bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of a Stimulant‐Focused Enhanced Program on the Outcome of Alcohol‐ and/or Stimulant‐Dependent Men
Authors: Smith Tom L. , Volpe Fredric R. , Hashima Jason N. , Schuckit Marc A.
Published: May 2006

Background

: The approaches to the treatment of most forms of substance dependence are similar. It is not clear whether specific treatment components need to be added to address specific substances. This study asks two questions: What is the impact of a more intense drug treatment program, and do different substance problems require different treatment interventions?

Methods

: The 383 veterans included in this study represent two groups of consecutive inpatient male admissions with current alcohol dependence and/or dependence on amphetamines or cocaine at the inpatient Alcohol and Drug Treatment Program of the Veterans Affairs San Diego Healthcare System. All were interviewed at intake by trained interviewers using a standardized semistructured assessment instrument, and a resource person interview also was conducted with 85% of them. The first group of men received the Standard Treatment Program (STP), whereas the second group received the Enhanced Treatment Program (ETP). The latter included an addition of 10 hr per week of intense treatment aimed at stimulants, including two newly developed manual‐driven groups (Relapse Prevention and Interpersonal Counseling), each of which met twice a week.

Results

: The patient follow‐up was 92% at 3 months and 83% at 12 months. Abstinence from substances of abuse for ETP and STP were 63% vs. 49% at 3 months and 43% vs. 24% at 12 months. Logistic regressions demonstrated that treatment type continued to predict outcome even in the context of other potentially predictive variables.

Conclusions

: Despite the ETP emphasis on stimulants, both alcohol‐ and stimulant‐dependent men appeared to benefit, suggesting a generic improvement in substance use.
Long‐Term Alcohol Consumption in the Rat Affects Femur Cross‐Sectional Geometry and Bone Tissue Material Properties
Authors: Hogan H. A. , Groves J. A. , Sampson H. W.
Published: May 2006

Background

: Alcohol consumption previously has been demonstrated to reduce the density and strength of cortical bone of young, actively growing rats. Osteoblast activity and trabecular bone volume were also significantly lower. A germane question arising from these studies is whether the detrimental effects would persist into adulthood. To address this issue, a long‐term study was undertaken with animals that consumed alcohol throughout their life and into old age.

Methods

: One‐month‐old female Sprague‐Dawley rats were divided into three diet groups: alcohol‐fed, pair‐fed, and chow‐fed. The alcohol‐fed animals received a modified Lieber‐DeCarli diet that contained 35% ethanol‐derived calories. The pair‐fed group served as a caloric‐equivalent control, and the chow‐fed animals served as a completely untreated control. Animals were euthanized after five time periods on the diets that represented three stages of the life span: young (3 months), adult (6, 9, 12 months), and aged (18 months). The left femur was isolated and mechanically tested in 3‐point bending for mechanical properties.

Results

: In the young animals, alcohol consumption produced dramatic reductions in both extrinsic (whole bone) and intrinsic (tissue material) properties, which is consistent with results from previous studies on growing rats. For the adult animals, however, the alcohol groups were only slightly lower and the differences were not statistically significant. The aged animals showed diminished properties due to alcohol, but only for the intrinsic material properties. The extrinsic properties remained similar to controls as a result of greater radial expansion in the femur diaphysis. Despite the cross‐sectional areas being the same, this expansion gave rise to higher cross‐sectional moment of inertia values in the alcohol animals. The thickness of the cortical wall was lowest in the alcohol group at all time points.

Conclusions

: Long‐term alcohol consumption produced two major effects in the oldest animals studied: the quality of the cortical bone tissue was diminished, as evidenced by reduced elastic modulus and ultimate strength values, and the bone seemed to compensate for this by expanding the cross‐section to produce larger cross‐sectional moment of inertia values. The reduced bone tissue quality is consistent with the lower ash percent values in the alcohol animals, but other factors such as the quality of the collagen and mineral crystal may also be important contributors.
Ethanol Pretreatment Enhances NMDA Excitotoxicity in Biogenic Amine Neurons: Protection by Brain Derived Neurotrophic Factor
Authors: Crews Fulton T. , Waage Heather G. , Wilkie Mary Beth , Lauder Jean M.
Published: May 2006

Background

: Biogenic amine neurons are involved in a number of mental diseases including addiction and alcohol dependence. Because chronic ethanol is known to cause supersensitivity to NMDA excitotoxicity in cortical neurons, this study sought to determine the effect of ethanol treatment on biogenic amine neurons.

Methods

: To determine if ethanol exposure alters the vitality of hiogenic amine neurons, cultures were prepared from E14 rat brain. After 24 hr in culture, cells were divided into control or ethanol (100 mM) treatment groups, cultured an additional 48 hr, and then half of them exposed to NMDA for 25 min. The NMDA was then removed and cells cultured in fresh media for an additional 24 hr to allow for excitotoxic delayed neuronal death. Cultures were then stained with antibodies to 5‐hydroxytryptamine or tyrosine hydroxylase to identify serotonin and dopamine neurons, respectively. Cultures were analyzed for cell number and neuronal morphology.

Results

: Ethanol treatment alone had no effect on hiogenic amine cell number, soma area, number of neurites, or terminal segments, although the field area of dopamine neurons was decreased. Treatment with 30 μM NMDA had no effect on controls, but significantly decreased dopamine neurons in ethanol‐treated cultures as well as reduced soma area, field area, number of neurites and number of terminal segments. Treatment with higher concentrations of NMDA reduced dopamine and serotonin neurons in both controls and ethanol‐treated groups, and ethanol treatment significantly enhanced NMDA excitotoxic effects. Treatment with Brain Derived Neurotrophic Factor (BDNF) prevented ethanol sensitization to NMDA excitotoxicity.

