Individual vulnerability to escalated aggressive behavior by a low dose of alcohol: decreased serotonin receptor mRNA in the prefrontal cortex of male

Low to moderate doses of alcohol consumption induce heightened aggressive behavior in some, but not all individuals. Individual vulnerability for this nonadaptive behavior may be determined by an interaction of genetic and environmental factors with the sensitivity of alcohol's effects on brain and behavior.

We used a previously established protocol for alcohol oral self-administration and characterized alcohol-heightened aggressive (AHA) mice as compared with alcohol non-heightened (ANA) counterparts. A week later, we quantified mRNA steady state levels of several candidate genes in the serotonin [5-hydroxytryptamine (5-HT)] system in different brain areas.

We report a regionally selective and significant reduction of all 5-HT receptor subtype transcripts, except for 5-HT₃, in the prefrontal cortex of AHA mice. Comparable gene expression profile was previously observed in aggressive mice induced by social isolation or by an anabolic androgenic steroid. Additional change in the 5-HT_1B receptor transcripts was seen in the amygdala and hypothalamus of AHA mice. In both these areas, 5-HT_1B mRNA was elevated when compared with ANA mice. In the hypothalamus, AHA mice also showed increased transcripts for 5-HT_2A receptor. In the midbrain, 5-HT synthetic enzyme, 5-HT transporter and 5-HT receptors mRNA levels were similar between groups.

Our results emphasize a role for postsynaptic over presynaptic 5-HT receptors in mice which showed escalated aggression after the consumption of a moderate dose of alcohol. This gene expression profile of 5-HT neurotransmission components in the brain of mice may suggest a vulnerability trait for alcohol-heightened aggression.

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Request Reprint E-Mail: schiaveg@usp.br
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A multidimensional assessment of the validity and utility of alcohol use disorder severity as determined by item response theory models

The relative severity of the 11 DSM-IV alcohol use disorder (AUD) criteria are represented by their severity threshold scores, an item response theory (IRT) model parameter inversely proportional to their prevalence. These scores can be used to create a continuous severity measure comprising the total number of criteria endorsed, each weighted by its relative severity.

Attempts to formulate a scalar measure of AUD will do as well by relying on simple counts of criteria or symptom items as by using scales weighted by IRT measures of severity.

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

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Effect of motivational interviewing on reduction of alcohol use

Methadone-maintained (MM) clients who engage in excessive alcohol use are at high risk for HIV and hepatitis B virus (HBV) infection. Nurse-led hepatitis health promotion (HHP) may be one strategy to decrease alcohol use in this population.

To evaluate the impact of nurse-led HHP, delivered by nurses compared to motivational interviewing (MI), delivered by trained therapists in group sessions or one-on-one on reduction of alcohol use.

As compared to two programs delivered by MI specialists, a culturally-sensitive and easy to implement nurse-led HHP program produced similar reductions in alcohol use over 6 months. Employing nurse-led programs may allow cost savings for treatment programs as well as a greater integration of alcohol reduction counseling along with a more comprehensive focus on general health-related issues than previously conducted.

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Request Reprint :anyamath@sonnet.ucla.edu

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Alcohol-related deaths in the United Kingdom 1991-2008

The number of alcohol-related deaths in the United Kingdom has consistently increased since the early 1990s, rising from the lowest figure of 4,023 (6.7 per 100,000) in 1992 to the highest of 9,031 (13.6 per 100,000) in 2008. Although figures in recent years suggested that the trend was levelling out, alcohol-related deaths in males increased further in 2008. Female rates have remained stable.

There are more alcohol-related deaths in men than in women. The rate of male deaths has more than doubled over the period from 9.1 per 100,000 in 1991 to 18.7 per 100,000 in 2008. There have been steadier increases in female rates, rising from 5.0 per 100,000 in 1991 to 8.7 in 2008, less than half the rate for males. In 2008, males accounted for approximately two-thirds of the total number of alcohol-related deaths. There were 5,999 deaths in men and 3,032 in women.

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Smoking, drinking and drug use among young people in England, findings by region 2006 to 2008

The survey of smoking, drinking and drug use among young people in England (SDD) has been carried out annually by the National Centre for Social Research (NatCen) and the National Foundation for Educational Research (NFER) since 2000. It is commissioned by the NHS Information Centre, with support from the Home Office; the Department for Children, Schools and Families (DCSF) also has an interest in the statistics.

