Testing a level of response to alcohol-based model of heavy drinking and alcohol problems in 1,905 17-year-olds

Background: The low level of response (LR) to alcohol is one of several genetically influenced characteristics that increase the risk for heavy drinking and alcohol problems. Efforts to understand how LR operates through additional life influences have been carried out primarily in modest‐sized U.S.‐based samples with limited statistical power, raising questions about generalizability and about the importance of components with smaller effects. This study evaluates a full LR‐based model of risk in a large sample of adolescents from the United Kingdom. Methods: Cross‐sectional structural equation models were used for the approximate first half of the age 17 subjects assessed by the Avon Longitudinal Study of Parents and Children, generating data on 1,905 adolescents (mean age 17.8 years, 44.2% boys). LR was measured with the Self‐Rating of the Effects of Alcohol Questionnaire, outcomes were based on drinking quantities and problems, and standardized questionnaires were used to evaluate peer substance use, alcohol expectancies, and using alcohol to cope with stress. Results: In this young and large U.K. sample, a low LR related to more adverse alcohol outcomes both directly and through partial mediation by all 3 additional key variables (peer substance use, expectancies, and coping). The models were similar in boys and girls. Conclusions: These results confirm key elements of the hypothesized LR‐based model in a large U.K. sample, supporting some generalizability beyond U.S. groups. They also indicate that with enough statistical power, multiple elements contribute to how LR relates to alcohol outcomes and reinforce the applicability of the model to both genders.     

Serotonergic function, behavioral disinhibition, and negative affect in children of alcoholics: the moderating effects of puberty

BACKGROUND: Serotonergic (5-HT) dysfunction has been implicated in both behavioral disinhibition and negative affect in adults. Although our group's previous work found decreased whole blood 5-HT in high versus low behavior problem children of alcoholics, some child/adolescent studies report conflicting results, and 5-HT's role in negative affect has been largely unexamined. Age-related developmental factors may play a role in these relationships. METHODS: This report is from an ongoing prospective study of the development of risk for alcohol abuse/dependence and other problematic outcomes in a sample of families subtyped by father's alcoholism classification. The present study extends previous work and examines relationships between whole blood 5-HT and both child behavioral disinhibition (an aggression index from the Child Behavior Checklist) and negative affect (Child Behavior Checklist Anxious/Depressed scale) in offspring from 47 families (N = 45 boys and 17 girls; mean age = 10.88+/-2.03 yr). RESULTS: The most important finding was that puberty moderated relationships between 5-HT and both behavioral disinhibition and negative affect with a relationship for pubescent children (n = 14, r = -0.54, p = 0.05: r = -0.57,p = 0.04, respectively) but no relationship for prepubescent children (n = 48, r = 0.05, p = 0.75; r = -0.15, p = 0.31, respectively). CONCLUSIONS: The moderating effects of puberty may help clarify inconsistencies in child/adolescent literature. Furthermore, there appears to be a relationship between 5-HT and negative affect which parallels that between 5-HT and behavioral disinhibition. Pubertal status may be an important variable to evaluate as a moderator in relation to the developmental context of the role 5-HT dysfunction may play in various models of behavior related to alcoholism over the early life course.     

Testing the level of response to alcohol: social information processing model of alcoholism risk--a 20-year prospective study

BACKGROUND: The low level of response (LR) to alcohol is a genetically influenced characteristic associated with an enhanced risk for alcohol use disorders (AUDs). An optimal understanding of how this intermediate phenotype relates to the AUD risk requires evaluation of the milieu in which LR operates, and this study tested an LR/social information processing model in adult men. METHODS: Almost 300 Caucasian males (97% of those eligible, to date) from the San Diego Prospective Study participated in an alcohol challenge at approximately age 20 and were evaluated with a structural equation model regarding their expectations of the effects of alcohol, drinking among peers, use of alcohol to cope with stress, and alcohol-related problems during follow-up. RESULTS: The direct paths in the structural equation model in these 40-year-old men explained 58% of the variance of the alcoholic outcome at age 40 and 35% at age 35 while demonstrating good fitness characteristics. The LR to alcohol was related to the family history of AUDs and to the alcoholic outcome; the latter primarily operated through the use of alcohol to cope with stress. Although drinking in peers and expectations of the effects of alcohol both contributed to the model in these 40-year-old men, they were not directly related to LR. CONCLUSIONS: The results continue to support the importance of the low LR to alcohol as a predictor of AUDs, even when evaluated in the context of additional relevant characteristics. Future evaluations of adolescent and young adult subjects will also explore the potential importance of expectations of the effects of alcohol and drinking among peers as mediators or moderators of alcoholism risk among subjects with a low LR.     

