Chronic Alcoholism-Mediated Impairment in the Medulla Oblongata: A Mechanism of Alcohol-Related Mortality in Traumatic Brain Injury?

Alcohol-related traumatic brain injury (TBI) is a common condition in medical and forensic practice, and results in high prehospital mortality. We investigated the mechanism of chronic alcoholism-related mortality by examining the effects of alcohol on the synapses of the medulla oblongata in a rat model of TBI.
Seventy adult male Sprague–Dawley rats were randomly assigned to either ethanol (EtOH) group, EtOH-TBI group, or control groups (water group, water-TBI group). To establish chronic alcoholism model, rats in the EtOH group were given EtOH twice daily (4 g/kg for 2 weeks and 6 g/kg for another 2 weeks). The rats also received a minor strike on the occipital tuberosity with an iron pendulum. Histopathologic and ultrastructure changes and the numerical density of the synapses in the medulla oblongata were examined. Expression of postsynaptic density-95 (PSD-95) in the medulla oblongata was measured by ELISA.

Compared with rats in the control group, rats in the chronic alcoholism group showed: (1) minor axonal degeneration; (2) a significant decrease in the numerical density of synapses (p < 0.01); and (3) compensatory increase in PSD-95 expression (p < 0.01). Rats in the EtOH-TBI group showed: (1) high mortality (50 %, p < 0.01); (2) inhibited respiration before death; (3) severe axonal injury; and (4) decrease in PSD-95 expression (p < 0.05).

Chronic alcoholism induces significant synapse loss and axonal impairment in the medulla oblongata and renders the brain more susceptible to TBI. The combined effects of chronic alcoholism and TBI induce significant synapse and axon impairment and result in high mortality.


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Relationships between the Level of Alcohol Consumption and Abnormality in Biomarkers According to Facial Flushing in Korean Male Drinkers.

 

This research investigated the association between facial flushing after drinking and alcohol-induced biomarker abnormalities.

This retrospective study included 374 male drinkers who visited the department of Family Medicine of Chungnam National University Hospital between January and December of 2010. The participants were classified into two groups: the flushing group (n = 107) and the non-flushing group (n = 267). The biomarkers assessed were % carbohydrate-deficient transferrin (CDT) and gamma glutamyl transferase (rGTP). The upper limits of %CDT and rGTP were set as 2.47 and 50, respectively. The receiver operating characteristic (ROC) curve was used to obtain the cut-off value for the amount of drinking that caused abnormal %CDT and rGTP levels in the two groups. The sensitivity and specificity of the cut-off drinking amount for %CDT and rGTP abnormalities were analyzed in each group.

In the flushing group, the cut-off value for alcohol-induced %CDT abnormality was 3.38 drinks (1 drink: 14 g of alcohol) per week, with sensitivity of 77.8% and specificity of 70.4%. In the non-flushing group, the cut-off value was 11.25 drinks per week, with sensitivity of 62.2% and specificity of 69.6%. The cut-off value for the amount of alcohol that induced rGTP abnormality was 3.38 drinks per week in the flushing group, with sensitivity of 68.0% and specificity of 76.8%, whereas it was 8.75 drinks in the non-flushing group, with sensitivity of 71.1% and specificity of 66.7%. The area under the ROC of the drinking level was 0.726 in the flushing group and 0.684 in the non-flushing group for %CDT. For rGTP, the value was 0.738 in the flushing group and 0.718 in the non-flushing group.

The weekly drinking amount required to induce biomarker abnormalities was lower in the flushers than in the non-flushers.


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Evaluating Alcoholics Anonymous's Effect on Drinking in Project MATCH Using Cross-Lagged Regression Panel Analysis

 


The objective of the study is to determine whether Alcoholics Anonymous (AA) participation leads to reduced drinking and problems related to drinking within Project MATCH (Matching Alcoholism Treatments to Client Heterogeneity), an existing national alcoholism treatment data set.

The method used is structural equation modeling of panel data with cross-lagged partial regression coefficients. The main advantage of this technique for the analysis of AA outcomes is that potential reciprocal causation between AA participation and drinking behavior can be explicitly modeled through the specification of finite causal lags.