Conclusions

: These studies suggest that ethanol treatment sensitizes biogenic amine neurons to excitotoxic insults. Ethanol sensitization of biogenic amine neurons to insults could contribute to the development of mental disease.
Birth Cohort Differences in Features of Antisocial Alcoholism Among Men and Women
Authors: Stoltenberg S.F. , Hill E.M. , Mudd S.A. , Blow F.C. , Zucker R.A.
Published: May 2006

Background: This study examines the relations between birth cohort, gender, and family history of alcohol problems on alcohol dependence, and on the endorsement of alcohol abuse/dependence symptoms related to antisocial behavior.

Methods: Mcn (n= 1365) and women (n= 625) were recruited from the community, hospitals, and other treatment sites and were given a structured diagnostic interview. Data were analyzed by using logistic regression.

Results: Age of first regular alcohol use was lower in more recent birth cohorts for both men and women, with those born in the most recent cohort reporting earliest regular use. The decline across cohort was more dramatic in women than in men. For those participants with a diagnosis of alcohol dependence, being born in a more recent cohort was associated with increased risk of dependence onset before age 25. Among those participants with onset of alcohol dependence before age 25 (nmen= 400; nwomen= 51), being born in a more recent cohort was associated with increased risk of fights while drinking, police involvement, and drunk driving trouble as well as with increased risk for a diagnosis of abuse or dependence on another drug.

Conclusions: These results suggest that the prevalence of antisocial alcoholism may be increasing for both men and women. These data exemplify how societal change may affect expression of underlying vulnerability for traits thought to be genetically influenced.
Glial Differences Between Naïve Withdrawal Seizure‐Prone and ‐Resistant Mice
Authors: Buckman J.F. , Meshul C.K.
Published: May 2006

Background: Withdrawal seizure‐prone (WSP) and withdrawal seizure‐resistant (WSR) mice were bred in replicate (i.e., WSP‐1 and WSP‐2) to exhibit differences in handling‐induced convulsion severity during ethanol withdrawal.

Methods: We examined the role of the glutamatergic system in susceptibility to ethanol‐withdrawal convulsions in naive mice by measuring the density of immunolabeling for several glutamate transporters and the glutamate‐metabolizing enzyme, glutamine synthetase. The density of glial fibrillary acidic protein immunolabeling (a marker of glial structure) and cytochrome oxidase activity (a marker of neuronal activity) were also characterized in naïve mice.

Results: We observed a significantly greater density of immunolabeling for the glial transporter, gluta‐mate/aspartate transporter, in CA1 subfield of the hippocampus (CA1) of naive WSP‐2 mice as compared to WSR‐2 mice. No other significant differences were observed. However, as compared to WSR mice, naïve WSP mice exhibited a trend toward (a) greater immunolabeling for the glial glutamate transporter, glutamate transporter‐1, in CA3, (b) greater immunolabeling for glial‐specific glutamate‐metabolizing enzyme, glutamine synthetase, in CA1 (replicate‐2 only), and (c) less immunolabeling for the glial structural protein, glial fibrillary acidic protein, in all brain regions tested. In contrast, no trends or significant differences in the labeling density for the neuronal transporter, excitatory amino acid carrier 1, or the neuronal activity marker, cytochrome oxidase, were observed between the selected lines.

Conclusions: These data suggest that the glutamatergic system and glia may play a pivotal role in the increased susceptibility to handling‐induced convulsions observed in WSP mice.
Time Course and Reproducibility of Urinary Excretion Profiles of Ethanol, Methanol, and the Ratio of Serotonin Metabolites After Intravenous Infusion of Ethanol
Authors: Jones A.W. , Helander A.
Published: May 2006

Background: The aim of this study was to determine the time course and reproducibility of urinary excretion profiles of ethanol, methanol, and ratio of serotonin metabolites, 5‐hydroxytlyptophol (5HTOL) to 5‐hydroxyindoleacetic acid (5HIAA), under strictly controlled conditions.

Methods: Nine healthy volunteers (6 women and 3 men) received 0.40 g of ethanomg of body weight on two occasions by constant rate intravenous infusion 30 min. Urine was voided before administration of ethanol and thereafter every 60 min for a total of 8 hr. Concentrations of ethanol and methanol in urine were determined by headspace gas chromatography, and the serotonin metabolites 5HTOL and 5HIAA were measured by gas chromatography‐mass spectrometry and high‐performance liquid chromatography, respectively.

Results: The peak concentration of ethanol in urine occurred at 30 or 60 min after the infusion ended. The peak concentration of methanol and the 5HTOL/5HIAA ratio developed more gradually, reaching a plateau at 213 to 220 min and 200 to 220 min postinfusion, respectively. The concentration‐time profiles of ethanol and the 5HTOL/5HIAA ratio varied more between subjects than within subjects (p < 0.001), whereas the inter‐ and intraindividual variation in the pharmacokinetics of methanol were not significantly different (p > 0.05). The concentration of methanol and the 5HTOL/5HIAA ratio remained above the endogenous levels at 8‐hr postinfusion despite the fact that urinary ethanol was no longer measurable (<0.01 g/liter) after 5 to 6 hr.