This note presents key survey findings by Government Office Region, for secondary school pupils in years 7 to 11 (mostly aged 11 to 15). Results are based on data from the three most recent survey years, 2006 to 2008, combined and weighted to be regionally representative.

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Adolescent C57BL/6J (but not DBA/2J) Mice Consume Greater Amounts of Limited-Access Ethanol Compared to Adults and Display Continued Elevated Ethanol

Alcohol use is common during the adolescent period, a time at which a number of crucial neurobiological, hormonal, and behavioral changes occur (Spear, 2000). In order to more fully understand the complex interaction between alcohol use and these age-typical neurobiological changes, animal models must be utilized. Rodents experience a developmental period similar to that of adolescence. Although rat models have shown striking adolescent-specific differences in sensitivity to ethanol, little work has been done in mice despite the fact that the C57BL/6J (B6) and DBA2/J (D2) mice have been shown to markedly differ in ethanol preference drinking and exhibit widely different sensitivities to ethanol.

Adolescent B6 mice consumed more ethanol than adults in the DID model. There was no difference between adolescent and adult D2 mice.

This work adds to the literature suggesting that adolescents will consume more ethanol than adults and that this exposure can result in altered adult intake. However, this effect seems largely dependent upon genotype. Future work will continue to examine age-related differences in ethanol intake, preference, and sensitivity in inbred mouse strains

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Request Reprint E-Mail: slboehm@iupui.edu

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Prevalence of Alcohol-Related Problems in an Elderly Population and Their Association With Cognitive Impairment and Dementia

Studies investigating the association between alcohol use and cognitive disorders in the elderly population have produced divergent results. Moreover, the role of alcohol in cognitive dysfunction is not clear. The aims of this study were to estimate the prevalence of alcohol-related problems in an elderly population from Brazil and to investigate their association with cognitive and functional impairment (CFI) and dementia.

"Heavy alcohol use" (CAGE ≥ 2) was found in 92 subjects (prevalence: 8.2%). It was associated with gender (males, p < class="i">p = 0.002), and low socioeconomic level (p = 0.001, in females; p = 0.002, in males). The Mini Mental State Examination exhibited a nonlinear relationship with alcohol-related problems in females; "mild–moderate alcohol use" (CAGE < class="i">p = 0.003 and p < class="i">p = 0.063 and 0.050, respectively).

Our findings suggest that alcohol use does not have a linear relationship with cognitive decline

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Request Reprint E-Mail: lopes@netsite.com.br

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Event-Related Oscillations Versus Event-Related Potentials in a P300 Task as Biomarkers for Alcoholism

It has been proposed that event-related oscillation (ERO) measures of EEG activity recorded in P300 tasks provide more powerful biomarkers of alcoholism than event-related potential (ERP) measures. This study examines this question in a group of long-term abstinent alcoholics (LTAAs).

Reduced evoked ERO power in the response to target stimuli provided an alternative and comparable representation of the reduced P3b amplitude in LTAA. This is not surprising as the evoked ERO power measures are derived from time-frequency representations of the ERP waveform. Induced theta oscillations might provide independent discriminatory information beyond ERP amplitude measures, but separate analysis of the event-related nonphase-locked activity is required to investigate this further.

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Request Reprint E-Mail: george@nbresearch.com
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Does Alcohol Involvement Increase the Severity of Intimate Partner Violence?

Most studies that have examined alcohol use immediately prior to intimate partner violence (IPV) have been limited to male-to-female partner violence (MFPV) and are subject to a number of methodological limitations. We add new information concerning the relationship between alcohol involvement and severity of IPV, MFPV, and female-to-male partner violence (FMPV).

Our findings suggest alcohol involvement of either or both in the couple increases the risk of severe IPV. Our findings also suggest female alcohol use may play an important role in determining the severity of IPV, MFPV or FMPV

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Request Reprint E-Mail: lori.rodriguez@utsouthwestern.edu
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GABRA2 and Alcohol Use Disorders: No Evidence of an Association in an Italian Case–Control Study

Alcoholism is a major health and social issue, a highly frequent disease and a cause of premature death. It is also the most expensive addictive disorder being related to high morbidity and mortality, violence, accidents, and social and legal problems. It is a quantitative disorder, where the combined incidence of environmental and multiple genetic factors varies from 1 subject to another. Recent association studies have identified several genes as candidates for alcoholism, including GABA_A receptor genes, due to their role in mediating several behavioral effects of alcohol, such as motor incoordination, anxiolysis, sedation, and withdrawal. The proposed association between the 3' half of the gene encoding the alpha-2 subunit of GABA receptor (3'-GABRA2) and alcohol use disorders (AUDs) has received several independent confirmations.

