Alda-1 is an agonist and chemical chaperone for the common human aldehyde dehydrogenase 2 variant

In approximately one billion people, a point mutation inactivates a key detoxifying enzyme, aldehyde dehydrogenase (ALDH2).

This mitochondrial enzyme metabolizes toxic biogenic and environmental aldehydes, including the endogenously produced 4-hydroxynonenal (4HNE) and the environmental pollutant acrolein, and also bioactivates nitroglycerin.

ALDH2 is best known, however, for its role in ethanol metabolism. The accumulation of acetaldehyde following the consumption of even a single alcoholic beverage leads to the Asian alcohol-induced flushing syndrome in ALDH2*2 homozygotes. The ALDH2*2 allele is semidominant, and heterozygotic individuals show a similar but less severe phenotype.

We recently identified a small molecule, Alda-1, that activates wild-type ALDH2 and restores near-wild-type activity to ALDH2*2.

The structures of Alda-1 bound to ALDH2 and ALDH2*2 reveal how Alda-1 activates the wild-type enzyme and how it restores the activity of ALDH2*2 by acting as a structural chaperone.

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Request Reprint E-Mail: thurley@iupui.edu.
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Supervised Disulfiram in Relapse Prevention in Alcohol-Dependent Patients Suffering From Comorbid Borderline Personality Disorder—A Case Series

Disulfiram is widely used to prevent alcoholic relapse. However, due to the intended adverse reaction with ethanol, some believe that its use is dangerous for patients with personality disorders or psychiatric comorbidities because of their increased risk of impulsivity or suicidal behaviour.

We examined the safety and efficacy in relapse prevention of a series of alcoholics with borderline personality disorder (BPD).

Two out of eight patients remained completely abstinent during the supervised disulfiram therapy over a mean period of 9.25 months. Adherence to treatment was 18.44 ± 21.78 months. The first relapse occurred after 1.38 ± 1.41 months. The cumulated time of abstinence was 16.88 ± 20.48 months. The overall tolerability was considered to be high; dizziness and fatigue appeared in all patients at the beginning of the therapy but did not persist. No serious adverse events or ethanol–disulfiram interactions were observed. No suicidal behaviour was reported.

Although case observations should be interpreted with caution, supervised disulfiram seems to deserve further investigation in patients with comorbid BPD, for whom it appears to help prevent alcoholic relapse.

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Request Reprint E-Mail: jochen.mutschler@puk.zh.ch :

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Use of Carbohydrate-Deficient Transferrin (CDT) and a Combination of GGT and CDT (GGT–CDT) to Assess Heavy Alcohol Consumption in Traffic Medicine

Carbohydrate-deficient transferrin (CDT) has become widely used in traffic medicine to detect chronic alcohol abuse among subjects applying for driving-license renewal or regranting. By defining cut-off values in a large population of abstainers and moderate drinkers, we report on CDT, GGT–CDT (a combination of gamma-glutamylaminotransferase (GGT) and CDT) and the association between blood alcohol concentration (BAC) and CDT among Italian drivers.

A common CDT cut-off (1.8%) and gender-specific GGT–CDT cut-off (4.15% for males, 3.56% for females) were calculated as 99.9th percentiles of the control population. Also, 3% and 27% of subjects were classified as CDT positive respectively among drivers applying for license regranting and drivers involved in car accidents. A significant association between BAC and both CDT values and CDT positivity was found, with a frequency up to 49% of CDT samples, suggesting chronic alcohol abuse, among drivers with BAC >2.5g/l. Concordance between CDT and GGT–CDT was only moderate (kappa = 0.44), with CDT performing better than GGT–CDT.

A relevant proportion of drivers with high BAC are chronic abusers. GGT–CDT, previously validated with CDT immunoassays, should not be applied to traffic medicine in its current form and its performances re-evaluated with CDT measured by HPLC.

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Request Reprint E-Mail: vidali@med.unipmn.it
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H2 haplotype at chromosome 17q21.31 protects against childhood sexual abuse-associated risk for alcohol consumption and dependence

Animal research supports a central role for corticotropin-releasing factor (CRF) in actions of ethanol on brain function.

An examination of alcohol consumption in adolescents reported a significant genotype × environment (G × E) interaction involving rs1876831, a corticotropin-releasing hormone receptor 1 (CRHR1) polymorphism, and negative events. and at least four other genes are located at 17q21.31 in an extremely large block of high linkage disequilibrium resulting from a local chromosomal inversion; the minor allele of rs1876831 is contained within the H2 haplotype.

Here, we examine whether G × E interactions involving this haplotype and childhood sexual abuse (CSA) are associated with risk for alcohol consumption and dependence in Australian participants (CRHR1n = 1128 respondents from 476 families) of the Nicotine Addiction Genetics project.

Telephone interviews provided data on DSM-IV alcohol dependence diagnosis and CSA and enabled calculation of lifetime alcohol consumption factor score (ACFS) from four indices of alcohol consumption. Individuals reporting a history of CSA had significantly higher ACFS and increased risk for alcohol dependence.

A significant G × E interaction was found for ACFS involving the H2 haplotype and CSA (P <>

Our results also suggest that severe early trauma may prove to be an important clinical covariate in the treatment of alcohol dependence.

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Request Reprint E-Mail: nelsone@wustl.edu
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Readiness to Change in Brief Motivational Interventions: A Requisite Condition for Drinking Reductions?