Conclusions: Measuring the concentrations of methanol and the ratio of serotonin metabolites (5HTOL/5HIAA) in urine is a more sensitive way to monitor recent drinking, compared with analysis of ethanol in body fluids. Moreover, the concentration‐time profiles of methanol and the 5HTOl/5HIAA ratio showed a good test‐retest stability. The present intravenous infusion experiment confirms previous work on these markers when ethanol was given perorally. The urinary methanol and the 5HTOL/5HIAA ratio have applications in forensic and clinical medicine as indicators of acute alcohol consumption.
Alcohol at Moderate Levels Decreases Fibrinogen Expression In Vivo and In Vitro
Authors: Wang Zhiqing , Barker Thomas H. , Fuller Gerald M.
Published: May 2006

Background: Consumption of moderate amounts of alcohol has been reported to exert a cardioprotective effect in individuals. The exact mechanism by which this occurs has not been fully explored. Circulating levels of the clotting protein fibrinogen have been unequivocally established as an independent risk factor for vascular diseases. This study examined the effects of moderate levels of ethanol on the expression of fibrinogen in an animal model and in hepatoma cells.

Methods: Out‐bred Sprague‐Dawley rats were fed 5% ethanol (v/v) in their water for 4 weeks, and circulating levels of fibrinogen were measured weekly via quantitative immunoassay. H4IIE rat hepatoma cells, which constitutively produce fibrinogen, were exposed to 10 and 20 mM ethanol, and fibrinogen production was determined. The effects of ethanol on fibrinogen messenger ribonucleic acids were determined by northern gel analyses.

Results: Our findings demonstrate that daily consumption of moderate amounts of ethanol decreases circulating levels of fibrinogen 18% to 20%. The decrease is reversible and is not gender specific. The cxposure of hepatoma cells to ethanol also diminishes fibrinogen production by 20% by decreasing the transcription of fibrinogen genes. Alcohol concentration of 10 to 20 mM did not affect hepatoma cell viability or doubling time.

Conclusions: The findings indicate that one likely positive benefit of moderate ethanol consumption is to diminish the production of fibrinogen, which reduces the potential risk exerted by this protein. The site of action of ethanol is, at least in part, exerted at the level of gene transcription.
Effects of Naltrexone on Alcohol Self‐Administration in Heavy Drinkers
Authors: Davidson Dena , Palfai Tibor , Bird Chris , Swift Robert
Published: May 2006

The mechanisms underlying the suppressant effects of naltrexone (NTX) on ad libitum alcohol drinking in a bar/restaurant setting were investigated in heavy beer drinkers. Fifty‐one male and female heavy drinkers (mean age = 22) received 50 mg of NTX or placebo (PBO), p.o., on two separate occasions in a randomized, double‐blind crossover protocol. After 7 days of taking medication, subjects were provided with the opportunity to consume beer ad libitum during two, 90‐min test sessions that were held 1 to 2 weeks apart. Blood samples were collected on test days to ensure medication compliance and to measure blood levels of NTX and the active β‐naltrexol. Less beer was consumed during NTX treatment. NTX decreased urges to consume alcohol. NTX‐treated subjects also took significantly longer to finish each glass of beer and were more likely to terminate beer drinking early. Self‐report stimulation and ratings of positive mood states were lower during NTX treatment. Negative side effects of NTX, such as nausea and headache, were reported more frequently with NTX. Not all of the subjects decreased their beer intake on NTX, and some subjects drank more beer. Nonresponders to NTX were not related to blood levels of the active metabolite β‐naltrexol or to a family history of alcoholism. Overall, the results of this study suggest that NTX affects a number of the components of alcohol drinking sequence, including lowering cravings, decreasing the positive reinforcing effects of alcohol, and increasing headache and nausea, each of which may contribute to reducing alcohol intake.
Assessment of the Role of Kindling in the Pathogenesis of Alcohol Withdrawal Seizures and Delirium Tremens
Authors: Wojnar Marcin , Bizoń Zdzisiaw , Wasilewski Dariusz
Published: May 2006

The aim of this study was to evaluate the hypothetical role of kindling phenomenon in the development and course of alcohol withdrawal (AW) seizures and delirium tremens (DT). The 2186 medical records of 1179 patients hospitalized in Nowowiejski Hospital in Warsaw from 1973 to 1987 were reviewed using a structured questionnaire. Investigating the role of kindling, a course of consecutive AW episodes of patients hospitalized several times was analyzed. The relationships of withdrawal seizures with the duration of alcohol abuse, the number of prior detoxification episodes, and other variables were also studied. Increasing severity of AW symptoms was observed during the course of consecutive episodes in 22.5% of patients. The first episode of DT was preceded by withdrawal seizures in 11 % of cases. First‐ever withdrawal seizures occurred more frequently in patients with head injury in the past and with coexisting symptoms of alcohol liver disease. Occurrence of withdrawal seizures and DTs did not correlate with the number of previous withdrawal episodes or with the length of period of intensive drinking. We concluded that the kindling model could be applied only to some cases in the development of AW seizures and DTs. Kindling should be considered as one of the multiple mechanisms involved in the pathogenesis of AW delirium.
Ritanserin In Relapse Prevention In Abstinent Alcoholics: Results From a Placebo‐Controlled Double‐Blind International Multicenter Trial
Authors: Wiesbeck G.A. , Weijers H.‐G. , Chick J. , Naranjo C.A. , Boening J. ,   Behalf of the Ritanserin in Alcoholism Work Group
Published: May 2006

