Circulating Cytokines as Biomarkers of Alcohol Abuse and Alcoholism

There are currently no consistent objective biochemical markers of alcohol abuse and alcoholism. Development of reliable diagnostic biomarkers that permit accurate assessment of alcohol intake and patterns of drinking is of prime importance to treatment and research fields. Diagnostic biomarker development in other diseases has demonstrated the utility of both open, systems biology, screening for biomarkers and more rational focused efforts on specific biomolecules or families of biomolecules.

Long-term alcohol consumption leads to altered inflammatory cell and adaptive immune responses with associated pathologies and increased incidence of infections. This has led researchers to focus attention on identifying cytokine biomarkers in models of alcohol abuse. Alcohol is known to alter cytokine levels in plasma and a variety of tissues including lung, liver, and very importantly brain.

A number of cytokine biomarker candidates have been identified, including: tumor necrosis factor-alpha, interleukin (IL)-1-alpha, IL-1-beta, IL-6, IL-8, IL-12, and monocyte chemoattractant protein-1.

This is an emerging and potentially exciting avenue of research in that circulating cytokines may contribute to diagnostic biomarker panels, and a combination of multiple biomarkers may significantly increase the sensitivity and specificity of the biochemical tests aiding reliable and accurate detection of excessive alcohol intake.

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Request Reprint E-Mail: kvrana@psu.edu
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Neuropeptide Y Signaling in the Central Nucleus of Amygdala Regulates Alcohol-Drinking and Anxiety-Like Behaviors of Alcohol-Prefering Rats

The neuropeptide Y (NPY) system of the central nucleus of amygdala (CeA) has been shown to be involved in anxiety and alcoholism. In this study, we investigated the molecular mechanisms by which NPY in the CeA regulates anxiety and alcohol drinking behaviors using alcohol-preferring (P) rats as an animal model.

We found that NPY infusion into the CeA produced anxiolytic effects, as measured by the LDB exploration test, and also decreased alcohol intake in P rats. NPY infusion into the CeA significantly increased levels of CaMK IV and phosphorylated cAMP responsive element-binding (pCREB) protein and increased mRNA and protein levels of NPY, but produced no changes in protein levels of CREB or the catalytic α-subunit of protein kinase A (PKA-Cα) in the CeA. We also observed that alcohol intake produced anxiolytic effects in P rats in the LDB test and also increased NPY expression and protein levels of pCREB and PKA-Cα without modulating protein levels of CREB or CaMK IV, in both the CeA and medial nucleus of amygdala. In addition, we found that CaMK IV-positive cells were co-localized with NPY in amygdaloid structures of P rats.

These results suggest that NPY infusion may increase the expression of endogenous NPY in the CeA, which is most likely attributable to an increase in CaMK IV-dependent CREB phosphorylation and this molecular mechanism may be involved in regulating anxiety and alcohol drinking behaviors of P rats.

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Request Reprint E-Mail: scpandey@uic.edu

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The Restraint Bias: How the Illusion of Self-Restraint Promotes Impulsive Behavior

Four studies examined how impulse-control beliefs—beliefs regarding one's ability to regulate visceral impulses, such as hunger, drug craving, and sexual arousal—influence the self-control process.

The findings provide evidence for a restraint bias: a tendency for people to overestimate their capacity for impulse control. This biased perception of restraint had important consequences for people's self-control strategies. Inflated impulse-control beliefs led people to overexpose themselves to temptation, thereby promoting impulsive behavior.

-In Study 4, for example, the impulse-control beliefs of recovering smokers predicted their exposure to situations in which they would be tempted to smoke. Recovering smokers with more inflated impulse-control beliefs exposed themselves to more temptation, which led to higher rates of relapse 4 months later.

The restraint bias offers unique insight into how erroneous beliefs about self-restraint promote impulsive behavior.

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Request Reprint E-Mail: L-nordgren@kellogg.northwestern.edu.
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The public face of binge drinking: British and Danish young women, recent trends in alcohol consumption and the European binge drinking debate

International and national data sets are utilized to compare changes in young women’s alcohol consumption between the UK and Denmark, two European countries renowned for their alcohol-related problems.