Brief motivational interventions (BMIs) have been found to be efficacious for reducing alcohol use and consequences among college student drinkers. Despite the putative emphasis on motivation, surprisingly little is known about the role of motivation in BMI-facilitated changes.

Using data from three published randomized trials implementing BMIs, we examined motivation or readiness to change (RTC) as a potential mechanism of behavior change.

Two of the three studies indicated that BMI were associated with increases in motivation to change alcohol use that are apparent immediately after BMI sessions and persist up to 6-months post-intervention.

However, RTC does not appear to be a mechanism of behavior change, as it did not mediate reductions in alcohol use or problems in any of the studies.

Issues regarding the conceptualization and measurement of RTC are discussed, as well as promising directions for future research.

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Neurokinin-1 receptors (NK1R:s), alcohol consumption, and alcohol reward in mice

Reduced voluntary alcohol consumption was recently found in neurokinin-1 receptor (NK1R)-deficient (KO) mice. It remains unknown whether this reflects developmental effects or direct regulation of alcohol consumption by NK1R:s, and whether the reduced consumption reflects motivational effects.

The objective of this study is to obtain an expanded preclinical validation of NK1R antagonism as a candidate therapeutic mechanism in alcohol use disorders.

Acute blockade of NK1R:s mimics the effects of NKR1 gene deletion on alcohol consumption, supporting a direct rather than developmental role of the receptor in regulation of alcohol intake. Inactivation of NK1R:s critically modulates alcohol reward and escalation, two key characteristics of addiction.

These data provide critical support for NK1R antagonism as a candidate mechanism for treatment of alcoholism.

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Request Reprint E-Mail: markus.heilig@mail.nih.gov

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Effect of prenatal stress on alcohol preference and sensitivity to chronic alcohol exposure in male rats

In rats, prenatal restraint stress (PRS) induces persistent behavioral and neurobiological alterations leading to a greater consumption of psychostimulants during adulthood. However, little is known about alcohol vulnerability in this animal model.

We examined in adolescent and adult male Sprague Dawley rats the long-lasting impact of PRS exposure on alcohol consumption.

Our data suggest that negative events occurring in utero do not modulate alcohol preference in male rats but potentiate chronic alcohol-induced molecular neuroadaptation in the brain reward circuitry.

Further studies are needed to determine whether the exacerbated ΔFosB upregulation in PRS rats could be extended to other reinforcing stimuli. lasting impact of PRS exposure on alcohol consumption.

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Request Reprint E-Mail: vincent.vanwaes@rosalindfranklin.edu
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Press Release - Teens Who Drink With Parents May Still Develop Alcohol Problems

Parents who try to teach responsible drinking by letting their teenagers have alcohol at home may be well intentioned, but they may also be wrong, according to a new study in the January issue of the Journal of Studies on Alcohol and Drugs.

In a study of 428 Dutch families, researchers found that the more teenagers were allowed to drink at home, the more they drank outside of home as well. What’s more, teens who drank under their parents’ watch or on their own had an elevated risk of developing alcohol-related
problems. . . . . . .

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Do Parents and Best Friends Influence the Normative Increase in Adolescents' Alcohol Use at Home and Outside the Home?

The present study explored the possible impact of parental supervision of adolescents' alcohol use and drinking with parents on concurrent and prospective associations between adolescents' drinking at home and drinking outside the home. The impact of drinking with their best friend, parental drinking behaviors, and sibling influence on adolescent alcohol use were also examined, as well as whether drinking at home and outside the home predicted problem drinking.

We used three waves of longitudinal full-family data (fathers, mothers, and two adolescent siblings; N = 428).

Bi-directional effects between drinking at home and drinking outside the home were found for both adolescents, with drinking in one setting predicting drinking in another setting over time. Both drinking at home and drinking outside the home predicted subsequent problem drinking. These associations did not differ as a function of adolescents drinking with parents or their best friend or of parental supervision of adolescents' alcohol use. Only adolescents' gender seemed to moderate these effects but solely in midadolescence. For 15-year-old boys (but not for girls), at-home drinking predicted outside-the-home drinking 1 year later.

Taken together, adolescents' alcohol use increases over time, regardless of setting or with whom they drink. According to these results, prevention workers should focus on making parents more aware of their role in delaying the age at drinking onset.

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Request Reprint E-Mail: h.vandervorst@pwo.ru.nl
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Trends in Adult Female Substance Abuse Treatment Admissions Reporting Primary Alcohol Abuse: 1992 to 2007

● Between 1992 and 2007, the proportion of adult female substance abuse treat-ment admissions that reported primary alcohol abuse declined from 47.4 per-cent to 33.4 percent; of these, there were declines in the proportion who reported only alcohol abuse (from 28.2 to 18.5 percent) and those who reported secondary or tertiary abuse of other substances (from 19.2 to 14.9 percent)

● Between 1992 and 2007, the proportion of adult female alcohol admissions aged 25 to 34 decreased from 43.2 to 23.2 percent, while the proportion aged 45 to 54 almost tripled from 9.4 to 24.1 percent

● The proportion of adult female admissions that reported primary alcohol abuse and the secondary or tertiary abuse of other substances increased from 40.5 percent in 1992 to 44.6 percent in 2007

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Determinants of Early Reductions in Drinking in Older At-Risk Drinkers Participating in the Intervention Arm of a Trial to Reduce At-Risk Drinking in

To describe differences between older at-risk drinkers, as determined using the Comorbidity Alcohol Risk Evaluation Tool, who reduced drinking and those who did not after an initial intervention and to determine factors associated with early reductions in drinking.