Despite previous reports, we did not find an association between AUDs and 3'-GABRA2 polymorphisms. This is probably due to the minimal comorbidity of our Italian sample suggesting that this gene is implicated in polysubstance dependence rather than in alcoholism alone.

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Request Reprint E-Mail: buscemi@univpm.it
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Prenatal Alcohol Exposure and Chronic Mild Stress Differentially Alter Depressive- and Anxiety-Like Behaviors in Male and Female Offspring

Fetal Alcohol Spectrum Disorder (FASD) is associated with numerous neurobehavioral alterations, as well as disabilities in a number of domains, including a high incidence of depression and anxiety disorders. Prenatal alcohol exposure (PAE) also alters hypothalamic-pituitary-adrenal (HPA) function, resulting in increased responsiveness to stressors and HPA dysregulation in adulthood. Interestingly, data suggest that pre-existing HPA abnormalities may be a major contributory factor to some forms of depression, particularly when an individual is exposed to stressors later in life. We tested the hypothesis that exposure to stressors in adulthood may unmask an increased vulnerability to depressive- and anxiety-like behaviors in PAE animals

We report here that the combination of PAE and CMS in adulthood increases depressive- and anxiety-like behaviors in a sexually dimorphic manner. PAE males showed impaired hedonic responsivity (sucrose contrast test), locomotor hyperactivity (open field), and alterations in affiliative and nonaffiliative social behaviors (social interaction test) compared to control males. By contrast, PAE and, to a lesser extent, PF, females showed greater levels of "behavioral despair" in the forced swim test, and PAE females showed altered behavior in the final 5 minutes of the social interaction test compared to control females.

These data support the possibility that stress may be a mediating or contributing factor in the psychopathologies reported in FASD populations.

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Request Reprint E-Mail: kim_hellemans@carleton.ca

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Altered Motor Cortex Excitability to Magnetic Stimulation in Alcohol Withdrawal Syndrome

Alcohol addiction is a complex brain disease caused by alterations in crucial neurotransmitter systems, including gamma-aminobutyric acid (GABA) and glutamate. These disturbances could be revealed by changes in cortical excitability parameters, as assessed by transcranial magnetic stimulation (TMS). This study was aimed to further investigate the complex pathophysiology of alcohol withdrawal syndrome (AWS).

Transcranial magnetic stimulation shows a selective increase in intracortical facilitation after ethanol withdrawal. Our findings support the theory that altered glutamatergic receptor function plays an important role in the pathogenesis of human alcohol withdrawal. This study provides further physiological evidence that antiglutamatergic approaches represent an efficacious alternative for treating alcohol withdrawal symptoms.

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Request Reprint E-Mail: raffaele.nardone@asbmeran-o.it
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Role of Dopamine D1 Receptors and Extracellular Signal Regulated Kinase in the Motivational Properties of Acetaldehyde as Assessed by Place Preference

The role of dopamine D₁ receptors and Extracellular signal Regulated Kinase (ERK) in the motivational properties of drugs can be studied by place-conditioning. Recent advances have shown that the motivational properties of ethanol, determined by place-conditioning, are mediated by its metabolic conversion into acetaldehyde. To date, the role of D₁ receptors and ERK activation in acetaldehyde-elicited place preference has not been determined. The aim of this study was to assess the role of D₁ receptors blockade and MEK inhibition in the acquisition of acetaldehyde-elicited conditioned place preference.

