) culture with ethanol, there was no induction of MnSOD by ethanol and there was a diminished induction of MnSOD in response to TNF. Further studies are needed to assess the effect of this diminished induction of MnSOD with chronic ethanol culture on HepG2 cell susceptibility to TNF cytotoxicity. We conclude that transfected liver cell lines can be used to evaluate mechanisms for increased injurious factors and decreased protective factors in alcoholic liver injury.
Anger in an Inpatient Treatment Sample of Chronic Alcoholics
Authors: Tivis Laura J. , Parsons Oscar A. , Nixon Sara J.
Published: May 2006

Four measures of anger were investigated in sober male and female alcoholics and nonalcoholic peers. The relationships among anger variables, past drinking behavior, and substance abuse consequences in alcoholics were explored. Additionally, the interrelationships among anger, depression, and anxiety in the groups were examined, and the relationships between an overall dysphoria index and drinking behavior and substance abuse consequences were determined. 104 alcoholics (sober 21 to 45 days) and 70 community controls, aged 21 to 56, were given the Spielberger Anger Expression Inventory, the Beck Depression Inventory, and the Spielberger State Anxiety Inventory. Alcoholics scored higher than controls on Trait Anger, Anger‐In, and Anger‐Out, but not on State Anger. There were no main effects of sex. Anger‐In was significantly negatively correlated with the Quantity‐Frequency Index in alcoholic males. Anger‐In was significantly positively correlated with depression in male and female alcoholics and with substance abuse consequences in the latter group. The depression measure was significantly correlated with consequences in female, but not in male alcoholics. These data have treatment implications, especially for female alcoholics.
Effects of Ethanol on Temporal Recovery of Auditory‐Evoked Potentials in Individuals at Risk for Alcoholism
Authors: Cohen H. L. , Porjesz B. , Stirnus A. T. , Begleiter H.
Published: May 2006

The present investigation examined the effects of placebo (P), low dose (LD), and high dose (HD) ethanol on auditory event‐related potential (AEP) recovery functions in a group of males at high risk to develop alcoholism (HR; n= 23, mean = 22.3 years) and a low risk (LR; n= 27, mean = 23.0 years) control group. Condition order was randomized, with one condition (P, LD, or HD) per day and a minimum 1‐day interval between conditions. For each subject, both blood alcohol levels (BALs) measured via breathalyzer, and event‐related potentials recorded with the entire 10/20 International System, were assessed prior to and at mean intervals of 20, 60, 90, and 130 min after P, LD, or HD administration. A series of binaural auditory stimuli with randomly interposed interstimulus intervals of 0.5, 1.0, and 10.0 sec were used to elicit the N100 and P200 components of the AEP. Between‐groups comparisons indicated that ethanol elicited risk group differences in recovery functions not present at baseline. The differences were manifested in the HR group as larger decrements in P200 amplitude during the ascending blood alcohol curve (acute sensitivity) and more rapid returns of both N100 and P200 to baseline levels during the descending blood alcohol curve (acute tolerance). These findings support Newlin and Thomson's (1990) Differentiator Model, suggesting that LR and HR individuals are differentially sensitive to the effects of ethanol.
Long‐Term Ethanol Consumption Selectively Impairs Ganglioside Pathway in Rat Brain
Authors: Ghosh Pradeep , Ender Ingo , Hale Eric A.
Published: May 2006