Thirty-nine percent of the sample had reduced drinking within 2 weeks of receiving the initial intervention. According to the final multiple logistic regression model, those who were concerned about alcohol-related risks , read through the educational booklet , or perceived that their physicians discussed risks and advised changing drinking behaviors had greater odds of reducing drinking by the first health educator call.

Concern about risks, reading educational material, and perception of physicians providing advice to reduce drinking were associated with early reductions in alcohol use in older at-risk drinkers. Understanding these factors will enable development of better intervention strategies to reduce unhealthy alcohol use.

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Request Reprint E-Mail: jlin1207@ucla.edu

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Mothers' maximum drinks ever consumed in 24 hours predicts mental health problems in adolescent offspring

The maximum number of alcoholic drinks consumed in a single 24-hr period is an alcoholism-related phenotype with both face and empirical validity. It has been associated with severity of withdrawal symptoms and sensitivity to alcohol, genes implicated in alcohol metabolism, and amplitude of a measure of brain activity associated with externalizing disorders in general. In a previous study we found that the maximum number of drinks fathers had ever consumed in 24 hrs was associated with externalizing behaviors and disorders in preadolescent and adolescent children.

The purpose of the present study was to determine whether maternal maximum consumption has similar correlates.

Maximum consumption was associated with conduct disorder, disruptive disorders in general, early substance use and misuse, and substance disorders in adolescent children regardless of sex. Associations were consistent across cohorts, providing internal replication. They also paralleled our previous findings regarding paternal status. They could not be explained by maternal alcohol dependence, effects of drinking during pregnancy, or paternal maximum consumption. They were not simple artifacts of the fact that maximum consumption is a continuous measure while alcohol dependence is dichotomous.

Despite deriving from a single question about lifetime behavior, parental maximum consumption appears to reflect vulnerability for mental health problems, especially substance-related ones, more directly than a diagnosis of alcohol dependence.

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Request Reprint E-Mail: smalone@umn.edu
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Alcohol and food: making the public health connections

'Alcohol and food: making the public health connections' (pdf), a literature review into the links surrounding alcohol and food, has been published by the the Liverpool John Moore's University.

Read More . . . .______________________________________

The Development of the Feighner Criteria: A Historical Perspective

This essay outlines the historical context in which the Feighner criteria emerged; reconstructs, as far as possible, the process by which the criteria were developed; and traces the influence the criteria had on subsequent developments in American psychiatry.

In the 1950s, when American psychiatry under psychoanalytic dominance had little interest in psychiatric diagnosis, Edwin Gildea recruited to the Department of Psychiatry at Washington University faculty who advocated a medical model for psychiatry in which diagnosis had a central role.

In 1967, at the urging of the then-resident John Feighner, a discussion group led by Eli Robins and including Sam Guze, George Winokur, Robert Woodruff, and Rod Muñoz began meeting with the initial goal of writing a review of prior key contributions to psychiatric diagnosis.

In their meetings over the next year, the task soon shifted to the development of a set of new diagnostic criteria. For three diagnoses, major depression, antisocial personality disorder, and alcoholism, the authors could identify the original criteria from which this group worked and the rationale for many of the changes they introduced.

Published in 1972, the Feighner criteria were soon widely cited and used in research, and they formed the basis for the development of the Research Diagnostic Criteria, which in turn were central to the development of DSM-III.

The team that developed the Feighner criteria made three key contributions to psychiatry: the systematic use of operationalized diagnostic criteria; the reintroduction of an emphasis on illness course and outcome; and an emphasis on the need, whenever possible, to base diagnostic criteria on empirical evidence.

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Request Reprint E-Mail: kendler@hsc.vcu.edu
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Prenatal Alcohol Exposure Alters Biobehavioral Reactivity to Pain in Newborns

To examine biobehavioral responses to an acute pain event in a Cape Town, South Africa, cohort consisting of 28 Cape Colored (mixed ancestry) newborns (n = 14) heavily exposed to alcohol during pregnancy (exposed), and born to abstainers (n = 14) or light (≤0.5 oz absolute alcohol/d) drinkers (controls).

There were no between-group differences in maternal age, marital status, parity, gravidity, depression, anxiety, pregnancy smoking, maternal education, or infant gestational age at birth (all ps > 0.15). In both groups, HR increased with the heel lance and decreased during the postlance period. The alcohol-exposed group had lower mean HR than controls throughout, and showed no change in RSA over time. Cortisol levels showed no change over time in controls but decreased over time in exposed infants. Although facial action analyses revealed no group differences in response to the heel lance, behavioral responses assessed on the Brazelton Neonatal Scale showed less arousal in the exposed group.

Both cardiac autonomic and hypothalamic–pituitary–adrenal stress reactivity measures suggest a blunted response to an acute noxious event in alcohol-exposed newborns. This is supported by results on the Brazelton Neonatal Scale indicating reduced behavioral arousal in the exposed group.

To our knowledge, these data provide the first biobehavioral examination of early pain reactivity in alcohol-exposed newborns and have important implications for understanding neuro-/biobehavioral effects of prenatal alcohol exposure in the newborn period.

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Request Reprint E-Mail: toberlander@cw.bc.ca

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Individual Differences in Alcohol Drinking Frequency Are Associated With Electrophysiological Responses to Unexpected Nonrewards

It has been suggested that alcohol use is related to sensitivity of the reward system. Although there are several studies using self-reported measures supportive of this notion, objective biological data in humans on this issue are lacking.