Gender Differences in Lifetime Psychiatric Disorders Between Sons and Daughters of Alcoholic Mothers: A Pilot Study

Lifetime prevalence of selected psychiatric disorders was assessed in 24 independent pairs of adult siblings (brother-sister) with an alcoholic mother, using the Diagnostic interview Schedule. Adult females were as likely as adult males to have had one or more lifetime diagnosis of psychiatric disorder. Lifetime prevalence of affective disorders was the same in male and female siblings. Although not statistically significant, compared with their sister, men were 3 times more likely to have had a diagnosis of alcohol abuse/dependence, and 3.5 times more likely to have had a diagnosis of general anxiety disorder. When compared with their brother, women were 1.66 times more likely to have had a diagnosis of drug abuse/dependence, 3 times more likely to have had a diagnosis of panic disorder, and 6 times more likely to have been diagnosed with phobia; however, these differences were not significant.     

Use of Transgenics, Null Mutants, and Antisense Approaches to Study Ethanol's Actions

Behavioral and biochemical responses mediating ethanol's actions have been difficult to study in humans and animals because of their complex polygenic nature. Recent progress in the creation of new animal models using recombinant DNA technology has provided a set of genetic tools by which the role of specific candidate genes in ethanol's actions can be examined. These techniques include the creation of transgenic and null mutant mice, as well as manipulation of protein synthesis with antisense treatments. These techniques are reviewed, and their potential applications to alcohol research are discussed.     

Visual and Auditory Event-Related Potentials in Young Children of Alcoholics from High- and Low-Density Families

Event-related potentials (ERPs), particularly the P3 wave, have been proposed as biological markers of genetic risk for alcoholism. The present study assesses the ERPs from 102 boys and girls (7 to 15 years old) divided into three groups: two groups of sons and daughters of alcoholic fathers, with and without other first- or second-degree relatives affected, and a control group of children of nonal-coholics. Both visual and auditory discrimination tasks with three stimuli (standard, target, and infrequent nontarget) were used. P3 amplitudes did not reach significant reduction for the high-risk males and were complex for females. There were significant differences among females in P3 visual latency elicited by targets; delays in this variable were associated with multigenerational familial alcoholism. Results are discussed in light of the tasks used for eliciting the ERPs and the characteristics of the selected sample.     

Eye Movement Effects of Diazepam in Sons of Alcoholic Fathers and Male Control Subjects

Both animal and human studies suggest that the GABA-benzodiaze-pine receptor complex may be involved in the acute effects of ethanol, as well as the development of tolerance and dependence with chronic ethanol use. The current study was performed to assess sensitivity to benzodiazepines, and thus the functional sensitivity of the GABA-benzodiazepine receptor system, in subjects at high risk for alcoholism. Sons of alcoholic fathers (SOAs; n = 27) were com-pared with male controls without a family history of alcoholism (n = 23) in response to diazepam versus placebo. SOAs and controls received four logarithmically increasing doses of intravenous diaze-pam or placebo in randomized order on 2 days at least 1 week apart. Effects of diazepam were assessed using two eye movement tasks, peak saccadic eye movement velocity, and average smooth pursuit eye movement gain, which provide reliable, quantitative measures of benzodiazepine effects. In addition, memory, self-rated sedation, and pleasurable drug effects were measured. In comparison with control subjects, SOAs displayed significantly less diazepam effects on peak saccade velocity, average smooth pursuit gain, memory, and self-rated sedation, but significantly greater pleasurable drug effects. Differences in response to diazepam between SOAs and male controls may reflect altered functional sensitivity of the central GABA-benzodiazepine receptor system or a more general difference between groups in the effects of CNS active or sedating drugs.     