Gangliosides are sialo‐glycosphingolipids that play important roles in the interaction of cells with their environment and are thus involved in the regulation of many cellular events. Sialic acid residues are important for the conformation of a glycomolecule, their structural stability and their functions. Although decreased brain ganglioside sialic acid has been previously reported as a result of chronic ethanol treatment in rats, no reports are available on the sialylation of specific gangliosides and/or the mechanism leading to depletion of their sialic acid residues. Therefore, in this investigation, we have examined the effects of chronic ethanol treatment on (1) incorporation of [4,5‐3H]N‐acetylmannosamine (ManNAc) into specific rat brain gangliosides, GD3, GD1a, GT1a, and GT1b; and (2) enzymatic activities of brain sialyltransferase and sialidase at specific subcellular levels. The experiments were done in male Wistar rats pair‐fed with either ethanol or control liquid diets for a period of 8 weeks. The rats were intracerebroventriculatly injected with labeled ManNAc (30 μCi/rat) and killed after 90 min. Radioactivity was determined in respective ganglioside bands separated on a thin layer chromatography system. Specific activities of sialyftansferase and sialidase were assessed using GM, and GD, as substrates, respectively. The results showed significant decreases of 57.7% (p < 0.001) and 68.9% (p < 0.001), respectively, in the labeled ManNAc incorporation into GD3 and GD1a fractions in rats of the ethanol group, compared with rats of the control group. No significant changes were noted in the incorporation of labeled ManNAc into GT1a or GT1b ganglioside fractions between the ethanol and control groups. Concomitantly, compared with control rats, a decrease of 18.9% (p < 0.05), 20.6% (p < 0.05), and 15.8% (p < 0.001) was found in the sialyltransferase activity, respectively, at the whole brain, and brain Golgi and synaptosomal levels. However, dramatic increases of 32.4% (p < 0.05), 105% (p < 0.001), and 150% (p < 0.001) in sialidase activity were found, respectively, at the whole brain and brain cytosol and synaptosomal fractions of rat treated chronically with ethanol. Thus, we conclude that the deleterious actions of ethanol on the sialylation of rat brain gangliosides is specific, and the reduced sialic acid label found in GD3 and GD1a in this study is mainly due to increased activity of brain sialidase. Furthermore, the study reaffirms our tenet that, regardless of whether it is the liver or the brain, glycosylation cascade is one of the main target of the deleterious attacks of ethanol.
The Effects of Chronic Ethanol Consumption on the Formation of Phosphatidylethanolamine Molecular Species and Their Appearance at the Plasma Membrane
Authors: Seenaiah Biradavolu , Bichenkov Evgeny , Ellingson John S.
Published: May 2006

The purpose of our study was to determine whether chronic ethanol consumption affected membrane assembly by altering the formation of specific molecular species of phosphatidylethanolamine (PE) and their subsequent incorporation into the plasma membrane (PM). We investigated the effects on the PE species made by the two major pathways in hepatocytes: (1) from CDP‐ethanolamine in the endo‐plasmic reticulum, and (2) by the decarboxylation of phosphatidylserine (PS) in the mitochondria. Ethanol consumption exerted significant effects on the formation of ethanolamine‐derived PE species and affected mainly two species, the 16:0/22:6 and 180/20:4 species. In cultured hepatocytes from ethanol‐fed rats labeled with methanolamine for 0.25 to 4 hr, the amount of the [3H]16:0/22:6 PE species was decreased compared with that in control cells, whereas the amount of [3H]1 80/20:4 species was increased. The amount of the [3H]1 6:0/22:6 PE species on the cell surface was also decreased in hepatocytes from ethanol‐fed rats, whereas the amount of [3H]18:0/20:4 species was increased. In contrast, the profile of [3H]PE species formed in cells treated with [3H]serine exhibited minor alterations, and the profile of the serine‐derived [3H]PE species on the cells surface was not altered after 4 hr of labeling. The changes in ethanolamine‐derived species were apparently caused by time‐dependent alterations in the metabolic processes, because the presence of 110 mM ethanol in the culture media did not affect the profiles of [3H]PE species in cells from control or ethanol‐fed rats and was not required to sustain the altered profiles. The results indicate that the synthesis of specific PE molecular species and their appearance on the PM may occur by compartmentalized processes which are distinguishable by different sensitivities to ethanol consumption. The results indicate that ethanol consumption may contribute alcoholic hepatic injury by interfering with the metabolism of specific PE molecular species and their assembly into the PM.
Development of Rapid Tolerance to Ethanol‐Stimulated Serotonin Release in the Ventral Hippocampus
Authors: Bare Dan J. , McKinzie Jamie H. , McBride William J.
Published: May 2006