This study is designed to test whether alcohol drinking frequency is associated with electrophysiological indices of reward processing.

Most importantly, the MFN to unpredicted nonrewards at the frontal midline (Fz) location correlated significantly with drinking frequency, with frequent drinkers showing larger MFN amplitudes. The results did not show a significant association between frequency and alcohol drinking and P2.

Although several studies showing increased reward-sensitivity in addictive behaviors, the present results indicate that, in frequent alcohol drinkers, electrophysiological responsiveness is particularly activated by unpredicted nonrewards. In general, this may point to the involvement of the reward system in alcohol drinking frequency.

More specifically, the results demonstrate an increased vulnerability of high frequency drinkers to signals of (frustrative) nonrewards.

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Request Reprint E-Mail: franken@fsw.eur.nl

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Research on alcohol and adolescent brain development: opportunities and future directions

In the past 15 years, both human and animal studies have advanced our understanding of the effects of adolescent alcohol exposure on behavioral and neural development, particularly in the areas of the ontogeny of initial sensitivity and tolerance to alcohol, the consequences of adolescent alcohol exposure on subsequent drinking patterns, as well as cognitive and neural function.

Despite these advances, there are still substantial gaps in our understanding of whether heavy adolescent drinking interferes with normal brain development at the cellular and molecular level, and if so, how these changes may translate into patterns of brain connectivity that result in the emergence of alcohol use disorders.

This article discusses our current knowledge of the cellular and molecular brain changes that stem from heavy alcohol exposure, including binge patterns, during adolescence.

Progress has been made in linking the behavioral effects of adolescent drinking to underlying cellular and molecular mechanisms.

However, it is suggested that future research on the etiology and consequences of adolescent drinking use an integrative approach to this problem by combining multiple levels, including genetic, cellular and molecular, systems (neuroimaging), and behavioral, with an emphasis on integrating the different levels of analysis.

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Request Reprint E-Mail: ewitt@mail.nih.gov
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A preliminary study of functional magnetic resonance imaging response during verbal encoding among adolescent binge drinkers

Binge alcohol use is common among teenagers with 28% of 12th graders reporting getting drunk in the past month. Chronic heavy drinking has been associated with verbal learning and memory deficits in adolescents and adults, yet verbal encoding in less frequently drinking teens has not yet been studied.

Here, we examined functional magnetic resonance imaging (fMRI) response during verbal encoding among adolescent binge drinkers.

Participants recruited from local high schools were of ages 16–18 and consisted of 12 binge drinkers and 12 demographically similar nondrinkers. Participants were all nonsmokers, and drinkers were abstinent from alcohol for an average of 33 days at the time of scanning.

Participants performed a verbal paired associates learning task during fMRI acquisition. Drinkers recalled marginally fewer words than nondrinkers (P = .07). Compared with nondrinkers, bingers showed more response in right superior frontal and bilateral posterior parietal cortices but less response in occipital cortex during novel encoding (Ps < .05, clusters >1,512 μL).

In addition, controls showed significant activation in the left hippocampus during novel encoding, whereas binge drinkers did not. Adolescent binge drinkers demonstrated (1) more response than nondrinkers in frontal and parietal regions, which could suggest greater engagement of working memory systems during encoding; (2) no hippocampal activation to novel word pairs; and (3) slightly poorer word pair recall, which could indicate disadvantaged processing of novel verbal information and a slower learning slope.

Longitudinal studies will be needed to ascertain the degree to which emergence of binge drinking is linked temporally to these brain response patterns.

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Request Reprint E-Mail: stapert@ucsd.edu

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Sensitization to social anxiolytic effects of ethanol in adolescent and adult Sprague–Dawley rats after repeated ethanol exposure

Ontogenetic studies using a social interaction paradigm have shown that adolescent rats are less sensitive to anxiolytic properties of acute ethanol than their adult counterparts. It is not known, however, whether adaptations to these anxiolytic effects on repeated experiences with ethanol would be similar in adolescents and adults.

The present study investigated sensitivity to the anxiolytic effects of ethanol in adolescent and adult male and female Sprague–Dawley rats after 7 days of exposure (postnatal day [P] 27–33 for adolescents and P62–68 for adults) to 1 g/kg ethanol or saline (intraperitoneally]) and in animals left nonmanipulated during this time. Anxiolytic effects of ethanol (0, 0.75, 1.0, 1.25, and 1.5 g/kg for adolescents and 0, 0.25, 0.5, 0.75, 1.0, and 1.25 g/kg for adults in experiments 1 and 2, respectively) were examined 48 h after the last exposure using a modified social interaction test under unfamiliar test circumstances.

At both ages, repeated ethanol exposure resulted in the development of apparent sensitization to anxiolytic effects of ethanol, indexed by enhancement of social investigation and transformation of social avoidance into social indifference or preference and expression of tolerance to the socially inhibiting effects induced by higher ethanol doses.

Evidence for the emergence of sensitization in adults and tolerance at both ages was seen not only after chronic ethanol but also after chronic saline exposure, suggesting that chronic manipulation per se may be sufficient to alter the sensitivity of both adolescents and adults to socially relevant effects of ethanol.