Ritanserin, a long‐acting specific 5‐HT2 receptor antagonist, revealed promising effects on alcohol intake behavior in both animal and preliminary human studies. To test its effectiveness in alcohol dependence this phase III clinical trial was initiated. In a placebo‐controlled, randomized, double‐blind international multicenter study 493 patients with moderate or severe alcohol dependence (DSM‐III‐R) were treated with three doses of ritanserin 2.5 mg/day (n= 122), 5 mg/day (n= 123), 10 mg/day (n= 126), or placebo (n= 122) over a period of 6 months. Ritanserin was well tolerated. The most frequent adverse experiences were headache and insomnia. A small increase in weight in the ritanserin‐treated patients was observed. There were no significant differences between any dose of ritanserin and placebo in the relapse‐rate, the time to relapse, craving for alcohol, or quantity and frequency of drinking after relapse. So far, neither ritanserin nor any other serotonergic medication has shown its specific effectiveness in relapse prevention in alcohol dependence.
Effects of Menstrual Cycle and Female Sex Steroids on Ethanol Pharmacokinetics
Authors: Mumenthaler Martin S. , Taylor Joy L. , O'Hara Ruth , Fisch Hans‐Ulrich , Yesavage Jerome A.
Published: May 2006

This study investigated the influence of menstrual cycle and female sex steroid levels on ethanol pharmacokinetics. In a within‐subjects design, 24 female volunteers each consumed 0.67 g. kg‐1 ethanol during the menstrual and luteal phases of their menstrual cycle. On each test day, we collected blood samples before ethanol administration to determine estradiol (E2) and progesterone (P) levels and to confirm ovulation. We took 20 or more postdrink breath ethanol concentration readings and examined pharmacokinetic differences between the two phases, using classical pharrnacokinetic measures, as well as Michaelis‐Menten measures. Despite highly significant differences in measured E2 as well as P levels on the 2 test days, and despite excluding subjects with anovulatory cycles from the analysis, there were no significant differences between menstrual and luteal phases for any of the pharmacokinetic variables. We found no correlation between E2 or P levels and any of the pharmacokinetic measures. In summary, we found no evidence that the tested menstrual cycle phases or varying E2 and progesterone levels significantly influence ethanol pharmacokinetics. Because previous studies about the topic have used few subjects and revealed controversial results, we consider our negative findings based on 24 subjects meaningful.
Buspirone Treatment of Alcoholism: Age of Onset, and Cerebrospinal Fluid 5‐Hydroxyindolacetic Acid and Homovanillic Acid Concentrations, But Not Medication Treatment, Predict Return to Drinking
Authors: George David T. , Rawlings Robert , Eckardt Michael J. , Phillips Monte J. , Shoaf Susan E. , Linnoila Markku
Published: May 2006

Disturbances in central nervous system serotonin (5‐HT) have been implicated in the pathophysiology of alcoholism. To test the hypothesis that increasing 5‐HT function could promote treatment compliance, we randomized patients who had completed a 5‐week inpatient treatment program for alcoholism to receive either buspirone or placebo for 1 year. Ten of the 49 patients remained in the study for the entire year. The days to relapse did not differ significantly between patients receiving buspirone or placebo. Regardless of the medication, late‐onset alcoholics had a longer time to relapse than early‐onset alcoholics. Cerebrospinal fluid showed that patients with high concentrations of both the 5‐HT metabolite, 5‐hydroxyindoleacetic acid, and the dopamine metabolite, homovanillic acid, were more likely to relapse, compared with patients with low concentrations of cerebrospinal fluid 5‐hydroxyindoleacetic acid and homovanillic acid.
Effects of Ethanol on the Intraovarian Insulin‐Like Growth Factor‐1 System in the Prepubertal Rat
Authors: Srivastava Vinod K. , Hiney Jill K. , Dees W. Les
Published: May 2006

Insulin‐like growth factor‐1 (IGF‐1) is considered to play an important role during ovarian development and function. Because ethanol (ETOH) is a gonadal toxin in men, as well as male and female rats, we hypothesized that this drug may be having detrimental effects in the ovary by altering the intraovarian actions of IGF‐1. In support of this notion, the present study was undertaken to examine the chronic effects of ETOH on the ovarian IGF‐1 system in prepubertal female rats. Each rat was implanted with a gastric cannula on day 24 and began receiving either a control or ETOH liquid diet on day 29. The animals were killed on day 34, confirmed to be in the late juvenile stage of development, and their ovaries and blood were collected. Using an RNase protection assay, we determined the expression of mRNAs encoding IGF‐1 and the Type 1 IGF receptor in the ovaries of control and ETOH‐treated rats. Results indicate that the ETOH‐treated rats showed an increase in the ovarian expression of IGF‐la (p < 0.0001) and IGF‐lb (p < 0.001) mRNA, the two alternatively spliced forms of the IGF‐1 gene. Conversely, ovarian IGF‐1 protein levels were depressed (p < 0.05) in ETOH‐treated rats as determined by radioimmunoassay. Furthermore, ETOH‐treated rats showed a decrease (p < 0.01) in the expression of Type‐1 IGF receptor mRNA with a subsequent decrease (p < 0.05) in the ovarian levels of IGF‐1 receptor protein, as determined by Western blot analysis. Also, using Western immunoblotting, we determined increases in immunoreactive IGF‐binding proteins‐3 (p < 0.05) and 5 (p < 0.01), but not 4, in ETOH‐treated rats as compared with controls. Furthermore, we observed a concomitant decrease (p < 0.01) in the serum levels of estradiol. These results demonstrate for the first time that chronic ETOH administration is capable of altering the prepubertal intraovarian IGF‐1 signaling system. We suggest that, at least in part, these effects contribute to altered prepubertal ovarian function after chronic exposure to ETOH.
Chronic Ethanol Increases Ganglioside Sialidase Activity in Rat Leukocytes, Erythrocytes, and Brain Synaptosomes
Authors: Marmillot Philippe , Rao Manjunath N. , Liu Qing‐Hong , Lakshman M. R.
Published: May 2006