This study was designed to examine the effects of acute intraperitoneal (ip) ethanol injection on the extracellular levels of serotonin (5‐HT) in the ventral hippocampus (vHIP) and to determine whether a single prior exposure to ethanol could alter the response to a second dose of ethanol given 24 hr later. In the first experiment, in vivo microdialysis coupled with high pressure liquid chromatography‐electrochemical detection (HPLC‐EC) was used to assess the effects of 1.0,1.75, and 2.5 g/kg ethanol on vHIP 5‐HT extracellular levels in ethanol‐naive adult male Wistar rats. The largest dose significantly increased the extracellular concentration of 5‐HT (p < 0.001) to a maximum of approximately 180% of baseline values within 50 min; thereafter, the levels of 5‐HT began to return toward baseline. The 1.75 gkg dose also transiently increased 5‐HT levels above baseline; however, no significant increase was observed with 1.0 g/kg ethanol. The results of the second experiment demonstrated that the ip dose of 2.5 g/kg ethanol had no significant effect on the extracellular levels of 5‐HT if rats had been given a single ip 2.5 g/kg dose of ethanol 24 hr earlier. Because the vHlP receives a major 5‐HT input from the median raphe nucleus (MRN), the results suggest that acute ethanol activates the MRN 5‐HT system projecting to the vHIP and that rapid tolerance develops to the activating effects of alcohol on this pathway.
Bone Age and Growth in Fetal Alcohol Syndrome
Authors: Habbick Brian F. , Blakley Patricia M. , Houston C. Stuart , Snyder Richard E. , Senthilselvan A. , Nanson J. L.
Published: May 2006

We have found delayed mean bone age in 63 children with fetal alcohol syndrome (FAS). The mean bone age Z‐score for boys (n= 31) was −2.12 SDs and for girls (n= 32) was ‐1.62 SDs. This might suggest that they have potential for catch‐up growth. However, experience with children with intrauterine growth retardation suggests that this will not be the case and that FAS children will be of reduced height at maturity. Further support for this assumption was gained from a sample of 26 patients who were followed until at least the age of 14 years for females and 16 years for males. There was no significant change in height Z‐scores from early childhood to early adulthood, the mean score being ‐2.16 SDs and ‐2.11 SDs at mean ages of 4.83 years and 18.69 years, respectively. On the other hand, there were significant changes in weight and head circumference. The mean weight Z‐score changed from ‐2.10 SDs to ‐1.14 SDs (p < 0.001). The head circumference mean Z‐score in 16 patients was ‐3.13 SDs at a mean age of 2.79 years and ‐2.63 SDs at a mean age of 17.37 years (p= 0.013). Short stature can continue to be used as a diagnostic criterion for FAS beyond childhood.
Compliance with Treatment and Follow‐up Protocols in Project MATCH: Predictors and Relationship to Outcome
Authors: Mattson Margaret E. , Del Boca Frances K. , Carroll Kathleen M. , Cooney Ned L. , DiClemente Carlo C. , Donovan Dennis , Kadden Ronald M. , McRee Bonnie , Rice Christopher , Rycharik Robert G. , Zweben Allen
Published: May 2006

Treatment and follow‐up session attendance data from Project MATCH, a multisite clinical trial investigating patient‐treatment matching, were analyzed to study compliance. High rates of compliance to both therapy and research protocols were achieved, enhancing treatment integrity and data quality. Strong baseline predictors of compliance did not emerge, and the small relationships found were consistent with reports from previous studies. Attendance at therapy sessions was moderately correlated with research follow‐up participation. Treatment compliance predicted drinking outcome, underscoring the importance of retaining patients in treatment. Future studies should examine the associations between compliance and structural features of the treatment environment, treatment delivery, and context‐features that are often under the control of the clinician/investigator.
Association of Alcohol or Other Drug Dependence with Alleles of the μ Opioid Receptor Gene (OPRM1)
Authors: Kranzler Henry R. , Gelernter Joel , O'Malley Stephanie , Hernandez‐Avila Carlos A. , Kaufman Daniel
Published: May 2006

Opioidergic neurotransmission and, specifically, the μ opioid receptor have been implicated in the reinforcing effects of a variety of drugs of abuse. Consequently, the present study examined the association of a polymorphic (CA)n repeat at the OPRM1 locus (the gene coding for the μ opioid receptor) to alcohol or drug dependence in 320 Caucasian and 108 African‐American substance‐dependent or control subjects. Among Caucasians, suggestion of a modest association, which could be interpreted as statistically significant (p= 0.03), was observed between OPRMl alleles and substance (alcohol, cocaine, or opioid) dependence. Analysis by specific substance showed only a trend level association to alcohol dependence. Comparisons among African Americans yielded no evidence for association. Further studies of the association between alleles of the OPRM1 gene and substance dependence appear warranted, particularly if they use a family‐based approach to control for population stratication. Phenotypes other than a broad diagnostic categorization, such as opioid antagonist effects on drinking behavior in alcoholics, may provide more consistent evidence of a role for OPRMl in behavioral variability.