Explanations for young women’s increased sessional drinking have previously focused on the public spectacle of the binge drinker and the notion of a ‘convergence’ between women’s and men’s consumption patterns, incomes and broader lifestyles.

An apparent decline in young women’s binge drinking and weekly drinking in both countries since 2000 is counterbalanced by more frequent drinking, home drinking and wine drinking into middle age, associated with professional occupations.

In the face of an enduring polarization of the public excesses of youth with supposedly civilized moderation within the home, the article argues for a more nuanced understanding of the relationship between alcohol, women’s changing lives and northern European drinking cultures.

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Request Reprint E-Mail: f.measham@lancaster.ac.uk

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Ecological Associations of Alcohol Outlets With Underage and Young Adult Injuries

This paper argues that associations between rates of 3 specific problems related to alcohol (i.e., accidents, traffic crashes, and assaults) should be differentially related to densities of alcohol outlets among underage youth and young adults based upon age-related patterns of alcohol outlet use.

Densities of off-premise alcohol outlets were significantly related to injuries from accidents, assaults, and traffic crashes for both underage youth and young adults. Densities of bars were associated with more assaults and densities of restaurants were associated with more traffic crash injuries for young adults.

The distribution of alcohol-related injuries relative to alcohol outlets reflect patterns of alcohol outlet use.

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Request Reprint E-Mail: paul@prev.org

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Mechanisms of Postural Control in Alcoholic Men and Women: Biomechanical Analysis of Musculoskeletal Coordination During Quiet Standing

Excessive sway during quiet standing is a common sequela of chronic alcoholism even with prolonged sobriety. Whether alcoholic men and women who have remained abstinent from alcohol for weeks to months differ from each other in the degree of residual postural instability and biomechanical control mechanisms has not been directly tested.

Reduction in sway and closed-loop activity during quiet standing with stabilizing factors shows some differential expression in men and women with histories of alcohol dependence. Nonetheless, enduring deficits in postural instability of both alcoholic men and alcoholic women suggest persisting liability for falling.

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Request Reprint E-Mail: edie@stanford.edu
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Subjective Response to Alcohol: A Critical Review of the Literature

Subjective response to alcohol (SR), which reflects individual differences in sensitivity to the pharmacological effects of alcohol, may be an important endophenotype in understanding genetic influences on drinking behavior and alcohol use disorders (AUDs). SR predicts alcohol use and problems and has been found to differ by a range of established risk factors for the development of AUDs (e.g., family history of alcoholism). The exact pattern of SR associated with increased risk for alcohol problems, however, remains unclear. The Low Level of Response Model (LLR) suggests that high-risk individuals experience decreased sensitivity to the full range of alcohol effects, while the Differentiator Model (DM) asserts that high risks status is associated with increased sensitivity to alcohol's positive effects but decreased sensitivity to negative effects.

Despite commendable advances in SR research, important questions remain unanswered. Inconsistent results across studies may be attributable to a combination of an inadequate understanding of the underlying construct and methodological differences across studies (e.g., number and timing of assessments across the BAC, inclusion of a placebo condition). With respect to the underlying construct, existing measures fail to adequately distinguish between cognitive/behavioral impairment and sedation, aspects of which may be perceived positively (e.g., anxiolysis) due to their ability to act as negative reinforcers.

Addressing the concerns raised by the current review will be integral to making meaningful scientific progress in the field of subjective response.

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Request Reprint E-Mail: Meghan.Morean@yale.edu

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The Effect of Moderate to Heavy Alcohol Consumption on Neuropsychological Performance as Measured by the Repeatable Battery for the Assessment of Neur

Excessive alcohol use is associated with damage to the structure and function of the brain and impairment of cognition and behavior. Traditional test batteries used to assess cognitive performance in alcoholics are extensive and costly, limiting their use across various clinical and research settings. The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) is a relatively new instrument that attempts to overcome some of these limitations. As yet the indiividual effect of moderate to heavy alcohol consumption on RBANS performance has not been examined.