These results confirm that acetaldehyde and ethanol elicit conditioned place preference and demonstrate that D₁ receptors are critically involved in these effects. Furthermore, the finding that PD98059 prevents the acquisition of acetaldehyde-elicited conditioned place preference highlights the importance of the D₁ receptor–ERK pathway in its motivational effects

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Request Reprint E-Mail: acquas@unica.it
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Ethanol Acutely Inhibits Ionotropic Glutamate Receptor-Mediated Responses and Long-Term Potentiation in the Developing CA1 Hippocampus

Developmental ethanol (EtOH) exposure damages the hippocampus, causing long-lasting alterations in learning and memory. Alterations in glutamatergic synaptic transmission and plasticity may play a role in the mechanism of action of EtOH. This signaling is fundamental for synaptogenesis, which occurs during the third trimester of human pregnancy (first 12 days of life in rats).

Acute EtOH exposure during the third-trimester equivalent of human pregnancy inhibits hippocampal glutamatergic transmission and LTP induction, which could alter synapse refinement and ultimately contribute to the pathophysiology of fetal alcohol spectrum disorder.

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Request Reprint E-Mail: fvalenzuela@salud.unm.edu
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MicroRNAs: Master Regulators of Ethanol Abuse and Toxicity?

Ethanol exerts complex effects on human physiology and health. Ethanol is not only addictive, but it is also a fetal teratogen, an adult neurotoxin, and an etiologic agent in hepatic and cardiovascular disease, inflammation, bone loss, and fracture susceptibility.

A large number of genes and signaling mechanisms have been implicated in ethanol's deleterious effects leading to the suggestion that ethanol is a "dirty drug."

An important question is, are there cellular "master-switches" that can explain these pleiotropic effects of ethanol? MicroRNAs (miRNAs) have been recently identified as master regulators of the cellular transcriptome and proteome. miRNAs play an increasingly appreciated and crucial role in shaping the differentiation and function of tissues and organs in both health and disease.

This critical review discusses new evidence showing that ethanol-sensitive miRNAs are indeed regulatory master-switches. More specifically, miRNAs control the development of tolerance, a crucial component of ethanol addiction. Other drugs of abuse also target some ethanol-sensitive miRNAs suggesting that common biochemical mechanisms underlie addiction.

This review also discusses evidence that miRNAs mediate several ethanol pathologies, including disruption of neural stem cell proliferation and differentiation in the exposed fetus, gut leakiness that contributes to endotoxemia and alcoholic liver disease, and possibly also hepatocellular carcinomas and other gastrointestinal cancers.

Finally, this review provides a perspective on emerging investigations into potential roles of miRNAs as mediators of ethanol's effects on inflammation and fracture healing, as well as the potential for miRNAs as diagnostic biomarkers and as targets for therapeutic interventions for alcohol-related disorders.

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Request Rerprint E-Mail: miranda@medicine.tamhsc.edu
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An Event-Related Potential Study of Response Inhibition in ADHD With and Without Prenatal Alcohol Exposure

The attention and cognitive problems seen in individuals with a history of prenatal alcohol exposure often resemble those associated with attention deficit hyperactivity disorder (ADHD), but few studies have directly assessed the unique influence of each on neurobehavioral outcomes.

Regardless of prenatal alcohol exposure, participants with childhood ADHD were less accurate at inhibiting responses. However, only the ADHD group without prenatal alcohol exposure showed a markedly diminished P3 difference between No-go and Go, which may reflect a more effortful strategy related to inhibitory control at the neural processing level.

This finding supports a growing body of evidence suggesting that the manifestation of idiopathic ADHD symptoms may stem from a neurophysiologic process that is different from the ADHD symptomatology associated with prenatal alcohol exposure. Individuals who have been prenatally exposed to alcohol and present with ADHD symptomatology may represent a unique endophenotype of the disorder, which may require different treatment approaches from those found to be effective with idiopathic ADHD.

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Request Reprint E-Mail: sandra.jacobson@wayne.edu

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Social and Financial Resources and High-Risk Alcohol Consumption Among Older Adults

This study examined long-term mutual predictive associations between social and financial resources and high-risk alcohol consumption in later life.

Over the 20-year interval, there was evidence of both social causation and social selection processes in relation to high-risk alcohol consumption. In support of a social causation perspective, higher levels of some social resources, such as participation in social activities, friends' approval of drinking, quality of relationship with spouse, and financial resources, were associated with a subsequent increased likelihood of high-risk alcohol consumption. Conversely, indicating the presence of social selection, high-risk alcohol consumption was associated with subsequent higher levels of friends' approval of drinking and quality of the spousal relationship, but lower quality of relationships with extended family members.