In view of the chronic alcohol‐mediated pathological changes in various sialic acid‐deficient glycoconjugates and the potential importance of sialidase in the generation of these glycoconjugates in the blood compartment and in the brain, we have investigated the effects of chronic ethanol feeding for 8 weeks on ganglioside sialidase activities in rat blood and brain. Ganglioside sialidase activity in erythrocytes (whether expressed as units/mg of protein or units/ml of blood) was 1.37‐ to 1.40‐fold higher (p< 0.01) in the ethanol‐fed group than in the control group. On the other hand, the same ethanol treatment increased sialidase activity in the leukocyte soluble fraction by 2.50‐ to 2.60‐fold (p< 0.01) and by 1.61 ‐ to 1.63‐fold (p< 0.01) in the leukocyte particulate fraction, compared with the control group. More importantly, most of the blood compartment sialidase activity was localized in the leukocytes particulate fraction (80 to 86% of total blood activity). Similarly, chronic ethanol treatment increased brain synaptosomal sialidase activity (whether expressed as unitdgram of brain or unitshg of protein) 2.16‐ to 2.43‐fold (p< 0.01). In contrast, brain lysosomal sialidase was not significantly altered by ethanol treatment, even though the major proportion of the brain sialidase activity was localized in the lysosomes. The proportion of synaptosomal sialidase activity as the percentage of total brain sialidase activity increased markedly from 13% in the control group to 24% in the ethanol group. Thus, chronic ethanol‐mediated increases in sialidase activity in the leukocytes and brain synaptosomes could account for alterations in the ganglioside status of the animal and consequent adverse effects of chronic ethanol on behavioral and pathological changes.
Decreased Ethanol Sensitivity and Tolerance Development in γ‐Protein Kinase C Null Mutant Mice Is Dependent on Genetic Background
Authors: Bowers Barbara J. , Owen Elizabeth H. , Collins Allan C. , Abeliovich Asa , Tonegawa Susumu , Wehner Jeanne M.
Published: May 2006

Initial sensitivity and tolerance development to the sedative‐hypnotic and hypothermic effects of ethanol were investigated in γ‐protein kinase C (PKC) null mutant mice. Null mutants from a C57BL/6J × 129/SvJ mixed genetic background demonstrated decreased ethanol sensitivity and failed to develop chronic tolerance after 10 days of ethanol liquid diet. However, when the null mutation was introgressed onto a C57BL/6J background for six generations, the “no tolerance” phenotype for sedative‐hypnotic and hypothermic effects of ethanol was no longer apparent. Outcrossing the γ‐PKC null mutation to a C57BL/6J × 129/SvEvTac mixed background restored the “no tolerance” phenotype to ethanol‐induced sedation after chronic ethanol diet; however, as measured by hypothermia, tolerance was still evident in the null mutant mice. These observations and the results of tests of chronic tolerance in the C57BL/6J, 129/SvJ, and 129/SvEvTac background inbred strains indicate that γ‐PKC plays an important role in initial sensitivity and tolerance to ethanol. However, the impact of γ‐PKC is modulated by the background genotype. These results stress the importance of including the effect of genetic background when evaluating the effects of single gene mutations on quantitative behavioral traits.
Independent Ethanol‐ and Sucrose‐Maintained Responding on a Multiple Schedule of Reinforcement
Authors: Czachowski Cristine L. , Samson Herman H. , Denning Charles E.
Published: May 2006

Assessment of drug effects on two different reinforcers at the same time requires that each reinforcer be sampled at approximately the same time. One procedure that effectively produces this result is the use of a multiple schedule of reinforcement in which two different reinforcers are presented in alternating 2‐min components. In our study, sucrose and ethanol solutions were made available after appropriate lever‐press responding. Subjects were trained to self‐administer 10% ethanol using a sucrose‐substitution procedure and to discriminate light cues associated with the different reinforcers until stable reinforcer‐directed responding was achieved on both the ethanol‐ and the sucrose‐associated lever during the changing 2‐min components of the schedule. Subsequently, the reinforcer solution presented on one lever was held constant while the concentration of the alternate reinforcer was manipulated, i.e., ethanol concentrations of 0 to 15% and sucrose concentrations of 0 to 10% were assessed. This multiple schedule procedure resulted in sustained and independent ethanol‐ and sucrose‐reinforced behavior. Manipulation of the characteristics of one reinforcer had no effect on behavior maintained by the alternate reinforcer. Increases in sucrose concentration resulted in increases in sucrose‐directed responding with no change in ethanol responding, and increases in ethanol concentration resulted in increases in ethanol intake with no change in sucrose responding. Our methods can be used to examine differential drug effects on ethanol‐ and sucrose‐reinforced behavior in the same animal over a single time course without the confounds or interference from the concurrently available reinforcer.
Thymocyte Development in Male Fetal Alcohol‐Exposed Rats
Authors: Taylor Anna N. , Tio Delia L. , Chiappelli Francesco
Published: May 2006