The primary aim of this study was to explore and quantify differences in performance between controls and drinkers on the RBANS and to examine the influence of age, gender, and alcohol use patterns on test performance.

Our results suggest that the RBANS is able to detect and characterize differences in verbal fluency, visuospatial skills, components of declarative memory, and psychomotor speed between healthy controls and moderate to heavy active alcohol users. Executive functions, commonly affected by alcoholism and not included in the RBANS, require assessment with additional measures.

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Request Reprint E-Mail: alisa@med.usyd.edu.au
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Gene Expression in the Neuropeptide Y System During Ethanol Withdrawal Kindling in Rats

Multiple episodes of ethanol intoxication and withdrawal result in progressive, irreversible intensification of the withdrawal reaction, a process termed "ethanol withdrawal kindling." Previous studies show that a single episode of chronic ethanol intoxication and withdrawal causes prominent changes in neuropeptide Y (NPY) and its receptors that have been implicated in regulating withdrawal hyperexcitability.

This study for the first time examined the NPY system during ethanol withdrawal kindling.

Multiple withdrawal episodes reversibly decreased NPY and NPY receptor mRNA levels at peak withdrawal, with smaller decreases in NPY mRNA levels and augmented decreases in Y1/Y5 mRNA levels compared with a SW episode. Multiple withdrawal-induced seizures increased the Y2 mRNA levels in PirCx. These complex changes in NPY system gene expression could play a role in the ethanol withdrawal kindling process.

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Request Reprint E-Mail: woldbye@sund.ku.dk
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Disruptions in Functional Network Connectivity During Alcohol Intoxicated Driving

Driving while under the influence of alcohol is a major public health problem whose neural basis is not well understood. In a recently published functional magnetic resonance imaging (fMRI) study (Meda et al., 2009), our group identified 5, independent critical driving-associated brain circuits whose inter-regional connectivity was disrupted by alcohol intoxication. However, the functional connectivity between these circuits has not yet been explored in order to determine how these networks communicate with each other during sober and alcohol-intoxicated states.

Connections between frontal-temporal-basal ganglia and cerebellum have recently been explored; these may be responsible in part for maintaining normal motor behavior by integrating their overlapping motor control functions. These connections appear to be disrupted by alcohol intoxication, in turn associated with an explicit type of impaired driving behavior.

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Rerquest Reprint E-Mail: crzepecki@harthosp.org
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Phosphatidylethanol and Alcohol Consumption in Reproductive Age Women

Fetal alcohol disorders are preventable, but self-reported alcohol consumption can be misleading and impede effective treatment. Biomarkers represent an alternative method for assessing alcohol use, and this study evaluated the relationship between blood phosphatidylethanol (PEth) and alcohol use in a sample of reproductive age women.

PEth is a highly sensitive indicator of moderate and heavy alcohol consumption in reproductive age women and may complement the use of self-report alcohol screens when additional objective markers of alcohol use are desirable.

However, choosing a highly valid cutoff concentration for PEth to differentiate various levels of alcohol consumption may not be feasible.

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Request Reprint E-Mail: stewarsh@musc.edu
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Phosphodiesterase Type 4 Inhibition Does Not Restore Ocular Dominance Plasticity in a Ferret Model of Fetal Alcohol Spectrum Disorders

There is growing evidence that deficits in neuronal plasticity account for some of the neurological problems observed in fetal alcohol spectrum disorders (FASD). Recently, we showed that early alcohol exposure results in a permanent impairment in visual cortex ocular dominance (OD) plasticity in a ferret model of FASD. This disruption can be reversed, however, by treating animals with a Phosphodiesterase (PDE) type 1 inhibitor long after the period of alcohol exposure.

Using in vivo electrophysiology we show that inhibition of PDE4 by rolipram does not restore OD plasticity in alcohol-treated ferrets.

This result suggests that contrary to PDE1, PDE4 inhibition does not play a role in the restoration of OD plasticity in the ferret model of FASD.