For the outpatient subsample (n = 952), the results strongly support the hypothesis that AA attendance leads to increases in alcohol abstinence and reduces drinking/ problems, whereas a causal effect in the reverse direction is unsupported. For the aftercare subsample (n = 774), the results are not as clear but also suggest that AA attendance leads to better outcomes.

Although randomized controlled trials are the surest means of establishing causal relations between interventions and outcomes, such trials are rare in AA research for practical reasons. The current study successfully exploited the multiple data waves in Project MATCH to examine evidence of causality between AA participation and drinking outcomes. The study obtained unique statistical results supporting the effectiveness of AA primarily in the context of primary outpatient treatment for alcoholism .



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Request Reprint E-Mail:    Stephen.Magura@wmich.edu

The societal costs of alcohol misuse in Australia

 

It is well documented that alcohol-related problems compromise individual and social health, and wellbeing (Homel, McIlwain & Carvolth 2004). However, much of the burden of such problems is initially born by first response and public emergency services including police, ambulance and hospital emergency departments (Collins & Lapsley 2002). The individual harms are numerous, including premature death, loss of enjoyment and loss of social utility through fear of crime and victimisation (ADCA 2000). Further, alcohol misuse is a problem for business that suffers due to lost worker productivity and absenteeism (Collins & Lapsley 2002). The misuse of alcohol, particularly among those most at risk in our community, presents a major challenge for all levels of government. How to effectively and efficiently moderate the high costs associated with risky drinking behaviour (eg binge drinking or drinking in high-risk areas such as entertainment districts) by young people has been a recent focus of policymakers. Not all alcohol use represents misuse; rather, misuse comprises use that is above the recommended limits in particular contexts (such as driving or use of equipment), use at levels that leads to health-related problems and use that has reached the level where dependency exists (NHS UK 2013).Results from a national-level study on the societal costs of alcohol-related problems in Australia are presented. These costs are based on 2010 data supplied from various agencies (eg Australian policing services, Australian Bureau of Statistics) and empirical evidence from peer-reviewed published papers. Incident data, together with estimates of rate of occurrence (eg percentage of all incidents attended by police that were found to be alcohol related) from empirical studies and cost estimates from past literature are used to generate a total cost estimate. All costs are adjusted where necessary to reflect present value in 2010 Australian dollars. The results include costs to the criminal justice system, costs to the health system, costs resulting from lost productivity and costs related to alcohol-related road accidents. They do not include self-reported assessments of costs (cf Laslett et al. 2010) but rather verifiable costs from objective sources. As such, the costs reported here can be regarded as conservative.


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NIAAA Spectrum

　

IN THIS ISSUE

FEATURES

1 Minority Health Research Gains Momentum at NIAAA
2 NIAAA Inspires Diversity in the Next Generation of Researchers


BY THE NUMBERS

4 Every Picture Tells (Part of) a Story


NEWS FROM THE FIELD

2 Alcohol and Pregnancy: The Long-Term Consequences

5 Women’s Stress-Related Drinking Linked toEarly Abuse

7 Disadvantaged Neighborhoods Affect Risk for Alcohol Problems

7 How Chronic Heavy Drinking Damages the Brain


A CLOSER LOOK

6 The Genetic Basis of Alcohol Flushing in Asian Populations
 

5 QUESTIONS WITH...

6 Judith Arroyo, Ph.D.



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Synergy between Seeking Safety and Twelve-Step Affiliation on substance use outcomes for women

 

The Recovery Management paradigm provides a conceptual framework for the examination of joint impact of a focal treatment and post-treatment service utilization on substance abuse treatment outcomes. We test this framework by examining the interactive effects of a treatment for comorbid PTSD and substance use, Seeking Safety, and post-treatment Twelve-Step Affiliation (TSA) on alcohol and cocaine use.

Data from 353 women in a six-site, randomized controlled effectiveness trial within the NIDA Clinical Trials Network were analyzed under latent class pattern mixture modeling. LCPMM was used to model variation in Seeking Safety by TSA interaction effects on alcohol and cocaine use.

Significant reductions in alcohol use among women in Seeking Safety (compared to health education) were observed; women in the Seeking Safety condition who followed up with TSA had the greatest reductions over time in alcohol use. Reductions in cocaine use over time were also observed but did not differ between treatment conditions nor were there interactions with post-treatment TSA.