We previously reported altered responses of thymocytes to mitogen stimulation after fetal alcohol exposure (FAE) in prepubertal male Sprague‐Dawley rats. The purpose of this study was to examine the effect of FAE on the developmental pattern of thymocyte subsets. In the first experiment, we found that the proportion of double‐labeled CD4+CD8+ thymocytes is identical in fetal alcohol‐exposed (E) and control (C) animals at 34 and 45 days of age. In the second experiment‐at 20,28,35, and 48 days of age‐we examined the proportion of CD4+ and CD8+ thymocytes that express or are devoid of the maturational markers, the 7alpha;/β configuration of the T‐cell receptor (TcR), and the restriction fragment C of the common leukocyte antigen (CD45RC). We found significant age‐dependent effects on the numbers of total double‐positive CD4‐TcR and CD8‐TcR or CD45RC thymocytes, and significantly lower numbers of total CD4+ and CD8+ cells in E than in C rats throughout this period‐a finding consistent with the significantly lower total number of thymocytes in E than in C rats. The developmental patterns for both markers were similar in E and C groups, in both the rising (days 20 to 28) and declining (days 35 to 48) phases. However, on day 35, E rats had significantly lower numbers of double‐positive CD8‐TcR and CD8‐CD45RC cells than C rats. It therefore seems that FAE tends to accelerate the decline of double‐positive CD8‐TcR and CD8‐CD45RC cells. The contribution of this phenotypic change to the thymic functional alterations induced by FAE remains to be determined.
A Twin Study of Genetic Influences on the Acute Adaptation of the EEG to Alcohol
Authors: O'Connor S. , Sorbel J. , Morzorati S. , Li T.‐K. , Christian J. C.
Published: May 2006

A two‐dose alcohol challenge protocol was used to study genetic influences on the acute adaptation of the EEG to alcohol in 53 monozygotic and 38 same‐sex dizygotic Caucasian twin pairs averaging 30 years of age. Equal doses of alcohol were administered at 10:00 and 11:00 AM, yielding mean peak breath alcohol concentrations of 0.057% and 0.099%, respectively. Eyes‐closed, resting EEG was recorded four times: at baseline; on the ascending limb of the overall experiment at a breath alcohol concentration (BrAC) near 0.06%; on the descending limb at a BrAC near the value when the subject's EEG was obtained on the ascending limb; and, finally, when the BrAC fell to 0.02%. Genetic analyses of log‐transformed values of total spectral power (L10TSP) and spectral band power (L10SBP) were performed on EEG spectra averaged across all 17 scalp lead locations. After adjusting for body weight, a significant fraction of population variance in L10TSP was attributable to genetic influence: H2 values for TSP were 0.73, 0.72, and 0.73 at the three postalcohol EEG recordings, respectively. Similar findings pertained to each L10SBP at each postalcohol recording, except for the delta band. The change in postethanol EEG power was examined for evidence that genes influence acute adaptations in brain function. Descending‐minus‐ascending limb L10TSP was normalized by the individual's ascending limb L10TSP to minimize nonalcohol‐related effects that can influence both measurements. Earlier analyses of the same sample's initial EEG response to alcohol noted a substantial increase in the ascending limb EEG power, compared with baseline. Thus, positive values of the postethanol change denote a progression away from baseline attributable to acute sensitization to alcohol; negative values signify a return toward baseline values suggesting acute tolerance to alcohol. Genetic analysis of the normalized difference in L10TSP had a highly significant H2 value of 0.70, indicating that both acute tolerance and acute sensitization to alcohol may represent adaptations reflecting substantial heritable influence. Slightly smaller, but significant values of H2 for the normalized difference in L10SPB were observed for delta, alpha‐slow and beta‐slow frequency bands. In contrast, H2 for the differences between the final and ascending limb EEG power were not significant, except for the theta band. Thus, heritable drowsiness may have contributed to detection of genetic influences on acute adaptation, but represent a potential confound only in the theta band.
Platelet Adenylyl Cyclase Activity as a Biochemical Trait Marker for Predisposition to Alcoholism
Authors: Ratsma Joëlle E. , Gunning W. Boudewijn , Leurs Rob , Schoffelmeer Anton N. M.
Published: May 2006

Previous studies demonstrated a reduced Gs‐protein stimulated adenylyl cyclase activity in the brain and blood cells of alcoholics. We investigated this phenomenon in platelets of children of alcoholics (COA), i.e., of children at high risk for the acquisition of alcoholism and (as yet) not regularly consuming alcohol. Gs‐protein mediated stimulation of adenylyl cyclase by 30 mM NaF and 50 μM forskolin stimulated adenylyl cyclase activity were assessed in platelet membranes of 23 (male and female) COA and 20 control children. Gs‐protein stimulated cAMP production by NaF, unlike that induced by direct stimulation of adenylyl cyclase with forskolin, in platelet membranes of COA was profoundly lower than in platelet membranes of control children. Moreover, such a reduced Gs‐protein functioning was only observed in platelet membranes of COA with a multigenerational family history of alcoholism. A reduction of Gs‐protein stimulated adenylyl cyclase activity in platelets may represent a sensitive and gender‐independent trait marker for predisposition to alcoholism, rather than a state marker for alcoholism.
Induction of Cyclooxygenase‐2 in Brain During Acute and Chronic Ethanol Treatment and Ethanol Withdrawal
Authors: Knapp Darin J. , Crews Fulton T.
Published: May 2006

Prostaglandins play an important role in the regulation of nervous system function including thermoregulation, autonomic nervous system function, hypothalamic regulation of pituitary function, and neuronal excitation. Prostaglandin synthesis is catalyzed by cyclooxygcnase (COX; prostaglandin synthase) which occurs as two isozymes, COX‐1 and COX‐2. COX‐1 and COX‐2 are constitutively expressed in brain whereas COX‐2 type is also inducible in brain by excitatory neurotransmission. Ethanol intoxication and the hypercxcitability of ethanol withdrawal may be influenced by inducible proteins, thus we investigated COX‐2 in the rat brain during acute and chronic ethanol treatment, ethanol withdrawal, and after peripheral administration of excitatory amino acids. Kainic acid or NMDA treatment increased COX‐2 immunoreactivity in the cortex, hippocampus, and amygdala. An acute dose of ethanol (5 g/kg. intragastric‐ig) increased COX‐2, particularly in the CA4 region of the hippocampus and agranular insular cortex. Chronic ethanol treatment (4 days‐intragastric) robustly induced COX‐2 in limbic cortex, isocortex, and amygdala. Particularly dense immunocytochemical staining was found in perirhinal and piriform cortices, dentate gyrus, and tenia tecta. During ethanol withdrawal, COX‐2 expression increased further in some regions, peaking in most areas 16 hr after the last dose of ethanol. These results indicate that COX‐2 immunoreactivity is: 1) increased in the brain during acute ethanol exposure that increases further during chronic treatment: 2) sensitive to excitatory amino acid receptor stimulation; and 3) dramatically increased during ethanol withdrawal. These studies suggest that COX‐2 induction may be involved in the acute and chronic effects of ethanol.
Ethanol Consumption and Place‐Preference Conditioning in the Alcohol‐Preferring C57BL/6 Mouse: Relationship with Motor Activity Patterns
Authors: Nocjar Christine , Middaugh Lawrence D. , Tavernetti Michael
Published: May 2006