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Request Reprint E-Mail: amedina@vcu.edu

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Feasibility of Using Interactive Voice Response to Monitor Daily Drinking, Moods, and Relationship Processes on a Daily Basis in Alcoholic Couples

Daily process research on alcohol involvement has used paper-and-pencil and electronic data collection methods, but no studies have yet tested the feasibility of using Interactive Voice Response (IVR) technology to monitor drinking, affective, and social interactional processes among alcoholic (ALC) couples. This study tested the feasibility of using IVR with n = 54 ALC couples.

Findings supported that IVR is a useful method for collecting daily drinking, mood, and relationship process data from alcoholic couples. Probands' compliance is strongly associated with their partners' compliance, and autFmated IVR calls may facilitate compliance on high anxiety, high conflict days.

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Request Reprint E-Mail: jcranfor@med.umich.edu
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Revisiting Intragastric Ethanol Intubation as a Dependence Induction Method for Studies of Ethanol Reward and Motivation in Rats

The purpose of this study was to re-examine intragastric ethanol intubation as a dependence induction method that effectively induces physical dependence upon ethanol over a short time period, is devoid of intrinsic stress artifacts, inexpensive, and easy to implement.

These findings suggest that intragastric ethanol administration produces a behavioral profile consistent with ethanol dependence (i.e., significant withdrawal signs after termination of ethanol exposure and elevated anxiety-like behavior persisting beyond completion of physical withdrawal), and that the intubation procedure itself does not produce lasting nonspecific anxiety-like effects. Thus, under the conditions employed here, this procedure provides an effective tool for inducing and evaluating the consequences of ethanol dependence in animal models of ethanol reward and motivation.

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Request Reprint E-Mail: nsidhp@scripps.edu
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Differential Central NOS-NO Signaling Underlies Clonidine Exacerbation of Ethanol-Evoked Behavioral Impairment

The molecular mechanisms that underlie clonidine exacerbation of behavioral impairment caused by ethanol are not fully known. We tested the hypothesis that nitric oxide synthase (NOS)-derived nitric oxide (NO) signaling in the locus coeruleus (LC) is implicated in this phenomenon.

Alterations in NOS-derived NO in the LC underlie clonidine–ethanol induced behavioral impairment. A decrease in nNOS activity, due at least partly to a reduction in nNOS phosphorylation, mediates rotorod impairment, while enhanced eNOS activity contributes to LORR, elicited by clonidine–ethanol combination.

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Request Reprint E-Mail: abdelrahmana@ecu.edu
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Moderate Alcohol Consumption Aggravates High-Fat Diet Induced Steatohepatitis in Rats

Nonalcoholic steatohepatitis (NASH) develops in the absence of chronic and excessive alcohol consumption. However, it remains unknown whether moderate alcohol consumption aggravates liver inflammation in pre-existing NASH condition.

These data suggest that even moderate alcohol consumption can cause more hepatic inflammation and cellular apoptosis in a pre-existing NASH condition.

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Request Reprint E-Mail: xiang-dong.wang@tufts.edu

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Exploring the Relationship Between Depressive and Anxiety Symptoms and Neuronal Response to Alcohol Cues

Depressive and anxiety symptoms tend to co-occur with heavy drinking. Specifically, their presence may exacerbate the severity and intractability of heavy drinking. Similarly, heavy drinking may increase the risk for and experience of depressive and anxiety symptoms. Although depressive and anxiety symptoms have been significantly correlated with alcohol craving in cue-exposure paradigms, physiological responses have not always mapped onto emotional responses. Therefore, this study sought to examine the role of depressive and anxiety symptoms using a more basic science approach, through examining functional brain changes.

Significant correlations were found between depressive symptoms, anxiety symptoms, and differential brain activation in response to an alcohol versus an appetitive control cue in an fMRI paradigm. Moreover, the pattern of activation mapped onto expected regions. This study strongly supports the posited relationships between depressive symptoms, anxiety symptoms, and differential brain activation in an alcohol cue-exposure paradigm with a sample of heavy drinking adults.