These findings reflect mutual influence processes in which older adults' social resources and high-risk alcohol consumption can alter each other. Older adults may benefit from information about how social factors can affect their drinking habits; accordingly, information about social causation effects could be used to guide effective prevention and intervention efforts aimed at reducing the risk that late-life social factors may amplify their excessive alcohol consumption.

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Request Reprint E-Mail: rmoos@stanford.edu

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Three-Year Changes in Adult Risk Drinking Behavior in Relation to the Course of Alcohol-Use Disorders*

This study examines the associations between the course of alcohol-use disorder (AUD) and changes in average daily volume of ethanol intake, frequency of risk drinking, and maximum quantity of drinks consumed per day over a 3-year follow-up interval in a sample of U.S. adults.

There were positive changes in all consumption measures associated with developing an AUD and negative changes associated with remission of an AUD, even among individuals who continued to drink. Increases and decreases associated with onset and offset of dependence exceeded those associated with onset/offset of abuse only, and the decreases associated with full remission from dependence exceeded those associated with partial remission. There were few changes in consumption among individuals whose AUD status did not change. Interactions of AUD transitions with other factors indicate that development of an AUD is associated with a greater increase in consumption among men, possibly reflecting their greater total body water and lower blood alcohol concentration in response to a given dose of ethanol, and among individuals with high baseline levels of consumption.

Changes in consumption associated with onset and offset of AUD are substantial enough to have important implications for the risk of associated physical and psychological harm.

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Reversal of Alcohol-Induced Learning Deficits in the Young Adult in a Model of Fetal Alcohol Syndrome

To evaluate whether treatment with neuroprotective peptides to young adult mice prenatally exposed to alcohol reverses alcohol-induced learning deficits in a mouse model of fetal alcohol syndrome, whether the mechanism involves the N-methyl-d-aspartate (NMDA) and γ-aminobutyric acid type A (GABA_A) receptors, and whether it is related to glial cells.

Treatment with D-NAPVSIPQ and D-SALLRSIPA reversed the alcohol-induced learning deficit in both learning tests as well as the NR2A and NR2B down-regulation in the hippocampus and the up-regulation of NR2A in the cortex and NR2B in the cortex and cerebellum (all P<.05). No significant differences were found in GABA_A expression. Moreover, the peptides changed activity-dependent neuroprotective protein expression in the cortex (P=.016) but not the down-regulation of VIP (P=.883), probably because the peptides are downstream from VIP.

Alcohol-induced learning deficit was reversed and expression of NR2A and NR2B was restored in the hippocampus and cortex of young adult mice treated with D-NAPVSIPQ and D-SALLRSIPA. Given the role of NMDA receptors in learning, this may explain in part the mechanism of prevention of alcohol-induced learning deficits by D-NAPVSIPQ and D-SALLRSIPA.

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Request Reprint E-Mail: incertim@mail.nih.gov.
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Corticotropin Releasing Factor–Induced Amygdala Gamma-Aminobutyric Acid Release Plays a Key Role in Alcohol Dependence

Corticotropin-releasing factor (CRF) and gamma-aminobutyric acid (GABA)ergic systems in the central amygdala (CeA) are implicated in the high-anxiety, high-drinking profile associated with ethanol dependence. Ethanol augments CeA GABA release in ethanol-naive rats and mice.

CRF and ethanol augmented CeA GABAergic transmission in naive rats via increased GABA release. Three CRF1 receptor (CRF₁) antagonists decreased basal GABAergic responses and abolished ethanol effects. Ethanol-dependent rats exhibited heightened sensitivity to CRF and CRF₁ antagonists on CeA GABA release. Intra-CeA CRF₁ antagonist administration reversed dependence–related elevations in GABA dialysate and blocked ethanol-induced increases in GABA dialyzate in both dependent and naive rats. Polymerase chain reaction studies indicate increased expression of CRF and CRF₁ in CeA of dependent rats. Chronic CRF₁ antagonist treatment blocked withdrawal-induced increases in alcohol drinking by dependent rats and tempered moderate increases in alcohol consumption by nondependent rats in intermittent testing.

These combined findings suggest a key role for specific presynaptic CRF-GABA interactions in CeA in the development and maintenance of ethanol dependence.

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Request Reprint E-Mail: mroberto@scripps.edu

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