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Request Reprint E-Mail: varlinsk@binghamton.edu

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Similar withdrawal severity in adolescents and adults in a rat model of alcohol dependence

Alcohol use during adolescence leads to increased risk of developing an alcohol use disorder (AUD) during adulthood. Converging evidence suggests that this period of enhanced vulnerability for developing an AUD may be due to the adolescent's unique sensitivity and response to alcohol.

Adolescent rats have been shown to be less sensitive to alcohol intoxication and withdrawal susceptibility; however, age differences in ethanol pharmacokinetics may underlie these effects.

Therefore, this study investigated alcohol intoxication behavior and withdrawal severity using a modified Majchrowicz model of alcohol dependence that has been shown to result in similar blood ethanol concentrations (BECs) despite age differences.

Adolescent (postnatal day, PND, 35) and adult rats (PND 70+) received ethanol according to this 4-day binge paradigm and were observed for withdrawal behavior for 17 h.

As expected, adolescents showed decreased sensitivity to alcohol-induced CNS depression as evidenced by significantly lower intoxication scores.

Thus, adolescents received significantly more ethanol each day (12.3 ± 0.1 g/kg/day) than adults (9.2 ± 0.2 g/kg/day). Despite greater ethanol dosing in adolescent rats, both adolescent and adult groups had comparable peak BECs (344.5 ± 10.2 and 338.5 ± 7.8 mg/dL, respectively). Strikingly, withdrawal severity was similar quantitatively and qualitatively between adolescent and adult rats. Further, this is the first time that withdrawal behavior has been reported for adolescent rats using this model of alcohol dependence. A second experiment confirmed the similarity in BECs at various time points across the binge.

These results demonstrate that after consideration of ethanol pharmacokinetics between adults and adolescents by using a model that produces similar BECs, withdrawal severity is nearly identical.

This study, in combination with previous reports on ethanol withdrawal in adolescents and adults, suggests only a BEC-dependent effect of ethanol on withdrawal severity regardless of age.

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

The influence of a chronic adolescent nicotine exposure on ethanol withdrawal severity during adulthood in C3H mice

Animal and human studies have shown tolerance, consumption, relapse, and behavioral interactions between ethanol and nicotine, but little is understood about their interaction, especially as it relates to ethanol withdrawal in adulthood for subjects who have an adolescent history of using these drugs.

This study investigated nicotine's influence on ethanol withdrawal seizures in two different age groups of male C3H mice.

Adolescent and adult male C3H mice, beginning at postnatal day 28 or 70, respectively, were subjected to a 7-day chronic exposure to ethanol only, ethanol plus nicotine, nicotine only, or vehicle treatment. Six weeks later, all the groups were subjected to chronic exposure to ethanol vapors and the severity of their ethanol withdrawal seizures was assessed by handling-induced convulsions.

An adolescent exposure to chronic nicotine resulted in an exacerbation of ethanol withdrawal seizures in adulthood. Given this, adolescence may contain a neurophysiological critical period that is sensitive to nicotine and which may result in an altered response to ethanol dependency in adulthood.

These findings have serious implications for the long-term consequences following co-abuse of these drugs during adolescence.

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Request Reprint E-Mail: Jim_Diaz-Granados@baylor.edu

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Alcohol response and consumption in adolescent rhesus macaques: life history and genetic influences

The use of alcohol by adolescents is a growing problem and has become an important research topic in the etiology of the alcohol use disorders.

A key component of this research has been the development of animal models of adolescent alcohol consumption and alcohol response. Because of their extended period of adolescence, rhesus macaques are especially well suited for modeling alcohol-related phenotypes that contribute to the adolescent propensity for alcohol consumption.

In this review, we discuss studies from our laboratory that have investigated both the initial response to acute alcohol administration and the consumption of alcohol in voluntary self-administration paradigms in adolescent rhesus macaques.

These studies confirm that adolescence is a time of dynamic change both behaviorally and physiologically, and that alcohol response and alcohol consumption are influenced by life history variables, such as age, sex, and adverse early experience in the form of peer-rearing.

Furthermore, genetic variants that alter functioning of the serotonin, endogenous opioid, and corticotropin-releasing hormone systems are shown to influence both physiological and behavioral outcomes, in some cases interacting with early experience to indicate gene by environment interactions.

These findings highlight several of the pathways involved in alcohol response and consumption, namely reward, behavioral dyscontrol, and vulnerability to stress, and demonstrate a role for these pathways during the early stages of alcohol exposure in adolescence.

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Request Reprint E-Mail: melanies@mail.nih.gov

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Alcohol during adolescence selectively alters immediate and long-term behavior and neurochemistry

Alcohol use increases across adolescence and is a concern in the United States. In humans, males and females consume different amounts of alcohol depending on the age of initiation, and the long-term consequences of early ethanol consumption are not readily understood.

The purpose of our work was to better understand the immediate and long-term impact of ethanol exposure during adolescence and the effects it can have on behavior and dopaminergic responsivity.

We have assessed sex differences in voluntary ethanol consumption during adolescence and adulthood and the influence of binge ethanol exposure during adolescence. We have observed that males are sensitive to passive social influences that mediate voluntary ethanol consumption, and early ethanol exposure induces long-term changes in responsivity to ethanol in adulthood.

Exposure to moderate doses of ethanol during adolescence produced alterations in dopamine in the nucleus accumbens septi during adolescence and later in adulthood.

Taken together, all of these data indicate that the adolescent brain is sensitive to the impact of early ethanol exposure during this critical developmental period.