Association of the ADH2*3 Allele With A Negative Family History Of Alcoholism in African American Young Adults

BACKGROUND: Two of the class I alcohol dehydrogenase (ADH) genes (ADH2 and ADH3) encode for multiple isozymes that differ in their kinetic properties. Polymorphisms at both of these gene loci have been linked to alcoholism and/or alcohol-induced disabilities in some populations. At the ADH2 locus, three polymorphisms are present (ADH2*1, ADH2*2, ADH2*3). ADH2*3 allele codes for a high Km and Vmax variant that has been reported to occur exclusively in African Americans and some tribes of Native Americans. In African Americans, the presence of the ADH2*3 allele is associated with protection from alcohol-related birth defects. However, its relationship to risk for alcoholism in African Americans remains relatively unexplored. METHODS: The participants were 97 African American young adults (18-25 years old). A structured interview was used to gather information on demographics, psychiatric diagnoses, personal drinking and drug use history, and familial history of alcohol use disorders. A blood sample was obtained from each participant and leukocyte DNA extracted and genotyped for the presence of ADH2*3 alleles. The specific aim of the study was to investigate the associations between the presence of the ADH2* 3 allele and personal and family history of alcohol use/abuse. RESULTS: Thirty participants (31%) had at least one ADH2*3 allele and two were homozygous for the allele. A significant association between the presence of an ADH2*3 allele and a negative family history of alcoholism was uncovered (p < 0.04). No significant associations of an ADH2*3 allele with personal history of alcohol use disorders or with current drinking were found; however, power to detect associations was limited in this population because half the population did not drink regularly. CONCLUSIONS: Because family history of alcoholism is one of the best predictors of the development of alcohol use disorders, this pilot study suggests that, in this sample of African American young adults, the ADH2*3 allele may be associated with a lowered risk for the development of alcoholism.     

Gender‐Related Influences of Parental Alcoholism on the Prevalence of Psychiatric Illnesses: Analysis of the National Epidemiologic Survey on Alcohol and Related Conditions

Background: Offspring of individuals with alcoholism are at increased risk for psychiatric illness, but the effects of gender on this risk are not well known. In this study, we tested the hypothesis that the gender of the parent with alcoholism and the gender of offspring affect the association between parental alcoholism and offspring psychiatric illness. Method: We analyzed the National Epidemiological Survey on Alcohol and Related Conditions (NESARC) data to examine the gender‐specific prevalence of axis I and axis II disorders in 23,006 male and 17,368 female respondents with and without a history of paternal or maternal alcoholism. Adjusted odds ratios were calculated for the disorders based on gender and presence of maternal or paternal alcoholism. Results: Maternal or paternal alcoholism was associated with a higher prevalence of every disorder examined, regardless of the gender of offspring. Gender‐related differences in prevalences were present in nearly all examined disorders, and the association between parental alcoholism and offspring psychiatric disorders was significantly different in men and women. These differences included stronger associations in female offspring of men with alcoholism (alcohol abuse without dependence); in female offspring of women with alcoholism (mania, nicotine dependence, alcohol abuse, and schizoid personality disorder); in male offspring of men with alcoholism (mania); and in male offspring of women with alcoholism (panic disorder). Conclusions: Interactions between gender and parental alcoholism were specific to certain disorders but varied in their effects, and in general female children of women with alcoholism appear at greatest risk for adult psychopathology.     

Evaluating a cognitive model of ALDH2 and drinking behavior

Background: Despite evidence for genetic influences on alcohol use and alcohol‐related cognitions, genetic factors and endophenotypes are rarely incorporated in cognitive models of drinking behavior. This study evaluated a model of ALDH2 and drinking behavior stipulating cognitive factors and alcohol sensitivity as accounting for genetic influences on drinking outcomes. Methods: Participants were Asian‐American young adults (n = 171) who completed measures of alcohol cognitions (drinking motives, drinking refusal self‐efficacy, and alcohol expectancies), alcohol sensitivity, drinking behavior, and alcohol‐related problems as part of a prospective study. Structural equation modeling (SEM) evaluated a model of drinking behavior that stipulated indirect effects of ALDH2 on drinking outcomes through cognitive variables and alcohol sensitivity. Results: The full model provided an adequate fit to the observed data, with the measurement model explaining 63% of the variance in baseline heavy drinking and 50% of the variance in alcohol‐related problems at follow‐up. Associations of ALDH2 with cognitive factors and alcohol sensitivity were significant, whereas the association of ALDH2 with drinking was not significant with these factors included in the model. Mediation tests indicated significant indirect effects of ALDH2 through drinking motives, drinking refusal self‐efficacy, and alcohol sensitivity. Conclusions: Results are consistent with the perspective that genetic influences on drinking behavior can be partly explained by learning mechanisms and implicate cognitive factors as important for characterizing associations of ALDH2 with drinking.