Findings advance understanding of the complexities for treatment and continuing recovery processes for women with PTSD and SUDs, and further support the chronic disease model of addiction.

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Participation of the nociceptin/orphanin FQ receptor in ethanol-mediated locomotor activation and ethanol intake in preweanling rats

Activation of nociceptin/orphanin FQ (NOP) receptors seems to attenuate ethanol-induced reinforcement in adult rodents. Since early ethanol exposure results in later increased responsiveness to ethanol, it is important to analyze NOP receptor modulation of ethanol-related behaviors during early ontogeny.

By measuring NOP involvement in ethanol intake and ethanol-induced locomotor activation, we analyzed the specific participation of NOP receptors on these ethanol-related behaviors in two-week-old rats. In each experiment animals were pre-treated with the endogenous ligand for this receptor (nociceptin/orphanin FQ at 0.0, 0.5, 1.0 or 2.0 μg) or a selective NOP antagonist (J-113397 at 0.0, 0.5, 2.0 or 5.0 mg/kg).

Results indicated that activation of the nociceptin receptor system had no effect on ethanol or water intake, while blockade of the NOP receptor has an unspecific effect on consummatory behavior: J-113397 increased ethanol (at a dose of 0.5 mg/kg) and water intake (at 0.5 and 5.0 mg/kg). Ethanol-mediated locomotor stimulation was attenuated by activation of the NOP system (nociceptin at 1.0 and 2.0 μg). Nociceptin had no effect on basal locomotor activity. Blockade of NOP receptors did not modify ethanol-induced locomotor activation. Contrary to what has been reported for adult rodents, nociceptin failed to suppress intake of ethanol in infants.

Attenuation of ethanol-induced stimulation by activation of NOP receptor system suggests an early role of this receptor in this ethanol-related behavior.


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Request Reprint E-Mail:   rmiranda@binghamton.edu

Alcohol tax, consumption and mortality in tsarist Russia: is a public health perspective applicable?

The public health perspective on alcohol comprises two main tenets: (i) population drinking impacts on alcohol-related harm and (ii) population drinking is affected by the physical and economic availability of alcohol, where alcohol taxes are the most efficient measure for regulating consumption. This perspective has received considerable empirical support from analyses of contemporary data mainly from Europe and North America. However, as yet, it has been little examined in a historical context. The aims of the present article are to use data from tsarist Russia to explore (i) the relation between changes in the tax on alcohol and per capita alcohol consumption and (ii) the relation between per capita alcohol consumption and alcohol mortality.                    

The material comprised annual data on alcohol taxes, alcohol consumption and alcohol mortality. The tax and alcohol consumption series spanned the period 1864–1907 and the mortality data covered the period 1870–94. The data were analysed by estimating autoregressive integrated moving average models on differenced data.

Changes in alcohol taxes were significantly associated with alcohol consumption in the expected direction. Increases in alcohol consumption, in turn, were significantly related to increases in alcohol mortality.

7This study provides support for the utility of the public health perspective on alcohol in explaining changes in consumption and alcohol-related harm in a historical context. We discuss our findings from tsarist Russia in the light of experiences from more recent alcohol policy changes in Russia.


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Request Reprint E-Mail:   totto@sofi.su.se

Alcohol consumption and social inequality at the individual and country levels—results from an international study

International comparisons of social inequalities in alcohol use have not been extensively investigated. The purpose of this study was to examine the relationship of country-level characteristics and individual socio-economic status (SES) on individual alcohol consumption in 33 countries.

Data on 101 525 men and women collected by cross-sectional surveys in 33 countries of the GENACIS study were used. Individual SES was measured by highest attained educational level. Alcohol use measures included drinking status and monthly risky single occasion drinking (RSOD). The relationship between individuals’ education and drinking indicators was examined by meta-analysis. In a second step the individual level data and country data were combined and tested in multilevel models. As country level indicators we used the Purchasing Power Parity of the gross national income, the Gini coefficient and the Gender Gap Index. 

For both genders and all countries higher individual SES was positively associated with drinking status. Also higher country level SES was associated with higher proportions of drinkers. Lower SES was associated with RSOD among men. Women of higher SES in low income countries were more often RSO drinkers than women of lower SES. The opposite was true in higher income countries.                    

