Biological vulnerability to alcoholism.

This article reviews the role of biological factors in the risk for alcoholism. The discussion notes the importance of the definition of primary alcoholism and highlights data indicating that this disorder is genetically influenced. The major emphasis is on studies of men at high risk for the future development of alcoholism. The most promising trait markers of a biological vulnerability to alcoholism include a decreased intensity of reaction to modest ethanol doses for sons of alcoholics compared with control subjects, a decreased amplitude of certain brain waves of the event-related potential, and a different pattern of background cortical electroencephalograms for young men at high risk for future alcoholism. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Biological, psychological and environmental predictors of the alcoholism risk: a longitudinal study

Interference reflection microscopy (IRM) was used to evaluate the status of cell matrix adhesions in the MCF-7 human mammary carcinoma cell line. Focal contacts were concentrated at the periphery of individual cells or small cell clusters. Close contact was detected as a band at cell peripheries and as localized patches throughout the ventral face of cells. The MCF-7 cells also exhibited a distinctive reflection pattern of an intensity midway between that of either focal or close contact. This novel reflection pattern was located primarily at the periphery of cells and often obscured visualization of focal contacts in live cells. A similar distinctive pattern was absent from the normal tissue-derived MCF-10A mammary epithelial cell line. Immunofluorescence staining using an antiserum that cross-reacts with both alpha(v)beta3 and alpha(v)beta5 integrins revealed a distribution of the vitronectin receptor similar to that of the novel adhesion pattern as well as to that of focal contacts. In addition, IRM demonstrated the presence of "tracks" associated with cells, which were also stained with the vitronectin receptor antiserum. The tracks are apparently residual material left behind as a result of cell migration. When MCF-7 cells were cultured in the absence of estradiol, the tracks were greatly diminished when visualized with either IRM or staining for the vitronectin receptor. In contrast, the addition of 17-beta-estradiol to the medium resulted in an increased presence of the tracks as well as the development of extensive close contacts throughout the ventral surface of cells and cell clusters. Cells treated with the estrogen antagonist ICI 182,720 in the presence of estradiol had few associated tracks, indicating that the process leading to the formation of these structures is dependent on an estrogen receptor-activated pathway. However, the antagonist did not prevent the estradiol-induced formation of extensive close contacts. The extensive close contact as well as the increase in trailing material suggests that estradiol may promote breast tumor cell motility. However, this migratory activity may be mediated by both estrogen receptor-dependent and -independent pathways.     

Familial transmission of substance dependence: alcohol, marijuana, cocaine, and habitual smoking: a report from the Collaborative Study on the Genetics of Alcoholism

BACKGROUND: Alcoholism and substance dependence frequently co-occur. Accordingly, we evaluated the familial transmission of alcohol, marijuana, and cocaine dependence and habitual smoking in the Collaborative Study on the Genetics of Alcoholism. METHODS: Subjects (n=1212) who met criteria for both DSM-III-R alcohol dependence and Feighner definite alcoholism and their siblings (n=2755) were recruited for study. A comparison sample was also recruited (probands, n=217; siblings, n=254). Subjects were interviewed with the Semi-Structured Assessment for the Genetics of Alcoholism. The familial aggregation of drug dependence and habitual smoking in siblings of alcohol-dependent and non-alcohol-dependent probands was measured by means of the Cox proportional hazards model. RESULTS: Rates of alcohol, marijuana, and cocaine dependence and habitual smoking were increased in siblings of alcohol-dependent probands compared with siblings of controls. For siblings of alcohol-dependent probands, 49.3% to 50.1% of brothers and 22.4% to 25.0% of sisters were alcohol dependent (lifetime diagnosis), but this elevated risk was not further increased by comorbid substance dependence in probands. Siblings of marijuana-dependent probands had an elevated risk of developing marijuana dependence (relative risk [RR], 1.78) and siblings of cocaine-dependent probands had an elevated risk of developing cocaine dependence (RR, 1.71). There was a similar finding for habitual smoking (RR, 1.77 in siblings of habitual-smoking probands). CONCLUSIONS: Alcohol, marijuana, and cocaine dependence and habitual smoking are all familial, and there is evidence of both common and specific addictive factors transmitted in families. This specificity suggests independent causative factors in the development of each type of substance dependence.     