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Request Reprint E-Mail: kirstein@cas.usf.edu

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Roles of neural stem cells and adult neurogenesis in adolescent alcohol use disorders

This review discusses the contributions of a newly considered form of plasticity, the ongoing production of new neurons from neural stem cells, or adult neurogenesis, within the context of neuropathologies that occur with excessive alcohol intake in the adolescents.

Neural stem cells and adult neurogenesis are now thought to contribute to the structural integrity of the hippocampus, a limbic system region involved in learning, memory, behavioral control, and mood.

In adolescents with alcohol use disorders (AUDs), the hippocampus appears to be particularly vulnerable to the neurodegenerative effects of alcohol, but the role of neural stem cells and adult neurogenesis in alcoholic neuropathology has only recently been considered.

This review encompasses a brief overview of neural stem cells and the processes involved in adult neurogenesis, how neural stem cells are affected by alcohol, and possible differences in the neurogenic niche between adults and adolescents. Specifically, what is known about developmental differences in adult neurogenesis between the adult and adolescent is gleaned from the literature, as well as how alcohol affects this process differently among the age groups.

Finally, this review suggests differences that may exist in the neurogenic niche between adults and adolescents and how these differences may contribute to the susceptibility of the adolescent hippocampus to damage. However, many more studies are needed to discern whether these developmental differences contribute to the vulnerability of the adolescent to developing an AUD.

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

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Adolescent ethanol exposure: does it produce long-lasting electrophysiological effects?

This review discusses evidence for long-lasting neurophysiological changes that may occur following exposure to ethanol during adolescent development in animal models.

Adolescence is the time that most individuals first experience ethanol exposure, and binge drinking is not uncommon during adolescence. If alcohol exposure is neurotoxic to the developing brain during adolescence, not unlike it is during fetal development, then understanding how ethanol affects the developing adolescent brain becomes a major public health issue. Adolescence is a critical time period when cognitive, emotional, and social maturation occurs and it is likely that ethanol exposure may affect these complex processes.

To study the effects of ethanol on adolescent brain, animal models where the dose and time of exposure can be carefully controlled that closely mimic the human condition are needed.

The studies reviewed provide evidence that demonstrates that relatively brief exposure to high levels of ethanol, via ethanol vapors, during a period corresponding to parts of adolescence in the rat is sufficient to cause long-lasting changes in functional brain activity. Disturbances in waking electroencephalogram and a reduction in the P3 component of the event-related potential (ERP) have been demonstrated in adult rats that were exposed to ethanol vapor during adolescence. Adolescent ethanol exposure was also found to produce long-lasting reductions in the mean duration of slow-wave sleep (SWS) episodes and the total amount of time spent in SWS, a finding consistent with a premature aging of sleep.

Further studies are necessary to confirm these findings, in a range of strains, and to link those findings to the neuroanatomical and neurochemical mechanisms potentially underlying the lasting effects of adolescent ethanol exposure.

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Request Reprint E-Mail: cindye@scripps.edu

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Mechanisms involved in the neurotoxic, cognitive, and neurobehavioral effects of alcohol consumption during adolescence

Studies over the last decade demonstrate that adolescence is a brain maturation period from childhood to adulthood. Plastic and dynamic processes drive adolescent brain development, creating flexibility that allows the brain to refine itself, specialize, and sharpen its functions for specific demands. Maturing connections enable increased communication among brain regions, allowing greater integration and complexity. Compelling evidence has shown that the developing brain is vulnerable to the damaging effects of ethanol. It is possible to infer, therefore, that alcohol exposure during the critical adolescent developmental stages could disrupt the brain plasticity and maturation processes, resulting in behavioral and cognitive deficits. Recent neuroimaging studies have provided evidence of the impact of human adolescent drinking in brain structure and functions. Findings in experimental animals have also given new insight into the potential mechanisms of the toxic effects of ethanol on both adolescent brain maturation and the short- and long-term cognitive consequences of adolescent drinking.

Adolescence is also characterized by the rapid maturation of brain systems mediating reward and by changes in the secretion of stress-related hormones, events that might participate in the increasing in anxiety and the initiation pattern of alcohol and drug consumption. Studies in human adolescents demonstrate that drinking at early ages can enhance the likelihood of developing alcohol-related problems. Experimental evidence suggests that early exposure to alcohol sensitizes the neurocircuitry of addiction and affects chromatin remodeling, events that could induce abnormal plasticity in reward–related learning processes that contribute to adolescents' vulnerability to drug addiction.

In this article, we review the potential mechanisms by which ethanol impacts brain development and lead to brain impairments and cognitive and behavioral dysfunctions as well as the neurobiological and neurochemical processes underlying the adolescent-specific vulnerability to drug addiction.

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Request Reprint E-Mail: guerri@cipf.es

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Effects of ethanol on hippocampal function during adolescence: a look at the past and thoughts on the future

It has been demonstrated by several laboratories that ethanol, both acute and chronic, produces effects that are age dependent.

Specifically, adolescent rats are less sensitive to the hypnotic and motor-impairing effects of ethanol but are more sensitive to the hypothermic effects of the drug.

However, the results on hippocampal function are not as clear. For example, there have been mixed findings regarding adolescent sensitivity of hippocampal-dependent (spatial) memory in response to ethanol.

The current review explores the present state of the field as it relates to ethanol's effects in the hippocampus, particularly as it relates to spatial memory. In addition, we review potential neurobiological mechanisms that might underlie the age-dependent effects of ethanol in the hippocampus.