For the most part, findings regarding SES and drinking in higher income countries were as expected. However, women of higher SES in low and middle income countries appear at higher risk of engaging in RSOD. This finding should be kept in mind when developing new policy and prevention initiatives.


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Request Reprint E-Mail:    ulrike.grittner@charite.de

Spring 2013 Meeting of the Interagency Coordinating Committee on Fetal Alcohol Spectrum Disorders (ICCFASD)

 

Date:

April 4, 2013 - 8:30am to 3:30pm

 

Details:

Registration is not required. The meeting is sponsored by National Institute on Alcohol Abuse and Alcoholism (NIAAA).

Wednesday, April 3, 2013, 9:00 a.m. to 4:00 p.m., ICCFASD Work Group Meetings (closed to the public)

Thursday, April 4, 2013, 8:30 a.m. to 3:30 p.m., General ICCFASD Meeting (open to the public)

Agenda: Draft agenda for April 4 program

Thursday, April 4, 2013 program will consist of:

1. Updates of FASD-relevant activities of ICCFASD Member Organizations
2. Reports of recent and upcoming activities of the ICCFASD Work Group on Diagnostic Issues and the ICCFASD Work Group on Justice Issues
3. A Panel Discussion on Diagnosing Young Children

 

Location:

5635 Fishers Lane
Terrace Level Conference Center
Rockville, Maryland 20852
 

Directions:

There is a parking garage behind 5635 Fishers Lane. For additional information, contact sanders1@mail.nih.gov.

 

Acute Alcohol Produces Ataxia and Cognitive Impairments in Aged Animals: A Comparison Between Young Adult and Aged Rats

 

Aging in both humans and rodents appears to be accompanied by physiological changes that increase biologic sensitivity to ethanol (EtOH) intoxication. However, animal models designed to investigate this increased alcohol sensitivity have yet to be established. For this reason, we sought to determine whether acute EtOH administration produces differential effects on motor coordination and spatial cognition in young adult and aged rats.

Male young adult (postnatal day 70 to 72) and aged (~18 months) Sprague-Dawley rats were assessed on 2 motor tasks (the accelerating rotarod [RR] and the aerial righting reflex [ARR]) and a single cognitive performance task (the Morris water maze [MWM]). Following acute EtOH exposure via intraperitoneal injection, animals' performance was reassessed.

Aged rats showed a dramatic increase in EtOH-induced ataxia on the RR and the ARR relative to young adult animals. Similarly, results from the MWM revealed that aged animals had slightly greater EtOH-induced impairments compared with young adult animals. Importantly, the increased impairments produced by EtOH were not due to differential blood EtOH levels.

We demonstrate for the first time that aged rats show greater EtOH-induced deficits compared with young adults in tasks of motor and cognitive performance. The possible role of protein kinase C as a mechanism for increased sensitivity to the motor-impairing effects of EtOH is discussed. Given the high prevalence of alcohol use among the elderly, increased vulnerability to alcohol-induced deficits may have a profound effect on injury in this population.


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Decreased Peripheral Blood CD4+/CD25+ Regulatory T Cells in Patients with Alcoholic Hepatitis

Development of alcoholic hepatitis (AH) may be favored by the activation of the innate immune response. Recently, decreased numbers of circulating regulatory T cells (Tregs) have been reported in diseases associated with an immune activation status, but no studies have focused so far, in investigating the distribution of Tregs in chronic alcoholism and its potential association with liver disease. Here, we analyzed for the first time the frequency of peripheral blood (PB) Tregs and Treg subsets in AH and its relationship with the production of inflammatory cytokines by PB monocytes and dendritic cells (DCs).

 

PB samples from 25 male patients with AH were studied; in parallel, 15 male chronic alcoholic patients without liver disease (AWLD) and 17 male healthy donors were also studied, as controls. The distribution of CD4⁺CD25^hiCD127^−/lo Tregs and their maturation subsets (naïve, central memory, and peripheral memory Tregs) was analyzed by flow cytometry. Spontaneous and in vitro-stimulated production of inflammatory cytokines by PB monocytes and DCs was analyzed by flow cytometry at the cytoplasmic level.