Platelet monoamine oxidase activity in subgroups of alcoholics and controls: results from the Collaborative Study on the Genetics of Alcoholism

OBJECTIVE: Platelet monoamine oxidase (MAO) B activity levels were evaluated to determine whether low platelet MAO activity is a marker for alcoholism, correlates of alcoholism (e.g., cigarette smoking), or a subtype of alcoholism. METHODS: Adult women (n = 788) and men (n = 685) participating in the Collaborative Study on the Genetics of Alcoholism study were evaluated with a semistructured interview, and blood samples were obtained for determination of platelet MAO activity using tryptamine (0.1 mM) as substrate. DSM-III-R alcohol-dependent individuals were subgrouped using four currently available methods (e.g., two variations of the type 1/type 2 scheme, primary versus secondary typology, type A/type B dichotomy). RESULTS: In the overall sample, subjects' gender, cigarette smoking status, and the Collaborative Study on the Genetics of Alcoholism site at which their platelets were prepared explained 22% of the variance in platelet MAO activity levels, and multivariate analysis showed that carrying a broad diagnosis of alcohol dependence did not uniquely explain any additional variance in platelet MAO activity levels. Furthermore, within each of the alcoholic subgrouping methods tested, there were no significant differences in platelet MAO activity for type 1 versus type 2, type A versus type B, or primary versus secondary alcoholics. CONCLUSIONS: Cigarette smoking and male gender are associated with decreased platelet MAO activity levels. After considering these factors, a diagnosis of alcohol dependence does not predict any additional variance in MAO-B activity. Phenotypes of alcoholics (e.g., type 1 versus type 2, type A versus type B, primary versus secondary) do not differ in platelet MAO activity. The results suggest that decreased platelet MAO activity is not a trait marker of alcoholism or one of its subtypes; but, rather, is a state marker of cigarette smoking.     

A family-based analysis of whether the functional promoter alleles of the serotonin transporter gene HTT affect the risk for alcohol dependence

A population association between a regulatory variation in the promoter of the serotonin transporter gene (HTT) and severe alcohol dependence was recently reported. We analyzed this potential association in a large number of systematically ascertained families in the United States; these families had at least three first-degree relatives who were alcohol-dependent. Analyses focused on individuals defined as alcohol-dependent by criteria from ICD-10 and on subsets of these individuals reporting withdrawal-related symptoms. Application of the transmission disequilibrium test did not provide support for either linkage or association between this functional polymorphism and alcohol dependence; there was no significant bias in the transmission of either allele to the alcohol-dependent offspring. We also report that African Americans differ from Caucasians in allele frequencies for this polymorphism.     

Alcohol dependence and mood disorders

This article explores the complex relationships between alcohol dependence and mood disorders. Although many alcoholics present with substance-induced depressions, once appropriate methodological controls are used, there does not appear to be a significant relationship between independent unipolar depression and alcohol dependence. However, the data support a small, but significant, relationship between bipolar manic-depressive disease and alcoholism. The literature does not support the relevance of self-medication as a course of alcoholism, unless one includes the use of alcohol to alleviate alcohol-induced psychological and neurochemical perturbations. The clinical importance of distinguishing between substance-induced and independent mood disorders is reviewed.     

The Self-Rating of the Effects of alcohol (SRE) form as a retrospective measure of the risk for alcoholism

AIMS: A low level of response (LR) to alcohol is a characteristic of sons of alcoholics and predicts an elevated future alcoholism risk. A 12-question Self-Rating of the Effects (SRE) of alcohol form has been shown to correlate cross-sectionally with a designation of a low LR determined by alcohol challenges. DESIGN: This study evaluates the potential usefulness of the SRE as a retrospective measure of both the response to alcohol and of subsequent alcoholism in two samples. SETTING: All subjects were studied in the United States, most in California. PARTICIPANTS: First, 94 sons of alcoholics and controls completed the SRE 15 years after an alcohol challenge, and SRE values were compared to their prior LR results and their alcoholic outcomes. Secondly, the relationship between SRE results and alcoholic status was determined in 551 men and women alcoholics, their relatives, and controls. MEASUREMENTS: Subjects were evaluated with face-to-face interviews. FINDINGS: Despite the interval of 15 years, the correlation between the SRE and the subjective high feelings on the alcohol challenge was between -0.3 and -0.4. For those 94 subjects the full SRE correlated with a diagnosis of alcohol dependence at 0.5, a figure that remained at 0.3 even when only the estimates related to the earliest drinking experiences were considered. For the 551 men and women, the correlation between the SRE and alcohol dependence diagnoses was 0.6, including 0.3 for the estimates of the first five times of drinking. All major findings in both samples remained robust when the recent drinking history or the number of items endorsed was considered, or when the most severe alcohol problem, passing out, was deleted from the analysis. CONCLUSIONS: When alcohol challenges are not possible, these retrospective reports indicate that the SRE is a potentially useful surrogate for determining a subgroup of people who might carry a low level of response to alcohol and a subsequent elevated risk for alcoholism.     