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Request Reprint E-Mail: sfeldstein@mrn.org
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Exercise Neuroprotection in a Rat Model of Binge Alcohol Consumption

Excessive alcohol intake produces structural and functional deficits in corticolimbic pathways that are thought to underlie cognitive deficits in the alcohol use disorders (AUDs). Animal models of binge alcohol administration support the direct link of high levels of alcohol consumption and neurotoxicity in the hippocampus and surrounding cortex. In contrast, voluntary wheel running enhances hippocampal neurogenesis and generally promotes the health of neurons

Rats that exercised prior to binge exposure were significantly less behaviorally intoxicated, which was not a result of enhanced hepatic metabolism. Rats that exercised prior to binge alcohol consumption had reduced loss of dentate gyrus granule cells and fewer FluoroJade B positive cells in the dentate gyrus and associated entorhinal-perirhinal cortex compared to nonexercisers. However, exercise did not protect against cell death in the piriform cortex nor protect against alcohol-induced decreases in cell proliferation, evidenced by a similar alcohol-induced reduction in Ki67 labeled cells between exercise and sedentary rats.

We conclude that exercise can reduce behavioral sensitivity to ethanol intoxication and protect vulnerable brain areas from alcohol-induced cell death. Exercise neuroprotection of alcohol-induced brain damage has important implications in understanding the neurobiology of the AUDs as well as in developing novel treatment strategies.

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Request Reprint E-Mail: kim-nixon@uky.edu

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Intoxication With Bourbon Versus Vodka: Effects on Hangover, Sleep, and Next-Day Neurocognitive Performance in Young Adults

This study assessed the effects of heavy drinking with high or low congener beverages on next-day neurocognitive performance, and the extent to which these effects were mediated by alcohol-related sleep disturbance or alcoholic beverage congeners, and correlated with the intensity of hangover.

After alcohol, people had more hangover and more decrements in tests requiring both sustained attention and speed. Hangover correlated with poorer performance on these measures. Alcohol decreased sleep efficiency and rapid eye movement sleep, and increased wake time and next-day sleepiness. Alcohol effects on sleep correlated with hangover but did not mediate the effects on performance. No effect of beverage congeners was found except on hangover severity, with people feeling worse after bourbon. Virtually no sex differences appeared.

As drinking to this level affects complex cognitive abilities, safety could be affected, with implications for driving and for safety-sensitive occupations. Congener content affects only how people feel the next day so does not increase risk. The sleep disrupting effects of alcohol did not account for the impaired performance so other mechanisms of effect need to be sought. As hangover symptoms correlate with impaired performance, these might be contributing to the impairment.

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Request Reprint E-Mail: Damaris_Rohsenow@brown.edu

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Common Genetic Contributions to Alcohol and Cannabis Use and Dependence Symptomatology

Despite mounting evidence that use of and dependence on alcohol and cannabis are influenced by heritable factors, the extent to which heritable influences on these phenotypes overlap across the 2 substances has only rarely been explored. In the current study, we quantified cross-substance overlap in sources of variance and estimated the degree to which within-substance associations between use and dependence measures are attributable to common genetic and environmental factors for alcohol and cannabis.

Over 60% of variance in alcohol consumption, cannabis use, and cannabis dependence symptoms, and just under 50% of variance in alcohol dependence (AD) symptoms were attributable to genetic sources. Shared environmental factors did not contribute significantly to the 4 phenotypes. Nearly complete overlap in heritable influences was observed for within-substance measures of use and dependence symptoms. Genetic correlations across substances were 0.68 and 0.62 for use and dependence symptoms, respectively.

Common heritable influences were evident for alcohol and cannabis use and for AD and cannabis dependence symptomatology, but findings indicate that substance-specific influences account for the majority of the genetic variance in the cannabis use and dependence phenotypes. By contrast, the substantial correlations between alcohol use and AD symptoms and between cannabis use and cannabis dependence symptoms suggest that measures of heaviness of use capture much of the same genetic liability to alcohol- and cannabis-related problems as dependence symptomatology.

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Request Reprint E-Mail: sartorc@psychiatry.wustl.edu
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