 

Patients with AH showed decreased (p < 0.05) numbers of PB CD4⁺CD25^hiCD127^−/lo Tregs at the expense of all maturation-associated subsets, while AWLD and healthy subjects showed a similar (p > 0.05) distribution of PB CD4⁺CD25^hiCD127^−/lo Tregs. Interestingly, significantly increased amounts of spontaneously produced inflammatory cytokines were found among circulating monocyte-derived DCs and monocytes from AH (and AWLD) patients in comparison with healthy donors. Conversely, the ability of these cell subsets to produce cytokines after in vitro stimulation was lower (p < 0.05) in AH versus the 2 control groups.

 

PB CD4⁺CD25^hiCD127^−/lo Tregs are significantly decreased in patients with AH when compared to both healthy and AWLD; this may contribute to explain the more pronounced activation of the innate immune response observed in AH, as reflected by an increased secretion of inflammatory cytokines by PB DCs and monocytes, and could facilitate the development of liver disease.


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Cyclic Adenosine Monophosphate and Brain-Derived Neurotrophic Factor Decreased Oxidative Stress and Apoptosis in Developing Hypothalamic Neuronal Cells: Role of Microglia

We have previously shown that ethanol (EtOH) increases cellular apoptosis to developing neurons via the effects on oxidative stress of neurons directly and via increasing production of microglia-derived factors. To study further the mechanism of EtOH action on neuronal apoptosis, we determined the effects of 2 well-known PKA activators, dibutyryl cAMP (dbcAMP) and brain-derived neurotrophic factor (BDNF), on EtOH-activated oxidative stress and apoptotic processes in the hypothalamic neurons in the presence and absence of microglial cells' influence.

 

In enriched neuronal cells from fetal rat hypothalami treated with EtOH or with conditioned medium from EtOH-treated microglia, we measured cellular apoptosis by the free nucleosome assay and the levels of cAMP, BDNF, O²⁻, reactive oxygen species (ROS), nitrite, glutathione (GSH), and catalase following treatment with EtOH or EtOH-treated microglial culture conditioned medium. Additionally, we tested the effectiveness of dbcAMP and BDNF in preventing EtOH or EtOH-treated microglial conditioned medium on cellular apoptosis and oxidative stress in enriched hypothalamic neuronal cell in primary cultures.

 

Neuronal cell cultures following treatment with EtOH or EtOH-activated microglial conditioned medium showed decreased production levels of cAMP and BDNF. EtOH also increased apoptotic death as well as oxidative status, as demonstrated by higher cellular levels of oxidants but lower levels of antioxidants, in neuronal cells. These effects of EtOH on oxidative stress and cell death were enhanced by the presence of microglia. Treatment with BDNF or dbcAMP decreased EtOH or EtOH-activated microglial conditioned medium-induced changes in the levels of intracellular free radicals, ROS and O²⁻, nitrite, GSH, and catalase.

 

These data support the possibility that EtOH by acting directly and via increasing the production of microglial-derived factors reduces cellular levels of cAMP and BDNF to increase cellular oxidative status and apoptosis in hypothalamic neuronal cells in primary cultures.


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Circadian Clock Period Inversely Correlates with Illness Severity in Cells from Patients with Alcohol Use Disorders

Clinical and genetic studies suggest circadian clock genes may contribute to biological mechanisms underlying alcohol use disorders (AUD). In particular, the Per2 gene regulates alcohol consumption in mutant animals, and in humans with AUD, the 10870 variant in PER2 has been associated with alcohol consumption. However, with respect to function, the molecular clock remains largely uncharacterized in AUD patients.

 

In skin fibroblast cultures from well-characterized human AUD patients (n = 19) and controls (n = 13), we used a bioluminescent reporter gene (Per2::luc) to measure circadian rhythms in gene expression at high sampling density for 5 days. Cells were genotyped for the PER2 10870 variant. The rhythm parameters period and amplitude were then analyzed using a case–control design and by genetic and clinical characteristics of the AUD subjects.

 

There were no differences between AUD cases and controls in rhythm parameters. However, period was inversely correlated with illness severity (defined as the number of alcohol dependence criteria met). The PER2 variant 10870 was not associated with differences in rhythm parameters.