Finally, future directions are proposed that will advance the state of the field as it relates to ethanol's effect during this developmental period.

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Request Reprint E-Mail: dmatthews@ntu.edu.sg

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An Open Trial of Gabapentin in Acute Alcohol Withdrawal Using an Oral Loading Protocol

Anticonvulsants are increasingly being advocated for the treatment of acute alcohol withdrawal syndrome (AWS) to avoid the addictive properties of established medications.

Because earlier works showed that moderate gabapentin doses were too low to clearly ameliorate severe AWS, we tested a higher gabapentin entry dose.

Twenty-seven (73%) were early responders (baseline CIWA-AR improved from 17.3 ± 2.6 to 8.0 ± 3.6 points). In the remaining 10 patients, baseline CIWA-AR deteriorated within 2 h (from 20.1 ± 4.6 to 21.5 ± 4.65 points). These patients were switched to clomethiazole (n = 4) or clonazepam (n = 6), which is the usual treatment. Three of the ‘early responders’ worsened in the next 36 h and were then reclassified and treated as ‘non-responders’. Among them, two developed an epileptic seizure.

Oral 800 mg gabapentin (loaded up to 3200 mg in the first 24 h) is helpful only in reducing less severe and less complicated acute AWS.

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Prevalence and Determinants of Binge Drinking in Middle Age in a Transitional Post-communist Country: A Population-based Study in Tirana, Albania

To assess the prevalence and determinants of binge drinking in the middle-age population of transitional post-communist Albania, for which data were previously unavailable.

Age-standardized to the 2005 census, 9.2% and 10.3% of men reported two to three or more annual episodes of drunkenness and hangovers, respectively. In women, the prevalence of both these markers of binging was 1.4% . Among men, 8.9% ( reported drinking 60 g alcohol per session. In multivariable-adjusted models in men, binge drinking was related to low educational level, financial loss in the pyramid collapse and religiosity (inversely) in both Muslims and Christians

Among men in this transitional Southeast European country, social disadvantage and financial stress appear to promote alcohol abuse (which is rare in women), and traditionalism may be protective.

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Direct and Mediational Links Between Parental Bonds and Neglect, Antisocial Personality, Reasons for Drinking, Alcohol Use, and Alcohol Problems

The self-medication model suggests that some individuals may use alcohol as a means to cope with their negative experiences. Antisocial personality reflects a lack of concern for others and is often linked to alcohol use disorders.

The aim of this investigation was to examine potential parental influences to both pathological reasons for drinking and antisocial personality as pathways to alcohol use and problems.

In general, the overall patterns among male and female respondents were distinct. Among women, perceptions of having a caring mother lowered the likelihood of having antisocial tendencies, and perceptions of being rejected by one's father were directly linked to pathological reasons for drinking. Feeling neglected by one's mother was also directly linked to alcohol-related problems among women. Conversely, feeling neglected by one's father was directly linked to alcohol-related problems among males, suggesting a parent-offspring gender match. For men, antisocial personality mediated the impact of mother rejection and father overprotection on alcohol use.

These findings suggest that parental influences regarding vulnerabilities for alcohol use are very complex and that the genders of the respondent and the parent must be considered jointly.

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Effects of Pretreatment and Posttreatment Depressive Symptoms on Alcohol Consumption Following Treatment in Project MATCH

This study examined the associations of pretreatment and posttreatment depressive symptoms with drinking outcomes in the year following treatment in Project MATCH (Matching Alcoholism Treatments to Client Heterogeneity), a multisite clinical trial of behavioral treatments for alcohol-use disorders.

Pretreatment Beck Depression Inventory (BDI) scores predicted more frequent and intense drinking in the year following treatment, although not after accounting for posttreatment BDI scores, which were associated with the drinking outcomes as hypothesized. Patients who reported more depressive symptoms in the year following treatment reported less abstinence (PDA) and more intense drinking (DDD) than patients with fewer posttreatment depressive symptoms.

Our findings underscore the importance of obtaining repeated assessments of depression during the course of substance use treatment. Moreover, the data suggest the potential utility of augmenting standard chemical dependency care with depression-focused interventions for alcohol-dependent patients whose depressive symptoms do not subside during treatment.

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Request Reperint E-Mail: Stephanie_Gamble@urmc.rochester.edu
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Combining Motivational Interviewing With Compliance Enhancement Therapy (MI-CET): Development and Preliminary Evaluation of a New, Manual-Guided Psych

Psychosocial interventions
that are practical, transportable, and effective in promoting treatment adherence and efficacy are greatly needed in both research and clinical settings involving alcohol-dependence pharmacotherapy.

In this article, we describe the development and preliminary evaluation of an integrative treatment blending motivational interviewing and compliance enhancement therapy (MI-CET) as a means of enhancing adherence and retention in an ongoing clinical trial.

High rates of medication adherence (79% of citalopram and 91% of placebo completers took ≥80% of doses), session attendance (average of 90% for citalopram and 93% for placebo groups), and study completion (81% for citalopram and 88% for placebo groups) were obtained in the present study using MI-CET. These rates were at least comparable to or were, in some cases, 20%-30% higher than rates obtained in the comparison trials.

These results suggest that MI-CET is feasible as a psychosocial adjunct to alcohol-dependence pharmacotherapy. Given its strengths as a clinical and research intervention (e.g., practicality, transportability), further evaluation of its efficacy is warranted.