Ethanol place‐preference conditioning (PC) was conducted in drug‐naive and ethanol pre‐exposed female and male C57BL/6J (C57) mice to assess whether environmental cues can develop positive incentive value for ethanol‐preferring animals when associated with administration of ethanol. After 12 days episodic access to free‐choice ethanol and/or water self‐administration, mice received eight ethanol injections (1.75 g/kg/ip) 5 min before placement in their nonpreferred PC chamber and eight saline injections paired with their preferred chamber. Control mice received eight saline injections (20 ml/kg) in both their preferred and nonpreferred chambers. Mice of both sexes developed strong ethanol PC. Correlational analysis indicated that the strength of ethanol PC for mice with a prior ethanol drinking experience was inversely related to the amount of ethanol consumed regardless of gender. Furthermore, depending on gender and previous ethanol drinking experience, ethanol PC was differentially related to initial baseline motor activity, the initial motor response to ethanol, or rapid change in the motor response to ethanol. Thus, a complicated relationship between neural systems that mediate ethanol reward and motor activity may exist as suggested by current addiction theory.
Conditioned Effects Produced by Naltrexone Doses That Reduce Ethanol‐Reinforced Responding in Rhesus Monkeys
Authors: Williams Keith L. , Woods James H.
Published: May 2006

Clinical trials have shown that naltrexone is effective in treating alcohol dependence; nausea and dysphoria have been reported as “side effects” in many of these studies. In primates, naltrexone reduces reinforced responding for oral ethanol, sucrose, and phencyclidine. This study was designed to determine if naltrexone reduces reinforced responding for various solutions by producing an interoceptive stimulus that may result in a conditioned taste aversion. Four opioid antagonist‐naive rhesus monkeys responded for solutions from a two‐spout operant panel for 30 min per day. During a conditioning phase, the monkeys received novel Kool‐Aid® solutions paired with either saline or naltrexone (0.32 mg/kg) given 30 min before the session. The monkeys then had seven choice sessions between the saline‐paired solution or the naltrexone‐paired solution. During the conditioning phase, the naltrexone reduced responding after five naltrexone/solution pairings. In addition, a conditioned taste aversion was produced; the naltrexone‐paired solution maintained significantly less responding than did the saline‐paired solution during the choice phase. In the next phase, the saline and naltrexone were given “unpaired” from any distinct part of the operant session, and another seven choice sessions followed. Naltrexone had no effect when given “unpaired” from the operant session. Then, another conditioning phase was undertaken followed by another series of choice sessions. During the replication of the conditioning, naltrexone reduced responding by the second pairing, although no conditioned aversion was observed in the subsequent choice sessions. Thus, given in the same manner (dose, route, and pretreatment time) as situations in which naltrexone reduces oral ethanol‐, sucrose‐, and phencyclidine‐reinforced responding, naltrexone produced a conditioned taste aversion. These results suggest that naltrexone‐induced nausea and its conditioned effects should be considered in naltrexone's effect in alcoholics.
Long‐Term Ethanol Exposure Alters the Sialylation Index of Plasma Apolipoprotein J (Apo J) in Rats
Authors: Ghosh Pradeep , Hale Eric A. , Lakshman Raj
Published: May 2006

We have previously shown that chronic ethanol treatment impairs the glycosylation of proteins in the rat liver. Changes in the microheterogeneity of transferrin, a N‐sialoprotein under chronic alcohol consumption are well established. Apolipoprotein J, another N‐glycoprotein, is a normal component of plasma high‐density lipoproteins in the rat and human. Apo J is also highly sialylated and, thus, may be vulnerable to the deleterious actions of ethanol. Therefore, to understand the specific nature of alterations of Apo J sialylation as a consequence of chronic ethanol treatment, we have determined: (1) the sialylation index of Apo J (moles sialic acid per mole Apo J protein) in rats administered ethanol for 4, 6, and 8 weeks and a gradual withdrawal and a follow‐up abstinence for 1, 2, and 4 weeks; and (2) enzymatic activities of hepatic sialyltransferase and plasma sialidase during the same periods of alcohol treatment and abstinence in rats. Although no significant differences in the Apo J sialylation index between rats of the control and ethanol groups were found at the 4th week of alcohol treatment, a highly significant loss of 24% (p < 0.001) and 44% (p < 0.001) was found after 6 and 8 weeks, respectively, of alcohol feeding of these animals. Furthermore, a significant recovery of 38% (p < 0.001), 78% (p < 0.001), 84% (p < 0.001) and 96% (p < 0.001) in the sialylation index of Apo J were found, respectively, during withdrawal and 1, 2, and 4 weeks of subsequent alcohol abstinence in these animals. These changes in the sialic acid content of Apo J were accompanied by a similar pattern of changes in the enzyme activities of hepatic sialyltransferase and plasma sialidase in animals undergoing chronic ethanol treatment, withdrawal, and abstinence periods. The analysis of the sialylation index of Apo J seems to be a simple and feasible method to use to evaluate the extent of ethanol exposure.
Ethanol Inhibits Lung Clearance ofPseudomonas aeruginosaby a Neutrophil and Nitric Oxide‐Dependent Mechanism, In Vivo
Authors: Greenberg Stan S. , Zhao Xinfang , Hua Li , Wang Ji‐Fang , Nelson Steve , Ouyang Jie
Published: May 2006