 

Our data suggest that differences in the cellular circadian clock are not pronounced in fibroblasts from AUD cases and controls. However, we found evidence that the circadian clock may be associated with an altered trajectory of AUD, possibly related to illness severity. Future work will be required to determine the mechanistic basis of this association.


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Request Reprint E-Mail:    mmccarthy@ucsd.edu

Activation of PPARγ by Pioglitazone Potentiates the Effects of Naltrexone on Alcohol Drinking and Relapse in msP Rats

Pioglitazone is a selective peroxisome proliferator-activated receptor γ (PPARγ) agonist used for the treatment of insulin resistance and type 2 diabetes. Previous studies conducted in our laboratory showed that activation of PPARγ by pioglitazone reduces alcohol drinking, stress-induced relapse, and alcohol withdrawal syndrome in rats. Pioglitazone was not able to prevent relapse elicited by alcohol cues. Conversely, the nonselective opioid antagonist naltrexone has been shown to reduce alcohol drinking and cue- but not stress-induced relapse in rodents.

 

Based on these findings, this study was sought to determine the efficacy of pioglitazone and naltrexone combination on alcohol intake and relapse behavior. Genetically selected alcohol-preferring Marchigian Sardinian (msP) rats were used for the study.

 

Pioglitazone (10 and 30 mg/kg) and naltrexone (0.25 and 1.0 mg/kg) each individually reduced alcohol drinking in msP rats. The combination of the 2 drugs resulted in a more potent alcohol drinking reduction than single agents. Confirming previous studies, pioglitazone (10 and 30 mg/kg) significantly reduced relapse induced by the pharmacological stressor yohimbine (1.25 mg/kg) but not by cues predictive of alcohol availability. Conversely, naltrexone reduced reinstatement of drug seeking elicited by alcohol cues but not by yohimbine.

 

The drug combination was effective in reducing both relapse behaviors. These findings open new vistas in the use pioglitazone in combination with naltrexone for the treatment of alcoholism.


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Request Reprint E-Mail:     roberto.ciccocioppo@unicam.it

Intraperitoneal Injection of Ethanol Results in Drastic Changes in Bone Metabolism Not Observed when Ethanol Is Administered by Oral Gavage

Chronic alcohol abuse is associated with increased risk of osteoporosis while light-to-moderate alcohol intake correlates with reduced osteoporosis risk. Addition of alcohol to a liquid diet is often used to model chronic alcohol abuse. Methods to model intermittent drinking (including binge drinking and light-to-moderate consumption) include (i) intragastric administration of alcohol by oral gavage or (ii) intraperitoneal (ip) administration of alcohol by injection. However, it is unclear whether the latter 2 methods produce comparable results. The purpose of this investigation was to determine the skeletal response to alcohol delivered daily by oral gavage or ip injection.

 

Ethanol (EtOH) or vehicle was administered to 4-month-old female Sprague–Dawley rats once daily at 1.2 g/kg body weight for 7 days. Following necropsy, bone formation and bone architecture were evaluated in tibial diaphysis (cortical bone) and proximal tibial metaphysis (cancellous bone) by histomorphometry. mRNA was measured for bone matrix proteins in distal femur metaphysis.

 

Administration of alcohol by gavage had no significant effect on body weight gain or bone measurements. In contrast, administration of the same dose of alcohol by ip injection resulted in reduced body weight, total suppression of periosteal bone formation in tibial diaphysis, decreased cancellous bone formation in proximal tibial metaphysis, and decreased mRNA levels for bone matrix proteins in distal femur.

 

Our findings raise concerns regarding the use of ip injection of EtOH in rodents as a method for modeling the skeletal effects of intermittent exposure to alcohol in humans. This concern is based on a failure of the ip route to replicate the oral route of alcohol administration.


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Request Reprint E-Mail:    urszula.iwaniec@oregonstate.edu

Selection for Drinking in the Dark Alters Brain Gene Coexpression Networks

 

Heterogeneous stock (HS/NPT) mice have been used to create lines selectively bred in replicate for elevated drinking in the dark (DID). Both selected lines routinely reach a blood ethanol (EtOH) concentration (BEC) of 1.00 mg/ml or greater at the end of the 4-hour period of access in Day 2. The mechanisms through which genetic differences influence DID are currently unclear. Therefore, the current study examines the transcriptome, the first stage at which genetic variability affects neurobiology. Rather than focusing solely on differential expression (DE), we also examine changes in the ways that gene transcripts collectively interact with each other, as revealed by changes in coexpression patterns.