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Request Reprint E-Mail: Jaimee.Heffner@psychiatry.uc.edu
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Alcohol Abuse in Pregnant Women: Effects on the Fetus and Newborn, Mode of Action and Maternal Treatment

Offspring of mothers using ethanol during pregnancy are known to suffer from developmental delays and/or a variety of behavioral changes.

Ethanol, may affect the developing fetus in a dose dependent manner. With very high repetitive doses there is a 6–10% chance of the fetus developing the fetal alcoholic syndrome manifested by prenatal and postnatal growth deficiency, specific craniofacial dysmorphic features, mental retardation, behavioral changes and a variety of major anomalies.

With lower repetitive doses there is a risk of "alcoholic effects" mainly manifested by slight intellectual impairment, growth disturbances and behavioral changes. Binge drinking may impose some danger of slight intellectual deficiency.

It is advised to offer maternal abstinence programs prior to pregnancy, but they may also be initiated during pregnancy with accompanying close medical care.

The long term intellectual outcome of children born to ethanol dependent mothers is influenced to a large extent by the environment in which the exposed child is raised.

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Gender Differences in Mutual-Help Attendance One Year After Treatment: Swedish and U.S. Samples

In the United States, many people turn to Alcoholics Anonymous (AA) and other mutual-help groups as a first source of help for an alcohol or drug problem, whereas others are introduced to AA while in treatment. Because AA and similar groups in the United States add to the treatment system and function without governmental funds, they represent an important element in ongoing care for individuals with substance-use disorders in the health care system. In countries with free (or more affordable) and more comprehensive systems of care, their role is less clearly defined.

In this study, we compared men and women from representative treatment samples from studies with parallel designs, one Swedish (n = 1,525) and the other American (n = 926), to explore whether rates and correlates of attendance at 1-year follow-up (63% and 78% followed) differ by gender. We explore individual characteristics (demographic, severity, motivational) and formal and informal influences (treatment, mutual help, coercive, social) as possible help-seeking correlates of attendance.

In both countries, similar proportions of men and women attended mutual-help groups. However, twice as many U.S. clients reported attendance. Moreover, twice as many U.S. clients set abstinence as a treatment goal. In multivariate models, having an abstinence goal, a perceived need for treatment, suggestions from one's employment environment, and prior mutual-help attendance predicted posttreatment attendance for men and women in both countries. Gender differences were also found.

Given the stages in which individuals seek care and the cyclical nature of relapse and recovery, mutual-help groups are an efficient resource in the continuum of services

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Reliability of Alcohol Recall After 15 Years and 23 Years of Follow-Up in the Johns Hopkins Precursors Study

Recall of past alcohol intake is used in many studies of chronic disease, but few studies have been able to examine its long-term reliability.

We sought to assess the reliability of recalled alcohol intake assessed at an average age of 70 years in 2001, after 15 and 23 years of follow-up, in a prospective study of medical students in classes 1948 to 1964.

Average reported alcohol intake 15 years and 23 years prior were 6.3 and 7.4 drinks per week, respectively. Recall of alcohol intake overestimated the concurrently reported intake after 15 years by a mean of 0.47 (95% CI [0.10, 0.85]) drinks per week and underestimated intake after 23 years by a mean of 0.79 (95% CI [-1.27, -0.30]) drinks per week, mostly driven by differences between concurrently reported and recalled distilled spirits consumption. Characteristics associated with underestimation of alcohol recall were age of 71 years or older in 2001, self-report of memory difficulties, and self-report of difficulties in physical functioning. In multivariate regression analyses combining 15- and 23-year recall, subjects who reported consumption of more than 14 alcoholic drinks per week in 2001 marginally overestimated recall by slightly more than 1 drink per week (M = 1.18 drinks/week, 95% CI [-0.03, 2.40]).

Although significant differences were detected, recalled alcohol intake after 15 and 23 years of follow-up is remarkably reliable.

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A Principal Components Analysis of the Abbreviated Desires for Alcohol Questionnaire (DAQ

The aim of this study was to examine the abbreviated Desires for Alcohol Questionnaire (DAQ) with respect to component structure and concurrent validity.

The DAQ was administered to 2,960 adults participating in the Collaborative Studies on the Genetics of Alcohol. Rotated principal components analysis was conducted on 1,500 subjects with an alcohol-use disorder (AUD) and on 1,460 non-AUD subjects. Total DAQ scores were compared for these two subsamples. In addition, correlations were computed between DAQ scores and the following: (1) a sum of alcohol symptoms, and (2) endorsement of a single interview craving question.

Similar solutions emerged in the AUD and non-AUD subsamples, with dimensions characterized by (1) strong desires/intentions to drink, (2) negative reinforcement, and (3) positive reinforcement ability to control drinking. Each component was significantly correlated with the alcohol symptom scale in both subsamples (r_s = .25-.64 and .31-.40, respectively, p < .0001) and with the interview craving item in the AUD subsample (r_s = .22-.55, p < .0001). Total DAQ score was significantly higher for AUD subjects (40.5) than for non-AUD subjects (23.1, p < .0001) and exhibited significant correlations with the alcohol symptom scale in the AUD and non-AUD subsamples (r_s = .61 and .39, respectively, p < .0001) and with the interview craving item in the AUD subsample (r_s = .51, p < .0001).

The DAQ is an appropriate measure of alcohol craving, as demonstrated by similar component structures across two samples as well as its concurrent validity.

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Request Reprint E-Mail: john-kramer@uiowa.edu
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