The life-time rates of three major mood disorders and four major anxiety disorders in alcoholics and controls

AIMS: While psychiatric symptoms are common in the general population and even more prevalent in alcoholics, their clinical implications are not clear. The goal of this study was to establish the life-time rates of several independent and concurrent mood and anxiety disorders in alcoholics, controls and their relatives. DESIGN: Structured interviews were administered to alcoholics entering treatment, their relatives, and controls. SETTING: The study was carried out in six different centers in the United States as part of the Collaborative Study on the Genetics of Alcoholism (COGA). PARTICIPANTS: Data were gathered from 2713 alcohol dependent subjects (probands and their alcoholic relatives) and 919 controls. MEASUREMENTS: The timeline-based Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA) interview was administered face to face by trained, closely supervised interviewers. The life-time rates for concurrent and independent disorders were determined for three DSM-III-R major mood and four major anxiety disorders. FINDINGS: Some form of independent mood disorder was seen during the life-time in slightly fewer alcoholics than controls (14.0% and 17.1%), but alcoholics did show higher rates of independent bipolar disorder (2.3% vs. 1.0%). The life-time rate for independent anxiety disorders was significantly higher in alcoholics than controls (9.4% vs. 3.7%), with most of the differential related to panic disorder (4.2% vs. 1.0%) and social phobia (3.2% vs. 1.4%), but no significant group differences for agoraphobia or obsessive-compulsive disorder. In general, these findings regarding mood and anxiety disorders were reflected in close relatives. CONCLUSIONS: The large majority of alcohol-dependent men and women in this sample did not have any of the independent mood or anxiety disorders evaluated here. However, there was evidence of enhanced risks among alcoholics for independent bipolar, panic and social phobic disorders. Studies which do not distinguish carefully between independent and concurrent mood and anxiety disorders in alcoholics are likely to report much higher rates of co-morbid psychiatric disorders than those that distinguish between the two types of syndromes.     

EEG dimension in sons of alcoholics

Recent advances in the field of nonlinear dynamics have provided new conceptual models, as well as novel analytical techniques applicable to studies in alcohol research. One measurement technique, which has been developed in an attempt to characterize nonlinear systems in physics and biology, is the estimation of attractor dimension. This dimension may be seen as a measure of the information required to describe the current behavior of a system. We have applied these techniques to the analysis of EEG collected from 17 men with alcoholic fathers and 19 men with no alcoholic relatives. The men with alcoholic fathers were found to have a lower EEG attractor dimension than their matched controls. This suggests that the EEG of young men with alcoholic fathers may be "more organized" or "less complex" than men with no alcoholic relatives. Although more studies will be needed to explore this hypothesis, these studies suggest that further development of nonlinear approaches to the analysis of brain systems are likely to generate new clinical measures, as well as new ways of viewing brain electrical function and alcoholism.     

Recent developments in the pharmacotherapy of alcohol dependence.

The effectiveness of a treatment for alcohol dependence can be appropriately determined only after controlling for the usual clinical course of alcoholism, subgroups of alcohol-dependent individuals, and placebo effects. The results of appropriate treatment trials must also be interpreted in light of the side effects and costs, and there must be assurances that the overall improvement in functioning observed with the drug is significant enough to outweigh the liabilities. In addition, medications are almost always used in combination with education, counseling, and behavioral therapies, and the impact of these additional treatments must be considered. Viewed from this perspective, 3 medications are quite promising regarding their potential future impact in the alcohol field, including naltrexone, the medication with the most available data in the United States. There are additional data regarding buspirone and acamprosate. Intriguing results have also been generated regarding medications that affect serotonin and dopamine brain activity and with alcohol-sensitizing drugs such as disulfiram. However, none of these medications has been proven to be clinically effective in the routine treatment of the average alcoholic… (PsycINFO Database Record (c) 2010 APA, all rights reserved)