 

Naïve mice (N = 48/group) were genotyped using the Mouse Universal Genotyping Array, which provided 3,683 informative markers. Quantitative trait locus (QTL) analysis used a marker-by-marker strategy with the threshold for a significant logarithm of odds (LOD) set at 10.6. Gene expression in the ventral striatum was measured using the Illumina Mouse 8.2 array. Differential gene expression and the weighted gene coexpression network analysis (WGCNA) were implemented largely as described elsewhere.

 

Significant QTLs for elevated BECs after DID were detected on chromosomes 4, 14, and 16; the latter 2 were associated with gene-poor regions. None of the QTLs overlapped with known QTLs for EtOH preference drinking. Ninety-four transcripts were detected as being differentially expressed in both selected lines versus HS controls; there was no overlap with known preference genes. The WGCNA revealed 2 modules as showing significant effects of both selections on intramodular connectivity. A number of genes known to be associated with EtOH phenotypes (e.g., Gabrg1, Glra2, Grik1, Npy2r, and Nts) showed significant changes in connectivity.

 

We found marked and consistent effects of selection on coexpression patterns; DE changes were more modest and less concordant. The QTLs and differentially expressed genes detected here are distinct from the preference phenotype. This is consistent with behavioral data and suggests that the DID and preference phenotypes are markedly different genetically.


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Request Reprint E-Mail:   iancuo@ohsu.edu

Chronic Ethanol (EtOH) Consumption Differentially Alters Gray and White Matter EtOH Methyl 1H Magnetic Resonance Intensity in the Primate Brain

In vivo magnetic resonance spectroscopy (MRS) has previously been used to directly monitor brain ethanol (EtOH). It has been proposed that the EtOH methyl ¹H resonance intensity is larger in EtOH-tolerant individuals than in sensitive individuals. To characterize the relationship between long-term EtOH exposure and the brain EtOH MRS intensity, we present data from a longitudinal experiment conducted using nonhuman primate subjects.

 

In vivo MRS was used to measure the gray matter (GM) and white matter (WM) EtOH methyl ¹H MRS intensity in 18 adult male rhesus macaques at 4 time points throughout the course of a chronic drinking experiment. Time points were prior to EtOH drinking, following a 3-month EtOH induction procedure, and following 6, and 12 subsequent months of 22 h/d of “open access” to EtOH (4% w/v) and water.

 

The EtOH methyl ¹H MRS intensity, which we observed to be independent of age over the range examined, increased with chronic EtOH exposure in GM and WM. In GM, MRS intensity increased from naïve level following the EtOH induction period (90 g/kg cumulative EtOH intake). In WM, MRS intensity was not significantly different from the EtOH-naïve state until after 6 months of 22-hour free access (110 to 850 g/kg cumulative intake range). The WM MRS intensity in the EtOH-naïve state was positively correlated with future drinking, and the increase in WM MRS intensity was negatively correlated with the amount of EtOH consumed throughout the experiment.

 

Chronic exposure to EtOH is associated with brain changes that result in differential increases in EtOH MRS intensity in GM and WM. The EtOH-naïve WM MRS intensity pattern is consistent with its previously proposed relationship to innate tolerance to the intoxicating effects of EtOH. EtOH-dependent MRS intensity changes in GM required less EtOH exposure than was necessary to produce changes in WM. Within WM, an unexpected, potentially age dependent, enhanced sensitivity to EtOH in light drinkers relative to heavy drinkers was observed.


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Request Reprint  E-Mail:    kroenkec@ohsu.edu

The Impact of Adolescent Binge Drinking and Sustained Abstinence on Affective State

While it is clear that affect is negatively impacted by heavy drinking in adulthood and that it improves with abstinence, little is known about effects of heavy drinking on mood during adolescence.