Pseudomonas aeruginosa(P. aeruginosa) is an opportunistic pathogen that can be found in individuals in which the immune system has been suppressed by HIV/AIDS or chronic alcoholism. We evaluated the role of inducible nitric oxide synthase (NOSII) as a modulator of lung concentrations ofP. aeruginosain normal rats and rats given a single dose of ethanol (ETOH). Rats were pretreated with either sterile saline (PBS, 0.1 ml/kg, iv) or the NOS II inhibitor L‐N6‐iminoethyl lysine (LNIL, 10 mg/kg, iv) 15 min before intraperitoneal administration of either PBS (4.5 ml/kg) or ETOH (4.5 g/kg). Thirty min after administration of PBS or ETOH the rats were placed in inhalation chambers and exposed to 45 min of an aerosol containingP. aeruginosa(5 × 104colony forming units, CFU). A group of rats (n= 5‐6/treatment/time period) were killed immediately (0 hr) or 4 hr after inhalation ofP. aeruginosa.The lungs were homogenized and theP. aeruginosawere grown in nutrient broth to determine the number of viable CFU remaining in the lung. The NOS II and TNFα mRNA and protein content lung alveolar macrophages (AM) and neutrophils (PMN) were measured with RT‐PCR and Western blot. The concentration of nitrate and nitrite anion in the bronchoalveolar lavage fluid (BALf) and ex vivo incubates of PMN were also measured. The CFU ofP. aeruginosapresent in the lungs of the four groups of rats at 0 hr did not differ. The CFU ofP. aeruginosain the lung increased (p< 0.05) in rats pretreated with ETOH when compared with that obtained from rats pretreated with PBS. However, pretreatment of rats with LNIL decreased (p<0.05) the 4 hr lung content ofP. aeruginosa.Coadministration of LNIL and ETOH to rats augmented the CFU ofP. aeruginosain lungs to amounts which did not differ from that of rats pretreated with ETOH. Inhalation ofP. aeruginosaincreased NOS II mRNA and protein in rat AM and PMN. Pretreatment of rats with ETOH alone, or in combination with LNIL, inhibitedP. aeruginosa‐induced NOS II transcription and translation and AM and PMN nitrate and nitrite generation whereas pretreatment with LNIL alone only inhibited nitrate and nitrite generation. Pretreatment of rats with ETOH suppressedP. aeruginosastimulated PMN recruitment into the lung whereas LNIL enhanced (p<0.05)P. aeruginosa‐stimulated PMN recruitment into the lung. ETOH‐induced increases of the lung content ofP. aeruginosawere associated with increased PKC delta isozyme in the membrane of the PMN but could not be explained by altered plasma concentrations of hydrocortisone or ETOH. The data demonstrate that selective inhibition of NOS II‐derived NO by LNIL decreases the lung content ofP. aeruginosawhereas ETOH inhibits the lung clearance ofP. aeruginosa.Speculatively, the difference between these effects of LNIL and ETOH may result from differences in drug‐induced changes in lung recruitment of PMN.
Immune Dysfunction During Alcohol Consumption and Murine AIDS: The Protective Role of Dehydroepiandrosterone Sulfate
Authors: Lee Jeongmin , Sepulveda Ramon T. , Jiang Shugang , Zhang Zhen , Inserra Paula , Zhang Yan , Hosseini Saeed , Watson Ronald R.
Published: May 2006

Acquired immune deficiency syndrome (AIDS) is a clinical disorder caused by the human immunodeficiency virus (HIV) after development of severe immunosuppressive changes. Chronic ethanol (EtOH) consumption accentuates the severity of murine AIDS (MAIDS). Because hormone production is often suppressed by chronic EtOH intake, as well as retrovirus infection, we investigated whether hormone supplementation during chronic EtOH consumption contributes to slowing immune dysfunction caused by LP‐BMS infection and/or EtOH use. Because dehydroepiandrosterone sulfate (DHEAS) was previously shown to have immune‐enhancing properties during MAIDS, we determined whether DHEAS reduced cytokine dysregulation otherwise exacerbated by chronic EtOH intake during MAIDS. Adult female C57BL/6 mice were infected with LP‐BMS murine retrovirus. Some were fed 40% EtOH in drinking water and agar gel for 16 weeks postinfection. EtOH consumption further inhibited T‐ and B‐cell proliferation beyond suppression due to retrovirus infection. Interleukin (1L)‐2 release produced by concanavalin A‐stimulated splenocytes was reduced by EtOH use by infected and uninfected mice. DHEAS overcame much of the ecffects induced by retrovirus infection and/or EtOH use. IL‐4 secretion and IL‐6 secretion were enhanced. Hepatic vitamin E levels were decreased by murine retrovirus infection, as well as by EtOH use in both uninfected and infected mice. In addition, DHEAS (0.01%) supplementation during MAIDS prevented the further dysrcgulation of cytokines and hepatic lipid peroxidation due to EtOH intake, partially restorcd T‐ and B‐cell proliferation, and maintained hepatic vitamin E levels to near normal levels.