 

This study examined negative mood states among 2 groups of 16- to 18-year-old high school students; youth with a history of recent heavy episodic drinking (HED; n = 39) and comparison youth with limited lifetime drinking experience (CON; n = 26). Affect was assessed at 3 time points during a 4- to 6-week period of monitored abstinence using the Hamilton Rating Scales for Anxiety and Depression; self-reports were obtained with the state portion of the State-Trait Anxiety Inventory, and experience sampling of current affect was assessed via daily text messages sent at randomly determined times in the morning, afternoon, and evening.

 

Youth with a recent history of HED reported more negative affect compared with nondrinking youth during early stages of abstinence (days since last HED at assessment 1: M = 6.46; SD = 5.06); however, differences in affect were not observed after 4 to 6 weeks of abstinence. Sex differences were evident, with HED girls reporting greater depression and anxiety than HED male peers. Although not significant, response patterns indicated that boys may experience faster resolution of negative emotional states than girls with sustained abstinence.

 

Findings suggest that high-dose drinking is associated with elevated negative affect for adolescents and that negative mood states may take longer to resolve for girls than for boys following heavy drinking episodes. Future research clarifying naturally occurring changes in affective response during early and sustained abstinence is necessary for improving programs designed to promote adolescent decision-making and to reduce risk for relapse.


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Request Reprint E-Mail:   sandrabrown@ucsd.edu

Genetic Polymorphisms of Alcohol Dehydrogenase-1B and Aldehyde Dehydrogenase-2 and Liver Cirrhosis, Chronic Calcific Pancreatitis, Diabetes Mellitus, and Hypertension Among Japanese Alcoholic Men

The presence of the less-active form of alcohol dehydrogenase-1B encoded by ADH1B*1/*1 (vs. *2 allele) and active form of aldehyde dehydrogenase-2 (ALDH2) encoded by ALDH2*1/*1 (vs. *2 allele) increases the risk of alcoholism in East Asians.

 

The subjects in this cross-sectional survey were 1,902 Japanese alcoholic men (≥40 years) who underwent ADH1B/ALDH2 genotyping.

 

Age-adjusted daily alcohol consumption did not differ according to the ADH1B/ALDH2 genotypes. The age-adjusted odds ratios (AORs; 95% confidence interval) for liver cirrhosis (LC; n = 359, 1.58 [1.19 to 2.09]), chronic calcific pancreatitis (CP; n = 80, 2.24 [1.20 to 4.20]), and diabetes mellitus (DM; n = 383, 1.51 [1.15 to 1.99]) were higher in the ADH1B*2 allele carriers than in the ADH1B*1/*1 carriers. The AORs for LC (1.43 [1.01 to 2.02]), CP (1.68 [0.80 to 3.53]), DM (1.63 [1.15 to 2.30]), and hypertension (HT; n = 495, 1.52 [1.11 to 2.07]) were higher in the ALDH2*1/*1 carriers than in the ALDH2*1/*2 carriers. The ADH1B*2-associated AOR for LC was 2.08 (1.46 to 2.94) among those aged 40 to 59 years, but 0.89 (0.56 to 1.43) among those aged 60 years or over, and the interaction between ADH1B genotype and age on the LC risk was significant (p = 0.009). When the group with non-LC and no/mild fibrosis was used as controls, the ADH1B*2-associated AORs increased according to the severity of their liver disease: 1.67 (1.32 to 2.11) for the group with non-LC and serum type IV collagen values ≥200 ng/ml, 1.81 (1.24 to 2.63) for the group of Child-Pugh class A LC, and 3.17 (1.98 to 5.07) for the group with Child-Pugh class B/C LC. Anti-hepatitis C virus (HCV) antibody was positive in 103 patients, and the groups with a high anti-HCV antibody titer and either the ADH1B*2/*2 genotype or the ALDH2*1/*1 genotype had the highest AORs (8.83 and 4.90, respectively). The population attributable fraction (PAF) due to the ADH1B*2 allele was 29% for LC, 47% for CP, and 27% for DM, and the PAF due to the ALDH2*1/*1 genotype was 26% for LC, 34% for DM, and 30% for HT.

 

The ADH1B*2 allele increased the AORs for LC, CP, and DM of the alcoholics, and the ALDH2*1/*1 genotype increased their AORs for LC, DM, and HT. HCV infection and genetic susceptibility had a synergistic effect on the AOR for LC.


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Alcohol News 13/2013

 

 

 

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